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A Study to Evaluate the Efficacy and Safety of Flexible Doses of Extended-release (ER) Paliperidone Compared With Flexible Doses of Quetiapine and Placebo in Patients With Bipolar I Disorder

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ClinicalTrials.gov Identifier: NCT00309699
Recruitment Status : Completed
First Posted : April 3, 2006
Last Update Posted : June 20, 2014
Sponsor:
Information provided by (Responsible Party):
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Tracking Information
First Submitted Date  ICMJE March 31, 2006
First Posted Date  ICMJE April 3, 2006
Last Update Posted Date June 20, 2014
Study Start Date  ICMJE April 2006
Actual Primary Completion Date September 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 3, 2008)
The primary effectiveness outcome is the change in the total YMRS score from baseline to the last assessment during the acute treatment phase. [ Time Frame: 3 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: March 31, 2006)
The primary effectiveness outcome is the change in the total YMRS score from baseline to the last assessment during the acute treatment phase.
Change History Complete list of historical versions of study NCT00309699 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2008)
The secondary effectiveness outcomes are the change in GAF from baseline to endpoint or the last assessment during the acute treatment phase and the change in total YMRS score from baseline to endpoint or the last assessment during the maintenance phase. [ Time Frame: 12 weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 31, 2006)
The secondary effectiveness outcomes are the change in GAF from baseline to endpoint or the last assessment during the acute treatment phase and the change in total YMRS score from baseline to endpoint or the last assessment during the maintenance phase.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Efficacy and Safety of Flexible Doses of Extended-release (ER) Paliperidone Compared With Flexible Doses of Quetiapine and Placebo in Patients With Bipolar I Disorder
Official Title  ICMJE Randomized, Double-Blind, Active- and Placebo-Controlled, Parallel Group, Multicenter Study to Evaluate the Efficacy and Safety of Flexibly-Dosed Extended-Release Paliperidone Compared With Flexibly-Dosed Quetiapine and Placebo in the Treatment of Acute Manic and Mixed Episodes in Bipolar Disorder
Brief Summary The purpose of this study is to evaluate the effectiveness and safety of flexible-doses paliperidone ER (3 to 12 mg as needed) compared with placebo over 3 weeks in patients with Bipolar I Disorder who are experiencing an acute manic or mixed episode. This study will also evaluate the effects of paliperidone ER on global functioning, and will compare the effectiveness of flexible doses of paliperidone ER to that of quetiapine over 12 weeks.
Detailed Description

Several treatments are available for the treatment of acute manic and mixed episodes associated with bipolar disorder. Some of these treatments although used for many years, are associated with well-known problems such as poor tolerability, significant toxicities, narrow therapeutic ranges, and drug interactions. Often, several drugs must be used in combination to achieve the best clinical effect. More recently, a group of compounds known as atypical antipsychotics, such as risperidone, have been licensed for use in this indication. Paliperidone has similar properties as risperidone and is expected to be as effective in the treatment of acute manic and mixed episodes associated with bipolar disorder. Paliperidone ER has been shown to be effective in schizophrenia and it has an improved drug delivery system with a reduced potential for drug interactions.

Study drug tablets are designed to deliver the appropriate amount of drug (3 mg or 6 mg) using a "Push-Pull" delivery system based on a patented oral osmotic pump technology (OROS) that allows the drug to be delivered at a relatively controlled rate for 24 hours. This study will test flexibly-dosed paliperidone ER (3 to 12 mg/day compared with placebo (inactive substance) or flexibly-dosed quetiapine (400 to 800 mg/day). There are 4 parts to the study: a screening and washout phase that lasts up to 7 days to determine if patients are eligible for the study and to discontinue all current medications, a double-blind (neither the patient nor the physician knows whether drug or placebo and what dosage is being taken) acute treatment phase that lasts for 3 weeks, a 9-week double-blind maintenance phase to see if the effects of paliperidone are maintained over a longer period, and a follow-up phase that lasts about 1 week after the final visit or early withdrawal from the study. During the acute treatment phase, patients are randomly assigned to receive treatment with placebo, 3 to 12 mg/day of paliperidone ER, or 400 to 800 mg/day of quetiapine. The dosage of paliperidone ER or quetiapine may be adjusted to meet the patient's needs. Patients who receive placebo during the acute phase (first 3 weeks) will receive paliperidone ER (beginning with 6 mg/day) during the maintenance phase (last 9 weeks). All other patients receive the same drug, i.e., either paliperidone ER or quetiapine, during both phases. The dosages during the acute phase begin at 6 mg/day for paliperidone ER and 100 mg/day for quetiapine, and may be adjusted thereafter by the study investigator to meet individual patient needs (after a forced titration of quetiapine to 400 mg/day). Patients will be hospitalized for at least the first 7 days of double-blind treatment, and may be discharged on the seventh day and followed as outpatients based on the judgment of the study doctor. End-of-study/early withdrawal procedures will be done after the last dose of study drug has been received and blood samples have been taken, or if a patient withdraws early. Patients will have a follow-up visit with safety evaluations approximately 1 week later. The study, including the screening and washout phases, will last approximately 98 days or 14 weeks.

Effectiveness will be primarily determined by the change in the total Young Mania Rating Scale (YMRS) score from the beginning (baseline) to the end of the acute treatment phase of the study. The YMRS is an 11-item established measure used to evaluate manic symptoms. A secondary measure of effectiveness is the change in the Global Assessment of Functioning (GAF) scale from baseline to the end of the acute treatment phase of the study. Other measures of effectiveness include the change from baseline to end of the maintenance phase in total YMRS score, the time to onset of therapeutic effect, responder rate (defined as 50% or more reduction from baseline in YMRS score) and changes from baseline to the end of the acute treatment phase in all other assessment scales. Additional assessment scales will be used to evaluate the clinical progress of the patient, psychotic features in bipolar disorder, quality of sleep and daytime drowsiness, health-related function, and rate the severity of the patient's bipolar disorder. Safety will be evaluated by the frequency, severity, and timing of side effects, clinical laboratory tests (including pregnancy tests), 12-lead electrocardiograms (ECGs), vital signs measurements, and physical and neurological examinations.

The study hypotheses for the primary and secondary effectiveness measures are that 1) flexibly dosed (dosages of 3 to 12 mg/day) paliperidone ER have more effect than placebo on the change from baseline in the YMRS total score at the end of 3 weeks of treatment, 2) flexibly-dosed paliperidone ER has more effect than placebo on the change from baseline in GAF score at the end of 3 weeks of treatment, and 3), flexibly-dosed paliperidone ER is not worse than quetiapine in the change in YMRS score at 12 weeks. The potential effect on the variation in genes related to paliperidone ER may be evaluated separately in patients who consent to DNA (deoxyribonucleic acid) testing. All study drug will be administered twice daily. The dosages during the acute phase (first 3 weeks) begin at 6 mg/day for paliperidone ER and 400 mg/day for quetiapine (after a forced titration from 100 mg/day), and may be adjusted thereafter by the investigator to meet individual patient needs within the ranges of 3-12 mg/day and 400-800 mg/day. Patients who receive placebo during the acute phase will receive paliperidone ER (starting with 6 mg/day) during the maintenance phase (last 9 weeks).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Bipolar Disorder
  • Mood Disorders
Intervention  ICMJE
  • Drug: Placebo
    Daily for 3 weeks
  • Drug: Quetiapine
    400 to 800 mg daily, initially titrated and flexibly dosed, for 12 weeks
  • Drug: Paliperidone ER
    3 to 12 mg daily, flexibly dosed, for 12 weeks
Study Arms  ICMJE
  • Placebo Comparator: 003
    Placebo Daily for 3 weeks
    Intervention: Drug: Placebo
  • Active Comparator: 002
    Quetiapine 400 to 800 mg daily, initially titrated and flexibly dosed, for 12 weeks
    Intervention: Drug: Quetiapine
  • Experimental: 001
    Paliperidone ER 3 to 12 mg daily, flexibly dosed, for 12 weeks
    Intervention: Drug: Paliperidone ER
Publications * Vieta E, Nuamah IF, Lim P, Yuen EC, Palumbo JM, Hough DW, Berwaerts J. A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord. 2010 May;12(3):230-43. doi: 10.1111/j.1399-5618.2010.00815.x.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 3, 2008)
493
Original Enrollment  ICMJE
 (submitted: March 31, 2006)
475
Actual Study Completion Date  ICMJE November 2007
Actual Primary Completion Date September 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Meets Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM IV) criteria for Bipolar I Disorder, Most Recent Episode Manic or Mixed (with or without psychotic features)
  • history of at least 1 previously documented manic or mixed episode requiring medical treatment within 3 years before the screening phase
  • total score of at least 20 on the YMRS at screening and at baseline
  • if taking mood stabilizers, antipsychotics, or antimanic drugs, must have discontinued that medication at least 3 days before baseline
  • women must be postmenopausal (no spontaneous menses for at least 2 years), surgically sterile, abstinent, or agree to practice an effective method of birth control if they are sexually active before entry and throughout the study (effective methods of birth control include prescription hormonal contraceptives, intrauterine devices, double-barrier method, and male partner sterilization)
  • able and willing to comply with self-administration of medication, or have consistent help or support available.

Exclusion Criteria:

  • Meets DSM-IV criteria for rapid cycling and schizoaffective disorder
  • In the opinion of the study doctor, is at significant risk for suicidal or violent behavior during the course of the study
  • Has used cocaine, phencyclidine, amphetamine, methylphenidate, pemoline, an opioid (excluding codeine), hallucinogen, or any other drug that may be associated with manic symptoms as evidenced by a positive urine drug screen
  • Has received benzodiazepines at doses equal to 4 mg/day of lorazepam or higher for a period of 3 months or longer immediately before the screening phase.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Greece,   Korea, Republic of,   Lithuania,   Russian Federation,   Taiwan,   Turkey,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00309699
Other Study ID Numbers  ICMJE CR010858
R076477BIM3002
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study Sponsor  ICMJE Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
PRS Account Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Verification Date June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP