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Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials
Open accessAbstract
Background The COVID-19 pandemic highlights the need for therapies that improve immune function in older adults, including interferon (IFN)-induced antiviral immunity that declines with age. In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults. Therefore, we aimed to investigate whether oral RTB101 upregulated IFN-induced antiviral responses and decreased the incidence of viral RTIs when given once daily for 16 weeks during winter cold and flu season. Methods We did a phase 2b and a phase 3 double-blind, randomised, placebo-controlled trial in adults aged at least 65 years enrolled in New Zealand, Australia, and the USA at 54 sites. In the phase 2b trial, patients were aged 65–85 years, with asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure, were current smokers, or had an emergency room or hospitalisation for an RTI within the past 12 months. In the phase 3 trial, patients were aged at least 65 years, did not have COPD, and were not current smokers. In the phase 2b trial, patients were randomly assigned to using a validated automated randomisation system to oral RTB101 5 mg, RTB101 10 mg once daily, or placebo in part 1 and RTB101 10 mg once daily, RTB101 10 mg twice daily, RTB101 10 mg plus everolimus once daily, or matching placebo in part 2. In the phase 3 trial, patients were randomly assigned to RTB101 10mg once daily or matching placebo. The phase 2b primary outcome was the incidence of laboratory-confirmed RTIs during 16 weeks of winter cold and influenza season and the phase 3 primary outcome was the incidence of clinically symptomatic respiratory illness defined as symptoms consistent with an RTI, irrespective of whether an infection was laboratory-confirmed. Patients, investigators, and sponsor were masked to treatment assignments. All patients who received at least part of one dose of study drug were included in the primary and safety analyses. The phase 2b trial was registered with ANZCTR, ACTRN12617000468325, ClinicalTrials.gov, NCT03373903, and the phase 3 trial was registered with ANZCTR, ACTRN12619000628145. Findings In the phase 2b trial, we recruited 652 participants in total between May 16, 2017, and Jan 10, 2018, 179 participants to part 1 of the study (randomly assigned 1:1:1 to RTB101 5 mg once daily [61 participants], RTB101 10 mg once daily [58 participants], or matching placebo [60 participants]) and 473 patients to part 2 (randomly assigned 1:1:1:1 to RTB101 10 mg once daily [118 participants], RTB101 10 mg twice daily [120 participants], RTB101 10 mg in combination with everolimus 0·1 mg daily [115 participants] or matching placebo [120 participants]). In our first prespecified statistical analysis of the primary efficacy endpoint for part 2 of the phase 2b trial efficacy of RTB101 10 mg in combination with everolimus 0·1 mg once daily compared with placebo did not meet statistical significance but, in our second prespecified analysis, which included data from part 1 and part 2, we found a statistically significant reduction in the proportion of patients who had one or more laboratory-confirmed RTIs in the RTB101 10 mg once daily treatment group (34 [19%] of 176) compared with the pooled placebo group (50 [28%] of 180; odds ratio [OR] 0·601 [90% CI 0·391–0·922]; p=0·02). In the phase 3 trial, we enrolled 1024 patients between May 7, 2018, and July 19, 2019. 513 (50·1%) participants were randomly assigned to RTB101 10 mg once daily and 510 (49·9%) to placebo. In the full analysis set of the phase 3 trial, RTB101 did not reduce the proportion of patients with clinically symptomatic respiratory illness (134 [26%] of 511 patients in the RTB101 treatment group vs 125 [25%] 510 patients in the placebo treatment group; OR 1·07 [90% CI 0·80–1·42]; p=0·65). In both trials, significantly more IFN-induced antiviral genes were upregulated in patients treated with RTB101 as compared with placebo. The study drug was found to be safe and well-tolerated across trials and treatment groups. Only one patient in the placebo group in the phase 3 trial had serious adverse events (nausea, fatigue, hyponatraemia, and arthralgia) which were considered related to study drug treatment. Three patients died in the phase 2b trial and one in the phase 3 trial but no deaths were considered related to study treatment. Interpretation The combined results indicate that low doses of the mTOR inhibitor RTB101 are well tolerated and upregulate IFN-induced antiviral responses in older adults. Further refinement of clinical trial endpoints and patient populations might be required to identify whether upregulation of IFN responses by mTOR inhibitors consistently decreases the incidence or severity of viral infections in older adults. Funding resTORbio and the Na
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TL;DR
In two randomized placebo-controlled trials in adults aged ≥65 years, oral mTOR inhibitor RTB101 10 mg once daily upregulated IFN-induced antiviral gene expression and was well tolerated, but it reduced laboratory-confirmed RTIs in phase 2b while failing to reduce clinically symptomatic respiratory illness in phase 3. The authors conclude that endpoint and population refinement may be needed to determine whether mTOR inhibitors consistently decrease viral infections in older adults.
Key findings
- In phase 2b (n=652), the second prespecified analysis including parts 1 and 2 found RTB101 10 mg once daily reduced the proportion with ≥1 laboratory-confirmed RTI versus pooled placebo: 34/176 (19%) vs 50/180 (28%); OR 0·601 (90% CI 0·391–0·922); p=0·02. The first prespecified part 2 analysis of RTB101 10 mg plus everolimus 0·1 mg did not meet statistical significance.
- In phase 3 (n=1024), RTB101 10 mg once daily did not reduce clinically symptomatic respiratory illness: 134/511 (26%) vs 125/510 (25%); OR 1·07 (95% CI 0·80–1·42); p=0·65.
- In both trials, significantly more IFN-induced antiviral genes were upregulated in RTB101-treated patients than in placebo-treated patients. Severe laboratory-confirmed RTIs were reduced in phase 2b: 8/176 (5%) vs 17/180 (9%); OR 0·44 (90% CI 0·21–0·92); p=0·034; in phase 3, severe laboratory-confirmed clinically symptomatic respiratory illness was 22/511 (4%) vs 31/510 (6%); OR 0·70 (95% CI 0·40–1·22); nominal p=0·21.
- RTB101 was safe and well tolerated across trials and treatment groups; no deaths were considered related to study treatment.
Methods
- Design: phase 2b and phase 3 double-blind, randomised, placebo-controlled trials. Phase 2b enrolled adults aged 65–85 years with asthma, type 2 diabetes, COPD, congestive heart failure, current smoking, or recent RTI-related emergency room/hospitalisation at 10 New Zealand and 17 USA sites. Phase 3 enrolled adults aged ≥65 years without COPD and not current smokers at 16 New Zealand and 15 Australia sites.
- Interventions: phase 2b part 1 randomised 1:1:1 to RTB101 5 mg, RTB101 10 mg once daily, or placebo; part 2 randomised 1:1:1:1 to RTB101 10 mg once daily, RTB101 10 mg twice daily, RTB101 10 mg plus everolimus 0·1 mg once daily, or placebo. Phase 3 randomised 1:1 to RTB101 10 mg once daily or placebo. Treatment lasted 16 weeks.
- Outcomes and analysis: phase 2b primary outcome was incidence of laboratory-confirmed RTIs over 16 weeks; phase 3 primary outcome was clinically symptomatic respiratory illness. Primary analyses used the full analysis set and logistic regression to estimate ORs with CIs. IFN-induced antiviral gene expression was measured in whole blood by qPCR for 20 genes at baseline and week 16.
Limitations
- Stated by the authors: possible explanations for divergent phase 2b and phase 3 results include the change in primary endpoint and symptom collection between trials; phase 3 eDiary symptoms may have included non-infectious causes such as allergies or underlying cardiopulmonary disease; phase 3 enrolled a healthier population with possibly less attenuated type 1 IFN responses; phase 3 was underpowered for the laboratory-confirmed secondary endpoint (placebo incidence 14%; 2494 patients would have been needed for 90% power to detect a 30% reduction); and the phase 2b positive result could have been type 1 error.
- Stated by the authors: upregulation of antiviral gene expression by RTB101 might be insufficient to decrease the incidence of viral RTIs, and benefit may be limited to subsets of older adults or viruses.
- Evident from the text: the phase 2b significant result came from a second prespecified analysis that did not adjust for multiplicity after the first prespecified analysis failed, and the negative phase 3 primary endpoint stopped formal statistical testing of subsequent endpoints.
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46 Own method · 40 Own result · 15 Own interpretation · 8 Partly supported · 2 Supported · 2 No basis given · 1 Supported so far · 1 Couldn’t confirm · 1 No full text of the sources · accuracy not yet measured
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In the paper
“The type 1 IFN response might be particularly important for fighting SARS-CoV-2 infections because a substantial proportion of patients with life-threatening COVID-19 pneumonia were reported to have genetic deficiencies in the type 1 IFN pathway or neutralising autoantibodies against type 1 IFN.6, 7”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Introduction
What the sources say
- Supportedcites [6] Bastard, 2020, Autoantibodies against type I IFNs in patients with life-threatening COVID-19, Science source
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- Supportedcites [7] Zhang, 2020, Inborn errors of type I IFN immunity in patients with life-threatening COVID-19, Science source
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In the paper
“Older adults might be particularly susceptible to viral RTIs due to an attenuated type 1 interferon (IFN) immune response to viruses.5”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Introduction
What the sources say
- Partly supportedcites [5] Pillai, 2016, Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease, Science sourceExperimental — accuracy not yet measured
The paper’s main text (indexed under Abstract; page unavailable) reports attenuated type I IFN responses in influenza-infected monocytes from older adults and suggests that impaired antiviral responses could contribute to their susceptibility to influenza. It does not establish this explanation for viral respiratory tract infections more broadly. (LLM, conf=0.82)
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In the paper
“The lack of treatment benefit seen in prespecified analyses in the phase 2b trial in current smokers and in patients with COPD (approximately half of whom were current smokers) is consistent with preclinical data that mTOR inhibitors increase cigarette smoke-induced inflammation.14, 15”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
What the sources say
- Could not verifycites [14] Mushaben, 2011, Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic asthma, J Immunol sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [15] Wang, 2018, MTOR Suppresses cigarette smoke-induced epithelial cell death and airway inflammation in chronic obstructive pulmonary disease, J Immunol source
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In the paper
“One of the best validated mechanisms underlying ageing biology is the activity of the protein kinase mTOR.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
What the sources say
- Supportedcites [18] Johnson, 2013, mTOR is a key modulator of ageing and age-related disease, Nature source
The section “mTOR and known longevity factors” describes genetic and drug studies in yeast, worms, fruitflies and mice, saying they firmly establish mTORC1 as a central, evolutionarily conserved regulator of longevity. This supports the characterization of mTOR activity as a well-validated mechanism in ageing biology. (LLM, conf=0.92)
- Partly supportedcites [19] Chen, 2009, mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells, Sci Signal sourceExperimental — accuracy not yet measured
The Introduction describes mTOR activation as a possible conserved mechanism of aging, and the Discussion reports a fundamental role for mTOR signaling in hematopoietic stem-cell aging in mice. The paper does not rank mTOR among the best-validated mechanisms of aging biology generally; its direct experimental evidence concerns mouse hematopoietic stem cells. (LLM, conf=0.84)
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In the paper
“Arguing against this possibility is the fact that not only in the phase 2b trial but also in two previous phase 2a trials, 10, 20 older adults treated with low doses of mTOR inhibitors reported fewer self-reported RTIs than older adults treated with placebo did.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
What the sources say
- Supportedcites [10] Mannick, 2018, TORC1 inhibition enhances immune function and reduces infections in the elderly, Sci Transl Med source
The trial results (section labeled Abstract; page unavailable) report that older adults receiving low-dose BEZ235, alone or with RAD001, had significantly fewer self-reported respiratory tract infections than those receiving placebo. This paper supports the finding for the trial it reports; the citing sentence also cites another source for the other trial. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [20] Mannick, 2014, mTOR inhibition improves immune function in the elderly, Sci Transl Med source
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In the paper
“In our first prespecified statistical analysis of the primary efficacy endpoint for part 2 of the phase 2b trial efficacy of RTB101 10 mg in combination with everolimus 0·1 mg once daily compared with placebo did not meet statistical significance”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
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“In the full analysis set of the phase 3 trial, RTB101 did not reduce the proportion of patients with clinically symptomatic respiratory illness (134 [26%] of 511 patients in the RTB101 treatment group vs 125 [25%] 510 patients in the placebo treatment group; OR 1·07 [90% CI 0·80–1·42]; p=0·65).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
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“in our second prespecified analysis, which included data from part 1 and part 2, we found a statistically significant reduction in the proportion of patients who had one or more laboratory-confirmed RTIs in the RTB101 10 mg once daily treatment group (34 [19%] of 176) compared with the pooled placebo group (50 [28%] of 180; odds ratio [OR] 0·601 [90% CI 0·391–0·922]; p=0·02).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
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“In both trials, significantly more IFN-induced antiviral genes were upregulated in patients treated with RTB101 as compared with placebo.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
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“Only one patient in the placebo group in the phase 3 trial had serious adverse events (nausea, fatigue, hyponatraemia, and arthralgia) which were considered related to study drug treatment.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
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“The proportion of patients with a laboratory-confirmed clinically symptomatic respiratory illness with severe symptoms was reduced in the RTB101 group as compared with in the placebo group (22 [4%] of 511 patients in the RTB101 group vs 31 [6%] of 510 patients in the placebo group; OR 0·70 [95% CI [0·40–1·22]; nominal p=0·21).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“Both RTB101 treatment arms were well tolerated”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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In the paper
“By contrast, the number of RTIs and severe RTIs caused by metapneumovirus, parainfluenza virus, or respiratory syncytial virus infections were not consistently lower in the RTB101 group as compared with in the placebo group in both trials (figure 4).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“Patients with serious adverse events were also generally well-balanced between active and placebo groups in both trials (Table 3, Table 4).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“73 (14%) of 510 patients in the placebo group of the phase 3 trial had a laboratory-confirmed clinically symptomatic respiratory illness, compared to 50 (28%) of 180 patients in the placebo group of the phase 2b trial had a laboratory-confirmed RTI (appendix p 3).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“A non-significant reduction in the proportion of patients experiencing one or more laboratory-confirmed RTIs was seen in patients who received RTB101 5 mg once daily (21 [34%] of 61) compared with the placebo group (26 [43%] of 60]; OR 0·618 [90% CI 0·325–1·176]; p=0·11).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“A statistically significant reduction in the proportion of patients experiencing one or more laboratory-confirmed RTIs was seen in those who received RTB101 10 mg once daily (14 [24%] of 58) compared with the placebo group (26 [43%] 60) in part 1 of the study (0·389 [0·195–0·776]; p=0·012).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“RTB101 10 mg once daily was observed to have consistent treatment effects in part 1 and part 2 of the trial for each patient group (appendix p 2).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“Although the numbers of RTIs caused by individual viruses were too low to assess statistical significance, the number of RTIs caused by coronavirus and rhinovirus were consistently lower in the RTB101 group as compared with in the placebo group in both trials (figure 4).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“only one patient in the placebo group in the phase 3 trial had serious adverse events (nausea, fatigue, hyponaetremia, and arthralgia) considered related to study drug treatment.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“The rate of laboratory-confirmed clinically symptomatic respiratory illness with severe symptoms was reduced in the RTB101 group as compared with in the placebo group (23 severe laboratory-confirmed RTIs in 511 patients in the RTB101 10 mg group vs 37 in 510 patients in the placebo group; rate ratio 0·65 [95% CI [0·38–1·11]; nominal p=0·11).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“All dosing regimens were well-tolerated in the phase 2b and phase 3 studies.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“but not the incidence of clinically symptomatic respiratory illness defined as respiratory symptoms consistent with an RTI irrespective of whether an infection was laboratory confirmed (the phase 3 primary endpoint).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
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“In support of this hypothesis, RTB101 was also associated with a greater reduction in the incidence of laboratory-confirmed RTIs than the incidence of RTIs diagnosed solely on the basis of respiratory symptoms in the phase 2b trial.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
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“The mTOR inhibitor RTB101 10 mg once daily for 16 weeks was well tolerated in adults aged at least 65 years”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
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“Additionally, the number of coronavirus, rhinovirus, and influenza virus infections with symptoms reported by patients to be severe in intensity were consistently lower in the RTB101 group compared with in the placebo group in both trials (figure 4).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
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“The phase 3 trial enrolled a healthier population than that of the phase 2b trial”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
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In the paper
“decreased the incidence of laboratory-confirmed RTIs (the phase 2b primary endpoint)”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No patients in the phase 2b trial had an serious adverse event that was considered related to study drug treatment”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The RTB101 10 mg once daily group had a reduced proportion of patients who had laboratory-confirmed RTIs with severe symptoms as compared with the placebo group (17 [9%] of 180 in the placebo group and eight [5%] of 176 in the RTB101 treatment group; OR 0·44 [90% CI 0·21–0·92]; p=0·034).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Secondary endpoint analysis revealed that RTB101 was not associated with a reduced number of patients who had symptoms that met the diagnostic criteria for an RTI, irrespective of whether or not an infection was laboratory-confirmed compared to placebo (56 [32%] of 176 in the RTB10110 mg once daily group vs 68 [38%] of 180 in the placebo group; OR 0·756 [90% CI 0·521–1·098]; p=0·11).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The OR of having a laboratory-confirmed clinically symptomatic respiratory illness in the RTB101 group (65 [13%] 511 patients) as compared with in the placebo group (73 [14%] of 510 patients) was 0·85 (95% CI 0·59–1·22; p=0·38).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plainn = 511- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In both the phase 2b and phase 3 trials, RTB101 was observed to upregulate significantly more IFN-induced antiviral genes as compared with placebo during the 16-week treatment period (figure 3 ).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the full analysis set, RTB101 did not reduce the proportion of patients with clinically symptomatic respiratory illness, the primary endpoint of the trial (134 [26%] of 511 patients in the RTB101 treatment group vs 125 [25%] 510 patients in the placebo treatment group; OR 1·07 [95% CI 0·80–1·42]; p=0·65).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plainn = 511- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of interest, in the phase 2b trial RTB101 was associated with a significant reduction in the incidence of laboratory-confirmed RTIs with severe symptoms.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this step-down analysis, efficacy of RTB101 10 mg in combination with everolimus 0·1 mg once daily compared with placebo was first tested at a one-sided α level of 0·05 and did not meet statistical significance (data not shown).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Decline in the function of the ageing immune system contributes to the increased incidence of infections and the decreased response to vaccination in older adults (aged at least 65 years).1”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Introduction
What the sources say
- Not checked — no full text of the sourcecites [1] Boraschi, 2013, The gracefully aging immune system, Sci Transl Med source
plaindirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sample size was calculated on the basis of a two-sided comparison between RTB101 and placebo from parts 1 and 2 of the phase 2b trial.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Second, the results suggest that therapies that target ageing biology in older adults might ameliorate at least some aspects of ageing organ system dysfunction (such as deficient IFN-induced antiviral responses).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, the results show that it is possible to target mechanisms underlying ageing biology safely with therapies such as mTOR inhibitors in older adults.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Several possible explanations exist for the divergent results of the phase 2b and phase 3 trials, including the change in primary endpoint and changes in the way respiratory symptoms were collected between the two trials.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because RTB101 upregulates antiviral gene expression, RTB101 is only likely to reduce the incidence or severity of respiratory symptoms due to viral infections.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“With a placebo incidence of 14%, we would have needed to randomly assign 2494 patients (1247 patients per group) to have 90% power to detect a 30% reduction at a two-sided α of 0·05.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
hedgedn = 510- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results of the phase 2b and phase 3 trials also raise the possibility that RTB101 decreases the incidence or severity of RTIs caused by only a subset of viruses such as coronaviruses that inhibit the host IFN response.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the occurrence of respiratory symptoms that have non-infectious causes in older adults such as allergies or underlying cardiopulmonary disease might have contributed to the negative result of the phase 3 trial.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Because of the lower than expected incidence of laboratory-confirmed clinically symptomatic respiratory illness in the phase 3 trial, the trial was underpowered for this endpoint.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plaindirectn = 510- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Baseline demographics between the treatment groups were similar (table 1 ).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, upregulation of IFN-induced antiviral immunity by RTB101 might have a greater effect on the severity than the incidence of RTIs.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Baseline demographics between the treatment groups were similar (table 2 ).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plainn = 1,024- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Second, the results suggest that therapies that target ageing biology in older adults might ameliorate at least some aspects of ageing organ system dysfunction (such as deficient IFN-induced antiviral responses).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Older adults have deficient IFN-induced antiviral responses.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, the results show that it is possible to target mechanisms underlying ageing biology safely with therapies such as mTOR inhibitors in older adults.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 47
- It may state two separate claims as one. 23
- The quote only partly states this claim. 2
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Respiratory tract infections (RTIs) are a leading cause of hospitalisation and deaths in older adults and are mainly caused by viruses.2, 3, 4”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Introduction
What the sources say
- Not checked — no full text of the sourcecites [2] Murphy, 2013, Deaths: final data for 2010, Natl Vital Stat Rep
- Not matchedcites [3] 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites [4] Jain, 2015, Community-acquired pneumonia requiring hospitalization among US adults, N Engl J Med sourceExperimental — accuracy not yet measured
The Introduction describes pneumonia as a leading infectious cause of hospitalization and death among U.S. adults, and the Results show hospitalization rates were highest in older adults. The paper studies pneumonia rather than all respiratory tract infections. Its Discussion says viruses were detected more often than bacteria, but no pathogen was detected in most patients, so it does not establish that these infections are mainly caused by viruses. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults.”
- Also stated in: § Introduction · plain
“Additionally, mTOR inhibition was found to increase IFN-induced antiviral gene expression and decrease the incidence of RTIs in older adults in a previous phase 2a clinical trial using RTB101 (previously known as BEZ235), an oral mTOR inhibitor.10”
- Also stated in: § Study design and participants · plain
“In a previous phase 2a clinical trial, RTB101, an oral mTOR inhibitor, was observed to increase type 1 IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections in older adults.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Background
What the sources say
- Partly supportedcites [10] Mannick, 2018, TORC1 inhibition enhances immune function and reduces infections in the elderly, Sci Transl Med sourceExperimental — accuracy not yet measured
The paper reports that BEZ235 alone significantly reduced the annualized rate of respiratory tract infections in older adults (section labeled Abstract; page unavailable). It found increased expression of interferon-induced antiviral genes only in the RAD001+BEZ235 combination group, not in a BEZ235-only group, so it does not establish both effects for RTB101 alone. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Introduction · plain
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In previous preclinical studies, inhibition of mechanistic target of rapamycin (mTOR) or a target downstream of mTOR protected mice from viral RTIs and upregulated IFN-induced antiviral immune responses.8, 9”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Introduction
What the sources say
- Partly supportedcites [8] York, 2015, Cell Limiting cholesterol biosynthetic flux spontaneously engages Type 1 IFN signaling, Cell sourceExperimental — accuracy not yet measured
The Results section, “Loss of SCAP protects from viral inflection” (page unavailable), reports that macrophage-specific SCAP deletion reduced lung viral load by over 90% after mice were challenged intranasally with MHV-68. “Induction of a type I IFN signature segregates with loss of SREBP2” reports heightened interferon-stimulated genes and antiviral resistance in deficient cells. Our copy does not establish that SCAP or SREBP2 is downstream of mTOR or report protection from direct mTOR inhibition; it also does not describe the mouse challenge specifically as a respiratory tract infection. (LLM, conf=0.84)
- Partly supportedcites [9] Smallwood, 2017, Targeting metabolic reprogramming by influenza infection for therapeutic intervention, Cell Rep sourceExperimental — accuracy not yet measured
The Results section ('BEZ235 rescues mice from lethal influenza infection'; page unavailable) reports improved survival and reduced viral titers in influenza-infected mice treated with the PI3K/mTOR inhibitor BEZ235. The paper does not report that treatment upregulated IFN-induced antiviral responses or that inhibiting a target downstream of mTOR protected mice. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“RTI symptoms collected using these methods were used to calculate the incidence of RTIs using predefined clinical criteria established by an expert consensus panel for surveillance of infections in older patients residing in long-term care facilities.13”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
What the sources say
- Supportedcites [13] Stone, 2012, Surveillance definitions of infections in long-term care facilities: revisiting the McGeer criteria, Infect Control Hosp Epidemiol source
The Methods—Review of Clinical Syndromes section says a SHEA group developed updated surveillance criteria for RTIs in long-term care facility residents and that the definitions were approved by the group and outside reviewers. The Definitions—Respiratory Tract Infections section sets out the RTI categories. The cited paper supports the criteria attributed to it; it does not need to report the citing trial’s incidence calculation. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Of interest, coronaviruses and influenza viruses, but not parainfluenza or respiratory syncytial viruses, have been reported to suppress the host IFN response.16”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
What the sources say
- Partly supportedcites [16] Blanco-Melo, 2020, Imbalanced host response to SARS-CoV-2 drives development of COVID-19, Cell sourceExperimental — accuracy not yet measured
The Introduction describes IFN antagonists in coronaviruses and influenza A virus. The Results report diminished IFN responses to SARS-CoV-2 and influenza A, versus high IFN induction with HPIV3 and RSV in the tested cells. That comparison supports the contrast, but does not establish the categorical claim that parainfluenza and respiratory syncytial viruses do not suppress host IFN responses. (LLM, conf=0.82)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Inhibition of mTOR has been shown to extend lifespan and to improve the function of ageing organ systems, including the immune system, in multiple preclinical species.18, 19”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
What the sources say
- Supportedcites [18] Johnson, 2013, mTOR is a key modulator of ageing and age-related disease, Nature source
The paper’s Future directions and perspectives section says mTORC1 inhibition slows ageing in yeast and invertebrates, extends lifespan in mice, and affects diverse age-related diseases. Its Stem cells section reports that rapamycin protects old mice against influenza challenge and enhances intestinal stem-cell function, supporting the claim about ageing organ systems, including the immune system. (LLM, conf=0.90)
- Partly supportedcites [19] Chen, 2009, mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells, Sci Signal sourceExperimental — accuracy not yet measured
The Results report that rapamycin extended lifespan in old mice, and the Discussion reports improved hematopoietic stem-cell function and immune responses in those mice. The Introduction mentions mTOR signaling and longevity in yeast, C. elegans, and Drosophila, but our copy does not establish that mTOR inhibition both extended lifespan and improved ageing organ-system function across multiple species. (LLM, conf=0.88)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Ageing is caused by a discreet set of biological mechanisms that can be targeted therapeutically as a new way to treat ageing-related conditions.17”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
What the sources say
- Partly supportedcites [17] López-Otín, 2013, The hallmarks of aging, Cell sourceExperimental — accuracy not yet measured
The Abstract identifies nine tentative hallmarks of aging and describes pharmaceutical targets to improve health during aging as a goal. The Introduction calls them candidate hallmarks and says not all are yet supported by interventions; the Conclusions say further studies are needed to establish causal evidence. The claim overstates these proposed mechanisms as an established, discrete set of causes and presents a future therapeutic aim as a way to treat age-related conditions. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the phase 2b trial, 28·2% of participants in the placebo group (excluding participants with COPD and current smokers) had a clinically symptomatic respiratory illness compared to patients in the RTB101 10 mg once daily group, and RTB101 was associated with a 30% reduction in the incidence of respiratory tract infections.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The study drug was found to be safe and well-tolerated across trials and treatment groups.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Three patients died in the phase 2b trial and one in the phase 3 trial but no deaths were considered related to study treatment.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the incidence of laboratory-confirmed RTIs in current smokers was higher in the RTB101 group than in the placebo treatment group, the incidence of laboratory-confirmed RTIs was low in current smokers and the differences between treatment groups did not meet statistical significance (appendix p 2).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“increased expression of IFN-stimulated antiviral genes in peripheral blood”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Multiple investigators in the phase 3 trial anecdotally noted that patients reported in their nightly eDiary respiratory illness symptoms such as cough or headache that were part of the prespecified diagnostic criteria for a clinically symptomatic respiratory illness even when the patient and the investigator did not think that the patient had an RTI.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this analysis we found a statistically significant reduction in the proportion of patients who had one or more laboratory-confirmed RTIs in the RTB101 10 mg once daily treatment group (34 [19%] of 176) compared with the pooled placebo group (50 [28%] of 180; OR 0·601 [90% CI 0·391–0·922]; p=0·025).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“RTB101 10 mg once daily had the greatest treatment benefit in patients who were aged at least 85 years and participants who were aged at least 65 years with asthma (appendix p 2).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“RTB101 10 mg twice daily and RTB101 10 mg in combination with everolimus 0·1 mg once daily were not associated with a significant reduction in the incidence of laboratory-confirmed RTIs as compared with placebo (data not shown).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“RTB101 had no benefit in patients with COPD and in current smokers (appendix p 2).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, the incidence and types of adverse events that occurred in both trials were consistent with what would be expected in the older populations we assesed and we found no clear differences in adverse event profiles between the RTB101 10 mg once daily group and placebo groups (Table 3, Table 4 ; appendix pp 4–5).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In part 1 of the study, participants were randomly assigned (1:1:1) to RTB101 5 mg, RTB101 10 mg once daily, or placebo using a validated automated randomisation system (Endpoint Clinical Interactive Response Technology).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Randomisation and masking
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All patients who received at least part of one dose of study drug were included in the primary and safety analyses.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Methods
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Randomisation was stratified by age 85 years and older, age 65 years and older, and age younger than 85 years with a medical history of asthma, and clinical frailty scale score at least 4 to prevent imbalance in treatment assignments.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Randomisation and masking
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Masking was achieved by the use of placebo that was identical in packaging, labelling, schedule of administration, appearance, and odour to the active drug.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Randomisation and masking
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Participants, investigators, site staff, and sponsor were masked until final database lock.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Randomisation and masking
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Randomisation was stratified by participant age and medical histories (asthma, COPD, diabetes, current smoker, congestive heart failure, and emergency room or hospital for an RTI within the past 12 months) to prevent imbalance in treatment assignments.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Randomisation and masking
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Masking was achieved by the use of placebo that was identical in packaging, labelling, schedule of administration, appearance and odour to the active drug.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Randomisation and masking
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We recruited participants at increased risk of RTI morbidity and mortality in a randomised, double-blind, placebo-controlled trial at ten clinical sites in New Zealand (part 1) and 17 clinical sites in the USA (part 2).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“As in the phase 2b trial, participants were randomly assigned to RTB101 or placebo treatment groups using a validated automated randomisation system at a 1:1 ratio.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Randomisation and masking
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“With the exception of the members of the data monitoring committee who did the interim analysis, participants, those giving the interventions, those assessing the outcomes, and those analysing the data were masked until final database lock.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Randomisation and masking
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In this randomised, double-blind, placebo-controlled trial, we recruited participants aged at least 65 years who did not have COPD and were not current smokers at 16 clinical sites in New Zealand and 15 clinical sites in Australia.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“During the clinic visit, the site staff obtained a nasopharyngeal swab for respiratory virus detection using an FDA-approved PCR panel assay (FILMARRAY respiratory panel, BioFire Diagnostics, Salt Lake City, UT, USA) that detects 17 viral and three bacterial respiratory pathogens.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“RNA samples were then analysed in triplicate per assay using the 96 × 96 Fluidigm Dynamic GE Array (Fluidigm Corporation, San Francisco, CA, USA).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“RNA isolation and Fluidigm gene expression was done according to good laboratory practice methods.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Samples from the same participant were analysed on the same assay to avoid inter-batch variability.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The phase 2b trial was registered with ANZCTR, ACTRN12617000468325, ClinicalTrials.gov, NCT03373903”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Methods
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“the phase 3 trial was registered with ANZCTR, ACTRN12619000628145.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Methods
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“20 genes known to be upregulated by IFNs and three housekeeping genes (DECR1, RPLP0, and MAPRE2) were measured for each sample.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“One calibrator, one no-enzyme control, and one no-template control were included with each batch of reverse transcription reactions.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“a second analysis of the primary endpoint was prespecified that did not adjust for multiplicity and also used a one-sided α of 0·05. This analysis assessed the proportion of participants with laboratory-confirmed RTIs in each of the active treatment groups compared with in the placebo group and included all data from part 1 and part 2 of the study.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The primary analysis of the primary efficacy endpoint was based on the intention-to-treat principle, comprising all participants who were randomly assigned and had received at least one dose of assigned study drug during the trial (defined as the full analysis set).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For the phase 3 analysis of antiviral gene expression analysis, whole-blood samples from 180 participants who received placebo and 180 participants who received RTB101 10 mg once daily treatment were processed in the same way as in the phase 2 trial.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
plainn = 180- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The first analysis accounted for multiplicity by using a fixed-sequence gatekeeping testing procedure that was limited to data from part 2 of the trial and controlled the overall one-sided type I error rate at 0·05.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Two different analyses of the key efficacy endpoints were prespecified.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This outcome was centrally assessed.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This sample size was based on the largest sample size that could be analysed with the available budget.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Procedures
plaindirectn = 180- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This primary efficacy model was adjusted for factors that might influence response to treatment for patients with clinically symptomatic respiratory illness, including age; frailty score; receipt of current season influenza vaccination; and medical history of asthma, congestive heart failure, or type 2 diabetes.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A fixed-sequence gatekeeping strategy was used to control the study-wise error rate at a two-sided α of 0·05.”
- Also stated in: § Results · plain
“In this study, a fixed-sequence gatekeeping strategy was used to control the study-wise error rate at a two-sided α of 0·05.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Also stated in: § Results · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“With an assumed incidence of clinically symptomatic respiratory illness at week 16 of 28·2% on placebo and of 19·7% in the RTB101 group, a total sample size of 1066 participants (equally randomised) would provide 90% power to detect a 30% reduction in the proportion of participants with clinically symptomatic respiratory illness between RTB101 and placebo using a two-sided test of 0·05”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
hedgeddirectn = 1,066- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The upregulation of antiviral gene expression was associated with a decrease in the incidence of laboratory-confirmed RTIs in the phase 2b study but not associated with a decrease in the incidence of clinically symptomatic respiratory illness in the phase 3 trial.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The combined results indicate that low doses of the mTOR inhibitor RTB101 are well tolerated and upregulate IFN-induced antiviral responses in older adults.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Interpretation
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results of the phase 2b and phase 3 trials done in over 1500 adults aged at least 65 years confirm the results of the previous phase 2a trial that mTOR inhibition with RTB101 was well tolerated and consistently upregulated IFN-induced antiviral gene expression in older adults.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
boosteddirectn = 1,500- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This result was calculated by using a logistic regression including a term for treatment, along with a term for each disease factor and age (continuous) as separate covariates, where a p value for each dose versus placebo was computed on the basis of the estimate of the treatment effect.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Ethics approval was provided by the Northern A Health and Disability Ethics Committee in New Zealand and the Bellberry Human Research Ethics Committee in Australia.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and the healthier adults might have had less attenuation of their type 1 IFN responses and, therefore, obtained less benefit from upregulation of IFN responses by RTB101.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Rests on an assumption: Older adults have deficient IFN-induced antiviral responses.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Also, upregulation of antiviral gene expression by RTB101 possibly has treatment benefit in only a subset of older adults or a subset of patients with viral infections.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The primary efficacy endpoint was analysed using a logistic regression model to obtain an estimate of the population OR and associated 95% CIs between RTB101 and placebo.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Ethics approval was provided by the Northern B Health and Disability Ethics Committee in New Zealand and by Advarra in the USA.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Clinical frailty was assessed at the baseline visit using a 7-point clinical frailty scale.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Study design and participants
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We prespecified an analysis of efficacy in the seven enrolled patient groups. However, two of the patient groups had too few participants to analyse, so we analysed the five remaining groups only.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plainn = 7- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Of the 1024 subjects enrolled, 970 (94·7%) completed tudy follow-up irrespective of whether they discontinued study drug early (figure 2 ).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plainn = 1,024- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Of the 652 patients enrolled, 616 (95%) completed the study (figure 1 ).”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plainn = 652- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analysis population included participants with a valid gene expression measurement at both baseline and week 16 for at least one gene of interest and who had given consent to participate in the biomaarker research study.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Two statistical analysis of the primary efficacy endpoint were prespecified.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The first accounted for multiplicity by using a fixed sequence testing procedure that was limited to data from Part 2 of the trial and controlled the overall type I error.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Because this was an exploratory phase 2b dose-finding trial, an additional analysis of the primary endpoint was prespecified that did not adjust for multiplicity.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Last, the upregulation of antiviral gene expression by RTB101 might be insufficient to decrease the incidence of viral RTIs and the positive results in the phase 2b trial were a result of type 1 error.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
Type 1 IFNs are the first line of defense against viruses and induce the expression of hundreds of antiviral genes that inhibit the replication of many different viruses.
“Type 1 IFNs are the first line of defense against viruses and induce the expression of hundreds of antiviral genes that inhibit the replication of many different viruses.”
The paper relies on this without support.
Inhibition of mTOR has been shown to extend lifespan and improve the function of multiple ageing organ systems including the immune system in animal models.
“Inhibition of mTOR has been shown to extend lifespan and improve the function of multiple ageing organ systems including the immune system in animal models.”
The paper relies on this without support.
Older adults have deficient IFN-induced antiviral responses.
“such as deficient IFN-induced antiviral responses”
The authors state this as an assumption.
Once daily RTB101 dosing achieves intermittent inhibition of mTOR, and twice daily RTB101 dosing or combination dosing with everolimus achieves persistent inhibition of mTOR.
“intermittent inhibition of mTOR (predicted to be achieved with with once daily RTB101 dosing) might be more effective than persistent inhibition (predicted to be achieved with twice daily RTB101 dosing or combination dosing with everolimus)”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Pre-treatment with MTORC1 inhibitors increased the immune response of elderly volunteers to immunization against influenza 138 and reduced viral respiratory infections in the ensuing winter 139”
From Hallmarks of aging: An expanding universe (2023) · cites this paper as [138]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In both trials, significantly more interferon-induced antiviral genes were upregulated in subjects treated with BEZ235 as compared to placebo.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [84]
The cited source says what the claim attributes to it.
In the citing paper
“In addition, mTOR inhibition has been shown to upregulate antiviral immunity in older adults 83,84.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [84]
The cited source says what the claim attributes to it.
In the citing paper
“Low doses of the mTOR inhibitor BEZ235 were observed to be well-tolerated and to decrease the incidence of laboratory-confirmed RTIs (the Phase 2b primary endpoint; OR 0.601 [90% CI 0.39, 0.92]; p-value 0.025) but not the incidence of clinically symptomatic respiratory illness”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [84]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“| Male | 33 (54%) | 31 (53)% | 36 (60%) | 100 (56%) | 52 (44%) | 61 (501%) | 57 (50%) | 53 (44%) | 223 (47%) |”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
Reported 501 · recomputed 50.833333
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
“513 (50·1%) participants were randomly assigned to RTB101 10 mg once daily and 510 (49·9%) to placebo.”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
“513 (50·1%) participants were randomly assigned to RTB101 10 mg once daily and 511 (49·9%) to placebo.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Abstract > Findings
“OR 1·07 [90% CI 0·80–1·42]; p=0·65”
§ Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials > Results
“OR 1·07 [95% CI 0·80–1·42]; p=0·65”
Citations
Cites
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19
Blanco-Melo, D., Nilsson-Payant, B. E., Liu, W.-C., Uhl, S., Hoagland, D., Møller, R., Jordan, T. X., Oishi, K., Panis, M., Sachs, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.026 · Cited by 4,222
Autoantibodies against type I IFNs in patients with life-threatening COVID-19
Bastard, P., Rosen, L. B., Zhang, Q., Michailidis, E., Hoffmann, H.-H., Zhang, Y., Dorgham, K., Philippot, Q., Rosain, J., Béziat, V., et al. (2020) · Science · doi:10.1126/science.abd4585 · Cited by 2,662
Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults
Jain, S., Self, W. H., Wunderink, R. G., Fakhran, S., Balk, R., Bramley, A. M., Reed, C., Grijalva, C. G., Anderson, E. J., Courtney, D. M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500245 · Cited by 2,323
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., Ogishi, M., Sabli, I. K. D., Hodeib, S., Korol, C., et al. (2020) · Science · doi:10.1126/science.abd4570 · Cited by 2,229
mTOR is a key modulator of ageing and age-related disease
Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013) · Nature · doi:10.1038/nature11861 · Cited by 1,676
National Vital Statistics Reports NCHS.pdf
Hoyert, D. (2012) · Medical Entomology and Zoology · Cited by 982
mTOR inhibition improves immune function in the elderly
Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., Lonetto, M. A., Maecker, H. T., Kovarik, J., Carson, S., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009892 · Cited by 786
Self-citationmTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells
Chen, C., Liu, Y., Liu, Y., & Zheng, P. (2009) · Science Signaling · doi:10.1126/scisignal.2000559 · Cited by 680
TORC1 inhibition enhances immune function and reduces infections in the elderly
Mannick, J. B., Morris, M., Hockey, H.-U. P., Roma, G., Beibel, M., Kulmatycki, K., Watkins, M., Shavlakadze, T., Zhou, W., Quinn, D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aaq1564 · Cited by 496
Self-citation
Cited by
Sorted by citations
Hallmarks of aging: An expanding universe
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023) · Cell · doi:10.1016/j.cell.2022.11.001 · Cited by 6,549
Biomarkers of aging for the identification and evaluation of longevity interventions
Moqri, M., Herzog, C., Poganik, J. R., Justice, J., Belsky, D. W., Higgins-Chen, A., Moskalev, A., Fuellen, G., Cohen, A. A., Bautmans, I., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.003 · Cited by 736
Self-citationTargeting the biology of aging with mTOR inhibitors
Mannick, J. B., & Lamming, D. W. (2023) · Nature Aging · doi:10.1038/s43587-023-00416-y · Cited by 372
Self-citationInterconnections between Inflammageing and Immunosenescence during Ageing
Teissier, T., Boulanger, É., & Cox, L. S. (2022) · Cells · doi:10.3390/cells11030359 · Cited by 323
Human trials exploring anti-aging medicines
Guarente, L., Sinclair, D. A., & Kroemer, G. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.007 · Cited by 266
Metadata
- Authors
- Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., Marshall, W., & Shergill, S.
- Affiliations
- Mersana Therapeutics (United States) (US)
- Dicerna Pharmaceuticals (United States) (US)
- Corresponding author
- Mannick, Joan B
- Venue
- The Lancet Healthy Longevity
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 2
- Issue
- 5
- Pages
- e250-e262
- ISSN
- 2666-7568 (ISSN-L)
- PMC
- PMC8102040
- OpenAlex
- W3158211524
- Cited by
- 131
- References
- 21
- Citations by year
- 2026: 34 · 2025: 33 · 2024: 20 · 2023: 25 · 2022: 13 · 2021: 6
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The Lancet Healthy Longevity (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pediatric health and respiratory diseases
- Keywords
- mTOR inhibitors, BEZ235, everolimus, immunosenescence, respiratory infections, respiratory viral infections, influenza, COVID-19 pandemic, adverse events, drug safety
- MeSH terms
- Everolimus, COVID-19, MTOR Inhibitors, Aged, Aging, Antiviral Agents, Biology, Diabetes Mellitus, Type 2, Humans, Immunity, Respiratory Tract Infections, Treatment Outcome, Pulmonary Disease, Chronic Obstructive, TOR Serine-Threonine Kinases, Pandemics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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