Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Major Depressive Disorder (CLARITY)

Study Overview
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Brief Summary
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To assess the efficacy of pimavanserin compared to placebo when given adjunctively to a selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant as treatment of patients with Major Depressive Disorder (MDD) and an inadequate response to antidepressant therapy

Official Title
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A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Major Depressive Disorder

Conditions
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Adjunctive Treatment of Major Depressive Disorder

Intervention / Treatment
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* Drug: Pimavanserin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, aged 18 years and above A clinical diagnosis of major depressive disorder (MDD) Is being treated with one of the following SSRI or SNRI antidepressants as monotherapy: Citalopram Escitalopram Paroxetine Fluoxetine Sertraline Duloxetine Venlafaxine Desvenlafaxine Venlafaxine XR Has a history of inadequate response to antidepressant treatments Exclusion Criteria: Patient has a psychotic disorder other than MDD Patient has current evidence of a serious and/or unstable neurologic, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies, which would affect the patient's ability to participate in the program Patient has a history or symptoms of long QT syndrome Patients will be evaluated at screening to ensure that all criteria for study participation are met. Patients may be excluded from the study based on these assessments (and specifically if it is determined that their baseline health and psychiatric condition do not meet all pre-specified entry criteria).

Ages Eligible for Study
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Minimum 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pimavanserin 34 mg + SSRI/SNRI<br>Drug- pimavanserin, 34 mg, taken as two 17 mg tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study. | Drug: Pimavanserin<br>* Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.<br>|
| Placebo Comparator: Placebo + SSRI/SNRI<br>Placebo, taken as two tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study. | Other: Placebo<br>* Placebo, taken as two tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 5 in the HAMD-17 Total Score | The Hamilton Rating Scale for Depression (HAMD-17) is a 17-item scale to assess depression. The HAMD-17 consists of 8 items with a score on a 3 point scale and 9 items with a score on a 5 point scale. Each item is rated from least (0) to most frequent or most severe, as applicable, with highest scores of 2 to 4, depending on the item. Items are summed up to calculate the HAMD-17 total score. The total score ranges from 0 to 52. A higher total score indicates more severe depression. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 5 in the SDS Total Score | The Sheehan Disability Scale is a 3-item patient-facing questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. All items are rated on an 11-point scale from 0 (no impairment) to 10 (most severe). The total SDS score ranges from 0 to 10. It is calculated as the arithmetic mean of the scores for all 3 items. A higher score indicates greater disability. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| Treatment Response and Remission Rates at the End of 5-week Treatment Period | The Hamilton Rating Scale for Depression (HAMD-17) is a 17-item scale to assess depression. Each item is rated from least (0) to most frequent or most severe, as applicable, with highest scores of 2 to 4 depending on the item. Items are summed up to calculate the HAMD-17 total score. A higher total score indicates more severe depression. Treatment response was defined as a reduction from Baseline in HAMD-17 total score of >=50%. Remission was defined as a HAMD-17 total score <=7. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| Change From Baseline to Week 5 in CGI-S Total Score | The Clinical Global Impression-Severity Scale is a 1-item scale, used to rate the severity of the disorder from 0 (not assessed) to 7 (among the most extremely ill patients). A higher CGI-I score denotes more severe depression. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| CGI-I Score at Week 5 | The Clinical Global Impression- Improvement scale is a 1-item scale, used to rate the global improvement of the patient since beginning of the study from 0 (not assessed) to 7 (very much worse). A higher CGI-I score denotes less improvement in depression. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| Change From Baseline to Week 5 in SF-12 Score | The 12-Item Short Form Health Survey is a patient-reported outcome measure that addresses 8 domains of physical functioning, role - physical, bodily pain, general health perceptions, vitality, social functioning, role - emotional, and mental health. Composite scores were obtained representing physical health and mental health composite summaries, Physical Component Summary (PCS) and Mental Component Summary (MCS), respectively. An algorithm was used to generate PCS and MCS for comparison to normative data. In normative data, the mean score was set to 50; thus, scores >50 indicate better physical or mental health than the mean and scores <50 indicate worse health. A higher score is indicative of a better health state. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| Change From Baseline to Week 5 in DAI-10 Score | The Drug Attitude Inventory-10 is a 6-item patient-facing questionnaire to evaluate a patient's perceptions and experiences of treatment. It contains 6 items that a patient who is fully adherent to prescribed medication would answer as True, and 4 items that a patient who is fully adherent would rate as False. Scores are allocated to each answer and the total score is calculated as the sum. A correct answer is scored +1 and an incorrect answer is scored -1. The total score ranges from -10 to 10 and is the sum of pluses and minuses. A positive total score indicates a positive subjective response (adherent) and a negative total score indicates a negative subjective response (nonadherent). Higher scores denoted better adherence. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| Change From Baseline to Week 5 in KSS Score | The Karolinska Sleepiness Scale is a patient-facing 1-item scale that measures the patient's drowsiness. Scoring is based on a 9-point verbally anchored scale ranging from extremely alert (1) to very sleepy, great effort to keep awake, fighting sleep (9). Higher scores denote more drowsiness. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| Change From Baseline to Week 5 in MGH-SFI Score | The Massachusetts General Hospital Sexual Functioning Index is a patient-facing questionnaire that quantifies sexual dysfunction into 5 functional domains (interest in sex, sexual arousal, ability to achieve orgasm, ability to maintain erection [males only], and sexual satisfaction). Patients rate each item using a 6-point scale ranging from 1 (good function) to 6 (poor function). The MGH-SFI score is calculated as the arithmetic mean of the item scores for the 5 domains. The mean MGH-SFI score ranges from a minimum value of 1 to a maximum value of 6. Higher scores denotes worse sexual dysfunction. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| Change From Baseline to Week 5 in BIS-11 Score | The Barratt Impulsiveness Scale-11 is a questionnaire for assessment of the personality/behavioral construct of impulsiveness. It is composed of 30 items describing common impulsive or non-impulsive (for reverse scored items) behaviors and preferences. Items are scored on a 4-point scale from Rarely/Never (1) to Almost Always/Always (4). Items are summed up to calculate the total score. The BIS-11 total score ranges from 30 to 120. Higher scores denotes more impulsiveness. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively | 
| Change From Baseline to Week 5 in SIS Score | The Sheehan Irritability Scale is a 7-item patient-reported outcome measure to measure the frequency, severity, and impairment associated with irritability in psychiatric patients. It includes items on: irritability, frustration, edginess/ impatience/ overreaction, moodiness, anger with self, anger with others, and temper. Items are answered on an 11-point rating scale where higher scores indicated greater severity (0=not at all, 10=extremely). Item responses are summed into a total score (range=0-70). Higher scores mean higher irritability. | Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively |