Efficacy and Safety Study of Low-Dose Ondansetron For Adjunctive Therapy In Adult Patients With Obsessive-Compulsive Disorder

Core period: Inclusion criteria for entry in prospective serotonin reuptake inhibitor (SRI) period (screening):

• Male or female adults 18 years of age or older
• Able to understand the study and provide informed consent
• Subjects who are fluent in English and/or Spanish (speaking, writing, and reading)
• Willing and able to comply with the requirements of the protocol and follow directions from the clinic staff
• Body mass index (BMI) ≤ 40 kg/m^2 (wearing indoor clothing without shoes)
• For all females: Female patients will be included if they are post-menopausal for at least two years or sterilized, or if they are of childbearing potential, they are not breastfeeding, their pregnancy test is negative, they have no intention of becoming pregnant during the course of the study, and are using adequate contraceptive drugs or devices. Medically acceptable methods of contraception that may be used by the patient and/or her partner are: oral contraceptives, progestin injection or implants, condom with spermicide, diaphragm with spermicide, IUD, vaginal spermicidal suppository, surgical sterilization or abstinence. Females using oral contraception must have started using the medication at least 8 weeks prior to screening. Surgical sterilization must have occurred at least 6 weeks prior to screening.
• Documented diagnosis of Obsessive-Compulsive Disorder (OCD) as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria
• At screening, documented history of stable and current regimen of one of the following five serotonin reuptake inhibitor (SRI) for at least 6 weeks prior to screening at the minimum daily dosage listed:
• clomipramine (Anafranil®) 150 mg
• fluvoxamine (Luvox®) 200 mg or fluvoxamine CR (Luvox CR®) 200 mg
• fluoxetine (Prozac®) 40 mg
• paroxetine (Paxil®) 40 mg (does not include paroxetine CR (Paxil CR®))
• sertraline (Zoloft®) 100 mg
• Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of ≥ 24
• Hamilton Depression Rating Scale (HAM-D) score of < 20

Inclusion criteria for randomization to double-blind treatment period:

• During run-in, documented use of stable and current regimen of one of the following five serotonin reuptake inhibitor (SRI) for at least 6 weeks prior to screening at the minimum daily dosage listed:
• clomipramine (Anafranil®) 150 mg
• fluvoxamine (Luvox®) 200 mg or fluvoxamine CR (Luvox CR®) 200 mg
• fluoxetine (Prozac®) 40 mg
• paroxetine (Paxil®) 40 mg (does not include paroxetine CR (Paxil CR®))
• sertraline (Zoloft®) 100 mg
• Demonstrated failure to adequately respond to serotonin reuptake inhibitor (SRI) treatment, defined by the following 2 criteria after 6 weeks of prospective treatment:
• Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score ≥ 21
• Less than 25% improvement in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score from Week -6 (screening)
• Hamilton Depression Rating Scale (HAM-D) score of ≤ 16

Extension Period - Inclusion criteria for randomization to double-blind extension treatment period:

• Completing 12 weeks of treatment in the double-blind core period
• Demonstrating compliance in the judgment of the investigator, with both the SRI and study drug as prescribed.

Core Period Exclusion Criteria:

• Presence of significant medical illnesses such as, but not restricted to, cardiovascular, (including congestive heart failure and bradyarrhythmias), endocrine or intestinal disorders that would interfere with the conduct of the study
• History of significant head injury, other significant brain trauma, or seizure disorder (not including a single childhood febrile seizure)
• Clinically significant abnormal laboratory findings. Presence of clinically significant electrolyte abnormalities will be exclusionary.
• Clinically significant abnormal findings on electrocardiogram (ECG). Diagnosis of congenital long QT syndrome will be exclusionary.
• Clinically significant abnormal findings on physical examination
• Positive pregnancy test
• Subjects who intend to donate blood or blood components while receiving study drug or within 1 month of the completion of treatment
• Hoarding as the primary Obsessive-Compulsive Disorder (OCD) symptom (secondary hoarding will be allowed)
• Obsessive-compulsive spectrum disorder as a primary disorder (secondary obsessive-compulsive spectrum disorders will be allowed)
• Requiring active behavioral therapy during the study period (run-in and treatment periods). Patients with a history of behavioral therapy may be enrolled as long as they will not be actively engaged in behavioral therapy during the study. However, booster sessions, occurring no more than quarterly (before and after the core study), are allowed. Supportive and other forms of psychotherapy will be permitted during the study as long as the patient has been engaged in such therapy for at least 8 weeks prior to study enrollment and there are no changes during the study.
• A history of substance dependence or drug or substance abuse, including alcohol abuse, within the past 12 months. A history of nicotine dependence will not be considered an exclusion criterion.
• Mental retardation or an IQ less than 70
• The following comorbid psychiatric conditions identified by current or past medical history or as a result of the Mini-International Neuropsychiatric Interview (MINI) or Structured Clinical Interview for DSM-IV-TR Axis II Personality Disorders (SCID-II) psychiatric interviews will be excluded:
• Schizophrenia or other psychotic disorders
• Schizotypal personality disorder
• Bipolar disorder
• Gilles de la Tourette syndrome
• Autism and autistic spectrum disorders
• Eating disorders
• Combat-related post-traumatic stress disorder
• Other comorbid anxiety disorders will be permitted if the severity will not interfere with study participation.
• Subjects who are believed to have suicidal or homicidal risk (i.e., after an assessment by a qualified mental health professional if the C-SSRS screening assessment warranted a suicidal risk assessment interview), or with a history of suicidality in the previous 3 months
• Taking trazodone or other medicinal products that have been associated with prolongation of the QT/QTc interval.
• Taking concomitant antipsychotic drugs, lithium, carbamazepine, oxcarbazepine, phenytoin, anti-anxiety drugs (other than the current SRI for treatment of OCD), or benzodiazepines prescribed for the treatment of anxiety. PRN use of FDA-approved benzodiazepine or non-benzodiazepine hypnotics will be allowed. In addition, the following 3 benzodiazepines will be allowed, provided that patients have been taking them only at bedtime as a sleep aid for at least 12 weeks at the maximum doses noted below:
• clonazepam (Klonopin®) up to 1 mg
• diazepam (Valium®) up to 5 mg
• lorazepam (Ativan®) up to 1 mg
• Taking more than one SRI at the time of screening or at any time in the previous 8 weeks
• A history of having failed more than 2 prior treatments, not including their current course of treatment, with serotonin reuptake inhibitors (SRIs), including clomipramine and selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) may only be considered after consultation with the medical monitor. Failure is defined as inadequate response, in the judgment of the treating physician, to an adequate dose of SRIs or SNRIs taken for at least 8 weeks.
• Taking any antidepressant drugs (including St. John's Wort), at the time of screening or at any time in the previous 8 weeks, other than the SRI identified in the retrospective and screening periods
• Likely to use triptans at any time during the run-in or double-blind portion of the trial