A Phase 3 Study of Fluvoxamine (SME3110) in Pediatric/Adolescent Patients With Obsessive Compulsive Disorder

Study Overview
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Brief Summary
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The objective of the first phase of this study is to evaluate the efficacy of fluvoxamine compared to placebo on change in total score of Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) 10-item from baseline to the last observation visit (10 weeks) in pediatric/adolescent participants with obsessive compulsive disorder (OCD). The objective of the second phase of the study is to evaluate the long-term safety and efficacy of fluvoxamine in pediatric/adolescent patients with OCD.

Detailed Description
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The first phase will be conducted in a randomized, placebo-controlled, double-blind manner to evaluate the efficacy of fluvoxamine on change from baseline to the last observation visit in the JCY-BOCS 10-item total score. Eligible patients will be allocated to the fluvoxamine group or placebo group in a 1:1 ratio using the experience of fluvoxamine treatment and age as stratification factors (dynamic allocation). The first phase consists of a screening period of 1-2 weeks, a forced titration dose period of 2 weeks, a dose adjustment period of 4 weeks, a maintained dose period of 4 weeks, and a tapering dose period of 0-4 weeks. The 2nd phase will be conducted in an open-label manner in participants who completed the first phase to evaluate the long-term safety of fluvoxamine. The 2nd phase consists of 3 periods; a forced titration dose period of 2 weeks, a flexible dose period of 50 weeks, and a tapering dose period of 0-4 weeks. After the last dose of study drug (including tapering dose period) or the early termination visit, participants will be followed for up to 30 days.

Official Title
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A Phase 3 Study of SME3110 (Fluvoxamine Maleate) in Pediatric/Adolescent Subjects With Obsessive Compulsive Disorder

Conditions
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Obsessive Compulsive Disorder

Intervention / Treatment
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* Drug: Fluvoxamine maleate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has at least 16 points on Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale 10-item total score and at least 5 points in Obsession sub-total score and in Compulsion sub-total score respectively at the Screening period and Baseline. Subject showed less than 25% reduction in Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale 10-item total score at Baseline compared to the score at the Screening period (Total score at Baseline ≥ Total score at Screening х 0.75). Subject has obsessive compulsive disorder symptoms at least for 2 months at informed consent. Body weight: ≥ standard weight - 2 standard deviation based on the standard weight for each age in the School Health Statistical Survey 2001. Subjects with parent or legal guardian who have received explanation about the purpose, procedure and meaning of the study sufficiently and is willing to give written informed consent for the subject. (if possible, written informed assent will be obtained from the subject). Exclusion Criteria: Subject has only trichotillomania (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 312.39) or nail-biting as his/her compulsive symptoms. Subject has Tourette's disorder (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 307.23). However, the simple motor tic is not excluded. Subject is diagnosed with the following psychiatric disorders. Schizophrenia (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 295.xx) and other psychotic disorders (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 295.40 [schizophreniform disorder], 295.70 [schizoaffective disorder], 297.1 [delusional disorder], 298.8 [brief psychotic disorder], 297.3 [shared psychotic disorder], 293.xx [psychotic disorder due to… {indicate the general medical condition}], substance induced psychotic disorder, 298.9 [psychotic disorder not otherwise specified]). Depressive disorders Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 296.xx [major depressive disorder], 296.2x [single episode], 296.3x [recurrent], 300.4 [dysthymic disorder], 311 [depressive disorder not otherwise specified]). Bipolar disorders (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 296.xx [bipolar I disorder], 296.0x [single manic episode], 296.40 [most recent episode hypomanic], 296.4x [most recent episode manic], 296.6x [most recent episode mixed], 296.5x [most recent episode depressed], 296.7 [most recent episode unspecified], 296.89 [bipolar II disorder], 301.13 [cyclothymic disorder], 296.80 [bipolar disorder not otherwise specified]). Mental retardation (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 317 [mild mental retardation], 318.0 [moderate mental retardation], 318.1 [severe mental retardation], 318.2 [profound mental retardation], 319 [mental retardation, severity unspecified]). Eating disorders (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 307.1 [anorexia nervosa], 307.51 [bulimia nervosa], 307.50 [eating disorder not otherwise specified]). Attention-deficit/hyperactivity disorder (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 314.xx) and attention deficit/hyperactivity disorder not otherwise specified (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 314.9). Obsessive compulsive personality disorder (Diagnostic and Statistical manual of Mental Disorders Forth Edition Text Revision: 301.4). Other patients with clinical neurological disorder. Subject who diagnose Major Depressive Disorder by The Mini-International Neuropsychiatric Interview for Children and Adolescents (A) at the Screening period. Subject has been treated with fluvoxamine within 2 months prior to informed consent. Except for the patient whose fluvoxamine dose is not fixed and the administration period of fluvoxamine is within 6 weeks.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>In the double-blind placebo-controlled phase participants received one placebo tablet a day in week 1, then one placebo tablet twice a day (BID) in week 2 followed by a dose adjustment period from weeks 3 to 6 where the dose could be escalated by one tablet/day/week up to a maximum of three tablets twice a day. From weeks 7 to 10 participants received the same dose that was given during week 6. At the end of the 10-week treatment period there was a dose-tapering period of up to 4 weeks where the dose was decreased by up to two tablets/day each week. In the open-label long-term phase participants received 25 mg fluvoxamine once a day for the first week, 25 mg BID in week 2 followed by a flexible dose period from weeks 3 to 52 where the dose could be escalated by one tablet/day/week up to a maximum of 150 mg/day (three tablets BID). At the end of the 52-week treatment period there was a dose-tapering period of up to 4 weeks where the dose was decreased by up to 50 mg/day each week. | Drug: Fluvoxamine maleate<br>* Film-coated tablet containing 25 mg of fluvoxamine maleate<br>* Other names: Depromel;Drug: Placebo<br>* Placebo tablet matching to fluvoxamine maleate<br>|
| Experimental: Fluvoxamine<br>In the double-blind placebo-controlled phase participants received 25 mg fluvoxamine once a day in week 1, 25 mg twice a day (BID) in week 2 followed by a dose adjustment period from weeks 3 to 6 where the dose could be escalated by 25 mg/day/week up to a maximum of 150 mg (three tablets BID). From weeks 7 to 10 participants received the same dose that was given during week 6. At the end of the 10-week treatment period there was a dose-tapering period of up to 4 weeks where the dose of decreased by up to 50 mg/day each week. In the open-label long-term phase participants received 25 mg fluvoxamine once a day for the first week, 25 mg BID in week 2 followed by a flexible dose period from weeks 3 to 52 where the dose could be escalated by 25 mg/day/week up to a maximum of 150 mg/day (three tablets BID). At the end of the 52-week treatment period there was a dose-tapering period of up to 4 weeks where the dose was decreased by up to 50 mg/day each week. | Drug: Fluvoxamine maleate<br>* Film-coated tablet containing 25 mg of fluvoxamine maleate<br>* Other names: Depromel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Japanese Children's Yale-Brown Obsessive Compulsive Scale 10-item Total Score at the End of Treatment in the First Phase | The Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) is a 10-item questionnaire assessing the severity of obsessive compulsive disorder (OCD) in the past 7 days. Severity of compulsions and obsessions are rated on a scale from 0 (none) to 4 (extreme). The total score is calculated by summing the 10 individual scores and ranges from 0 to 40, where higher scores indicate more extreme symptoms. | Baseline and week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the JCY-BOCS 10-item Total Score at the End of Treatment in the First Phase Stratified by Age | The Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) is a 10-item questionnaire assessing the severity of OCD in the past 7 days. Severity of compulsions and obsessions are rated on a scale from 0 (none) to 4 (extreme). The total score is calculated by summing the 10 individual scores and ranges from 0 to 40, where higher scores indicate more extreme symptoms. | Baseline and week 10 | 
| Mean Change From Baseline in the JCY-BOCS 10-item Total Score at the End of Treatment in the First Phase Stratified by Gender | The Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) is a 10-item questionnaire assessing the severity of OCD in the past 7 days. Severity of compulsions and obsessions are rated on a scale from 0 (none) to 4 (extreme). The total score is calculated by summing the 10 individual scores and ranges from 0 to 40, where higher scores indicate more extreme symptoms. | Baseline and week 10 | 
| Mean Change From Baseline in the JCY-BOCS 10-item Total Score at Each Visit During the First Phase | The Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) is a 10-item questionnaire assessing the severity of OCD in the past 7 days. Severity of compulsions and obsessions are rated on a scale from 0 (none) to 4 (extreme). The total score is calculated by summing the 10 individual scores and ranges from 0 to 40, where higher scores indicate more extreme symptoms. | Baseline and weeks 2, 4, 6, 8 and 10 | 
| JCY-BOCS 10-item Total Score at Each Visit During the First Phase | The Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) is a 10-item questionnaire assessing the severity of OCD in the past 7 days. Severity of compulsions and obsessions are rated on a scale from 0 (none) to 4 (extreme). The total score is calculated by summing the 10 individual scores and ranges from 0 to 40, where higher scores indicate more extreme symptoms. | Baseline and weeks 2, 4, 6, 8 and 10 | 
| Percentage of Participants Much Improved in Clinical Global Impression Improvement Assessment During the First Phase | The investigator evaluated Clinical Global Impression (CGI) to rate participants' clinical symptomatology according to the following seven categories at each visit compared to the day of the first dose of study medication: Very much improved Much improved Minimally improved No change Minimally worse Worse Very much worse Much improved includes CGI score categories 'very much improved' and 'much improved'. | Weeks 1, 2, 3, 4, 5, 6, 8, and 10 | 
| Percentage of Participants With a ≥ 25% Decrease From Baseline in JCY-BOCS (10-item) Total Score at the End of Treatment in the First Phase | The Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) is a 10-item questionnaire assessing the severity of OCD in the past 7 days. Severity of compulsions and obsessions were rated on a scale from 0 (none) to 4 (extreme). The total score was calculated by summing the 10 individual scores and ranges from 0 to 40, where higher scores indicate more extreme symptoms. | Baseline and week 10 | 
| Percentage of Participants With a ≥ 35% Decrease From Baseline in JCY-BOCS (10-item) Total Score at the End of Treatment in the First Phase | The Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) is a 10-item questionnaire assessing the severity of OCD in the past 7 days. Severity of compulsions and obsessions were rated on a scale from 0 (none) to 4 (extreme). The total score was calculated by summing the 10 individual scores and ranges from 0 to 40, where higher scores indicate more extreme symptoms. | Baseline and week 10 | 
| Mean Change From Baseline in the JCY-BOCS 10-item Total Score at Each Visit During the Second Phase | The Japanese version of the Children's Yale-Brown Obsessive Compulsive Scale (JCY-BOCS) is a 10-item questionnaire assessing the severity of OCD in the past 7 days. Severity of compulsions and obsessions are rated on a scale from 0 (none) to 4 (extreme). The total score is calculated by summing the 10 individual scores and ranges from 0 to 40, where higher scores indicate more extreme symptoms. Baseline for the 2nd phase was the first visit of the 2nd phase after completion of the tapering period in the first phase and prior to study drug administration in the 2nd phase. | Baseline of the 2nd phase and weeks 2, 8, 16, 28, 40, and 52 of the 2nd phase | 
| Percentage of Participants Much Improved in Clinical Global Impression Improvement Assessment During the Second Phase | The investigator evaluated Clinical Global Impression (CGI) to rate participants' clinical symptomatology according to the following seven categories at each visit compared to the day of the first dose of study medication in the 2nd phase: Very much improved Much improved Minimally improved No change Minimally worse Worse Very much worse Much improved includes CGI score categories 'very much improved' and 'much improved'. | Baseline of the 2nd phase and weeks 1, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Number of Participants With Adverse Events During the First Phase | An adverse event (AE) was assessed as treatment-related by the investigator if there was evidence to suggest a causal relationship between the study drug and the adverse event. The investigator used the following definitions to rate the severity of each adverse event: Mild: The adverse event was transient and easily tolerated by the participant; Moderate: The adverse event caused the participant discomfort and interrupted usual activities. Severe: The adverse event caused considerable interference with the participant's usual activities and may have been incapacitating or life-threatening. A serious adverse event was any event that resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, congenital anomaly, persistent or significant disability/incapacity, or was an important medical event requiring medical or surgical intervention to prevent a serious outcome. | From the first dose of the study drug up to 30 days after the last dose of the study drug, approximately 18 weeks in the first phase. | 
| Number of Participants With Adverse Events During the Second Phase | An adverse event was assessed as treatment-related by the investigator if there was evidence to suggest a causal relationship between the study drug and the adverse event. The investigator used the following definitions to rate the severity of each adverse event: Mild: The adverse event was transient and easily tolerated by the participant; Moderate: The adverse event caused the participant discomfort and interrupted usual activities. Severe: The adverse event caused considerable interference with the participant's usual activities and may have been incapacitating or life-threatening. A serious adverse event was any event that resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, congenital anomaly, persistent or significant disability/incapacity, or was an important medical event requiring medical or surgical intervention to prevent a serious outcome. | From the first dose of the study drug up to 30 days after the last dose of the study drug, approximately 60 weeks in the second phase of the study. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obsessive Compulsive Disorder, Adolescent Subjects, Pediatric Subjects