Patient Centered Outcomes Research in obsessive compulsive disorder (pcori)

Specific Aims:

  1. To determine comparative benefits and patient-reported outcomes of the three treatment options (supported by US and UK guidelines) for adults with Obsessive-Compulsive Disorder (OCD) in the setting of a large sequential multiple assignment randomized trial (SMART). Critical decisions include which intervention to provide first and which intervention to provide second if the initial response is unsuccessful.

    Hypothesis: Differences in outcomes between the three phase I treatments (SSRI, CBT, combination treatment) will occur after the initial 16 weeks of treatment; nonresponders to phase 1 monotherapy (SSRI or CBT) will respond to phase II switch or combination intervention; and SSRI and combination therapy will be superior to CBT at 1 year of treatment.

  2. To determine the heterogeneity of treatment effects through the conduct of the trial with a sufficiently large sample size. This will allow us to establish who will benefit from different arms of treatment (predictors) and also to determine the factors (moderators) that could help match patients to the optimal intervention.

  3. To contribute to PCORnet Commons by 1) providing access to the online prescreening questionnaires used in the study to collect patient-reported information and recruit patients within PPRNs and PCORnet Commons, 2) developing tools such as educational videos, online training materials and questionnaires, electronic handouts that can be used across PPRNs and notably within the MoodNetwork and NYC-CDRN to help patients better manage symptoms of OCD, depression, anxiety and stress.

Background:

OCD is a disabling condition, with a lifetime prevalence of 2.3% in U.S. adults. US practice guidelines1 developed by Koran, Hollander et al. in 2007, state that CBT and serotonin reuptake inhibitors (SSRI) or their combination are recommended as safe and effective first-line treatments for OCD. In contrast, UK NICE guidelines co-developed by Fineberg et al. in 2005 recommend CBT as the first line treatment for OCD. Our recent optimal treatment for OCD (OTO) feasibility study conducted in 49 adults with OCD provided evidence that even if at the 16 weeks time-point combined treatment was associated with the largest improvement, SSRI treatment alone might lead to greatest clinical effectiveness between 16 and 52 weeks of treatment. OCD subjects with greater severity may respond preferentially to combination treatment; those with mild severity may benefit from CBT and moderators may include gender, comorbidity and duration of untreated illness. OCD subjects with a family history of OCD experience a six fold decrease in the effect size of CBT monotherapy versus those without a family history of OCD.

Significance:

This study answers questions that patients care about and has the potential to improve their care. Implementation of these findings into clinical practice would allow us to improve delivery of care and update current clinical and practice guidelines.

Approach:

  1. Study Design: We prospectively randomize 648 young people and adults with OCD in a setting of a partially blinded, randomized controlled trial (patients and clinicians not blinded; assessors are blinded). We will address gaps in evidence central to decision-making by comparing the effectiveness of (1) phase I cognitive-behavioral therapy (CBT), followed by phase II switch or combination treatment (for those who don’t respond to CBT); or (2) phase I selective serotonin re-uptake inhibitors (SSRI), followed by phase II switch or combination treatment (for those who don’t respond to SSRI); or (3) combined therapy (CBT+SSRI) in young people and adults with OCD (defined by DSM-5 criteria) for 1) change in total Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores within and between the three treatment arms (primary outcome), 2) reducing stress, anxiety and depressive symptoms 3) increasing quality of life and 4) functioning (secondary outcomes). Systematic evaluation will be conducted at baseline, week 16 (after acute phase I treatment; primary endpoint), week 32 (after acute phase II switch or combination treatment (in phase I monotherapy non-responders)), and week 52 (final endpoint).

  2. Engagement Approach: We leveraged our ongoing relationships with patient and advocacy stakeholders, including the NIHR Obsessive Compulsive and Related Disorders Clinical Research Group members (OTOCARD), the MoodNetwork PPRN US national team, Royal College of Psychiatrists Network for Obsessive Compulsive And Related Disorders (OCARD), OCD North Carolina, the OCD Action Charity director, Orchard Charity foundation for Advancing Global OCD research, the Triumph over Phobia development manager, the National Alliance of Mental Illness (NAMI), Anxiety and Depression Association of America (ADAA) representatives and the clinicians and stakeholders from the International College of Obsessive- Compulsive Spectrum Disorders (ICOCS) and the Obsessive Compulsive and Related Disorders Network (OCRN). 22 patient advocate stakeholders are already actively engaged in all aspects of the proposed study. We received feedback that a larger study engaging approximately 600 people needs to be definitely conducted using the same primary and secondary outcome measures as the OTO feasibility study.

  3. Study Population and Setting: Treatment-seeking OCD participants (age 16-65 y.o.) identified from routine referrals, primary healthcare services referrals and advertisement, and collaboration with NYC CDRN PPRN network physicians and ICOCS/OCRN network. The study will be conducted within typical clinical care and community care settings.

  4. Comparators: All three comparators are currently available and include: (1) phase I sertraline (50-200mg) for 16 weeks followed by phase II switch or combination treatment for SSRI non-responders (2) phase I cognitive behavioral therapy (CBT) with ERP (a total of 16 hrs over 8 weeks) with follow up sessions at weeks 16, 32 and 52, followed by phase II switch or combination treatment for CBT non-responders at week 16 of treatment (3) Combination of sertraline (50-200mg) over 52 weeks plus CBT with ERP (a total of 16 hrs over 8 weeks) with follow up at weeks 16, 32 and 52.

  5. Outcomes: While reviewing the current APA1 and NICE guidelines the OCRN/ICOCS and NIHR Obsessive Compulsive and Related Disorders Clinical Research Group (OTOCARD-CRG;2014-2015) working groups, consisting of patient stakeholders, international advocacy stakeholders and US and EU clinicians, achieved strong consensus that further comparative investigation of the different available treatment interventions for OCD is of the utmost importance for patients and clinicians. They concluded that the primary outcome measure should be change in Y-BOCS score after 16 weeks and 1 year of initial treatment.

  6. Analytic Plan: We will use sequential multiple assignment randomized trial (SMART) design. Phase I will use mixed model regression analysis for equivalence and non-inferiority testing as described by Mascha et al. This approach would allow us to incorporate all longitudinal measurements while accounting for potentially confounding baseline clinical and demographic variables. Our primary analysis will use the intention to treat (ITT) approach. Phase II will incorporate SMART design analyses to determine differences between the second stage intervention options (switch or combination) for non-responding participants that may improve the primary outcome through greater individuation.

  7. Sample Size and Power: The estimated sample size of 648 adults randomized across all sites will have ample power. In order to recruit this number, we expect to screen approximately 1200 OCD patients over 36 months across all study centers. Based upon the recruitment rates in the OTO feasibility study, we expect around 75% to be broadly suitable for the study. The current study is powered to detect a difference between the treatment arms with d=0.35, assuming a two sided test, with alpha=0.05 and 1-beta=0.9. For an expected difference of this magnitude a sample size of N=173 per arm is required. With 25% attrition this would give a sample size of N=216.

Bibliography:

  1. APA. American Psychiatric Association (APA) Practice Guideline for Obsessive-Compulsive Disorder. Available from: https://psychiatry.online.org/guidelines. 2007.

  2. NICE. The National Institute for Health and Care Excellence (NICE). Obsessive-compulsive disorder and body dysmorphic disorder: treatment clinical guideline Available from: https://www.nice.org.uk/guidance/CG31/chapter/1-Guidance#steps-35-treatment-options-for-people-with-ocd- or-bdd. 2005

  3. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15(1):53-63.

  4. Fineberg NA, Baldwin DS, Drummond LM, et al. Optimal treatment for obsessive compulsive disorder: a randomized controlled feasibility study of the clinical-effectiveness and cost-effectiveness of cognitive- behavioural therapy, selective serotonin reuptake inhibitors and their combination in the management of obsessive compulsive disorder. Int Clin Psychopharmacol. 2018;33(6):334-348.

  5. Maher MJ, Huppert JD, Chen H, et al. Moderators and predictors of response to cognitive-behavioral therapy augmentation of pharmacotherapy in obsessive-compulsive disorder. Psychol Med. 2010;40(12):2013-2023.

  6. Garcia AM, Sapyta JJ, Moore PS, et al. Predictors and moderators of treatment outcome in the Pediatric Obsessive Compulsive Treatment Study (POTS I). J Am Acad Child Adolesc Psychiatry. 2010;49(10):1024-1033; quiz 1086.

  7. Skapinakis P, Caldwell DM, Hollingworth W, et al. Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2016;3(8):730-739.

  8. NICE pathways. The National Institute for Health and Care Excellence (NICE). Obsessive-compulsive disorder and body dysmorphic disorder pathways. https://pathways.nice.org.uk/pathways/obsessive-compulsive-disorder- and-body-dysmorphic-disorder#path=view%3A/pathways/obsessive-compulsive-disorder-and-body- dysmorphic-disorder/steps-35-treatment-options-for-adults-with-obsessive-compulsive-disorder-or-body- dysmorphic-disorder.xml&content=view-node%3Anodes-treatment-options. 2018.

  9. Dell'Osso B, Benatti B, Hollander E, et al. Childhood, adolescent and adult age at onset and related clinical correlates in obsessive-compulsive disorder: a report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). Int J Psychiatry Clin Pract. 2016;20(4):210-217.

  10. Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989;46(11):1006-1011.

  11. Dell'Osso B, Benatti B, Arici C, et al. Prevalence of suicide attempt and clinical characteristics of suicide attempters with obsessive-compulsive disorder: a report from the International College of Obsessive- Compulsive Spectrum Disorders (ICOCS). CNS Spectr. 2018;23(1):59-66.

  12. Dell'Osso B, Benatti B, Buoli M, et al. The influence of age at onset and duration of illness on long-term outcome in patients with obsessive-compulsive disorder: a report from the International College of Obsessive Compulsive Spectrum Disorders (ICOCS). Eur Neuropsychopharmacol. 2013;23(8):865-871.

  13. Dell'Osso B, Benatti B, Rodriguez CI, et al. Obsessive-compulsive disorder in the elderly: A report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). Eur Psychiatry. 2017;45:36-40.

  14. Dell'Osso B, Nicolini H, Lanzagorta N, et al. Cigarette smoking in patients with obsessive compulsive disorder: a report from the International College of Obsessive Compulsive Spectrum Disorders (ICOCS). CNS Spectr. 2015;20(5):469-473.

  15. Lochner C, Fineberg NA, Zohar J, et al. Comorbidity in obsessive-compulsive disorder (OCD): a report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). Compr Psychiatry. 2014;55(7):1513- 1519.

  16. Menchon JM, van Ameringen M, Dell'Osso B, et al. Standards of care for obsessive-compulsive disordercentres. Int J Psychiatry Clin Pract. 2016;20(3):204-208.

  17. Fineberg NA, Baldwin DS, Menchon JM, et al. Manifesto for a European research network into obsessive-compulsive and related disorders. Eur Neuropsychopharmacol. 2013;23(7):561-568.

  18. Mascha EJ, Sessler DI. Equivalence and noninferiority testing in regression models and repeated-measures designs. Anesth Analg. 2011;112(3):678-687.