Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents (the TECTO trial): a statistical analysis plan for the randomised clinical trial

Markus Harboe Olsen, Julie Hagstrøm, Nicole Nadine Lønfeldt, Camilla Uhre, Valdemar Uhre, Linea Pretzmann, Sofie Heidenheim Christensen, Christine Thoustrup, Nicoline Løcke Jepsen Korsbjerg, Anna-Rosa Cecilie Mora-Jensen, Melanie Ritter, Janus Engstrøm, Jane Lindschou, Hartwig Roman Siebner, Frank Verhulst, Pia Jeppesen, Jens Richardt Møllegaard Jepsen, Signe Vangkilde, Per Hove Thomsen, Katja Hybel, Line Katrine Harder Clemmesen, Christian Gluud, Kerstin Jessica Plessen, Anne Katrine Pagsberg, Janus Christian Jakobsen, Markus Harboe Olsen, Julie Hagstrøm, Nicole Nadine Lønfeldt, Camilla Uhre, Valdemar Uhre, Linea Pretzmann, Sofie Heidenheim Christensen, Christine Thoustrup, Nicoline Løcke Jepsen Korsbjerg, Anna-Rosa Cecilie Mora-Jensen, Melanie Ritter, Janus Engstrøm, Jane Lindschou, Hartwig Roman Siebner, Frank Verhulst, Pia Jeppesen, Jens Richardt Møllegaard Jepsen, Signe Vangkilde, Per Hove Thomsen, Katja Hybel, Line Katrine Harder Clemmesen, Christian Gluud, Kerstin Jessica Plessen, Anne Katrine Pagsberg, Janus Christian Jakobsen

Abstract

Background: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder which affects up to 3% of children and adolescents. OCD in children and adolescents is generally treated with cognitive behavioural therapy (CBT), which, in more severely affected patients, can be combined with antidepressant medication. The TECTO trial aims to compare the benefits and harms of family-based CBT (FCBT) versus family-based psychoeducation/relaxation training (FPRT) in children and adolescents aged 8 to 17 years. This statistical analysis plan outlines the planned statistical analyses for the TECTO trial.

Methods: The TECTO trial is an investigator-initiated, independently funded, single-centre, parallel-group, superiority randomised clinical trial. Both groups undergo 14 sessions of 75 min each during a period of 16 weeks with either FCBT or FPRT depending on the allocation. Participants are randomised stratified by age and baseline Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score. The primary outcome is the CY-BOCS score. Secondary outcomes are health-related quality of life assessed using KIDSCREEN-10 and adverse events assessed by the Negative Effects Questionnaire (NEQ). Primary and secondary outcomes are assessed at the end of the intervention. Continuous outcomes will be analysed using linear regression adjusted for the stratification variables and baseline value of the continuous outcome. Dichotomous outcomes will be analysed using logistic regression adjusted for the stratification variables. The statistical analyses will be carried out by two independent blinded statisticians.

Discussion: This statistical analysis plan includes a detailed predefined description of how data will be analysed and presented in the main publication before unblinding of study data. Statistical analysis plans limit selective reporting bias. This statistical analysis plan will increase the validity of the final trial results.

Trial registration: ClinicalTrials.gov NCT03595098. July 23, 2018.

Keywords: Cognitive behavioural therapy; Family-based psychoeducation/relaxation training; Obsessive-compulsive disorder; Randomised clinical trial; Statistical analysis plan.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Psychopathology and family burden based on simulated data. Presentation of the timeline of the primary outcome (light blue background), secondary outcomes (light red background), and exploratory outcomes, with results from the analyses, with baseline correction for the outcomes assessed at baseline, with p-values for the secondary outcomes corrected for multiplicity. CY-BOCS, Children’s Yale–Brown Obsessive Compulsive Scale; COIS-R, Child Obsessive-Compulsive Impact Scale-Revised; CGI-S, Clinical Global Impressions Severity; CGI-I, Clinical Global Impressions Improvement; CGAS, Children’s Global Assessment Scale; TOCS, Toronto Obsessive-Compulsive Scale; FAS, Family Accommodation Scale for Obsessive-Compulsive Disorder; PSS, Parental Stress Scale
Fig. 2
Fig. 2
Response status at 16 weeks based on simulated data. The response status at follow-up, by categorising CY-BOCS into severity and the proportion of remitted participants assessed using K-SADS-PL, and responders defined as a 30% reduction in CY-BOCS score compared to baseline. CY-BOCS, Children’s Yale–Brown Obsessive Compulsive Scale; K-SADS-PL, Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version
Fig. 3
Fig. 3
The Negative Effects Questionnaire based on simulated data. Adverse events assessed using the Negative Effects Questionnaire (NEQ). Assessment at weeks 4 and 8 reflect the last 4 weeks, while the assessment at week 16 reflects the last 8 weeks. NEQ per week is calculated using the average weekly score

References

    1. Heyman I, Fombonne E, Simmons H, Ford T, Meltzer H, Goodman R. Prevalence of obsessive-compulsive disorder in the British nationwide survey of child mental health. Int Rev Psychiatry. 2003;15:178–184.
    1. Lack CW, Storch EA, Keeley ML, Geffken GR, Ricketts ED, Murphy TK, et al. Quality of life in children and adolescents with obsessive-compulsive disorder: base rates, parent-child agreement, and clinical correlates. Soc Psychiatry Psychiatr Epidemiol. 2009;44:935–942.
    1. O’Kearney R, Anstey KJ, Von Sanden C. Behavioural and cognitive behavioural therapy for obsessive compulsive disorder in children and adolescents. Cochrane Database Syst Rev. 2006.
    1. Piacentini J, Bergman RL, Keller M, McCracken J. Functional impairment in children and adolescents with obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2003;13 Suppl 1:S61–S69.
    1. Obsessive-compulsive disorder and body dysmorphic disorder: treatment [Internet]. NICE; 2005 [cited 2021 Jun 11]. Available from:
    1. National guideline for treatment of obsessive compulsive disorder (National klinisk retningslinje for behandling af obsessiv-kompulsiv tilstand (OCD)) [Internet]. Sundhedsstyrelsen. 2016 [cited 2021 Jun 11]. Available from:
    1. Piacentini J, Langley AK. Cognitive-behavioral therapy for children who have obsessive-compulsive disorder. J Clin Psychol. 2004;60:1181–1194.
    1. Ginsburg GS, Kingery JN, Drake KL, Grados MA. Predictors of treatment response in pediatric obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2008;47:868–878.
    1. Jonsson U, Alaie I, Parling T, Arnberg FK. Reporting of harms in randomized controlled trials of psychological interventions for mental and behavioral disorders: a review of current practice. Contemp Clin Trials. 2014;38:1–8.
    1. Crawford MJ, Thana L, Farquharson L, Palmer L, Hancock E, Bassett P, et al. Patient experience of negative effects of psychological treatment: results of a national survey†. Br J Psychiatry. 2016;208:260–265.
    1. Uhre CF, Uhre VF, Lønfeldt NN, Pretzmann L, Vangkilde S, Plessen KJ, et al. Systematic review and meta-analysis: cognitive-behavioral therapy for obsessive-compulsive disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2020;59:64–77.
    1. Pagsberg AK, Uhre CF, Uhre VF, Pretzmann L, Christensen SH, Thoustrup C, et al. Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents: protocol for a randomised clinical trial (the TECTO trial). BMC Psychiatry. 2022; in press.
    1. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al. Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36:980–988.
    1. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown obsessive compulsive scale. I. Development, use, and reliability. Arch gen psychiatry. Arch Gen Psychiatry. 1989;46:1006–1011.
    1. Piacentini J, Lindsey Bergman R, Chang S, Langley A, Peris T, Wood JJ, et al. Controlled comparison of family cognitive behavioral therapy and psychoeducation/relaxation training for child OCD. J Am Acad Child Adolesc Psychiatry. 2011;50:1149–1161.
    1. Thomsen PH, Torp NC, Dahl K, Christensen K, Englyst I, Melin KH, et al. The Nordic long-term OCD treatment study (NordLOTS): rationale, design, and methods. Child Adolesc Psychiatry Ment Health. 2013;7:41.
    1. Ravens-Sieberer U, Gosch A, Rajmil L, Erhart M, Bruil J, Duer W, et al. KIDSCREEN-52 quality-of-life measure for children and adolescents. Expert Rev Pharmacoecon Outcomes Res. 2005;5:353–364.
    1. Rozental A, Kottorp A, Boettcher J, Andersson G, Carlbring P. Negative effects of psychological treatments: an exploratory factor analysis of the negative effects questionnaire for monitoring and reporting adverse and unwanted events. PLoS One. 2016;11:e0157503.
    1. Ravens-Sieberer U, Erhart M, Rajmil L, Herdman M, Auquier P, Bruil J, et al. Reliability, construct and criterion validity of the KIDSCREEN-10 score: a short measure for children and adolescents’ well-being and health-related quality of life. Qual Life Res. 2010;19:1487–1500.
    1. Piacentini J, Peris TS, Bergman RL, Chang S, Jaffer M. Functional impairment in childhood OCD: development and psychometrics properties of the child obsessive-compulsive impact scale-revised (COIS-R) J Clin Child Adolesc Psychol. 2007;36:645–653.
    1. Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont) 2007;4:28–37.
    1. Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, et al. A children’s global assessment scale (CGAS) Arch Gen Psychiatry. 1983;40:1228–1231.
    1. Park LS, Burton CL, Dupuis A, Shan J, Storch EA, Crosbie J, et al. The Toronto obsessive-compulsive scale: psychometrics of a dimensional measure of obsessive-compulsive traits. J Am Acad Child Adolesc Psychiatry. 2016;55:310–318.e4.
    1. Calvocoressi L, Mazure CM, Kasl SV, Skolnick J, Fisk D, Vegso SJ, et al. Family accommodation of obsessive-compulsive symptoms: instrument development and assessment of family behavior. J Nerv Ment Dis. 1999;187:636–642.
    1. Olsen MH, Morthorst B, Pagsberg AK, Heinrichsen M, Møhl B, Rubæk L, et al. An internet-based emotion regulation intervention versus no intervention for non-suicidal self-injury in adolescents: a statistical analysis plan for a feasibility randomised clinical trial. Trials. 2021;22:1–8.
    1. Jakobsen JC, Ovesen C, Winkel P, Hilden J, Gluud C, Wetterslev J. Power estimations for non-primary outcomes in randomised clinical trials. BMJ Open. 2019;9:e027092.
    1. Rozental A, Kottorp A, Forsström D, Månsson K, Boettcher J, Andersson G, et al. The negative effects questionnaire: psychometric properties of an instrument for assessing negative effects in psychological treatments. 2019.
    1. Jakobsen JC, Tamborrino M, Winkel P, Haase N, Perner A, Wetterslev J, et al. Count data analysis in randomised clinical trials. J Biom Biostat. 2015;06.
    1. Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullén S, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384:2283–2294.
    1. Olagnier D, Mogensen TH. The COVID-19 pandemic in Denmark: big lessons from a small country. Cytokine Growth Factor Rev. 2020;53:10–12.
    1. Nissen JB, Højgaard DRMA, Thomsen PH. The immediate effect of COVID-19 pandemic on children and adolescents with obsessive compulsive disorder. BMC Psychiatry. 2020;20:511.
    1. Guessoum SB, Lachal J, Radjack R, Carretier E, Minassian S, Benoit L, et al. Adolescent psychiatric disorders during the COVID-19 pandemic and lockdown. Psychiatry Res. 2020;291:113264.
    1. Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC med res Methodol. BMC Med Res Methodol. 2017;17:162.
    1. Nielsen EE, Nørskov AK, Lange T, Thabane L, Wetterslev J, Beyersmann J, et al. Assessing assumptions for statistical analyses in randomised clinical trials. BMJ evidence-based Med. 2019;24:185–189.
    1. Nørskov AK, Lange T, Nielsen EE, Gluud C, Winkel P, Beyersmann J, et al. Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how. BMJ Evid-based Med. 2021;26:121–126.
    1. Gold SM, Enck P, Hasselmann H, Friede T, Hegerl U, Mohr DC, et al. Control conditions for randomised trials of behavioural interventions in psychiatry: a decision framework. Lancet Psychiatry. 2017;4:725–732.
    1. Dwan K, Altman DG, Clarke M, Gamble C, Higgins JPTT, Sterne JACC, et al. Evidence for the selective reporting of analyses and discrepancies in clinical trials: a systematic review of cohort studies of clinical trials. PLoS Med. 2014;11:e1001666.
    1. Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ. 2010;340:637–640.
    1. Dwan K, Gamble C, Williamson PR, Altman DG. Reporting of clinical trials: a review of research funders’ guidelines. Trials. 2008;9:66.
    1. Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Doré C, et al. Guidelines for the content of statistical analysis plans in clinical trials. JAMA. 2017;318:2337–2343.
    1. Finfer S, Bellomo R. Why publish statistical analysis plans? Crit Care Resusc. 2009;11:5–6.
    1. Jakobsen JC, Gluud C, Winkel P, Lange T, Wetterslev J. The thresholds for statistical and clinical significance - a five-step procedure for evaluation of intervention effects in randomised clinical trials. BMC Med Res Methodol. 2014;14:34.
    1. Potkin SG, Siu CO. Dropouts and missing data in psychiatric clinical trials. Am J Psychiatry. 2009;166:1295.
    1. Caldwell PHY, Murphy SB, Butow PN, Craig JC. Clinical trials in children. Lancet (London, England) 2004;364:803–811.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner