A Sequential Multiple Assignment Randomized Trial (SMART) study of medication and CBT sequencing in the treatment of pediatric anxiety disorders

Classified as probably not a substantial claim.

Tolerance of exposure, with inhibition of an associated avoidance response, is considered the key element in cognitive behavioral therapy of anxiety disorders.

“Tolerance of exposure, with inhibition of an associated avoidance response, is considered the key element in the cognitive behavioral therapy of anxiety disorders [77, 78].”

• cites [77] Weisman JS, Rodebaugh TL. Exposure therapy augmentation: a review and extension of techniques informed by an inhibitory learning approach. Clin Psychol Rev. 2018;59:41–51. sourceNot checked — no full text of the source
• cites [78] Craske MG, Treanor M, Conway CC, Zbozinek T, Vervliet B. Maximizing exposure therapy: an inhibitory learning approach. Behav Res Ther. 2014;58:10–23. sourceSupported

May combine two claims.

Evidence suggests that CBT or medication can modify the cascade of responses to real or perceived threat - CBT by altering behavioral avoidance and information processing related to threat detection and coping, and medication by altering neurotransmitter levels that affect the function and structure of brain circuits.

“Evidence suggests that CBT or medication can modify the cascade of responses to real or perceived threat – CBT by altering behavioral avoidance and information processing related to threat detection and coping [56, 57], and medication by altering neurotransmitter levels that affect the function and structure of brain circuits [58–60].”

• cites [56] Siegel P, Warren R, Wang Z, Yang J, Cohen D, Anderson JF, et al. Less is more: neural activity during very brief and clearly visible exposure to phobic stimuli. Hum Brain Mapp. 2017;38(5):2466–81. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [57] Siegel P, Wang Z, Murray L, Campos J, Sims V, Leighton E, et al. Brain-based mediation of non-conscious reduction of phobic avoidance in young women during functional MRI: a randomised controlled experiment. Lancet Psychiatry. 2020;7(11):971–81. sourceNot checked — no full text of the source
• cites [58] Craske MG, Stein MB. Anxiety. Lancet. 2016;388(10063):3048–59. sourceNot checked — no full text of the source
• cites [59] Bansal R, Hellerstein DJ, Peterson BS. Evidence for neuroplastic compensation in the cerebral cortex of persons with depressive illness. Mol Psychiatry. 2018;23(2):375–83. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [60] Posner J, Hellerstein DJ, Gat I, Mechling A, Klahr K, Wang Z, et al. Antidepressants normalize the default mode network in patients with dysthymia. JAMA psychiatry. 2013;70(4):373–82. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

In the CAMS trial comparing CBT to medication, the patient sample was 78% Caucasian and 75% middle or upper class.

“In the CAMS trial comparing CBT to medication, for example, the patient sample was 78% Caucasian and 75% middle or upper class [10].”

• cites [10] Kendall PC, Compton SN, Walkup JT, Birmaher B, Albano AM, Sherrill J, et al. Clinical characteristics of anxiety disordered youth. J Anxiety Disord. 2010;24(3):360–5. sourceSupported

May combine two claims.

Guidelines often recommend CBT as the first-line treatment, but without evidence that it yields better patient outcomes than beginning with medication.

“They often recommend CBT as the first-line treatment, but without evidence that it yields better patient outcomes than beginning with medication [44–46].”

• cites [44] National Institute for Health and Care Excellence: Clinical Guidelines. Social Anxiety Disorder: Recognition, Assessment and Treatment. Leicester (UK) 2013.Not checked yet

  Not checked in the free run.

• cites [45] Connolly SD, Bernstein GA. Work group on quality I. practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(2):267–83. sourceSupported
• cites [46] Anxiety and Depression in Children and Youth – Diagnosis and Treatment. Guidelines & Protocols Advisory Committee, British Columbia Medical Services Commission. 2010.Not checked yet

  Not checked in the free run.

May combine two claims.

SSRI treatment effects begin to emerge within 2 weeks, sooner with higher doses.

“SSRI treatment effects begin to emerge within 2 weeks, sooner with higher doses [21]”

• cites [21] Strawn JR, Mills JA, Sauley BA, Welge JA. The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis. J Am Acad Child Adolesc Psychiatry. 2018;57(4):235–44.e2. sourceSupported

May combine two claims.

Both time spent in exposure tasks and level of difficulty of the exposures tolerated predicted better outcomes to Coping Cat within the CAMS sample.

“Of note, both time spent in exposure tasks, and level of difficulty of the exposures tolerated, predicted better outcomes to Coping Cat within the CAMS sample [119].”

• cites [119] Peris TS, Caporino NE, O’Rourke S, Kendall PC, Walkup JT, Albano AM, et al. Therapist-reported features of exposure tasks that predict differential treatment outcomes for youth with anxiety. J Am Acad Child Adolesc Psychiatry. 2017;56(12):1043–52. sourceSupported

Classified as probably not a substantial claim.

Randomization will be stratified by study site, age group [8-17], and baseline symptom severity, dichotomizing SCARED-41 scores as ≤33 or >33 based on the median SCARED-41 score for participants having scores ≥25 in the CAMS and LAMS studies.

“Randomization will be stratified by study site, age group [8–17], and baseline symptom severity (dichotomizing SCARED-41 scores as ≤33 or > 33, based on the median SCARED-41 score for participants having scores ≥25 in the CAMS [49] and LAMS [163] studies).”

• cites [49] Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753–66. sourcePartly supported

  The Methods (Randomization and Masking; page unavailable) identify this as a randomized childhood-anxiety study, supporting its identification as the CAMS study. The paper reports stratification by age, sex, and study center, but does not report a median SCARED-41 score of 33 among participants scoring at least 25; its Outcome Assessments section instead describes the Pediatric Anxiety Rating Scale. Thus it does not substantiate the cutoff attributed to CAMS. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [163] Van Meter AR, You DS, Halverson T, Youngstrom EA, Birmaher B, Fristad MA, et al. Diagnostic Efficiency of Caregiver Report on the SCARED for Identifying Youth Anxiety Disorders in Outpatient Settings. J Clin Child Adolesc Psychol. 2018;47(sup1):S161–s75. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

CAMS found large effect sizes for combined medication+CBT compared to monotherapy, with a somewhat larger difference compared to CBT alone than medication alone.

“However, CAMS did find large ESs for combined medication+CBT compared to monotherapy, with a somewhat larger difference compared to CBT alone than medication alone.”

• cites [42] Piacentini J, Bennett S, Compton SN, Kendall PC, Birmaher B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53(3):297–310. sourcePartly supported

  The Results (Outcomes at Weeks 24 and 36; page unavailable) report that combined treatment outperformed both CBT and sertraline alone. They describe the effect sizes as generally moderate at week 24 (0.51–0.81) and small at week 36 (0.34–0.41), not broadly large. The passage does not establish a larger effect relative to CBT than relative to medication. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

In CAMS, the CBT maintenance protocol was designed to reflect how the treatment would be delivered in clinical settings over an extended care time frame and focused on exposure practice and coping skills review, without the addition of other new material.

“In CAMS, this was “designed to reflect how the … treatment would be delivered in clinical settings” over an extended care time frame and focused on exposure practice and coping skills review, without the addition of other new material [49].”

• cites [49] Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753–66. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Previous findings suggest that disadvantaged youth may have lower engagement in key tasks of CBT and may have less mastery of material, leading to poorer outcomes.

“Third and finally, our focus on practice and intensity was informed by previous findings suggesting that disadvantaged youth may have lower engagement in key tasks of CBT and may have less mastery of material, leading to poorer outcomes.”

• cites [41] Gordon-Hollingsworth AT, Becker EM, Ginsburg GS, Keeton C, Compton SN, Birmaher BB, et al. Anxiety disorders in Caucasian and African American children: a comparison of clinical characteristics, treatment process variables, and treatment outcomes. Child Psychiatry Hum Dev. 2015;46(5):643–55. sourcePartly supported

  The Results (Treatment Process Variables) report lower therapist-rated involvement, compliance, and CBT-content mastery among African American youth than Caucasian youth; after adjustment for SES and home living situation, the differences in involvement and compliance were no longer significant. The Results (Treatment Outcome Variables) link greater involvement, mastery, and compliance to higher odds of remission. The claim extends these findings in clinically anxious African American youth to disadvantaged youth generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [124] Lee P, Zehgeer A, Ginsburg GS, McCracken J, Keeton C, Kendall PC, et al. Child and adolescent adherence with cognitive behavioral therapy for anxiety: predictors and associations with outcomes. J Clin Child Adolesc Psychol. 2019;48(sup1):S215–S26. sourcePartly supported

  The Results (Predictors of Adherence; page unavailable) report that youth from higher-SES families attended more CBT sessions, while the Discussion (Youth Adherence and Treatment Outcomes; page unavailable) links therapist-rated compliance with better outcomes. The paper does not establish that disadvantaged youth engage less in key CBT tasks or master less material; SES predicted attendance, not task compliance or mastery. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Patient non-adherence (poor attendance, low homework completion, poor compliance in session) was associated with number of parents present in the home (with best outcomes for two-parent families), although indices of non-adherence varied in their power to predict clinical outcomes.

“Similarly, patient non-adherence (poor attendance, low homework completion, poor compliance in session) was associated with number of parents present in the home (with the best outcomes for two-parent families), although indices of non-adherence varied in their power to predict clinical outcomes [124].”

• cites [124] Lee P, Zehgeer A, Ginsburg GS, McCracken J, Keeton C, Kendall PC, et al. Child and adolescent adherence with cognitive behavioral therapy for anxiety: predictors and associations with outcomes. J Clin Child Adolesc Psychol. 2019;48(sup1):S215–S26. sourceSupported

May combine two claims.

Coping Cat training has demonstrated effectiveness with clinicians ranging from graduate students to experienced psychotherapists, with strong treatment effects in each case.

“Coping Cat training has demonstrated effectiveness with clinicians ranging from graduate students [180, 181] to experienced psychotherapists [49], with strong treatment effects in each case.”

• cites [180] Kendall PC. Treating anxiety disorders in children: results of a randomized clinical trial. J Consult Clin Psychol. 1994;62(1):100–10. sourceNot checked — no full text of the source
• cites [181] Kendall PC, Flannery-Schroeder E, Panichelli-Mindel SM, Southam-Gerow M, Henin A, Warman M. Therapy for youths with anxiety disorders: a second randomized clinical trial. J Consult Clin Psychol. 1997;65(3):366–80. sourceNot checked — no full text of the source
• cites [49] Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753–66. sourceSupported

Classified as probably not a substantial claim. May combine two claims.

Non-responders in the treatment arms were referred to community providers for general outpatient treatment, and non-responders to the placebo condition were offered their choice of active study interventions.

“Non-responders in the treatment arms were referred to community providers for general outpatient treatment, and non-responders to the placebo condition were offered their choice of active study interventions.”

• cites [42] Piacentini J, Bennett S, Compton SN, Kendall PC, Birmaher B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53(3):297–310. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Latent class/profile analysis has been proposed as an alternative to subgroup analysis in clinical trials, using observed data to identify latent group classifications that may suggest individual characteristics related to greater responses to treatment.

“Latent class/profile analysis has been proposed as an alternative to subgroup analysis in clinical trials. As an exploratory analysis, it uses observed data (e.g., clinical characteristics, randomized treatments) to identify latent group classifications that may suggest individual characteristics related to greater responses to treatment [205].”

• cites [205] Lanza ST, Rhoades BL. Latent class analysis: an alternative perspective on subgroup analysis in prevention and treatment. Prev Sci. 2013;14(2):157–68. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Q-learning is a regression approach recommended for SMART data to identify tailoring variables that modify treatment responses and suggest enhancements to sequential decision-making of an adaptive intervention.

“This is a regression approach recommended for SMART data to identify tailoring variables that modify treatment responses and suggest enhancements to the sequential decision-making of an adaptive intervention [197].”

• cites [197] Nahum-Shani I, Qian M, Almirall D, Pelham WE, Gnagy B, Fabiano GA, et al. Q-learning: a data analysis method for constructing adaptive interventions. Psychol Methods. 2012;17(4):478–94. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Teenagers desired outcomes including feeling comfortable around peers, feeling confident in the classroom, feeling less worried about things outside their control, and being better able to manage emotions.

“Desired outcomes for teenagers included feeling comfortable around peers, feeling confident in the classroom, feeling less worried about things outside their control, and being better able to manage emotions.”

Classified as probably not a substantial claim.

Parents in community engagement reported that shame/stigma creates a significant barrier to accessing treatment services for youth with a mental health condition.

“Parents discussed the shame that youth with a mental health condition feel, the secrecy they keep, and how this shame/stigma creates a significant barrier to accessing treatment services.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Parents voiced desired outcomes including their child sleeping through the night, managing change without anger or panic attacks, interacting positively with peers and teachers, and attending school more consistently without emotional outbursts.

“Parents voiced wanting their child to be able to sleep through the night, manage change without anger or panic attacks, interact positively with peers and teachers, and attend school more consistently and without emotional outbursts.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Following Research 101, parents demonstrated increased knowledge about research, study methods, and designs.

“Following Research 101, parents demonstrated increased knowledge about research, study methods, and designs.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Parents have many fears and misperceptions about research and the intentions of researchers.

“In general, we heard that parents have many fears and misperceptions about research and the intentions of researchers.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Extensive discussions with leaders of the pediatric primary care network suggested that once-daily dosing, the wide range of safe doses, and simple upward titration in 10 mg increments will facilitate the training and comfort of pediatricians in prescribing medication in this study.

“Finally, extensive discussions with leaders of our pediatric primary care network have suggested that the once-daily dosing, the wide range of doses over which fluoxetine administration is deemed safe in pediatric patients, and the simple upward titration in 10 mg increments will facilitate the training and comfort of pediatricians in prescribing medication in this study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Parents expressed concern about randomization as potentially "unfair" if treatment is withheld.

“Parents also expressed concern about randomization as potentially “unfair” if treatment is withheld.”

May combine two claims.

The total number of patients seen in the age range across the 9 sites is >300,761 annually (601,522 over 2 years of recruitment), and 2.9% of them already carry a diagnosis of anxiety disorder in their electronic medical record.

“The total number of patients seen in our age range across these 9 sites is > 300,761 annually (601,522 over 2 years of recruitment), and 2.9% of them already carry a diagnosis of anxiety disorder in their electronic medical record.”

May combine two claims.

Early intervention may reduce anxiety prevalence in adults, attenuate the frequent worsening of symptoms, and lessen the associated impairment over time.

“suggesting that early intervention may reduce anxiety prevalence in adults, attenuate the frequent worsening of symptoms and lessen the associated impairment over time [1, 5, 6].”

• cites [1] Copeland WE, Angold A, Shanahan L, Costello EJ. Longitudinal patterns of anxiety from childhood to adulthood: the Great Smoky Mountains study. J Am Acad Child Adolesc Psychiatry. 2014;53(1):21–33. sourceNot checked yet

  Not checked in the free run.

• cites [5] Kendall PC, Safford S, Flannery-Schroeder E, Webb A. Child anxiety treatment: outcomes in adolescence and impact on substance use and depression at 7.4-year follow-up. J Consult Clin Psychol. 2004;72(2):276–87. sourceNot checked — no full text of the source
• cites [6] Patel V, Flisher AJ, Hetrick S, McGorry P. Mental health of young people: a global public-health challenge. Lancet. 2007;369(9569):1302–13. sourceNot checked — no full text of the source

May combine two claims.

Pediatric anxiety disorders are chronic, recurrent, and unstable in diagnostic classification over time, with new anxiety disorders appearing together with or replacing the initial primary diagnosis.

“Systematic reviews and meta-analyses have consistently shown that pediatric anxiety disorders, like their adult counterparts, are chronic, recurrent, and unstable in their diagnostic classification over time”

• cites [16] Scholten WD, Batelaan NM, Penninx BWJH, Balkom AJLMv, Smit JH, Schoevers RA, et al. Diagnostic instability of recurrence and the impact on recurrence rates in depressive and anxiety disorders. J Affect Disord. 2016;195:185–90. sourceNot checked — no full text of the source
• cites [17] Hovenkamp-Hermelink JHM, Riese H, van der Veen DC, Batelaan NM, Penninx BWJH, Schoevers RA. Low stability of diagnostic classifications of anxiety disorders over time: a six-year follow-up of the NESDA study. J Affect Disord. 2016;190:310–5. sourceNot checked — no full text of the source

May combine two claims.

Systematic reviews and meta-analyses have documented substantial therapeutic effects for psychotherapy, particularly CBT, and medication, especially SSRIs.

“Systematic reviews and meta-analyses have also documented substantial therapeutic effects for both psychotherapy, particularly CBT (Cognitive Behavioral Therapy) [18, 19], and medication, especially SSRIs (selective serotonin reuptake inhibitors) [20–22].”

• Also stated in: § Conceptual framework of the SMART design · boosted

  “though substantial evidence supports the effectiveness of both SSRI’s and CBT in treating pediatric anxiety”

• cites [18] Weisz JR, Kuppens S, Ng MY, Eckshtain D, Ugueto AM, Vaughn-Coaxum R, et al. What five decades of research tells us about the effects of youth psychological therapy: a multilevel meta-analysis and implications for science and practice. Am Psychol. 2017;72(2):79–117. sourceNot checked — no full text of the source
• cites [19] Higa-McMillan CK, Francis SE, Rith-Najarian L, Chorpita BF. Evidence base update: 50 years of research on treatment for child and adolescent anxiety. J Clin Child Adolesc Psychol. 2016;45(2):91–113. sourceNot checked — no full text of the source
• cites [20] Wang Z, Whiteside S, Sim L, Farah W, Morrow A, Alsawas M, et al. Anxiety in children. Comparative effectiveness. AHRQ comparative effectiveness reviews. Review no. 192 (prepared by the Mayo Clinic evidence-based practice center under contract no. 290–2015-00013-I.) ed. Rockville (MD): Agency for Healthcare Research and Quality; 2017. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [21] Strawn JR, Mills JA, Sauley BA, Welge JA. The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis. J Am Acad Child Adolesc Psychiatry. 2018;57(4):235–44.e2. sourceNot checked yet

  Not checked in the free run.

• cites [22] Dobson ET, Bloch MH, Strawn JR. Efficacy and Tolerability of Pharmacotherapy for Pediatric Anxiety Disorders: A Network Meta-Analysis. J Clin Psychiatry. 2019;80(1):e1-e14. sourceNot checked — no full text of the source

May combine two claims.

Long-term outcomes in pediatric anxiety are poor and relapses are common, similar to adult anxiety disorders where relapse approaches 60%.

“Long-term follow-up in pediatric studies is rare, but data suggest that outcomes are poor and relapses common, similar to what is observed in adult anxiety disorders, where relapse approaches 60% [16, 28].”

• cites [16] Scholten WD, Batelaan NM, Penninx BWJH, Balkom AJLMv, Smit JH, Schoevers RA, et al. Diagnostic instability of recurrence and the impact on recurrence rates in depressive and anxiety disorders. J Affect Disord. 2016;195:185–90. sourceNot checked — no full text of the source
• cites [28] Scholten WD, Batelaan NM, van Balkom AJLM. Wjh. Penninx B, Smit JH, van Oppen P. recurrence of anxiety disorders and its predictors. J Affect Disord. 2013;147(1):180–5. sourceNot checked — no full text of the source

May combine two claims.

Ethnic minorities tend to view CBT as less feasible for their lifestyle, thereby limiting their treatment adherence.

“but they also tend to view CBT as less feasible for their lifestyle [40], thereby limiting their treatment adherence [41].”

• cites [40] Chavira DA, Stein MB, Bailey K, Stein MT. Parental opinions regarding treatment for social anxiety disorder in youth. J Dev Behav Pediatr. 2003;24(5):315–22. sourceNot checked — no full text of the source
• cites [41] Gordon-Hollingsworth AT, Becker EM, Ginsburg GS, Keeton C, Compton SN, Birmaher BB, et al. Anxiety disorders in Caucasian and African American children: a comparison of clinical characteristics, treatment process variables, and treatment outcomes. Child Psychiatry Hum Dev. 2015;46(5):643–55. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

May combine two claims.

Predictors of poor acute treatment outcomes include more severe symptoms, more functional impairment, low socioeconomic status, and a primary diagnosis of social phobia.

“Predictors of poor acute treatment outcomes include more severe symptoms, more functional impairment [29, 31], low socioeconomic status (SES) [32], and a primary diagnosis of social phobia [31, 32].”

• cites [29] Ginsburg GS, Becker-Haimes EM, Keeton C, Kendall PC, Iyengar S, Sakolsky D, et al. Results from the child/adolescent anxiety multimodal extended long-term study (CAMELS): primary anxiety outcomes. J Am Acad Child Adolesc Psychiatry. 2018;57(7):471–80. sourceNot checked — no full text of the source
• cites [31] Wergeland GJH, Fjermestad KW, Marin CE, Bjelland I, Haugland BSM, Silverman WK, et al. Predictors of treatment outcome in an effectiveness trial of cognitive behavioral therapy for children with anxiety disorders. Behav Res Ther. 2016;76:1–12. sourceNot checked — no full text of the source
• cites [32] Kodal A, Fjermestad KW, Bjelland I, Gjestad R, Öst L-G, Bjaastad JF, et al. Predictors of long-term outcome of CBT for youth with anxiety disorders treated in community clinics. J Anxiety Disorder. 2018;59:53–63. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Classified as probably not a substantial claim.

Consensus panels generally agree that CBT and either SSRI or SNRI pharmacotherapies have the strongest evidence for efficacy.

“They generally agree that CBT and either SSRI or SNRI pharmacotherapies have the strongest evidence for efficacy [20].”

• cites [20] Wang Z, Whiteside S, Sim L, Farah W, Morrow A, Alsawas M, et al. Anxiety in children. Comparative effectiveness. AHRQ comparative effectiveness reviews. Review no. 192 (prepared by the Mayo Clinic evidence-based practice center under contract no. 290–2015-00013-I.) ed. Rockville (MD): Agency for Healthcare Research and Quality; 2017. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

May combine two claims.

The CAMS study compared CBT and medication but was an efficacy study conducted in academic centers rather than real-world community clinics.

“(the CAMS study did, but it was an efficacy study conducted in academic centers rather than in “real world” community clinics [10]).”

• cites [10] Kendall PC, Compton SN, Walkup JT, Birmaher B, Albano AM, Sherrill J, et al. Clinical characteristics of anxiety disordered youth. J Anxiety Disord. 2010;24(3):360–5. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Findings on the association of baseline individual tailoring and environmental variables with later clinical outcomes can inform the use of individual patient information for initial treatment assignment.

“Findings on the association of baseline individual tailoring and environmental variables with later clinical outcomes can inform the use of individual patient information for initial treatment assignment.”

May combine two claims.

Therapeutic alliance provides expectancy and hope for change and fosters fortitude to confront problems through treatment.

“It provides expectancy and hope for change and fosters the fortitude to confront the problems through treatment [80–83].”

• cites [80] Zilcha-Mano S, Roose SP, Brown PJ, Rutherford BR. Not Just Nonspecific Factors: The Roles of Alliance and Expectancy in Treatment, and Their Neurobiological Underpinnings. Front Behav Neurosci. 2019;12:293. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [81] Zilcha-Mano S, Brown PJ, Roose SP, Cappetta K, Rutherford BR. Optimizing patient expectancy in the pharmacologic treatment of major depressive disorder. Psychol Med. 2019;49(14):2414-20. sourceNot checked — no full text of the source
• cites [82] Rutherford BR, Wall MM, Brown PJ, Choo T-H, Wager TD, Peterson BS, et al. Patient expectancy as a mediator of placebo effects in antidepressant clinical trials. Am J Psychiatr. 2017;174(2):135–42. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [83] Zilcha-Mano S, Wang Z, Peterson BS, Wall MM, Chen Y, Wager TD, et al. Neural mechanisms of expectancy-based placebo effects in antidepressant clinical trials. J Psychiatr Res. 2019;116:19–25. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

May combine two claims.

Neither SSRI nor CBT works well for all youth.

“neither treatment works well for all youth”

May combine two claims.

In the CAMS study, combined CBT + sertraline improved clinical response more than either modality alone, but primarily in those with severe anxiety, and not in long-term follow-up.

“In the CAMS study, combined CBT + sertraline improved clinical response more than either modality alone [49], but primarily in those with severe anxiety [50], and not in long-term follow-up [29].”

• cites [49] Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753–66. sourceNot checked yet

  Not checked in the free run.

• cites [50] Taylor JH, Lebowitz ER, Jakubovski E, Coughlin CG, Silverman WK, Bloch MH. Monotherapy insufficient in severe anxiety? Predictors and moderators in the child/adolescent anxiety multimodal study. J Clin Child Adolesc Psychol. 2018;47(2):266-81. sourceNot checked yet

  Not checked in the free run.

• cites [29] Ginsburg GS, Becker-Haimes EM, Keeton C, Kendall PC, Iyengar S, Sakolsky D, et al. Results from the child/adolescent anxiety multimodal extended long-term study (CAMELS): primary anxiety outcomes. J Am Acad Child Adolesc Psychiatry. 2018;57(7):471–80. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S2 (checkable).

Empirical evidence contributing to individualized treatment regimens based on tailoring variables, treatment history, and current response status will have the added advantage of supporting shared decision-making by the child and parents with an empirically-informed clinician.

“Empirical evidence contributing to individualized treatment regimens based on tailoring variables, treatment history, and current response status will have the added advantage of supporting shared decision-making by the child and parents with an empirically-informed clinician [65, 66]”

• cites [65] Drake RE, Cimpean D, Torrey WC. Shared decision making in mental health: prospects for personalized medicine. Dialogues Clin Neurosci. 2009;11(4):455–63. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [66] Legare F, Witteman HO. Shared decision making: examining key elements and barriers to adoption into routine clinical practice. Health Aff. 2013;32(2):276–84. sourceNot checked — no full text of the source

May combine two claims.

Because adaptive approaches approximate intervention sequences used in clinical practice, they can be used to develop, test, and refine algorithms for clinical decision-making and inform the development and validation of practice guidelines.

“Because adaptive approaches approximate intervention sequences used in clinical practice, they can be used to develop, test, and refine algorithms for clinical decision-making and inform the development and validation of practice guidelines [64].”

• cites [64] Sherrill JT. Adaptive treatment strategies in youth mental health: a commentary on advantages, challenges, and potential directions. J Clin Child Adolesc Psychol. 2016;45(4):522–7. sourceNot checked — no full text of the source

May combine two claims.

Practicing these skills in different fear-inducing contexts supports generalization of inhibitory learning and stronger extinction of fear responses.

“Practicing these skills in different fear-inducing contexts supports generalization of inhibitory learning and stronger extinction of fear responses [78].”

• cites [78] Craske MG, Treanor M, Conway CC, Zbozinek T, Vervliet B. Maximizing exposure therapy: an inhibitory learning approach. Behav Res Ther. 2014;58:10–23. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Exposure generates new learning of safety-based associations that inhibit former fear response associations to the feared stimulus, thereby either extinguishing the fear response or enabling a level of fear tolerance that reduces anxious distress.

“This exposure generates new learning of safety-based associations that inhibit former fear response associations to the feared stimulus [77, 78, 118], thereby either extinguishing the fear response or enabling a level of fear tolerance that reduces anxious distress.”

• cites [77] Weisman JS, Rodebaugh TL. Exposure therapy augmentation: a review and extension of techniques informed by an inhibitory learning approach. Clin Psychol Rev. 2018;59:41–51. sourceNot checked — no full text of the source
• cites [78] Craske MG, Treanor M, Conway CC, Zbozinek T, Vervliet B. Maximizing exposure therapy: an inhibitory learning approach. Behav Res Ther. 2014;58:10–23. sourceNot checked yet

  Not checked in the free run.

• cites [118] McLean CP, Foa EB. Prolonged exposure therapy for post-traumatic stress disorder: a review of evidence and dissemination. Expert Rev Neurother. 2011;11(8):1151–63. sourceNot checked — no full text of the source

May combine two claims.

Prior studies have shown that a better therapeutic alliance precedes and predicts better outcomes, and better outcomes precede and predict an improved therapeutic alliance.

“Prior studies have shown that a better therapeutic alliance precedes and predicts better outcomes, and better outcomes precede and predict an improved therapeutic alliance [71, 73, 84].”

• cites [71] Cuijpers P, Reijnders M, Huibers MJH. The role of common factors in psychotherapy outcomes. Annu Rev Clin Psychol. 2019;15:207–31. sourceNot checked yet

  Not checked in the free run.

• cites [73] DeRubeis RJ, Brotman MA, Gibbons CJ. A conceptual and methodological analysis of the nonspecifics argument. Clin Psychol Sci Pract. 2005;12(2):174–83. sourceNot checked — no full text of the source
• cites [84] Zilcha-Mano S. Is the alliance really therapeutic? Revisiting this question in light of recent methodological advances. Am Psychol. 2017;72(4):311–25. sourceNot checked — no full text of the source

May combine two claims.

Two factors common to all clinical encounters, alliance-building and reward, are explicitly components of Coping Cat CBT and at least implicitly components of the psychopharmacological treatments.

“Of the many potential factors common to all clinical encounters, two are explicitly components of Coping Cat CBT, “alliance-building” and “reward”, and they are at least implicitly components of the psychopharmacological treatments as well (Table 1).”

• cites Table 1Not matched

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

Probably not a substantial claim: may not pass S2 (checkable).

Adaptive interventions resemble clinical practice, in that different interventions are assigned to different individuals and within individuals over time, with the intervention(s) ideally varying in response to patient needs and patient response.

“Adaptive interventions resemble clinical practice, in that different interventions are assigned to different individuals and within individuals over time, with the intervention(s) ideally varying in response to patient needs and patient response [62].”

• cites [62] Collins LM, Murphy SA, Bierman KL. A conceptual framework for adaptive preventive interventions. Prev Sci. 2004;5(3):185–96. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

All study assessments have been selected as parent- and youth-reports that require minimal to no interactions with research staff, thereby minimizing or eliminating rater bias from study staff.

“Nevertheless, all study assessments have been selected as parent- and youth-reports that require minimal to no interactions with research staff, thereby minimizing or eliminating rater bias from study staff.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study statistician will develop and monitor fidelity to the randomization sequence.

“The study statistician will develop and monitor fidelity to the randomization sequence.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Participants are often concerned about being randomized to a less effective treatment.

“Participants are often concerned about being randomized to a less effective treatment [141, 142], but here the 2 treatment arms will be in true clinical equipoise [143].”

• cites [141] Food & Drug Administration. FDA Executive Summary: 2017 Meeting Materials of the Patient Engagement Advisory Committee 2017 [Available from: https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PatientEngagementAdvisoryCommittee/ucm578522.htm.Not checked yet

  Not checked in the free run.

• cites [142] Ross S, Grant A, Counsell C, Gillespie W, Russell I, Prescott R. Barriers to participation in randomised controlled trials: a systematic review. J Clin Epidemiol. 1999;52(12):1143–56. sourceNot checked — no full text of the source

May combine two claims.

Paroxetine has a risk of increased suicidality, which may be higher compared to other SSRIs, and it does not have any FDA-approved pediatric indications.

“Because of its risk of increased suicidality, which may be higher when compared to other SSRIs [166], and because it does not have any FDA-approved pediatric indications, we elected not to include paroxetine in this protocol.”

• cites [166] Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. JAMA Psychiatry. 2006;63(3):332–9. sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

404 children ages 8-17 who have an anxiety disorder will be randomized 1:1 to receive 12 weeks of either fluoxetine in upward-titrated dosages or weekly CBT implemented using the Coping Cat CBT model.

“404 children ages 8–17 who have an anxiety disorder will be randomized 1:1 to receive 12 weeks of either the medication fluoxetine in upward-titrated dosages or weekly CBT implemented using the Coping Cat CBT model [128].”

• cites [128] Kendall PC, Hedke KA. Cognitive behavioral therapy for anxious children: therapist manual. 3rd ed. Admore: PA; 2006.Not checked — no full text of the source

May combine two claims.

The trial is a single-blind SMART with two levels of randomization, one in each of two 12-week stages.

“This is a single-blind Sequential Multiple Assignment Randomized Trial (SMART) of 24 weeks duration with two levels of randomization, one in each of two 12-week stages.”

May combine two claims.

SSRI therapeutic response is significantly greater and faster than SNRI response.

“We selected the SSRI fluoxetine rather than an SNRI because SSRI therapeutic response is significantly greater and faster [21, 22, 129].”

• cites [21] Strawn JR, Mills JA, Sauley BA, Welge JA. The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis. J Am Acad Child Adolesc Psychiatry. 2018;57(4):235–44.e2. sourceNot checked yet

  Not checked in the free run.

• cites [22] Dobson ET, Bloch MH, Strawn JR. Efficacy and Tolerability of Pharmacotherapy for Pediatric Anxiety Disorders: A Network Meta-Analysis. J Clin Psychiatry. 2019;80(1):e1-e14. sourceNot checked — no full text of the source
• cites [129] Jakubovski E, Johnson JA, Nasir M, Müller-Vahl K, Bloch MH. Systematic review and meta-analysis: dose–response curve of SSRIs and SNRIs in anxiety disorders. Depress Anxiety. 2019;36(3):198–212. sourceNot checked — no full text of the source

May combine two claims.

This will be a single-blind SMART design of 24-week treatment duration that will employ two sequential levels of randomization, one in each of two 12-week stages.

“This will be a single-blind [126, 127] SMART design [51, 52] of 24-week treatment duration that will employ two sequential levels of randomization, one in each of two 12-week stages of the study (Fig. 2).”

• cites [126] Duddy A, Franke K, Whihcher DM, Moloney RM, Karkare SU. Making Informed Decisions: Assessing the Strengths and Weaknesses of Study Designs and Analytic Methods for Comparative Effectiveness Research. In: Velengtas P, Mohr P, Messner DA, editors. National Pharmaceutical Council; 2012.Not checked yet

  Not checked in the free run.

• cites [127] Olsen LA, McGinnis JM. Redesigning the Clinical Effectiveness Research Paradigm: Innovation and Practice-Based Approaches: Workshop Summary. Institute of Medicine (US) Roundtable on Value & Science-Driven Health Care. Washington (DC): The National Academies Collection: Reports funded by National Institutes of Health; 2010.Not checked yet

  Not checked in the free run.

• cites [51] Murphy SA. An experimental design for the development of adaptive treatment strategies. Stat Med. 2005;24(10):1455–81. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [52] Ogbagaber SB, Karp J, Wahed AS. Design of sequentially randomized trials for testing adaptive treatment strategies. Stat Med. 2016;35(6):840–58. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

May combine two claims.

ROC curves for the Child Trauma Screen indicate that requiring a parent reaction score ≥10 will miss approximately 22% of true PTSD cases but will not exclude any who are incorrectly diagnosed.

“ROC curves for this screener [134, 135] indicate that by requiring a score of ≥10 on the parent report for child reaction to past trauma, we will miss diagnosing approximately 22% of true PTSD cases but we will not exclude any who are incorrectly diagnosed.”

• cites [134] Lang JM, Connell CM. Development and validation of a brief trauma screening measure for children: the child trauma screen. Psychol Trauma. 2017;9(3):390–8. sourceNot checked — no full text of the source
• cites [135] Lang JM, Connell CM. The child trauma screen: a follow-up validation. J Trauma Stress. 2018;31(4):540–8. sourceNot checked — no full text of the source

May combine two claims.

In CAMS, African-American youths attended fewer CBT and medication management sessions, and were rated by therapists as less involved and compliant with treatment and possibly as showing a lower level of mastery of CBT concepts.

“In CAMS, African-American youths attended fewer CBT and medication management sessions, and they were rated by therapists as less involved and compliant with treatment and, possibly as a consequence, as showing a lower level of mastery of CBT concepts [41].”

• cites [41] Gordon-Hollingsworth AT, Becker EM, Ginsburg GS, Keeton C, Compton SN, Birmaher BB, et al. Anxiety disorders in Caucasian and African American children: a comparison of clinical characteristics, treatment process variables, and treatment outcomes. Child Psychiatry Hum Dev. 2015;46(5):643–55. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

May combine two claims.

Sertraline may require twice daily dosing for optimal use at lower doses, which can adversely affect treatment adherence and complicate prescribing by pediatricians who are new to prescribing psychotropics.

“In addition, like escitalopram, sertraline may require twice daily dosing for optimal use at lower doses [170], which can adversely affect treatment adherence and complicate prescribing by pediatricians who are new to prescribing psychotropics.”

• cites [170] Axelson DA, Perel JM, Birmaher B, Rudolph GR, Nuss S, Bridge J, et al. Sertraline pharmacokinetics and dynamics in adolescents. J Am Acad Child Adolesc Psychiatry. 2002;41(9):1037–44. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Randomization will be blocked with a relatively small block size to ensure balanced randomization over the short term, and block size will not be revealed to investigators or trial staff.

“Randomization will be further blocked, with a relatively small block size to ensure balanced randomization over the short term; block size will not be revealed to investigators or trial staff.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The randomization sequence will not be viewable.

“The randomization sequence will not be viewable.”

May combine two claims.

Serotonin HT1b receptors on the presynaptic terminal also desensitize, further increasing presynaptic transmission and increasing serotonin available to stimulate postsynaptic neurons.

“Serotonin HT1b receptors on the presynaptic terminal then also desensitize, further increasing presynaptic transmission and increasing the serotonin available to stimulate postsynaptic neurons.”

• cites [122] Fasipe O. Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Archiv Med Health Sci. 2018;6(1):81–94. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

May combine two claims.

Efficacy measures in the CAMS trial outperformed specific measures of cognitive change in mediational models on Coping Cat effects, suggesting that development of coping efficacy may mediate CBT outcomes.

“In addition, efficacy measures in the CAMS trial outperformed specific measures of cognitive change in mediational models on Coping Cat effects, suggesting that development of coping efficacy may mediate CBT outcomes [120].”

• cites [120] Kendall PC, Cummings CM, Villabø MA, Narayanan MK, Treadwell K, Birmaher B, et al. Mediators of change in the child/adolescent anxiety multimodal treatment study. J Consult Clin Psychol. 2016;84(1):1–14. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

May combine two claims.

Optimization of medication dosing often is not complete within the first 12 weeks, particularly for younger participants, and the effects of any given dose may not fully manifest for 12 weeks or more.

“Third, optimization of medication dosing often is not complete within the first 12 weeks, particularly for younger participants, and the effects of any given dose may not fully manifest for 12 weeks or more [21, 22, 129]; thus, the effects of Stage 1 dose increases may not manifest until Stage 2.”

• cites [21] Strawn JR, Mills JA, Sauley BA, Welge JA. The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis. J Am Acad Child Adolesc Psychiatry. 2018;57(4):235–44.e2. sourceNot checked yet

  Not checked in the free run.

• cites [22] Dobson ET, Bloch MH, Strawn JR. Efficacy and Tolerability of Pharmacotherapy for Pediatric Anxiety Disorders: A Network Meta-Analysis. J Clin Psychiatry. 2019;80(1):e1-e14. sourceNot checked — no full text of the source
• cites [129] Jakubovski E, Johnson JA, Nasir M, Müller-Vahl K, Bloch MH. Systematic review and meta-analysis: dose–response curve of SSRIs and SNRIs in anxiety disorders. Depress Anxiety. 2019;36(3):198–212. sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

The stringency of the remission criteria is based on reviewed prior studies indicating the importance of achieving diagnostic remission, with few residual symptoms and minimal functional impairment, in optimizing long-term clinical outcomes.

“The stringency of these remission criteria is based on the reviewed prior studies indicating the importance of achieving diagnostic remission, with few residual symptoms and minimal functional impairment, in optimizing long-term clinical outcomes.”

Classified as probably not a substantial claim.

An intent-to-treat analysis will compare youth randomized to fluoxetine first versus those randomized to CBT first.

“An intent-to-treat analysis will compare youth randomized to fluoxetine first versus those randomized to CBT first (“Main Effect 1”).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Medication adherence will be assessed with pill counts at each clinic visit.

“Medication adherence will be assessed with pill counts at each clinic visit.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Los Angeles County is one of the most racially, ethnically, and socioeconomically diverse regions in the world.

“Los Angeles County (LAC) is one of the most racially, ethnically, and socioeconomically diverse regions in the world [131].”

• cites [131] "B03002 HISPANIC OR LATINO ORIGIN BY RACE - Los Angeles County - 2019 American community survey 1-year estimates". US Census Bureau July 1, 2019. Retrieved March 12, 2021.Not checked yet

  Not checked in the free run.

May combine two claims.

Patient nonadherence (poor attendance, low homework completion, poor compliance in session) was associated with number of parents present in the home, with best outcomes for two-parent families, although indices of nonadherence varied in their power to predict clinical outcomes.

“Similarly, patient nonadherence (poor attendance, low homework completion, poor compliance in session) was associated with number of parents present in the home (with the best outcomes for two-parent families), although indices of nonadherence varied in their power to predict clinical outcomes [124].”

• cites [124] Lee P, Zehgeer A, Ginsburg GS, McCracken J, Keeton C, Kendall PC, et al. Child and adolescent adherence with cognitive behavioral therapy for anxiety: predictors and associations with outcomes. J Clin Child Adolesc Psychol. 2019;48(sup1):S215–S26. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study is designated "single blind" in the sense that patients and clinicians are not blinded but assessments minimize rater bias.

“It is in this sense that we designate this study “single blind”.”

Classified as probably not a substantial claim.

Use of patient-report measures to define remission at Week 12 will allow the study to quickly evaluate clinical status and move to either maintenance treatment or second-stage randomization with minimum disruption in care.

“Our use of patient-report measures to define remission at Week 12 will allow us to quickly evaluate clinical status and move to either maintenance treatment or second-stage randomization with minimum disruption in care.”

Probably not a substantial claim: may not pass S3 (load-bearing).

This protocol, version 1.0, was registered in ClinicalTrials.gov on February 17, 2021 with Identifier: NCT04760275.

“This protocol, version 1.0, was registered in ClinicalTrials.gov on February 17, 2021 with Identifier: NCT04760275.”

May combine two claims.

SSRIs inhibit presynaptic reuptake of serotonin after its release into the synaptic cleft, which over time desensitizes HT1a serotonin receptors on or near the cell body of the presynaptic neuron.

“SSRIs inhibit the presynaptic reuptake of serotonin after its release into the synaptic cleft, which in turn, over time, desensitizes HT1a serotonin receptors on or near the cell body of the presynaptic neuron [122].”

• cites [122] Fasipe O. Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Archiv Med Health Sci. 2018;6(1):81–94. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S3 (load-bearing).

Prospective prescribers will undergo a 3-hour training with two senior psychopharmacologists before being assigned any patients for treatment.

“They will undergo a 3-hour training for the study with two senior psychopharmacologists before being assigned any patients for treatment.”

Classified as probably not a substantial claim.

All participants who do not remit in Stage 1 will be randomized 1:1 to either optimization of their Stage 1 treatment or optimization of their Stage 1 treatment and addition of the other treatment modality.

“All participants who do not remit in Stage 1 will be randomized 1:1 to either (1) optimization of their Stage 1 treatment, or (2) optimization of their Stage 1 treatment and addition of the other treatment modality (Fig. 2).”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Because PCORI guidelines preclude paying for any component of clinical care, insurance will need to pay for study treatments, which in turn will preclude blinding patients and clinicians to treatment assignment.

“Because PCORI guidelines preclude paying for any component of clinical care, insurance will need to pay for study treatments, which in turn will preclude blinding patients and clinicians to treatment assignment.”

May combine two claims.

The risk of early withdrawal from CBT is low and the number will likely be small.

“This suggests that the risk of early withdrawal from CBT is low and that the number will likely be small.”

• AssumptionRests on an assumption: Service utilization data from the authors' treatment sites mirror the prior findings of low early withdrawal from CBT.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The trial data management protocol will include immediate post-data entry notifications, tracking of rectifications of missing data, and daily review of new data entries with immediate notification to data entry personnel and site coordinator for rectifications needed for missing data.

“The trial data management protocol will include immediate post-data entry notifications, tracking of rectifications of missing data, and daily review of new data entries with immediate notification to data entry personnel and site coordinator for rectifications needed for missing data.”

May combine two claims.

Rates of relapse in pediatric anxiety disorders are very high (approximately 60%), particularly in those who have more residual symptoms and functional impairment following acute treatment.

“and rates of relapse are very high (approximately 60%) [16, 28, 29], particularly in those who have more residual symptoms and functional impairment following acute treatment [29].”

• cites [16] Scholten WD, Batelaan NM, Penninx BWJH, Balkom AJLMv, Smit JH, Schoevers RA, et al. Diagnostic instability of recurrence and the impact on recurrence rates in depressive and anxiety disorders. J Affect Disord. 2016;195:185–90. sourceNot checked — no full text of the source
• cites [28] Scholten WD, Batelaan NM, van Balkom AJLM. Wjh. Penninx B, Smit JH, van Oppen P. recurrence of anxiety disorders and its predictors. J Affect Disord. 2013;147(1):180–5. sourceNot checked — no full text of the source
• cites [29] Ginsburg GS, Becker-Haimes EM, Keeton C, Kendall PC, Iyengar S, Sakolsky D, et al. Results from the child/adolescent anxiety multimodal extended long-term study (CAMELS): primary anxiety outcomes. J Am Acad Child Adolesc Psychiatry. 2018;57(7):471–80. sourceNot checked — no full text of the source

May combine two claims.

The remaining 50% of improvement occurs over the last 8 weeks of treatment, approaching asymptote by week 12.

“suggesting that the remaining 50% of improvement occurs over the last 8 weeks of treatment, approaching asymptote by week 12.”

Classified as probably not a substantial claim. May combine two claims.

The planned adaptation is designed to intensify the maintenance protocol from CAMS by increasing the total number of sessions from 6 to 12 and the density of delivery from monthly to weekly, and thus to optimize the dose of exposure learning.

“Our planned adaptation is designed to intensify the maintenance protocol from CAMS by increasing the total number of sessions (from 6 to 12) and the density of delivery (weekly versus monthly) and thus to optimize the dose of exposure learning.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In the post-acute phase of CAMS, patients in the CBT arm were offered 6 additional CBT sessions over 6 months, focusing on additional exposure practice and coaching to maintain application of CBT skills.

“In the post-acute phase of CAMS, patients in the CBT arm were offered 6 additional CBT sessions to be delivered over 6 months, focusing on additional exposure practice and coaching to maintain application of CBT skills in the face of emerging life stressors [42].”

• cites [42] Piacentini J, Bennett S, Compton SN, Kendall PC, Birmaher B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53(3):297–310. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S3 (load-bearing).

All electronic connections to the REDCap environment are encrypted.

“All electronic connections to the REDCap environment are encrypted.”

Classified as probably not a substantial claim.

A trained fidelity rater will listen to all 12 sessions of a randomly selected study case from each clinician and rate fidelity using a standardized fidelity checklist developed for Coping Cat.

“We will randomly select 1 study case from each clinician (assigned after their initial 2 training cases); a trained fidelity rater will listen to all 12 sessions of this case and rate fidelity using a standardized fidelity checklist developed for Coping Cat [180, 181].”

• cites [180] Kendall PC. Treating anxiety disorders in children: results of a randomized clinical trial. J Consult Clin Psychol. 1994;62(1):100–10. sourceNot checked — no full text of the source
• cites [181] Kendall PC, Flannery-Schroeder E, Panichelli-Mindel SM, Southam-Gerow M, Henin A, Warman M. Therapy for youths with anxiety disorders: a second randomized clinical trial. J Consult Clin Psychol. 1997;65(3):366–80. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The authors will institute policies that temporarily deactivate user accounts that have not logged into the system within a specified time; automatically require staff to change passwords at regular intervals; match current users against current study staff, and terminate user accounts for staff who no longer are associated with the project; and institute independent audits at regular intervals by

“We will institute policies that (a) temporarily deactivate user accounts that have not logged into the system within a specified time; (b) automatically require staff to change passwords at regular intervals; (c) match current users against current study staff, and terminate user accounts for staff who no longer are associated with the project; and (d) institute independent audits at regular”

Probably not a substantial claim: may not pass S3 (load-bearing).

A measure of general therapy competence that has been used with Coping Cat will be included to help assess the quality of treatment delivery, including exposure practices.

“We will also include a measure of general therapy competence that has been used with Coping Cat and can help assess the quality of treatment delivery, including exposure practices [185].”

• cites [185] Brown RC, Southam-Gerow MA, McLeod BD, Wheat EB, Tully CB, Reise SP, et al. The global therapist competence scale for youth psychosocial treatment: development and initial validation. J Clin Psychol. 2018;74(4):649–64. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S3 (load-bearing).

The study will attempt to complete trial outcomes at protocol-specified assessment times on all randomized persons, even those who have dropped from the study.

“We will attempt to complete trial outcomes at protocol-specified assessment times on all randomized persons, even those who have dropped from the study.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The project analyst will review data weekly to ensure completeness; a weekly report to investigators and study coordinators will identify outstanding missing data.

“Our project analyst will review data weekly to ensure completeness; a weekly report to investigators and study coordinators will identify outstanding missing data that needs to be completed, as well as a time field indicating number of days since the missing data query was first generated.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Even within efficacy trials for CBT, crisis management sessions are built into the design of the protocol, as they represent good clinical care, compliance with legal requirements, and appropriate adherence to evidence-based treatment.

“Note that even within efficacy trials for CBT, crisis management sessions are built into the design of the protocol, as they represent good clinical care, compliance with legal requirements (e.g., mandated reporting), and appropriate adherence to evidence-based treatment [42].”

• cites [42] Piacentini J, Bennett S, Compton SN, Kendall PC, Birmaher B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53(3):297–310. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

May combine two claims.

In CAMS, outcomes did not differ significantly in CBT alone vs medication alone (though group mean differences on the PARS slightly favored medication over CBT).

“Outcomes did not differ significantly in CBT alone vs medication alone (though group mean differences on the PARS slightly favored medication over CBT).”

• cites [42] Piacentini J, Bennett S, Compton SN, Kendall PC, Birmaher B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53(3):297–310. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Classified as probably not a substantial claim.

The CAMS maintenance treatment consisted of 6 additional CBT sessions delivered over 6 months, focusing on additional exposure practice and coaching in the application of CBT skills to emerging life stressors.

“This maintenance treatment consisted of 6 additional CBT sessions to be delivered over 6 months, focusing on additional exposure practice and coaching in the application CBT skills to emerging life stressors [42].”

• cites [42] Piacentini J, Bennett S, Compton SN, Kendall PC, Birmaher B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53(3):297–310. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

REDCap is a secure, HIPAA-compliant, widely used web-based research application that supports calculations and branching logic programming.

“REDCap is a secure, HIPAA-compliant, widely used web-based research application that supports calculations and branching logic programming.”

• cites [165] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

If clinicians are trained in both Coping Cat CBT and fluoxetine administration, their caseloads will be balanced with patients from each arm of the study to control for any possible clinician-level effects.

“If clinicians are trained in both Coping Cat CBT and fluoxetine administration, their caseloads will be balanced with patients from each arm of the study to control for any possible clinician-level effects.”

May combine two claims.

Amount of time spent in session on exposures, focus on mastery of difficult exposures, and child adherence with tasks and mastery of skills predicted better clinical outcomes in the CAMS trial.

“Amount of time spent in session on exposures, focus on mastery of difficult exposures, and child adherence with tasks and mastery of skills -- all these elements of treatment delivery predicted better clinical outcomes in the CAMS trial [119].”

• cites [119] Peris TS, Caporino NE, O’Rourke S, Kendall PC, Walkup JT, Albano AM, et al. Therapist-reported features of exposure tasks that predict differential treatment outcomes for youth with anxiety. J Am Acad Child Adolesc Psychiatry. 2017;56(12):1043–52. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

The goal of achieving clinical remission is imperative in improving outcomes, which requires assertive optimization of medication dosing.

“Therefore, the goal of achieving clinical remission is imperative in improving outcomes, which requires assertive optimization of medication dosing.”

May combine two claims.

In Phase 1 of CAMS, youths were randomized to CBT, SSRI, Combination (COMB), or placebo and clinical outcomes assessed at 12 weeks.

“In Phase 1 of the CAMS anxiety trial, youths were randomized with either CBT, SSRI, Combination (COMB), or placebo and clinical outcomes assessed at 12 weeks.”

• cites [42] Piacentini J, Bennett S, Compton SN, Kendall PC, Birmaher B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53(3):297–310. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Programming the REDCap database to require responses to all survey and interview questions and real-time documentation of reasons for missing data will reduce missing data due to data entry errors.

“We will program our REDCap database to require responses to all survey and interview questions and real-time documentation of reasons for missing data. Reasons for truly missing data (e.g., if participants are uncomfortable completing specific items) will be completed at the time of data collection and documented during data entry. This will also reduce missing data due to data entry errors.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The authors will ensure that the database systems, data access policies, and data transmission protocols exceed HIPPA regulations and data security standards for IRBs.

“We will ensure the database systems, data access policies, and data transmission protocols exceed HIPPA regulations and data security standards for IRBs.”

Classified as probably not a substantial claim.

After the acute phase, in Phase 2, responders were offered 6 months of continuing monthly maintenance treatment in their originally assigned condition.

“After this acute phase, in Phase 2, responders were offered 6 months of continuing monthly maintenance treatment in their originally assigned condition.”

• cites [42] Piacentini J, Bennett S, Compton SN, Kendall PC, Birmaher B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53(3):297–310. sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Classified as probably not a substantial claim. May combine two claims.

All Coping Cat therapists will undergo Coping Cat training and participate in ongoing consultation and fidelity measurement.

“All will undergo Coping Cat training and participate in ongoing consultation and fidelity measurement.”

May combine two claims.

In a prior study, 139 children randomized to 12 weeks of Coping Cat treatment, none withdrew during the entire 12 weeks (though 6 (4.3%) were lost to study).

“in a relevant prior study [49], 139 children were randomized to 12 weeks of Coping Cat treatment, and none of those children withdrew from treatment during the entire 12 weeks (though 6 (4.3%) were lost to the study).”

• cites [49] Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753–66. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The CBT strategies that form the core of Coping Cat have been subjected to years of extensive research through clinical trials, have been shown to be highly efficacious in addressing symptoms of a range of anxiety disorders, and are widely available at low cost.

“The CBT strategies that form the core of Coping Cat have been subjected to years of extensive research through clinical trials [183, 184], have been shown to be highly efficacious in addressing symptoms of a range of anxiety disorders, and are widely available at low cost.”

• cites [183] Craske MG, Stein MB, Sullivan G, Sherbourne C, Bystritsky A, Rose RD, et al. Disorder-specific impact of coordinated anxiety learning and management treatment for anxiety disorders in primary care. Arch Gen Psychiatry. 2011;68(4):378–88. sourceNot checked yet

  Not checked in the free run.

• cites [184] Craske MG, Roy-Byrne P, Stein MB, Sullivan G, Hazlett-Stevens H, Bystritsky A, et al. CBT intensity and outcome for panic disorder in a primary care setting. Behav Ther. 2006;37(2):112–9. sourceNot checked — no full text of the source

May combine two claims.

The authors' primary aims and hypotheses are tested as two main effects and their interaction, which require a sample size considerably smaller than for a 6-way ANCOVA.

“That analysis, however, does not correspond with our primary aims and hypotheses, which are tested as two main effects and their interaction, and which require a sample size considerably smaller than for a 6-way ANCOVA [54].”

• cites [54] Almirall D, Nahum-Shani I, Sherwood NE, Murphy SA. Introduction to SMART designs for the development of adaptive interventions: with application to weight loss research. Transl Behav Med. 2014;4(3):260–74. sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

Upward titrations will be slowed in some youth due to the emergence of side effects or because clinicians will be reluctant to increase the dose only 2 weeks after the last dose increase.

“In addition, upward titrations will be slowed in some youth due to the emergence of side effects or because clinicians will be reluctant to increase the dose only 2 weeks after the last dose increase, instead wanting more time to observe for clinical improvement.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

All data files transmitted to investigators will be encrypted and password-protected at the highest level of data encryption, then transmitted via a secure File Transfer Protocol.

“All data files transmitted to investigators will be encrypted and password-protected at the highest level of data encryption, then transmitted via a secure File Transfer Protocol.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Any deviations from the manualized structure and content of Coping Cat will be recorded via a session adherence form completed by the clinician and presented/discussed at study team meetings.

“Any deviations from the manualized structure and content of Coping Cat will be recorded via a session adherence form completed by the clinician and presented/discussed at study team meetings.”

May combine two claims.

Coping Cat is an established evidence-based CBT treatment for pediatric anxiety that has been studied rigorously for more than 25 years.

“Coping Cat is an established evidence-based CBT treatment for pediatric anxiety [180–182] that has been studied rigorously for more than 25 years.”

• cites [180] Kendall PC. Treating anxiety disorders in children: results of a randomized clinical trial. J Consult Clin Psychol. 1994;62(1):100–10. sourceNot checked — no full text of the source
• cites [181] Kendall PC, Flannery-Schroeder E, Panichelli-Mindel SM, Southam-Gerow M, Henin A, Warman M. Therapy for youths with anxiety disorders: a second randomized clinical trial. J Consult Clin Psychol. 1997;65(3):366–80. sourceNot checked — no full text of the source
• cites [182] Flannery-Schroeder EC, Kendall PC. Group and individual cognitive-behavioral treatments for youth with anxiety disorders: a randomized clinical trial. Cogn Ther Res. 2000;24(3):251–78. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The REDCap server is housed behind multiple firewalls in a locked and guarded USC data center equipped with security cameras and intrusion detection systems that is staffed by security at all times.

“The REDCap server is housed behind multiple firewalls in a locked and guarded USC data center equipped with security cameras and intrusion detection systems that is staffed by security at all times.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Crosswalks linking participant names and medical record numbers to study numbers will be kept by the Principal Investigator in a locked file and destroyed at the end of the study.

“Crosswalks that link a participant’s name and medical record number to that person’s study number will be kept by the Principal Investigator in a locked file and will be destroyed at the end of the study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The PI and study staff will immediately report to the DSMB any adverse patient or caregiver outcomes.

“They also will immediately report to the DSMB any adverse patient or caregiver outcomes.”

Probably not a substantial claim: may not pass S3 (load-bearing).

No data containing participant identifiers will be transferred outside CHLA or USC.

“No data containing participant identifiers will be transferred outside CHLA or USC.”

May combine two claims.

With an estimated 20% dropout, the study will have power to detect effect sizes of 0.52 for 60% subgroup representation (n=116), 0.58 for 50% (n=96), and 0.64 for 40% (n=78) for Main Effect 2 (total n=194).

“For Main Effect 2 (total n = 194), we will be able to detect: (1) Effect Size = 0.52 for 60% representation (n = 116); (2) Effect Size = 0.58 for 50% representation (n = 96); (3) Effect Size = 0.64 for 40% representation (n = 78).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The study will convene a Data Safety Monitoring Board (DSMB) that is fully independent from the sponsor and competing interests.

“We will convene a Data Safety Monitoring Board (DSMB) that is fully independent from the sponsor and competing interests.”

Classified as probably not a substantial claim.

Statistical significance of the direct effect coefficient c2 signifies that mediation by M is partial.

“We will assess the significance of the direct effect (coefficient c2 in eq. 3): statistical significance of this term will signify that mediation by M is partial [206, 207].”

• cites [206] MacKinnon DP, Krull JL, Lockwood CM. Equivalence of the mediation, confounding and suppression effect. Prev Sci. 2000;1(4):173–81. sourceNot checked — no full text of the source
• cites [207] Zhao X, Lynch JG, Chen Q. Reconsidering baron and Kenny: myths and truths about mediation analysis. J Consum Res. 2010;37(2):197–206. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Participants will be identified only by a random subject ID number on both raw and electronic study data, in lieu of names or medical record numbers.

“In lieu of participant names or medical record numbers, participants will be identified only by a random subject ID number on both the raw and electronic study data.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Study personnel will be required to sign confidentiality agreements and will be trained in the protection of human subjects.

“Study personnel will be required to sign confidentiality agreements and will be trained in the protection of human subjects.”

May combine two claims.

With an estimated 20% dropout, the study will have power to detect effect sizes of 0.40 for 60% subgroup representation (n=194), 0.44 for 50% (n=162), and 0.50 for 40% (n=130) for Main Effect 1 (total n=324).

“With an estimated 20% dropout, we will be able to detect the following effect sizes for Main Effect 1 (total n = 324) in various subgroups by sample representation (n): (1) Effect Size = 0.40 for 60% representation (n = 194); (2) Effect Size = 0.44 for 50% representation (n = 162); (3) Effect Size = 0.50 for 40% representation (n = 130).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The study will include sensitivity analyses to assess the impact of analytic and modelling assumptions related to covariate selection, missing data handling, and adherence to randomized intervention.

“These will assess the impact of analytic and modelling assumptions related to selection of covariates, handling of missing data, and adherence to randomized intervention.”

May combine two claims.

An RCT comparing telehealth vs in-person CBT over 24 weeks in 115 youth with adolescent anxiety disorder found an effect size for the Clinician Severity Rating outcome measure of 0.05 (95% CI -0.77, 0.95), a non-significant difference with the direction of effect favoring in-person CBT.

“The second [196] is an RCT comparing telehealth vs in-person CBT over 24 weeks (the same duration as our study) in 115 youth with adolescent anxiety disorder. For consistency with our sample size calculations (which used the primary outcome from the CAMS trial, the clinician-rated Pediatric Anxiety Rating Scale), we estimated the effect size for the Clinician Severity Rating outcome measure, which”

• cites [196] Spence SH, Donovan CL, March S, Gamble A, Anderson RE, Prosser S, et al. A randomized controlled trial of online versus clinic-based CBT for adolescent anxiety. J Consult Clin Psychol. 2011;79(5):629–42. sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The primary outcome (Youth SCARED) will be tested at an α = 0.05.

“The primary outcome (Youth SCARED) will be tested at an α = 0.05.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Research staff members who collect study data will do so only from one of the study's 9 clinical facilities or research sites.

“Research staff members who collect study data will do so only from one of our 9 clinical facilities or research sites.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The data safety-monitoring plan is designed to ensure the safety of participants, the validity of the data collected, and the appropriate termination of the study in the event that significant benefits or risks are uncovered, or if it appears that the trial cannot be concluded successfully.

“Our data safety-monitoring plan is designed to ensure the safety of participants, the validity of the data collected, and the appropriate termination of the study in the event that significant benefits or risks are uncovered, or if it appears that the trial cannot be concluded successfully.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

This study protocol was reviewed and approved under the SMART Institutional Review Board (IRB) mechanism, with Children's Hospital Los Angeles the designated lead IRB.

“This study protocol was reviewed and approved under the SMART Institutional Review Board (IRB) mechanism, with Children’s Hospital Los Angeles the designated lead IRB.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The DSMB will meet every six months to review study progress and adverse events.

“The board will meet every six months to review study progress and adverse events.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All participants will be provided contact information for the DSMB to register complaints or other problems.

“All participants will be provided contact information for the DSMB to register complaints or other problems.”

Probably not a substantial claim: may not pass S3 (load-bearing).

To evaluate baseline comparability, the authors will compare demographic and clinical characteristics, and trial outcome measures, at baseline between treatment groups.

“To evaluate baseline comparability, we will compare demographic and clinical characteristics, and trial outcome measures, at baseline between treatment groups.”

Probably not a substantial claim: may not pass S3 (load-bearing).