Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Respiratory tract infections are a leading cause of hospitalisation and deaths in older adults and are mainly caused by viruses.

“Respiratory tract infections (RTIs) are a leading cause of hospitalisation and deaths in older adults and are mainly caused by viruses.2, 3, 4”

• cites [2] Murphy, 2013, Deaths: final data for 2010, Natl Vital Stat RepNot checked — no full text of the source
• cites [3] 2016Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [4] Jain, 2015, Community-acquired pneumonia requiring hospitalization among US adults, N Engl J Med sourcePartly supported

  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)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

In a previous phase 2a trial, RTB101 (an oral mTOR inhibitor) increased IFN-induced antiviral gene expression and decreased the incidence of respiratory tract infections in older adults.

“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.”

• cites [10] Mannick, 2018, TORC1 inhibition enhances immune function and reduces infections in the elderly, Sci Transl Med sourcePartly supported

  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)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

In previous preclinical studies, inhibition of mTOR or a target downstream of mTOR protected mice from viral RTIs and upregulated IFN-induced antiviral immune responses.

“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”

• cites [8] York, 2015, Cell Limiting cholesterol biosynthetic flux spontaneously engages Type 1 IFN signaling, Cell sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites [9] Smallwood, 2017, Targeting metabolic reprogramming by influenza infection for therapeutic intervention, Cell Rep sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, the incidence of RTIs was calculated using predefined clinical criteria established by an expert consensus panel for surveillance of infections in older patients residing in long-term care facilities.

“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”

• cites [13] Stone, 2012, Surveillance definitions of infections in long-term care facilities: revisiting the McGeer criteria, Infect Control Hosp Epidemiol sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Coronaviruses and influenza viruses, but not parainfluenza or respiratory syncytial viruses, have been reported to suppress the host IFN response.

“Of interest, coronaviruses and influenza viruses, but not parainfluenza or respiratory syncytial viruses, have been reported to suppress the host IFN response.16”

• cites [16] Blanco-Melo, 2020, Imbalanced host response to SARS-CoV-2 drives development of COVID-19, Cell sourcePartly supported

  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)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

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.

“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”

• cites [18] Johnson, 2013, mTOR is a key modulator of ageing and age-related disease, Nature sourceSupported
• cites [19] Chen, 2009, mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells, Sci Signal sourcePartly supported

  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)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Ageing is caused by a discreet set of biological mechanisms that can be targeted therapeutically as a new way to treat ageing-related conditions.

“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”

• cites [17] López-Otín, 2013, The hallmarks of aging, Cell sourcePartly supported

  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)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

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.

“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.”

It may state two separate claims as one.

The study drug was found to be safe and well-tolerated across trials and treatment groups.

“The study drug was found to be safe and well-tolerated across trials and treatment groups.”

It may state two separate claims as one.

Three patients died in the phase 2b trial and one in the phase 3 trial but no deaths were considered related to study 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.”

It may state two separate claims as one.

In the phase 2b trial, the incidence of laboratory-confirmed RTIs in current smokers was higher in the RTB101 group than in the placebo group, but the incidence was low and the differences did not meet statistical significance.

“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).”

The quote only partly states this claim.

RTB101 10 mg once daily for 16 weeks increased expression of IFN-stimulated antiviral genes in peripheral blood.

“increased expression of IFN-stimulated antiviral genes in peripheral blood”

Probably not a substantial claim.

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.

“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.”

The quote only partly states this claim.

In part 2 of the phase 2b trial, RTB101 10 mg once daily was associated with a statistically significant reduction in the proportion of patients who had one or more laboratory-confirmed RTIs compared with pooled placebo (34 [19%] of 176 vs 50 [28%] of 180; OR 0·601 [90% CI 0·391-0·922]; p=0·025).

“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).”

It may state two separate claims as one.

In the phase 2b trial, RTB101 10 mg once daily had the greatest treatment benefit in patients aged at least 85 years and participants aged at least 65 years with asthma.

“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).”

It may state two separate claims as one.

In the phase 2b trial, 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 compared with placebo.

“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).”

It may state two separate claims as one.

In the phase 2b trial, RTB101 had no benefit in patients with COPD and in current smokers.

“RTB101 had no benefit in patients with COPD and in current smokers (appendix p 2).”

It may state two separate claims as one.

In both trials, the incidence and types of adverse events were consistent with what would be expected in the older populations assessed, and there were no clear differences in adverse event profiles between the RTB101 10 mg once daily group and placebo groups.

“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).”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, participants were randomly assigned using a validated automated randomisation system.

“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).”

Probably not a substantial claim.

All patients who received at least part of one dose of study drug were included in the primary and safety analyses.

“All patients who received at least part of one dose of study drug were included in the primary and safety analyses.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 3 trial, 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.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, masking was achieved by the use of placebo identical in packaging, labelling, schedule of administration, appearance, and odour to the active drug.

“Masking was achieved by the use of placebo that was identical in packaging, labelling, schedule of administration, appearance, and odour to the active drug.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 3 trial, participants, investigators, site staff, and sponsor were masked until final database lock.

“Participants, investigators, site staff, and sponsor were masked until final database lock.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, 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.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 3 trial, masking was achieved by the use of placebo identical in packaging, labelling, schedule of administration, appearance and odour to the active drug.

“Masking was achieved by the use of placebo that was identical in packaging, labelling, schedule of administration, appearance and odour to the active drug.”

Probably not a substantial claim.

The phase 2b trial was a randomised, double-blind, placebo-controlled trial.

“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).”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 3 trial, participants were randomly assigned using a validated automated randomisation system at a 1:1 ratio.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, participants, those giving the interventions, those assessing the outcomes, and those analysing the data were masked until final database lock.

“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.”

Probably not a substantial claim.

The phase 3 trial was a randomised, double-blind, placebo-controlled trial.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, nasopharyngeal swabs were tested for respiratory viruses using an FDA-approved PCR panel assay that detects 17 viral and three bacterial respiratory pathogens.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b antiviral gene expression analysis, RNA samples were analysed in triplicate per assay using the 96 × 96 Fluidigm Dynamic GE Array.

“RNA samples were then analysed in triplicate per assay using the 96 × 96 Fluidigm Dynamic GE Array (Fluidigm Corporation, San Francisco, CA, USA).”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In both trials, RNA isolation and Fluidigm gene expression was done according to good laboratory practice methods.

“RNA isolation and Fluidigm gene expression was done according to good laboratory practice methods.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b antiviral gene expression analysis, samples from the same participant were analysed on the same assay to avoid inter-batch variability.

“Samples from the same participant were analysed on the same assay to avoid inter-batch variability.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The phase 2b trial was registered with ANZCTR, ACTRN12617000468325, ClinicalTrials.gov, NCT03373903.

“The phase 2b trial was registered with ANZCTR, ACTRN12617000468325, ClinicalTrials.gov, NCT03373903”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The phase 3 trial was registered with ANZCTR, ACTRN12619000628145.

“the phase 3 trial was registered with ANZCTR, ACTRN12619000628145.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b antiviral gene expression analysis, 20 genes known to be upregulated by IFNs and three housekeeping genes (DECR1, RPLP0, and MAPRE2) were measured for each sample.

“20 genes known to be upregulated by IFNs and three housekeeping genes (DECR1, RPLP0, and MAPRE2) were measured for each sample.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b antiviral gene expression analysis, one calibrator, one no-enzyme control, and one no-template control were included with each batch of reverse transcription reactions.

“One calibrator, one no-enzyme control, and one no-template control were included with each batch of reverse transcription reactions.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

In the phase 2b trial, the second prespecified analysis did not adjust for multiplicity and used a one-sided α of 0·05, including all data from part 1 and part 2.

“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.”

Probably not a substantial claim.

In the phase 3 trial, 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 (full analysis set).

“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).”

Probably not a substantial claim.

In the phase 3 antiviral gene expression analysis, whole-blood samples from 180 participants who received placebo and 180 participants who received RTB101 10 mg once daily were processed.

“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.”

Probably not a substantial claim.

In the phase 2b trial, the first prespecified analysis accounted for multiplicity by using a fixed-sequence gatekeeping testing procedure limited to data from part 2 and controlled the overall one-sided type I error rate at 0·05.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, two different analyses of the key efficacy endpoints were prespecified.

“Two different analyses of the key efficacy endpoints were prespecified.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, the primary endpoint was centrally assessed.

“This outcome was centrally assessed.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The phase 3 antiviral gene expression sample size was based on the largest sample size that could be analysed with the available budget.

“This sample size was based on the largest sample size that could be analysed with the available budget.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 3 trial, the primary efficacy model was adjusted for age; frailty score; receipt of current season influenza vaccination; and medical history of asthma, congestive heart failure, or type 2 diabetes.

“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.”

Probably not a substantial claim.

In the phase 3 trial, a fixed-sequence gatekeeping strategy was used to control the study-wise error rate at a two-sided α of 0·05.

“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.”

Probably not a substantial claim.

In the phase 3 trial, 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测试

“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”

It may state two separate claims as one.

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.

“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.”

It may state two separate claims as one.

The combined results indicate that low doses of the mTOR inhibitor RTB101 are well tolerated and upregulate IFN-induced antiviral responses in older adults.

“The combined results indicate that low doses of the mTOR inhibitor RTB101 are well tolerated and upregulate IFN-induced antiviral responses in older adults.”

It may state two separate claims as one.

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.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, the primary endpoint result was calculated using a logistic regression including a term for treatment, along with a term for each disease factor and age (continuous) as separate covariates.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Ethics approval for the phase 3 trial was provided by the Northern A Health and Disability Ethics Committee in New Zealand and the Bellberry Human Research Ethics Committee in Australia.

“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.”

Probably not a substantial claim.

The healthier adults in the phase 3 trial might have had less attenuation of their type 1 IFN responses and, therefore, obtained less benefit from upregulation of IFN responses by RTB101.

“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.”

• AssumptionRests on an assumption: Older adults have deficient IFN-induced antiviral responses.

It may state two separate claims as one.

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.

“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.”

Probably not a substantial claim.

In the phase 3 trial, 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.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Ethics approval for the phase 2b trial was provided by the Northern B Health and Disability Ethics Committee in New Zealand and by Advarra in the USA.

“Ethics approval was provided by the Northern B Health and Disability Ethics Committee in New Zealand and by Advarra in the USA.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Clinical frailty was assessed at the baseline visit using a 7-point clinical frailty scale.

“Clinical frailty was assessed at the baseline visit using a 7-point clinical frailty scale.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

In the phase 2b trial, an analysis of efficacy was prespecified in seven enrolled patient groups, but two groups had too few participants to analyse, so only the five remaining groups were analysed.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 3 trial, 970 (94·7%) of 1024 enrolled subjects completed study follow-up.

“Of the 1024 subjects enrolled, 970 (94·7%) completed tudy follow-up irrespective of whether they discontinued study drug early (figure 2 ).”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the phase 2b trial, 616 (95%) of 652 enrolled patients completed the study.

“Of the 652 patients enrolled, 616 (95%) completed the study (figure 1 ).”

Probably not a substantial claim.

The antiviral gene expression 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 biomarker research study.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Two statistical analyses of the primary efficacy endpoint were prespecified in the phase 2b trial.

“Two statistical analysis of the primary efficacy endpoint were prespecified.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

The first prespecified analysis accounted for multiplicity by using a fixed sequence testing procedure limited to Part 2 data and controlled the overall type I error.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

An additional analysis of the primary endpoint that did not adjust for multiplicity was prespecified for the exploratory phase 2b dose-finding trial.

“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.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

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.

“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.”