E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Major Depressive Disorder |
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E.1.1.1 | Medical condition in easily understood language |
Major Depressive Disorder |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025454 |
E.1.2 | Term | Major depressive disorder, recurrent episode |
E.1.2 | System Organ Class | 100000004873 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of adjunctive pimavanserin compared to placebo in subjects with major depressive disorder who have an inadequate response to antidepressant therapy |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy and benefits of adjunctive pimavanserin compared to placebo in subjects with major depressive disorder who have an inadequate response to antidepressant therapy on the following: • Functional impairment • Clinician’s global impression of severity and improvement of depressive symptoms • Sexual functioning • Sleepiness • Treatment response and remission • Anxiety • Impulsiveness •Early response to treatment
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Is a male or female ≥18 years of age 2. Can understand the nature of the study and protocol requirements and is willing to comply with study drug administration requirements and discontinue prohibited concomitant medications 3. Provides written informed consent to participate in the study 4. Is capable of communicating with the site personnel, able to complete subject-reported outcome measures and can be reliably rated on assessment scales (in the opinion of the Investigator) 5. Has a clinical diagnosis of major depressive disorder with or without anxious distress by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by the Mini-International Neuropsychiatric Interview (MINI) during the screening period. Subject may have either recurrent or single episode of major depressive disorder. 6. Is treated during the current major depressive episode with one of the following SSRI/SNRI antidepressants at a minimally effective dose for at least 8 weeks with at least the same stable dose over 4 weeks prior to the SAFER State versus trait, Assessability, Face validity, Ecological validity, and Rule of three Ps (pervasive, persistent, and pathological) remote interview: a. Citalopram b. Escitalopram c. Paroxetine d. Fluoxetine e. Sertraline f. Duloxetine g. Venlafaxine h. Desvenlafaxine I. Venlafaxine XR The dose level of the antidepressant is expected to remain stable throughout the study. Adherence to the antidepressant should be reviewed throughout the study. 7. Must have a detectable blood level of a prescribed SSRI/SNRI during Screening. A negative screening test may be repeated as assessed by the Medical Monitor when the subject and/or site can provide additional evidence of subject adherence to antidepressant treatment or evidence of sample or laboratory error. 8. During the screening period, the subject's inadequate response to SSRI/SNRI antidepressant treatment is confirmed by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ) through the SAFER remote interview and the subject continues to exhibit an inadequate response to treatment at the time of the SAFER interview. 9. Subjects who are currently taking a second antidepressant or antidepressant augmentation agent at a subtherapeutic dose or for inadequate duration at Screening are eligible for inclusion in the study if it is clinically appropriate to discontinue the drug before the Baseline visit (in the opinion of the Investigator); the second antidepressant/augmentation agent must be discontinued and washed out at least 5 half-lives prior to Baseline. This second antidepressant/augmentation agent should not be discontinued solely to make the subject eligible for enrollment in the study. 10. Has a Montgomery-Asberg Depression Rating Scale (MADRS) total score >20 at both Screening and Baseline 11. Has a Clinical Global Impression–Severity (CGI-S) score ≥4 (moderately ill or worse) for depression at both Screening and Baseline 12. If the subject is female, she must not be pregnant or breastfeeding. She must also be of non-childbearing potential (defined as either surgically sterilized or at least 1 year postmenopausal) OR must agree to use TWO clinically acceptable methods of contraception for at least 1 month prior to Visit 2 (Baseline), during the study, and 1 month following completion of the study. Acceptable methods of contraception include the following: a. A barrier method, condom, diaphragm, or cervical cap with spermicide b.Hormonal contraception, including oral, injectable, transdermal, or implantable methods c.Intrauterine device (IUD) Only one of the two clinically acceptable methods can be a hormonal method. |
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E.4 | Principal exclusion criteria |
1 Has a history of schizophrenia or other psychotic disorder, major depressive disorder with psychotic features, bipolar I or II disorder. Subjects who are currently being treated or require treatment for post-traumatic stress disorder, acute stress disorder, panic disorder, or obsessive compulsive disorder are also not eligible. 2 Has a current primary diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder, according to DSM-5 criteria 3 Has met DSM-5 criteria for substance use disorders within the last 6 months prior to Screening, except for disorders related to the use of caffeine or nicotine 4 Is suicidal at Visit 1 (Screening) or Visit 2 (Baseline) as defined below: a An answer of “yes” to C SSRS questions 4 or 5 (current or over the last 6 months) OR b.Has attempted suicide within 1 year prior to Visit 1 (Screening); OR c.Is actively suicidal in the Investigator’s judgment 5. Has current evidence of delirium or an unstable neurological, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies that, in the judgment of the Investigator or medical monitor , would jeopardize the safe participation of the subject in the study or significantly interfere with the conduct or interpretation of the study 6 Has a history of epilepsy 7 Has atrial fibrillation unless adequately anti-coagulated 8 Has a history of myocardial infarction, unstable angina, acute coronary syndrome, or cerebrovascular accident 9 Has a history of any of the following: a Greater than New York Heart Association (NYHA) Class II congestive heart failure b Grade II or greater angina pectoris (by Canadian Cardiovascular Society Angina Grading Scale) c Sustained ventricular tachycardia d Ventricular fibrillation e Torsade de pointes f Syncope due to an arrhythmia g An implantable cardiac defibrillator 10 Has laboratory evidence of hypothyroidism at Screening, as measured by thyroid stimulating hormone (TSH) and reflex free thyroxine (T4). If TSH is abnormal and the reflex free T4 is normal, the subject may be enrolled 11 Has current unstable diabetes or glycosylated hemoglobin (HbA1c) >8% at Screening 12 Has a known history of a positive hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) test 13 Has a history of neuroleptic malignant syndrome or serotonin syndrome 14 Has a known personal or family history of long QT syndrome or family history of sudden cardiac death 15 Has any of the following ECG results at Visit 1 (Screening) or Visit 2 (Baseline): a If the subject is not on citalopram, escitalopram, or venlafaxine (immediate or extended release): i QTcF >450 ms, if QRS duration <120 ms ii QTcF >470 ms, if QRS duration ≥120 ms b If the subject is on citalopram, escitalopram, or venlafaxine (immediate or extended release) i QTcF >425 ms, if QRS duration <120 ms ii QTcF >450 ms, if QRS duration ≥120 ms At Screening, if the set of triplicate ECGs has a prolonged QTcF due to an identifiable cause, and it is medically appropriate to address that cause, a repeat set of triplicate ECGs may be performed during Screening at the discretion of the Medical Monitor. 16 Has a heart rate <50 beats per minute as measured by peripheral pulse rate, not explained by regular exercise or medication in discussion with the Medical Monitor. If bradycardia is secondary to iatrogenic or treatable causes and these causes are treated, a heart rate assessment can be repeated during the screening period. 17 Requires treatment with a medication or other substance that is prohibited by the protocol 18 At Screening, has a body mass index (BMI) <18.5 kg/m2 or >35 kg/m2 19 Has a positive test for an illicit drug or cannabis at Screening or Baseline. Subjects who test positive for a controlled substance and who have a valid prescription may be retested during Screening if they agree to abstain from the medication for the length of their participation in the study. The repeat test during Screening must be negative for them to participate in the study. Additionally, DSM-5 criteria for substance use disorders should not be met. 20 Has received electroconvulsive therapy, transcranial magnetic stimulation, or vagal nerve stimulation, or has received deep brain stimulation in the current episode of depression 21 Has received new-onset psychotherapy or had a change in the intensity of psychotherapy within 8 weeks prior to Screening 22 Has participated in or is participating in a noninterventional study or clinical trial of any investigational or marketed drug, device, or intervention, within 30 days or 5 half lives, whichever is longer, of Visit 2 23 Has previously been enrolled in any prior clinical study with pimavanserin or is currently taking pimavanserin 24 Has a significant sensitivity or allergic reaction to pimavanserin or its excipients
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from Baseline in the Hamilton Depression Scale (17 items) (HAMD 17) total score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After final Database lock |
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E.5.2 | Secondary end point(s) |
•Change from Baseline in Sheehan Disability Scale (SDS) score •Change from Baseline in Clinical Global Impression–Severity (CGI-S) score for depressive symptoms •Clinical Global Impression–Improvement (CGI-I) score for depressive symptoms •Change from Baseline in the Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14) •Change from Baseline in Karolinska Sleepiness Scale (KSS) score •Treatment responder rates. Treatment response is defined as a reduction from Baseline in HAMD-17 total score of 50% or more. •Treatment remission rates. Treatment remission is defined as a HAMD-17 total score ≤7. •Change from Baseline in the Hamilton Depression (HAMD) Anxiety/Somatization factor score •Change from Baseline in the Barratt Impulsiveness Scale (BIS-11) •Change from Baseline to Week 1 in the HAMD-17 total score
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After final Database lock |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Czech Republic |
Finland |
Poland |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Ukraine |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |