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

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: FAS Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~FAS Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

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.

Time frame: Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Population: Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1.~Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.