Pragmatic Trial of Obsessive-compulsive Disorder

Study Overview
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Brief Summary
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This study includes a sequenced clinical trial in order to assess the efficacy of several switching or augment strategies when initial treatment is ineffective，and to provide strong evidence for clinical practice and international guidelines for Obsessive-Compulsive Disorder treatments.

Detailed Description
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Selective Serotonin Reuptake Inhibitors(SSRIs) are the first line pharmacotherapy for Obsessive-Compulsive Disorder (OCD) according to APA（American Psychological Association）guideline. Nevertheless, a large proportion (40% or more) of patients response only partially or not at all to treatment with a SSRI. On the basis of the existing sparse literature, several pharmacotherapy options for OCD patients who do not respond, or who respond but do not remit, have been outlined in current treatment guidelines. These include 1) treatment with higher than usual doses of an SSRI, 2) switch to a different SSRI, 3) switch to a different class of medication, 4) augmentation with a dopamine blocker, and 5) augmentation with a glutamatergic agent. There is a need for additional data, particularly real-world data, on how best to choose between these options. This proposed Randomized Controlled Trial (RCT) study is a multi-center clinical study with a total of 13 centers that specialize in OCD patients. A randomized block design will be used in this study and all eligible participants accepted into this study will undergo an initial course of pharmacotherapy (phase I), and non-remmitters will be randomly allocated to five treatment arms (phase II). In phase I all participants will be treated with sertraline for 12 weeks.In phase II,The 5 arms will comprise 1) treatment with higher than usual doses of sertraline, 2) switch to fluvoxamine, 3) switch to venlafaxine, 4) augmentation with memantine, and 5) augmentation with aripiprazole. Clinicians and patients will know which treatment arm is being employed, but raters will be kept blind to treatment group.

Official Title
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A Pragmatic Trial of Pharmacotherapy Options Following Unsatisfactory Initial Treatment in OCD

Conditions
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Obsessive-Compulsive Disorder

Intervention / Treatment
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* Drug: Sertraline 200 milligram(mg)
* Drug: Sertraline 300 milligram(mg)
* Drug: Fluvoxamine
* Drug: Venlafaxine
* Drug: Augment with Memantine
* Drug: Augment with Aripiprazole


Participation Criteria
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Eligibility Criteria
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Inclusion criteria:They meet DSM-5 diagnostic criteria for OCD as the primary diagnosis ; are in the age range from 18 to 65 years; have a score of at least 20 on Yale-Brown Obsessive-Compulsive Scale (Y-BOCS); have never received medication for OCD, and have not received any form of psychotherapy for OCD in the past 1 month; have provided written informed consent. exclusion criteria: They have met the DSM-5 diagnostic criteria for Schizophrenia Spectrum and Other Psychotic Disorders, or the Bipolar and Related Disorders; have a moderate or higher risk of suicide (⩾9 on the Suicide Module in the Mini-International Neuropsychiatric Interview (MINI)); have substance use that is sufficiently severe to possibly impact negatively on treatment adherence in the past 1 year; have severe depression with Beck Depression Inventory (BDI) score of ≥29; have comorbid psychiatric or medical disorders that may impact negatively on adherence to or on the efficacy of medication (eg borderline personality disorder, CNS disorders)； are pregnant or lactating females.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: In phase I all the participants will be initially treated for sertraline for 12 weeks.non-remmitters will be randomly allocated to five treatment arms for another 12 weeks in phase II.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: serotonin treatment<br>In experimental phase I, all recruited subjects provide written informed consent before any related procedures. Participants will receive sertraline, initially at 50mg/d, with a weekly 50mg/d further increase, to the maximum recommended dosage (200mg/d) or to the maximum tolerated dosage (less than 200mg/d). Patients will be on their maximum dose by week 4, so allowing an assessment of response at 12 weeks | Drug: Sertraline 200 milligram(mg)<br>* All included participants will receive sertraline, initially at 50mg/d, with a weekly 50mg/d further increase, to the maximum recommended dosage (200mg/d) or to the maximum tolerated dosage (less than 200mg/d). Patients will be on their maximum dose by week 4, so allowing an assessment of response at 12 weeks<br>|
| Active Comparator: sequenced treatment alternatives<br>If participants in In Experimental phase I do not achieve remission, they will be will be randomly assigned to the second-step treatment (Experimental phase II). The second-step therapy will consist of five treatment options including higher-than-usual-maximal dosage of sertraline, switching to fluvoxamine, switching to venlafaxine, augmentation with memantine, and augmentation with aripiprazole. | Drug: Sertraline 300 milligram(mg)<br>* In experimental phase II, the patients in this group will remain on sertraline (higher dosage): where sertraline 200mg has been tolerated, dosage will be increased by 50mg fortnightly to a maximal dose of 300mg/d or to the maximum tolerable dose (less than 300mg/d).<br>Drug: Fluvoxamine<br>* Fluvoxamine will be initiated at a dose of 50mg/d, increasing quickly to a maximal dose of 300mg/d or the maximum tolerated dose by week 4.<br>Drug: Venlafaxine<br>* venlafaxine will be initiated at 75mg/d, increasingly weekly by 75mg/day, to a maximal dose of 300 mg/d or the maximum tolerated dose.<br>Drug: Augment with Memantine<br>* Sertraline will be augmented with memantine initially at 5mg/d, and increasing by 5mg/d weekly to a maximal dose of 20mg/d (10mg twice daily) or the maximum tolerated dose<br>Drug: Augment with Aripiprazole<br>* Sertraline will be augmented with aripiprazole, initially at 5mg/d, and increasing by 5mg/d weekly to a maximal dose of 20mg/d or the maximum tolerated dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) | Y-BOCS is a clinician-rated, 10-item scale, each item rated from 0 (no symptoms) to 4 (extreme symptoms), with separate subtotals for severity of obsessions and compulsions.Patients will be assessed at baseline, week 2, week 4, week 8, week 12, week 16, week 20, month 6. | from baseline to 12 weeks, and 12 weeks to month 6. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Clinical Global Impression (CGI) | The Clinical Global Impression (CGI; National Institute of Mental Health) is a clinician-rated scale to assess treatment response in patients with mental disorders. The scale contains three items: Severity of Illness; Global Improvement; Efficacy Index. It requires the clinician to rate how much the patient's illness has improved or worsened relative to a baseline measurement. Patients will be assessed at week 2, week 4, week 8, week 12, week 16, week 20, month 6. | from 2 weeks to 12 weeks, and 12 weeks to month 6. | 
| Beck Anxiety Inventory (BAI) | BAI is a 21-item inventory which identifies anxiety symptoms and quantifies their intensity. Patients will be assessed at baseline, week 2, week 4, week 8, week 12, week 16, week 20, month 6. | from baseline to 12 weeks, and 12 weeks to month 6. | 
| Beck Depression Inventory(BDI) | BDI is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression.Patients will be assessed at baseline, week 2, week 4, week 8, week 12, week 16, week 20, month 6. | from baseline to 12 weeks, and 12 weeks to month 6. | 
| Obsessive-Compulsive Inventory-Revised(OCI-R) | OCI-R is the measure of election for the assessment of obsessive-compulsive behaviors, given its validity and the short time that its administration requires. Patients will be assessed at baseline, week 2, week 4, week 8, week 12, week 16, week 20, month 6. | from baseline to 12 weeks, and 12 weeks to month 6. | 
| Treatment Emergent Symptom Scale (TESS) | The Treatment Emergent Symptom Scale (TESS) is used to record side effects. The side effects are assessed on a five-point scale ranging from 0 (no side effects) to 4 (severe side effects). Patients will be assessed at week 2, week 4, week 8, week 12, week 16, week 20, month 6. | from 2 weeks to 12 weeks , and 12 weeks to month 6. | 
| Tolerability scale | The tolerability of treatment will be defined as side effect discontinuation in this study. as defined by the proportion of patients who discontinued treatment due to adverse events during the study.Patients will be assessed at week 2, week 4, week 8, week 12, week 16, week 20, month 6. | from 2 weeks to 12 weeks , and 12 weeks to month 6. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obsessive-Compulsive Disorder, Pharmacotherapy, Treatment-naïve, Alternatives