Conditions: Major Depressive Disorder
Keywords: Major Depressive Disorder MIN-117
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 360
Healthy volunteers: no

Brief summary:
MIN-117C03 is a 6-week, 3-arm, randomized, double-blind, placebo controlled study to investigate the safety and efficacy of MIN-117 in male and female patients with Major Depressive Disorder, aged 18 to 65 years. Approximately 324 patients were to be randomly assigned to 1 of 3 treatment arms, including placebo, 2.5 mg MIN-117, or 5.0 mg MIN-117, in a 2:1:1 ratio.

Detailed description:

Arms:
arm 1: MIN-117 5.0 mg (consisting of two 2.5 mg capsules) orally daily for 6 weeks arm 2: MIN-117 2.5 mg (consisting of one 2.5 mg capsule and one placebo capsule) orally daily for 6 weeks arm 3: Placebo (consisting of two placebo capsules) orally daily for 6 weeks

Interventions: intervention 1: MIN-117 5.0 mg intervention 2: MIN-117 2.5 mg intervention 3: Placebo
Intervention descriptions: intervention 1: 5.0 mg MIN-117 administered as two MIN-117 2.5 mg capsules as a single dose once daily intervention 2: 2.5 mg MIN-117 administered as one MIN-117 2.5 mg capsule and one Placebo capsule as a single dose once daily intervention 3: Placebo administered as two Placebo capsules as a single dose once daily

Protocol document:
Prot_000.pdf: 
Minerva Neurosciences, Inc. 
Protocol MIN-117C03 
Confidential 
_______________________________________________________________________ 
Amendment 1, 20 November 2018 
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Minerva Neurosciences, Inc. 
 
Clinical Protocol 
A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Study to 
Evaluate the Efficacy and Safety of 2 Fixed Doses (5.0 mg or 2.5 mg) of MIN-117 in 
Adult Patients with Major Depressive Disorder 
 
Protocol MIN-117C03; Phase 2b   
AMENDMENT 1  
 
MIN-117 
 
 
EudraCT NUMBER: 
2017-005149-64 
 
 
Sponsor: 
Minerva Neurosciences, Inc. 
 
1601 Trapelo Road 
 
Waltham, MA 02451, USA 
 
 
CRO: 
 
 
 
 
 
 
 
Status: 
Approved 
Issue Date: 
20 November 2018 
Prepared by: 
Minerva Neurosciences, Inc. 
Department: 
Clinical Development 
Document No.: 
MIN-117C03.v2.1 
 
 
Protocol Version 
Issue Date 
Original Protocol
09 January 2018
Amendment 1 
20 November 2018 
 
 
 
Compliance:  This study will be conducted in compliance with this protocol, Good Clinical Practice, and applicable 
regulatory requirements. 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential 
and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to 
whom the information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you 
that is indicated as privileged or confidential. 
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TABLE OF CONTENTS 
LIST OF IN-TEXT TABLES ...................................................................................................... 5 
LIST OF IN-TEXT FIGURES ..................................................................................................... 5 
SYNOPSIS ................................................................................................................................ 6 
TIME AND EVENTS SCHEDULE ......................................................................................... 14 
ABBREVIATIONS ................................................................................................................... 16 
1. 
INTRODUCTION ........................................................................................................ 19 
1.1. 
Background on the Disease ....................................................................................... 19 
1.2. 
MIN-117 Pharmacological Profile and Rationale as a Unique Antidepressant .......... 19 
1.3. 
Nonclinical Studies ..................................................................................................... 20 
1.3.1. 
Pharmacologic Profile ................................................................................ 20 
1.3.2. 
Safety Pharmacology ................................................................................. 20 
1.3.3. 
Toxicology .................................................................................................. 21 
1.3.4. 
Pharmacokinetic Profile.............................................................................. 22 
1.3.5. 
Behavioral and Pharmacodynamics Studies ............................................. 23 
1.4. 
Clinical Studies ........................................................................................................... 24 
1.4.1. 
Pharmacokinetics ....................................................................................... 25 
1.4.2. 
Efficacy ....................................................................................................... 26 
1.4.3. 
Safety ......................................................................................................... 26 
1.5. 
Overall Rationale for the Study................................................................................... 29 
2. 
OBJECTIVES ............................................................................................................. 31 
3. 
OVERVIEW OF STUDY DESIGN .............................................................................. 32 
3.1. 
Study Design Rationale .............................................................................................. 34 
4. 
STUDY POPULATION ............................................................................................... 36 
4.1. 
Inclusion Criteria ......................................................................................................... 36 
4.2. 
Exclusion Criteria ........................................................................................................ 38 
4.3. 
Prior and Concomitant Therapy.................................................................................. 40 
4.3.1. 
Prior Therapy .............................................................................................. 40 
4.3.2. 
Concomitant Therapy ................................................................................. 40 
4.3.3. 
Contraception ............................................................................................. 41 
4.3.4. 
Exposure to Partners During the Study...................................................... 41 
4.3.5. 
Sperm Donation ......................................................................................... 42 
4.3.6. 
Pregnancy .................................................................................................. 42 
5. 
TREATMENT ALLOCATION AND BLINDING ......................................................... 42 
5.1. 
Randomization ............................................................................................................ 42 
5.2. 
Blinding ....................................................................................................................... 42 
6. 
DOSAGE AND ADMINISTRATION ........................................................................... 43 
7. 
TREATMENT COMPLIANCE .................................................................................... 43 
8. 
STUDY EVALUATIONS ............................................................................................. 44 
8.1. 
Study Procedures ....................................................................................................... 44 
8.1.1. 
Overview .................................................................................................... 44 
8.1.2. 
Screening Period (Visit 1) .......................................................................... 44 
8.1.3. 
Double-Blind Treatment Phase .................................................................. 45 
8.1.3.1. 
Visits 2 (Baseline Visit /Randomization) 3, 4, and 5/Early Withdrawal 
(Weeks 1, 2, 4, and 6) – Double-Blind Phase ......................................... 45 
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8.1.3.2. 
Visit 6 (Post-Study Follow-up; Week 8 or 2 Weeks after Early 
Withdrawal) ............................................................................................. 45 
8.2. 
Efficacy ....................................................................................................................... 45 
8.2.1. 
Efficacy Evaluations ................................................................................... 45 
8.2.2. 
Efficacy Criteria .......................................................................................... 48 
8.3. 
Pharmacokinetic Evaluations ..................................................................................... 49 
8.3.1. 
Sample Collection and Handling ................................................................ 49 
8.3.2. 
Analytical Procedures................................................................................. 49 
8.3.3. 
Pharmacokinetic Evaluations ..................................................................... 50 
8.4. 
Pharmacodynamic Evaluations .................................................................................. 50 
8.5. 
Pharmacogenomic Evaluations .................................................................................. 50 
8.6. 
Safety Evaluations ...................................................................................................... 50 
9. 
PATIENT COMPLETION/WITHDRAWAL ................................................................. 53 
9.1. 
Completion.................................................................................................................. 53 
9.2. 
Withdrawal from the Study and Replacement. ........................................................... 53 
10. 
STATISTICAL METHODS ......................................................................................... 54 
10.1. 
Sample Size Determination ........................................................................................ 54 
10.2. 
Data Set ...................................................................................................................... 54 
10.3. 
Patient Information ..................................................................................................... 54 
10.4. 
Extent of Exposure and Treatment Compliance......................................................... 55 
10.5. 
Efficacy Analyses ....................................................................................................... 55 
10.5.1. 
Primary Endpoint ........................................................................................ 56 
10.5.2. 
Secondary and Exploratory Endpoints ....................................................... 57 
10.5.3. 
Additional Efficacy Analyses ...................................................................... 57 
10.6. 
Interim Analysis .......................................................................................................... 58 
10.7. 
Pharmacokinetics ....................................................................................................... 58 
10.8. 
Safety Analyses .......................................................................................................... 58 
10.8.1. 
Adverse Events .......................................................................................... 58 
10.8.2. 
Clinical Laboratory Tests ............................................................................ 58 
10.8.3. 
Vital Signs .................................................................................................. 59 
10.8.4. 
Electrocardiogram (ECG) ........................................................................... 59 
10.8.5. 
Physical Examination ................................................................................. 59 
10.8.6. 
Other Safety Parameters ........................................................................... 59 
10.8.6.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................... 59 
11. 
ADVERSE EVENT REPORTING ............................................................................... 59 
11.1. 
Definitions ................................................................................................................... 59 
11.1.1. 
Adverse Event Definitions and Classifications ........................................... 59 
11.1.2. 
Attribution Definitions ................................................................................. 61 
11.1.3. 
Severity Criteria .......................................................................................... 61 
11.1.4. 
Action Taken and Outcome ........................................................................ 61 
11.2. 
Special Reporting Situations ...................................................................................... 62 
11.3. 
Procedures ................................................................................................................. 62 
11.3.1. 
All Adverse Events ..................................................................................... 62 
11.3.2. 
Serious Adverse Events ............................................................................. 63 
11.3.3. 
Pregnancy .................................................................................................. 64 
11.4. 
Contacting Sponsor Regarding Safety ....................................................................... 64 
12. 
PRODUCT QUALITY COMPLAINT HANDLING ...................................................... 64 
12.1. 
Procedures ................................................................................................................. 64 
12.2. 
Contacting Sponsor Regarding Product Quality ......................................................... 65 
13. 
STUDY DRUG INFORMATION ................................................................................. 65 
13.1. 
Physical Description of Study Drug(s) ........................................................................ 65 
13.2. 
Packaging ................................................................................................................... 65 
13.3. 
Labeling ...................................................................................................................... 65 
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13.4. 
Preparation, Handling, and Storage ........................................................................... 65 
13.5. 
Drug Accountability ..................................................................................................... 65 
14. 
STUDY-SPECIFIC MATERIALS................................................................................ 66 
15. 
ETHICAL ASPECTS .................................................................................................. 66 
15.1. 
Study-Specific Design Considerations ....................................................................... 66 
15.2. 
Regulatory Ethics Compliance ................................................................................... 68 
15.2.1. 
Investigator Responsibilities ....................................................................... 68 
15.2.2. 
Independent Ethics Committee or Institutional Review Board (IEC/IRB) .. 68 
15.2.3. 
Informed Consent ....................................................................................... 69 
15.2.4. 
Privacy of Personal Data ............................................................................ 70 
15.2.5. 
Country Selection ....................................................................................... 70 
16. 
ADMINISTRATIVE REQUIREMENTS ....................................................................... 70 
16.1. 
Protocol Amendments ................................................................................................ 70 
16.2. 
Regulatory Documentation ......................................................................................... 71 
16.2.1. 
Regulatory Approval/Notification ................................................................ 71 
16.2.2. 
Required Pre-study Documentation ........................................................... 71 
16.3. 
Patient Identification, Enrollment, and Screening Logs .............................................. 71 
16.4. 
Source Documentation ............................................................................................... 72 
16.5. 
Case Report Form Completion ................................................................................... 72 
16.6. 
Data Quality Assurance/Quality Control ..................................................................... 72 
16.7. 
Record Retention ........................................................................................................ 72 
16.8. 
Monitoring ................................................................................................................... 73 
16.9. 
Study Completion/Termination ................................................................................... 73 
16.9.1. 
Study Completion ....................................................................................... 73 
16.9.2. 
Study Termination ...................................................................................... 74 
16.10. On-Site Audits............................................................................................................. 74 
16.11. Use of Information and Publication ............................................................................ 74 
16.12. Registration of Clinical Studies and Disclosure of Results ......................................... 75 
17. 
REFERENCES ........................................................................................................... 76 
ATTACHMENT 1:  ALLOWED/PROHIBITED CONCOMITANT MEDICATIONS ................. 79 
ATTACHMENT 2: MONTGOMERY-ASBERG DEPRESSION RATING SCALE (MADRS) . 80 
ATTACHMENT 3: HAMILTON ANXIETY SCALE (HAM-A) .................................................. 85 
ATTACHMENT 4: CLINICAL GLOBAL IMPRESSION – SEVERITY RATING (CGI-S) ....... 92 
ATTACHMENT 5: CLINICAL GLOBAL IMPRESSION – IMPROVEMENT RATING (CGI-
I) .................................................................................................................................. 93 
ATTACHMENT 6: INVENTORY OF DEPRESSIVE SYMPTOMS - SUBJECT-RATED 
(IDS-SR30) ................................................................................................................... 94 
ATTACHMENT 7: SNAITH–HAMILTON PLEASURE SCALE (SHAPS) .............................. 97 
ATTACHMENT 8: PERCEIVED STRESS SCALE (PSS) ...................................................... 98 
ATTACHMENT 9: ARIZONA SEXUAL EXPERIENCES SCALE (A-SEX) .......................... 100 
ATTACHMENT 10: DIGIT SYMBOL SUBSTITUTION TEST (DSST) ................................. 102 
ATTACHMENT 11: COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ........... 103 
 
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LIST OF IN-TEXT TABLES 
Table 1:  Characteristics of the Treatment and Dosage ............................................. 43 
Table 2:  Estimated Blood Volume Drawn ................................................................. 44 
 
LIST OF IN-TEXT FIGURES 
Figure 1:  Study Design Diagram (Timelines not to scale) .............................. 33 
 
 
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SYNOPSIS 
Title, Protocol Number/Phase 
A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Study to Evaluate the 
Efficacy and Safety of 2 Fixed Doses (5.0 mg or 2.5 mg) of MIN-117 in Adult Patients 
with Major Depressive Disorder  
MIN-117C03 / Phase 2b 
Objectives: 
Primary 
To evaluate the efficacy of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 compared with 
placebo in reducing the symptoms of major depression measured by the change in 
Montgomery-Asberg Depression Rating Scale (MADRS) total score over 6 weeks of 
treatment in adult patients with major depressive disorder (MDD). 
Secondary 
1. To assess the change from Baseline of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 
compared with placebo over 6 weeks of treatment on: 
 The symptoms of anxiety using the Hamilton Anxiety Scale (HAM-A). 
 The severity of illness and improvement using the Clinical Global Impression of 
Severity Scale and Clinical Global Impression of Improvement Scale (CGI-S and 
CGI-I). 
2. To evaluate the safety of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 compared with 
placebo over 6 weeks of treatment in adult patients with MDD. 
Exploratory 
1. To assess the change from Baseline of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 
compared with placebo over 6 weeks of treatment on: 
 Commonly associated symptoms of MDD by using the Inventory of Depressive 
Symptoms - Subject-Rated [IDS-SR30]. 
 The ability to experience hedonic capacity by using the Snaith-Hamilton Pleasure 
Scale (SHAPS). 
 Cognitive function as measured by digit symbol substitution test (DSST). 
 Perception of stress using the Perceived Stress Scale (PSS). 
 Sexual functioning by using the Arizona Sexual Experiences Scale (A-SEX). 
 Sleep parameters as assessed by Somno-Art methodology. 
 Neurotrophic/inflammatory factors. 
2. To explore the pharmacokinetics (PK) of MIN-117 
 and assess 
the pharmacokinetic/pharmacodynamics (PK/PD) relationship. 
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Hypotheses 
The primary hypothesis is that at least 1 dose of MIN-117 will be superior to placebo on 
the change from Baseline in the MADRS total score at the end of 6 weeks of treatment. 
Study Design 
This is a 6-week, 3-arm, randomized, double-blind, placebo- controlled study to investigate 
the safety and efficacy of MIN-117 in male and female patients with MDD, aged 18 to 65.  
Approximately 324 patients will be randomly assigned to 1 of 3 treatment arms, including 
placebo, 5.0 mg MIN-117, or 2.5 mg MIN-117, in a 2:1:1 ratio (i.e., approximately 162 
patients in the placebo group and approximately 81 patients in each of the MIN-117 
treatment groups). 
The study design has 3 phases:  a screening phase of up to 3 weeks (including washout), a 
6-week double-blind treatment phase, and a post-study follow-up visit, occurring 
approximately 2 weeks after completing the double-blind treatment phase.  
Screening Phase: Patients with an acute exacerbation of a major depressive episode will be 
screened for this study. Screening will include informed consent (for the overall study as 
well as for optional pharmacogenomic research), evaluation for eligibility in the study, and 
assessment of medical history .  Patients must meet Diagnostic and Statistical Manual of 
Mental Disorders-Fifth Edition (DSM-5) diagnostic criteria for moderate to severe MDD, 
with anxious distress and without psychotic features.  The diagnosis should be confirmed 
by the Structured clinical interview for DSM-5 (SCID-5).  Patients will undergo additional 
physical and psychiatric evaluations, as well as safety evaluations.  If patients give 
informed consent to participate and meet all study entry criteria at Screening, they will be 
tapered off their current psychotropic medications.  Patients will be free of any 
psychotropic medications for a period of 1 week [or 2 weeks for a monoamine oxidase 
(MAO) inhibitor, 4 weeks for fluoxetine] prior to randomization.  
Double-blind Treatment Phase: After at least 1-week of psychotropic drug-free period, 
patients will undergo evaluation for eligibility, and if they still meet the study entry criteria, 
they will be randomly assigned in a 2:1:1 ratio to receive placebo, 5.0 mg MIN-117, or 
2.5 mg MIN-117,respectively, once daily for 6 weeks. Clinic visits will occur at Visits 2, 
3, 4, and 5/Early Withdrawal (Weeks 1, 2, 4, and 6, respectively). 
Post-Study Visit: At the end of the study, patients will be evaluated for safety/tolerability 
at the Post-Study Visit, approximately 2 weeks after completing the Double-blind 
Treatment Phase.  Any patient who terminates from the study early will undergo the Early 
Withdrawal visit procedures and will have a Post-Study Visit within approximately 2 
weeks. 
Study Population  
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation in 
this study: 
1. 
Patients must be able to read and understand the consent forms, complete study-
related procedures, and communicate with the study staff.  
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2. 
Patients must have provided written consent to participate in the study and 
understand that they are free to withdraw from the study at any time. 
3. 
Patients must have signed the informed consent form for pharmacogenomic research 
indicating willingness to participate in the pharmacogenomic component of the 
study in order to participate in the optional pharmacogenomic component of this 
study. Refusal to consent for this component does not exclude a patient from 
participation in the clinical study. 
4. 
Patients must be aged 18 to 65 years, inclusive, at Screening (Visit 1). 
5. 
Meet DSM-5 criteria for diagnosis of moderate or severea major depression with 
anxious distress and without psychotic features at Screening based on clinical 
assessment and on the SCID-5 (DSM-5 codes: 296.32, 296.33; ICD-10 codes: F33.1, 
F33.2).  Their major depressive episode must be deemed "valid" using the 
Massachusetts General Hospital (MGH) SAFERb criteria interview administered by 
remote, independent raters. 
6. 
Patients must be within a body mass index (BMI) of  18 to < 35 kg/m2 [BMI = 
weight (kg)/height (m)2] at Screening (Visit 1). 
7. 
Patients have a history of at least one previous episode of depression prior to the 
current episode.  
8. 
Patient must have been treated with an antidepressant administered at an adequate 
dose and duration in the past for the treatment of Major Depression.  An adequate 
treatment is defined as an antidepressant treatment for at least 4 weeks at at least the 
minimum therapeutic dose, for any particular antidepressant. 
9. 
Current major depressive episode of at least 4 weeks in duration. 
10. 
At Screening (Visit 1) and Baseline (Visit 2), patients must have a score  40 on the 
patient rated IDS-SR30. 
11. 
At Screening (Visit 1) and Baseline (Visit 2), patients must have a score  18 on 
HAM-A.  
12. 
At Screening (Visit 1) and Baseline (Visit 2), patients must have a score  4 on the 
investigator-rated CGI-S. 
13. 
Patients must be outpatients at the time of randomization (Baseline [Day 1]).  
14. 
Patients must be in good general health prior to study participation with no clinically 
relevant abnormalities as assessed by the investigator and determined by: medical 
history, physical examination, vital signs, blood chemistry, hematology, urinalysis, 
and electrocardiogram (ECG). 
                                               
a  Several symptoms in excess of those required to make the diagnosis of MDD AND symptoms markedly 
interfere with occupational functioning or with usual social activities or relationships with others. 
b The acronym SAFER stands for interview’s attention to the following criteria: State versus trait; 
Assessability; Face validity; Ecological validity; and Rule of three Ps [pervasive, persistent, and 
pathological]. 
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15. 
If female, the patient must: 
 be post-menopausal, or 
 have had a hysterectomy or tubal ligation or be otherwise incapable of pregnancy, 
or 
 must agree to consistent use of 2 methods of contraception for the duration of the 
study and until 90 days after the last dose of study medication.  One of which 
must be a highly effective method defined as one that results in a low failure rate 
(i.e. less than 1% per year) when used consistently and correctly.  The following 
highly effective contraception methods acceptable for this study are hormonal 
contraception (oral or parenteral hormonal contraceptive) or placement of an 
intrauterine device.   The following methods can be used as a second form of 
contraception during the study: Barrier methods for female patients include their 
partner’s use of a condom or the subject’s use of an occlusive cap (diaphragm or 
cervical/ vault caps) with spermicidal foam, gel, film, cream or suppository. 
16. 
If male with partner of childbearing potential, must be willing to use one barrier 
method of contraception with his partner throughout the study (a condom or his 
partner’s use of an occlusive cap [diaphragm or cervical/ vault caps]).  His partner 
must also be using a highly effective method of birth control defined as one that 
results in a low failure rate (i.e. less than 1% per year) when used consistently and 
correctly such as sterilization, implants, injectables, combined oral contraceptives, 
and intrauterine devices for up to 90 days after the last dose of study treatment. The 
patient must agree to inform the investigator if his partner becomes pregnant during 
the course of the study. 
17. 
Male patients who have been sterilized or have partners of non-childbearing 
potential (including homosexual men) are required to use one barrier method of 
contraception.  This is to prevent unintended exposure of the partner to the study 
drug via seminal fluid (for male subjects, this must be a condom or their partner's 
use of an occlusive cap [diaphragm or cervical/vault caps].  
18. 
Female patients of childbearing potential must have a negative serum pregnancy test 
at Screening (Visit 1) and negative serum and urine pregnancy test at Baseline 
(Visit 2) 
Exclusion Criteria 
Potential patients who meet any of the following criteria will be excluded from participating 
in the study: 
1. 
A DSM-5 diagnosis of current (active): panic disorder, obsessive compulsive 
disorder (OCD), post-traumatic stress disorder (PTSD), anorexia nervosa, or 
bulimia nervosa. 
2. 
History or current diagnosis of a psychotic disorder, bipolar disorder, mental 
retardation, or borderline personality disorders, mood disorder with postpartum 
onset, somatoform disorders, fibromyalgia, or idiopathic medical conditions. 
3. 
At significant clinical risk for suicidal or violent behavior. 
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4. 
History of treatment within last 6 months with electroconvulsive therapy (ECT), 
Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), or Transcranial 
Magnetic Stimulation (TMS). 
5. 
Potential patient who in the opinion of the investigator should not discontinue, or 
participate in washout of a prohibited concomitant medication. 
6. 
Potential patient who demonstrate a greater than 25% decrease in depressive 
symptoms as reflected by the IDS-SR30 total score from Screening visit to Baseline 
visit. 
7. 
Active cardiovascular disease (including but not limited to: atrial fibrillation or 
flutter, 
second 
and 
third-degree 
atrioventricular 
heart 
block, 
resting 
supraventricular tachycardia >100 beats per minute, unstable ischemic heart 
disease, valvular abnormality, sick sinus syndrome or other condition requiring 
pacemaker) or diastolic blood pressure > 105 mmHg. 
8. 
Any serious, untreated, or unstable illnesses, such as: liver or renal insufficiency. 
9. 
Any significant pulmonary, endocrine, or metabolic disturbances. 
10. 
Documented disease of the central nervous system that could interfere with the 
study assessments (including but not limited to: stroke, tumor, multiple sclerosis, 
Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, seizure disorder 
requiring current anti-convulsants, traumatic brain injury or trauma, and 
neurosyphilis. 
11. 
Hypothyroidism or hyperthyroidism, unless stabilized by appropriate medication 
for at least 3 months prior to Screening (a normal thyroid-stimulating hormone 
[TSH] is required prior to randomization at Baseline).  
12. 
Any medical condition that can potentially alter oral enteral absorption (e.g., 
gastrectomy), metabolism (e.g., liver failure), or excretion (e.g., renal failure) of the 
study drug. 
13. 
History of alcohol or substance use disorders (except nicotine and caffeine) meeting 
DSM-5 criteria within 1-year prior to Screening visit. 
14. 
Positive alcohol and urine drug screen for opiates, cocaine, barbiturates, 
tetrahydrocannabinol, methadone, tricyclic antidepressants, benzodiazepines and 
amphetamine/methamphetamine at Screening or Baseline. Patients with positive 
testing due to prescribed benzodiazepines, tricyclic antidepressants, barbiturates, or 
opiates at Screening are accepted but must test negative at Baseline (Visit 2). 
15. 
Male patients who have pregnant partners. 
16. 
Female patients who are breastfeeding. 
17. 
Received an experimental drug or used an experimental medical device within 60 
days before the planned start of treatment (Day 1) or have participated in 2 or more 
clinical trials in the previous 2 years. 
18. 
QTcF interval at Screening or Baseline greater than 450 msec for males and 
470 msec for females.  
19. 
Patients requiring treatment with drugs likely to prolong QT. 
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20. 
Patients with known hypersensitivity to MIN-117 or placebo or their excipients 
(refer to Section 13.1 of the protocol). 
21. 
Positive hepatitis B surface antigen, or hepatitis C antibody or Human 
Immunodeficiency Virus (HIV) 1 and 2 antibodies at Screening. 
22. 
Employees of the investigator or study center, when the employee has direct 
involvement in the proposed study or other studies under the direction of that 
investigator or study center; also family members of the employee or the 
investigator. 
Treatments 
Patients will be free of any psychotropic medications for a period of 1 week (or 2 weeks 
for a MAO inhibitor, 4 weeks for fluoxetine) prior to randomization. Eligible patients will 
the be randomized in a 2:1:1 ratio to the following groups: 
 Placebo 
 5.0 mg MIN-117 
 2.5 mg MIN-117 
Treatments will be administered orally, once a day in the morning for up to 6 weeks. 
Efficacy Evaluations 
The primary efficacy endpoint will be the change in MADRS total score from Baseline 
(i.e., the start of double-blind treatment) to the end of the double-blind treatment period 
(i.e., Week 6). The primary comparisons will be between each MIN-117 dose group 
(5.0 mg and 2.5 mg) and the placebo group. 
Secondary and exploratory efficacy evaluations include the: HAM-A, CGI-S, CGI-I, 
IDS-SR30, SHAPS, DSST, PSS, ASEX, and sleep parameters as assessed by Somno-Art 
(at select sites). 
Safety Evaluations 
Safety and tolerability will be assessed by monitoring adverse events, clinical laboratory 
tests (including hematology, serum chemistry, urinalysis, lipid profile, and pregnancy 
tests), vital sign assessments, physical and neurologic examinations, and ECGs.  Suicidal 
ideation/behavior will be assessed using the Columbia Suicide Severity Rating Scale 
(C-SSRS).  
Pharmacokinetic Evaluations  
Blood samples (6 mL) for assessing MIN-117 concentration in plasma will be obtained at 
Baseline (Visit 2), during the double-blind period at Weeks 2, 4, and 6 (Visits 3, 4, and 5), 
and during the Post-Study Visit (Visit 6).  Samples will be taken at pre-dose (within 1 hour 
of dosing) and at approximately 2 to 4 hours after dosing (Cmax) at Baseline (Visit 2) and 
Weeks 2, 4, and 6 (Visits 3, 4 and 5/Early Withdrawal).  Only 1 sample will be taken at the 
Post-Study Visit (Visit 6).  
Pharmacodynamic Evaluations  
Blood samples will be collected for pharmacodynamic assessment of brain derived 
neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), vascular 
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endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), fibroblast growth 
factor-2, C-reactive protein, cortisol, amyloid-A, interleukin-1 beta (IL-1β), interleukin-6 
(IL-6), and interleukin-10 (IL-10) at Baseline and Week 6 (Visit 5). 
Statistical Methods 
Sample Size Determination  
The sample size for this study is based on the assumption of a treatment difference of at 
least 4 points in the mean change from Baseline to end point in MADRS total score between 
any MIN-117 dose group and placebo.  A standard deviation of 9 in the change in MADRS 
total score from Baseline is used.  Using the Bonferroni multiplicity adjustment for multiple 
comparisons of 2 MIN-117 dose groups with placebo and assuming an allocation of 2:1:1 
for placebo and the 2 MIN-117 doses, 146 patients in the placebo group and 73 patients in 
each MIN-117 dose group are required to detect the treatment difference of 4 points with a 
power of 80% at an overall 2-sided significance level of 0.05.  When adjusted for a rate of 
10% of patients who will not have either Baseline or post-Baseline efficacy assessments, 
the required number of patients becomes 162 for the placebo group and 81 for each of the 
two MIN-117 dose groups.  Therefore, the total number of patients across the 3 treatment 
groups will be 324. 
Efficacy Analyses 
The intent-to-treat analysis set is defined as all randomized patients who receive at least 1 
dose of study drug during the 6-week double-blind period. This analysis set will be used 
for efficacy and safety analyses of the 6-week double-blind period. Analyses of change 
from Baseline will include only patients who have both Baseline and post-Baseline data 
during the 6-week double-blind period. 
The primary efficacy endpoint will be the change in the MADRS total score from Baseline 
to Week 6.  This endpoint will be analyzed using a mixed model repeated measures 
(MMRM) model with treatment arm (5.0 mg MIN-117, 2.5 mg MIN-117, and placebo), 
pooled study center (by country or region based on enrollment), visit, and treatment arm-
by-visit interaction as fixed effects, patient nested in treatment as random effect, and 
Baseline total MADRS score as covariate.  An unstructured covariance matrix will be used 
to model the covariance of within-patient scores.  The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom.  In this analysis in which the MMRM 
is fitted to all post-Baseline data, patients in the intent-to-treat (ITT) analysis set who do 
not have complete data will still contribute to the estimates at Week 6, but will have less 
weight in the analysis than those patients with complete data.  Comparisons against placebo 
will be performed using the appropriate contrasts from this model at Week 6.  An analysis 
of observed scores available at each visit will also be performed. 
The adjustment for multiplicity within the family of primary hypotheses will utilize the 
conventional Hochberg procedure for the purpose of reporting of results.  This procedure 
will allow the null hypothesis of no treatment difference for both the 5.0 mg and 2.5 mg 
doses versus placebo to be rejected if largest p-value of comparing either of these 2 doses 
versus placebo is at or below 0.050.  Otherwise, the lowest of these 2 p-values must be at 
or below 0.025 to allow for rejecting the null hypothesis for the representative dose. 
The overall type I error rate for testing the 2 MIN-117 doses versus placebo for the primary 
and the key secondary endpoint will be controlled at the 2-sided 0.05 level.  The primary 
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family of hypotheses (corresponding to the primary endpoint) and the secondary family of 
hypotheses (corresponding to the key secondary endpoint, the change from Baseline in 
HAM-A total score) will be tested in a sequential manner with suitable adjustment for 
multiplicity within the family of primary hypotheses and within the family of the secondary 
hypotheses such that a MIN-117 dose versus placebo null hypothesis contrast testing within 
the secondary family can be evaluated only when the same null hypothesis contrast in the 
primary family was rejected. 
Sensitivity analyses of the primary endpoint will also be performed and will be detailed 
further in the statistical analysis plan. These will include an analysis of covariance 
(ANCOVA) model with factors for treatment and region and Baseline MADRS total score 
as a covariate. In this analysis, patients without a MADRS total score at Week 6 will have 
an earlier post-Baseline score imputed using the last-observation-carried-forward (LOCF) 
method. Other sensitivity analyses may also be performed to investigate the robustness of 
treatment estimates to the observed pattern of, and/or reason for, early withdrawals. 
The change from Baseline in CGI-S and observed CGI-I scores will be analyzed by means 
of an ANCOVA of ranked data, with treatment (MIN-117 and placebo) as a factor, and 
Baseline CGI-S value as a covariate. 
Change from Baseline for efficacy parameters, IDS-SR30, SHAPS, DSST, PSS, A-SEX, 
and sleep parameters will be analyzed using the same MMRM model and weighted 
combination test procedure as described above. 
Pharmacokinetic Analyses 
Individual plasma levels of MIN-117 
 will be tabulated with the 
corresponding time related to study drug administration. Descriptive statistics will be 
summarized for MIN-117 
.  Population pharmacokinetic analysis of plasma 
concentration-time data of MIN-117 
 will be performed using nonlinear 
mixed-effects modeling. Data may be combined with those of a selection of Phase 1 studies 
to support a relevant structural model.  Available patient characteristics (demographics, 
laboratory variables, genotypes, etc.) will be tested as potential covariates affecting 
pharmacokinetic parameters. 
Safety Evaluations 
All patients randomized to treatment who receive at least one dose of double-blind study 
drug will be included in the safety analyses.  Summary statistics will be provided for all 
safety data using appropriate descriptive statistics adverse events, C-SSRS, laboratory tests, 
ECGs, and vital signs. 
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TIME AND EVENTS SCHEDULE 
Procedures and Evaluations 
Screening 
Baseline 
Double-Blind Phase 
Post Study 
Follow-Up 
Visit#a 
1 
2 
3 
4 
5 / EWb 
6 
Week 
-3 
1 
2 
4 
6 
8 
Day 
-21 to -1 
1 
15 
29 
43 
57 
Screening/Administrative  
 
 
 
 
 
 
Informed consent
X
Pharmacogenomic informed 
consentc
X 
 
 
 
 
 
Inclusion/exclusion criteria
X
X
Medical history, SCID-5, MGH-
SAFER
X 
 
 
 
 
 
Prior medications
X
X
Preplanned surgery/procedures
X
Height
X
Pregnancy testd
X
X
X
X
X
Alcohol and Drug Screen
X
X
TSH, serology
X
Taper of psychotropic drugs
Xe
Xe
Randomization
Xf
Study Drug 
 
 
 
 
 
 
Administer/Dispense study drug
X 
X
X
Xg
Study drug accountability
X
X
X
Pharmacokinetics 
 
 
 
 
 
 
Blood sample collectionh
X
X
X
X
X
Pharmacodynamics 
 
 
 
 
 
 
Blood sample collection
X
X
Pharmacogenomics 
Blood sample collection
Xi
Efficacy 
 
 
 
 
 
 
Investigator-Rated: MADRS, 
HAM-A, CGI-S
X 
X 
X 
X 
X 
 
Investigator-Rated: CGI-I
X
X
X
Investigator-Rated: DSST 
X
X
X
X
Subject-Rated: SHAPS, A-SEX
X
X
X
X
X
Subject-Rated: IDS-SR30
X
X
X
Subject-Rated: PSS 
X
X
Sleep recording (Somno-Art) j 
X
X
X
Safety 
 
 
 
 
 
 
Physical examination 
X
X
X
X
12-Lead ECG (triplicate) k
X 
X
X 
X 
X
Vital signs, temperature, weightl
X
X
X
X
X
X
Clinical laboratory testsm
X
X
X
X
C-SSRS
X
X
X
X
X
X
Adverse Events 
Continuous
Concomitant therapy
Continuous
Abbreviations and footnotes on the following page. 
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Abbreviations: A-SEX = Arizona Sexual Experiences Scale; CGI-I = Clinical Global Impression of 
Improvement Scale; CGI-S = Clinical Global Impression of Severity Scale; C-SSRS = Columbia Suicide 
Severity Rating Scale; DSST = digit symbol substitution test; HAM-A = Hamilton anxiety scale; IDS-SR30 
= Inventory of Depressive Symptoms - Subject-Rated; MADRS = Montgomery-Asberg Depression Rating 
Scale; PSS = Perceived Stress Scale; SCID-5 = Structured clinical interview for DSM-5; SHAPS = Snaith-
Hamilton Pleasure Scale. 
a Visits 3 to 6 may occur within a 3-day window relative to Baseline (Visit 2). Visit 2 may occur within +7 
day window relative to Visit 1 (i.e., the sceening period may be extended to 28 days) upon Sponsor’s 
decision. 
b Visit 5 represents the end-of-treatment or early withdrawal (EW) visit, and patients who discontinue the 
study prematurely should undergo all assessments indicated for this visit.  
c To participate in the optional pharmacogenomic component of this study, patients must sign the 
pharmacogenomic informed consent form, indicating their willingness to participate. 
d For all women of childbearing potential, serum pregnancy testing will be performed at Screening (Visit 1), 
Baseline (Visit 2), and post study visit (Visit 6). Urine pregnancy testing will be performed at Baseline 
(Visit 2), and Visits 4, 5, and 6. 
e After meeting eligibility criteria during their Screening visit, patients will taper off their current 
psychotropic medications.  Patients will be free of any psychotropic medications for a period of 1 week (or 
2 weeks for a MAO inhibitor, 4 weeks for fluoxetine) prior to randomization. 
f All procedures (except dispensing of study medication) should be completed on Day 1 before 
randomization. 
g Only drug administration at Visit 5.   
h Samples will be obtained within 1 hour prior to dosing, and approximately 2 to 4 hours after dosing (the 
approximate time of maximum plasma concentration for MIN-117) on Visits 2, 3, 4, and 5.  Additionally, 
1 sample will be taken on Visit 6. 
i A 10-mL blood sample will be collected only from patients who give informed consent for the 
pharmacogenomic component of this study. A sample collected at a later time point does not constitute a 
protocol violation and would not require protocol amendment. 
j Sleep recording by using Somno-Art for 1 night after Screening, 1 night before dosing, and 1 night after 
dosing on Visit 2 and Visit 5. 
k Triplicate ECGs to be performed at least 1 minute apart within 5 minutes, while the patient is supine for 
≥10 minutes. 
l Patients will be weighed clothed (lightly) and without shoes. 
m Clinical laboratory tests will include hematology, serum chemistry (including serum lipid profile, and 
fasting blood glucose), and urinalysis. Patients must fast for 8 hours before the blood sample is taken. 
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ABBREVIATIONS 
ADR
Adverse drug reaction
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
APD90
Action potential duration at 90%
aPTT
Activated partial thromboplastin time
A-SEX
Arizona Sexual Experience
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve 
BSE
Bovine spongiform encephalopathy
BDNF
Brain-derived neurotrophic factor
BMI
Body mass index
BUN
Blood urea nitrogen
C-SSRS
Columbia Suicide Severity Rating Scale (C-SSRS)
CGI-I
Clinical Global Impression - Improvement Scale
CGI-S
Clinical Global Impression - Severity Scale
CHMP
Committee for Medicinal Products for Human Use
CL
Clearance
Cmax
Maximum drug concentration (in plasma or serum)
CMS
Chronic mild stress
CNS
Central nervous system
CPK
Creatinine phosphokinase
CRO
Contract research organization
CSF
Cerebrospinal fluid
CYP
Cytochrome
DA
Dopamine
DAT
Dopamine transport
DBS
Deep brain stimulation
DOPAC
Dihydroxyphenylacetic acid
DSM-5
Diagnostic And Statistical Manual Of Mental Disorders-Fifth Edition
DSST
Digit Symbol Substitution Test
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ECT
Electroconvulsive therapy
ED50
Median effective dose
EEG
Electroencephalogram
EOS
End-of-Study
F
bioavailability
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GDNF
Glial cell line-derived neurotrophic factor
GGT
Gamma-glutamyl transferase
5HIAA
5-Hydroxyindoleacetic acid
5-HT
5-Hydroxytryptamine
5-HTT
5-Hydroxytryptamine transporter
5-HTTLPR
Serotonin transporter gene promoter polymorphism
HAM-A
Hamilton Anxiety Scale 
HBsAg
Hepatitis B surface antigen
HDL
High density lipoprotein
hERG
Human ether-à-go-go-related gene
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HIV
Human immunodeficiency virus
HVA
Homovanillic acid
IC50
Median inhibitory concentration
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IGF-1
Insulin like growth factor-1
IL
Interleukin
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous, intravenously
IWRS
Interactive Web Response System
LC-MS/MS
Liquid chromatography-mass spectrometry
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LOCF
Last observation carried forward
MADRS
Montgomery-Asberg Depression Rating Scale
MAO
Monoamine oxidase
MB
Marble burying
MGH
Massachusetts General Hospital
MDD
Major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model repeated measures
NE
norepinephrine
NET
Norepinephrine transporter
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NOR
Novel object recognition test
OCD
Obsessive compulsive disorder
8-OH-DPAT
8-hydroxy-2-(di-n-propylamino) tetralin
OR
Odds ratio
PCA
p-chloroamphetamine
PD
Pharmacodynamic
PK 
Pharmacokinetic 
PO
Orally, by mouth
PQC
Product quality complaint
PTSD
Post-traumatic stress disorder
QD
Quaque Die (ie, once daily)
QTc
QT interval value corrected for heart rate
QTcB
QT interval value corrected for heart rate using Bazett’s formula
QTcF
QT interval value corrected for heart rate using Fridericia’s formula
RBC
Red blood cell
REM
Rapid eye movement
SAE
Serious adverse event
SAFER 
State versus trait, assessability, face validity, ecological validity; and Rule 
of three Ps [pervasive, persistent, and pathological]
SAP
Statistical Analysis Plan
SCID-5
Structured clinical interview for DSM-5
SNRI
Serotonin norepinephrine reuptake inhibitor
SSRI
Serotonin reuptake inhibitor
TEAE
Treatment-emergent adverse event
T1/2
Terminal elimination half-life
TCA
Tricyclic antidepressant
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Tmax
Time to maximum drug concentration (in plasma or serum)
TMS
Transcranial magnetic stimulation
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
Vd/F
Volume of distribution
VEGF
Vascular endothelial growth factor
VNS
Vagal nerve stimulation
Vss
Volume of distribution at steady state
WBC
White blood cell
WHO
World Health Organization
WHO-DD
World Health Organization-drug dictionary
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1. 
INTRODUCTION 
1.1. 
Background on the Disease 
Major depressive disorder (MDD) is a common, serious, recurrent disorder, with 
worldwide lifetime prevalence estimates ranging from 1% in the Czech Republic to 17% 
in the United States (US).  Its negative impact on role functioning in various settings (e.g., 
school performance, marriage, parenting, and the workplace), quality of life, physical 
health, and life expectancy has been well-documented.  Loss of work production and 
absenteeism due to major depressive episodes or MDD has been estimated to account for 
approximately 30 to 50 billion dollars in annual human capital (Kessler 2013).  In fact, as 
of October 2015, and with an estimated 350 million sufferers, depression has been ranked 
by the World Health Organization as the leading cause of disability worldwide, and the 
prevalence is rising (WHO 2015).  MDD is associated with significant comorbid medical 
conditions which include diabetes, hypertension, and cardiovascular disease, and there is 
an increased risk of early mortality in patients with MDD (Kessler 2013).  
While existing therapies for this disease are available, their effectiveness is limited due to 
unacceptable side effects, different levels of efficacy for individual subjects requiring a 
physician to test, check, and alter (or change) therapies during treatment, and subject 
adherence due to the need for multiple daily doses (Rush 2006).  
The use of antidepressants for the treatment of MDD is well established.  However, effect 
sizes of currently available antidepressants are rather small than medium (Kirsch 2008; 
Turner 2008).  Most subjects with major depression are best treated with a combination of 
antidepressants and psychotherapy.  It is generally 1 to 4 weeks before antidepressants take 
effect.  This delayed clinical response to the antidepressant makes it difficult to establish 
the optimal dose quickly, which is of paramount importance for the treatment of a clinically 
depressed subject.  The individual dose is usually decided by trial and error, with the 
subject’s previous response being the most useful guide (Spigset 1999). 
1.2. 
MIN-117 Pharmacological Profile and Rationale as a Unique 
Antidepressant 
MIN-117 is an investigational antidepressant belonging to a new chemical class, the 
benzofuran derivatives. The chemical designation is (2S)-1-[4-(3,4-Dichlorophenyl) 
piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol 
monohydrochloride. MIN-117 is characterized by its affinity for 5-HT1A pre-synaptic auto-
receptors and 5-hydroxytryptamine transporters (5-HTT). The Ki values for 5-HT1A 
receptors and 5-HTT of human were 5.0 and 0.81 nmol/L, respectively.  MIN-117 acts as 
a serotonin reuptake inhibitor.  In addition, MIN-117 has high affinity for adrenergic alpha 
(α)1 and serotoninergic 5-HT2A and acts as antagonist to each receptor.  MIN-117 is also 
active as a dopamine transport (DAT), by inhibiting reuptake of dopamine from the 
synaptic cleft. Furthermore, MIN-117 has moderate affinity for 5-HT2C and also acts as a 
moderate norepinephrine transporter (NET) inhibitor. 
For the most accurate and current information regarding the efficacy and safety of 
MIN-117, refer to the latest version of the Investigator's Brochure for MIN-117. 
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1.3. 
Nonclinical Studies 
1.3.1. 
Pharmacologic Profile 
An in vitro functional assay, MIN-117 showed a slight antagonist activity at 5-HT2B 
receptor (Kb=0.79µM ) and no agonist activity at 5-HT2B.  
MIN-117 inhibited monoamine uptake of the cells transfected with human recombinant 
transporters. Median inhibitory concentration (IC50) values for the inhibiting effects of 
MIN-117 on 5-HT, norepinephrine and dopamine uptake are 6.0, 170 and 20 nmol/L, 
respectively.  Reuptake inhibition of MIN-117 on 5-HT uptake was evaluated in vivo and 
compared with fluvoxamine, fluoxetine, and paroxetine of SSRI, venlafaxine of serotonin 
norepinephrine reuptake inhibitor (SNRI), and imipramine of tricyclic antidepressant 
(TCA). MIN-117 inhibited ex vivo binding to 5-HTT and 5-HT uptake and p-
chloroamphetamine (PCA)-induced hyper-locomotion in rats at the dose range of 
1-10 mg/kg, orally (PO) and the median effective dose (ED50) values were 1.1, 7.1, and 
1.7 mg/kg, PO, respectively. 
The effects of MIN-117 on the release of the three main catecholamines, 5-HT, dopamine 
(DA) and norepinephrine (NE) were investigated in rats using microdialysis.  Citalopram 
(10 mg/kg) was included as the reference compound of the SSRI type with clinically proven 
efficacy in patients with MDD.  MIN-117 at the three tested doses induced modifications 
in the levels of the catecholamines.  The findings showed no dose proportional effects.  For 
the dose 0.1 mg/kg a very important increase in 5-HT (300%) and DA levels (235%) 
accompanied by some minor increases in the two metabolites dihydroxyphenylacetic acid 
(DOPAC) and Homovanillic acid (HVA) were observed.  For the dose of 0.3 mg/kg an 
increase of 5-HT was observed (120%).  For DA the observed increase was very important 
(270%) accompanied by some minor effects on DOPAC and HVA.  An increase in NE 
levels could also be described at this dose (140%).  For the dose of 3 mg/kg 5-HT levels 
increased (150%) concomitantly with a decrease of the serotonin metabolite 5-
hydroxyindoleacetic acid (5-HIAA) levels.   
1.3.2. 
Safety Pharmacology 
The effects of MIN-117 on the general condition and behavior, central nervous system 
(CNS), respiratory and cardiovascular systems, digestive system, and water and 
electrolytes metabolisms were investigated.  In in vivo experiments, MIN-117 was 
administered orally at doses of 1, 10, and 100 mg/kg, except that the rabbit orthostatic 
hypotension study employed intravenous doses of 0.1, 0.3, and 1 mg/kg and oral doses of 
30, 100, and 300 mg/kg. As for in vitro experiments, MIN-117 was applied at 
concentrations of 3×10-7, 3×10-6, and 3×10-5 mol/L for measurements of action potential 
parameters in the isolated guinea pig papillary muscle and at 2×10-8, 2×10-7, and 2×10-6 
mol/L for an ion channel assay (hERG or human ether-a-go-go-related gene). 
MIN-117 at 1 mg/kg PO had no effects on general condition or behavior in rats. Decrease 
in spontaneous activity, suppression of reactivity, and narrowing of palpebral opening were 
observed at ≥ 10 mg/kg. Diarrhea was also observed at 100 mg/kg.  All the noted changes 
disappeared within 24 hours after dosing. 
MIN-117 at 1 mg/kg PO had no effect on the central nervous system in rats.  Decrease in 
body temperature was noted at ≥ 10 mg/kg, and a decrease in spontaneous locomotor 
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activity and an inhibition of motor coordination at 100 mg/kg. There was no pro-convulsive 
effect at doses up to 100 mg/kg. 
The telemetry study was conducted in conscious monkeys.  MIN-117 increased heart rate 
at 100 mg/kg, but no effects on blood pressure or ECG parameters (PR interval, QRS 
duration, QT interval, or QTc) at doses up to 100 mg/kg.  In the in vitro electrophysiology 
studies, MIN-117 blocked hERG channel (human Ikr channel expressed in CHO cells) at 
IC50 of 0.43×10-6 mol/L. MIN-117 showed a prolongation of action potential duration in 
the isolated guinea pig papillary muscle preparations (5% prolongation for action potential 
duration at 90% (APD90) compared to the pretreatment value) at the highest concentration 
of 3×10-5 mol/L. Effects on the orthostatic hypotension were evaluated by the head-up 
method in rabbits.  There were no effects on any cardiovascular parameter by intravenous 
(IV) administration at doses up to 1 mg/kg. In the oral administration study, MIN-117 at 
300 mg/kg decreased systolic and diastolic pressures after the recovery from tilting at 2, 8, 
12, and 24 hours after dosing.  At 100 mg/kg, low levels in diastolic pressure were also 
noted at 12 hours after dosing. 
1.3.3. 
Toxicology 
The toxicity of MIN-117 was characterized in rats and monkeys in oral single dose (1000 & 
2000 mg/kg) and repeated dose studies (1, 3, 10, 30, 100, & 300 mg/kg) for up to 13 weeks 
duration. 
At both doses in the single dose studies in rats, blepharoptosis was observed from 1 hour 
after dosing in both males and females; reddening of scrotum from 2 hours after dosing in 
males; and soiled perineal region from Day 1 in females. All the clinical signs disappeared 
by Day 10.  Decreases in body weight gain were observed on Day 1 in both males and 
females, and continued to Day 7 in males at 2000 mg/kg. 
At both doses in the single dose studies in monkeys, yellowish-white stool was observed in 
males and females from the day of dosing in the 2000 mg/kg group or from Day 2 in the 
1000 mg/kg group and disappeared by Day 7.  Increase of blood urea nitrogen (BUN) in 
males at both doses observed on Day 7.   
At the 1000 mg/kg dose, vomiting was observed immediately after dosing in females. 
A decrease in triglycerides was observed in males and females and an increase of alanine 
aminotransferase (ALT) observed in males on Day 1. An increase in triglycerides was 
observed in males on Day 7. 
At the 2000 mg/kg dose, soft stool was observed only on the dosing day in both males and 
females. Also observed was a decrease in food consumption on Day 1 and activated partial 
thromboplastin time (aPTT) prolongation on Day 13 in males. There was also an increase 
in triglycerides observed in males and females on Day 7. 
In the 13-week (3, 10, 30, 100 mg/kg/day) rat study, 13 rats died or were sacrificed during 
the study: 8 males and 5 females at 100 mg/kg.  Test article-changes in clinical signs, food 
consumption and body weight were only observed at 100 mg/kg/day: incomplete eyelid 
opening was sporadically observed until Day 7 of dosing; a decrease in body weight or 
suppression of body weight gain, together with a decrease in food consumption was noted 
from week 4; decrease in spontaneous activity and edema in the face, swelling in the 
extremities, and signs of deterioration were observed. 
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In the 13-week (3, 10, 100 and 300 mg/kg/day) monkey study, 5 monkeys died or were 
sacrificed during the study: 2 males and 2 females at 300 mg/kg, and 1 male at 100 mg/kg.  
Test article-changes in clinical signs, food consumption and body weight were observed 
from 100 mg/kg/day: increase in spontaneous activity for the first 2 weeks of dosing, 
stereotypy only at 300 mg/kg, decrease in spontaneous activity observed thereafter at 
300 mg/kg and in monkey that died at 100 mg/kg; lateral position, disappearance of sound 
and touch response, decrease in papillary light reflex, hypothermia observed in monkeys 
that died or were sacrificed; soft stool, diarrhea, vomiting and emaciation; salivation 
observed in the latter half of the dosing in monkeys that survived at both doses; decreases 
in food consumption and body weight.   
No lethal effect of MIN-117 was seen up to 30 mg/kg/day in rats and 10 mg/kg/day in 
monkeys in any of the repeated dose toxicity studies performed in both species.  In the 
13-week long-term toxicity studies, the No Observable Adverse Effect Level (NOAEL) 
was considered to be 3 mg/kg/day in rats, and 10 mg/kg/day in monkeys. 
Reprotoxicity studies were performed in rats and rabbits. In rats, the NOAEL for maternal 
parameters was considered to be 30 mg/kg/day (corresponding to an AUC0-t of 18540 
ng.h/mL and a Cmax of 850 ng/mL for MIN-117).  The No Observed Effect Level (NOEL) 
for effects on embryo-fetal development was considered to be 30 mg/kg/day. In the 
pregnant rabbits after oral (gavage) administration of MIN-117 the NOAEL for maternal 
toxicity is therefore 5 mg/kg/day (corresponding to a mean AUC0-24h of test item MIN-117 
of 578 ng.h/m).  There was no overt teratogenic potential of MIN-117. The NOAEL for 
embryo-foetal toxicity is therefore set at 45 mg/kg/day (corresponding to a mean AUC0-24h 
of test item MIN-117 of 3449 ng.h/mL). 
No genotoxic potential of MIN-117 was demonstrated in mutagenicity tests including the 
Bacterial reverse mutation tests in Salmonella typhimurium and Escherichia coli and the in 
vitro chromosomal aberration test with Chinese hamster lung cells; and the micronucleus 
test in mice and the in vivo/in vitro Unscheduled DNA Synthesis test in rat hepatocytes, 
where animals were adequately exposed to MIN-117. 
1.3.4. 
Pharmacokinetic Profile 
Pharmacokinetic studies of MIN-117 have been performed mainly in rats and monkeys.  
After oral administration of 14C-MIN-117 in rats and monkeys, the plasma concentration 
of radioactivity reached Cmax at 9.8 hours and 5.0 hours, respectively. It then declined with 
a terminal elimination half-life (t1/2)  (12 to 72 hours) of 19.9 hours in rats and 20.7 hours in 
monkeys and t1/2 (72 h-t) of 33.2 hours in rats and 50.1 hours in monkeys (t: last quantifiable 
time point). The absorption rate estimated by dividing AUC0-∞, PO by AUC0-∞, IV was 
85.3% for rats and 73.3% for monkeys. 
The plasma concentration of unchanged MIN-117, detected after oral administration of 
MIN-117 in rats, reached the maximum level (Cmax) at 6.0-6.8 h and then declined with a 
t1/2 of 8.8 to 9.6 hours.  The bioavailabilities (F) at 0.3, 1, and 3 mg/kg were 81.3, 95.5, and 
95.2%, respectively. After intravenous administration at a dose of 1 mg/kg, total clearance 
(CL) and volume of distribution at steady state (Vss) were 1.15 L/h/kg and 10.04 L/kg, 
respectively.  In monkeys, the plasma concentration of unchanged MIN-117 reached Cmax 
at 1.0 to 1.5 hours and then declined with a t1/2 of 3.0 to 6.8 hours.  F at 0.3, 1, and 3 mg/kg 
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were 14.4, 14.6, and 12.3%, respectively and after intravenous administration at a dose of 
1 mg/kg, CL and Vss were 0.78 L/h/kg and 2.40 L/kg, respectively. 
Following a single oral administration to male rats, the tissue concentration of radioactivity 
reached the peak level at 3 hours after administration in thyroid gland, trachea, liver, 
stomach and small intestine and at 7 to 12 hours after administration in the other tissues.  
In almost all the tissues, the concentration of radioactivity was higher than that in plasma. 
At 3 to 24 hours after administration, relatively higher levels of radioactivity are detected 
in harderian gland, liver, lung, adrenal gland, pancreas, pituitary gland, fat and brown fat 
except gastro-intestinal tissues.  At 168 hours after administration, the radioactivity 
concentration in all of the tissues was declined to 2% or less of the maximum concentration.  
Following repeated oral administration rats, mostly all radioactivity concentrations in the 
tissues reached their maxima at 7 h after administration on Day 1 and after 7, 14, and 21 
days of administration, and declined after single, 7 days, 14 days, and 21 days of 
administration to 0%, 4% or less, 16% or less and 18% or less (33% or less for females) of 
their maxima at 168h post-dosing respectively. 
Finally distribution rate of radioactivity in blood cells was 33.8% to 42.9% in rats, 
8.6% to 12.2% in monkeys, and 2.1% to 9.6% in humans. The plasma protein binding rate 
of 14C-labeled MIN-117 or unlabeled MIN-117 was 82.3 to 96.1% in rats, and over 96.5% 
in monkeys and humans. The protein binding rate was over 99.6% in human serum 
albumin, 84.4% in human ϒ-globulin, and 97.1% in human α1-acid glycoprotein. 
The major route of elimination of radioactivity was fecal excretion via the bile.  The 
excretion rates in feces of radioactivity of the dose after oral administration were 78.3% in 
rats and 65.2% in monkeys up to 168 hours.  The enterohepatic circulation rate was 50.2% 
in rats. 
1.3.5. 
Behavioral and Pharmacodynamics Studies 
MIN-117 was tested in four kinds of animal models to evaluate its antidepressant effects. 
Successive oral administration of MIN-117 0.3 mg/kg for 3 days completely reversed the 
locomotor activities reduced by the handling stress in F344 rats. In this model, fluoxetine, 
venlafaxine and imipramine also reversed the motor activity, but the onset of these drugs 
was prominently slower than that of MIN-117. MIN-117 also reversed sucrose 
consumption of rats in the depression model of chronic mild stress (CMS).  The magnitude 
of action of the most active doses of MIN-117 (0.001 and 1.0 mg/kg) was comparable to 
that of imipramine (10 mg/kg); by the end-of-treatment period the sucrose consumption in 
stressed animals treated with these doses was restored to the pre-stress level.  The onset of 
action of these doses was clearly faster than that of imipramine; the enhancement of sucrose 
intakes reached statistical significance already following the first week of administration, 
compared to four weeks required by imipramine.  The CMS procedure decreased the 
recognition index measured in the Novel Object recognition test.  In stressed animals 
MIN-117, administered at doses of 0.001, 0.01 and 0.1 mg/kg, restored the recognition 
index to the level of the vehicle- or drug-treated control animals, while Imipramine was 
ineffective.  
In the forced swimming test, MIN-117 shortened the immobility time with an ED50 of 
15 mg/kg PO. In the marble burying (MB) test, results showed that MIN-117 suppresses 
the MB behavior without affecting locomotor activity in mice. 
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The reinforcing effect of MIN-117 was investigated in the self-administration experiment 
in monkeys. Results suggested that MIN-117 possessed a reinforcing effect but of very 
weak intensity considered compared to that of cocaine. 
MIN-117 was tested in order to evaluate potential sexual side effects following acute 
(1 day), subchronic (7 days) and chronic (14 days) of treatment in a model of sexual 
dysfunction in rats. The serotonin reuptake inhibitor (SSRI) compounds Paroxetine 
Hydrochloride (10 mg/kg) and Citalopram (10 mg/kg) were used as reference compounds 
as SSRIs have a known inhibitory effect on the display of male sexual behavior. In the 
study, the SSRI reference compounds, Citalopram and Paroxetine, decrease sexual 
performance as measured by different parameters (increased latencies to display the first 
mount and the first ejaculation, slight reduction in the total number of ejaculations). 
MIN-117 had a significant effect to decrease the latency to display the first mount attempt. 
The dose of 0.03 mg/kg displayed a significant increase in number of mount attempts 
compared to vehicle group. The MIN-117 compound had no significant effect on the 
number of intromissions displayed by male rats, nor in the total number of ejaculations. 
1.4. 
Clinical Studies 
To date, 97 healthy subjects have received at least one oral dose of MIN-117, with 24 
subjects receiving placebo, in a total of 2 completed and 1 ongoing clinical pharmacology 
studies (Studies Wf-516-E01, SON-117C01, and MIN-117C02, respectively).  To date, 42 
patients with MDD have recieved up to 6-weeks of daily dosing of 0.5 mg (N=21) or 2.5 
mg (N=21) of MIN-117, with 21 patients receiving placebo, in one completed phase 2a 
study (MIN-117C01). 
Study Wf-516-E01: assessed the safety, tolerability, PK, and PD profiles of 6 single-
ascending doses of SON-117 (now known as MIN-117; 2.5, 5.0, 7.5, 10.0, 12.5, and 
15.0 mg) in healthy male subjects.  A total of 50 subjects participated in the study with 
38 subjects exposed to MIN-117 and 12 subjects exposed to placebo. 
Study 
SON-117C01: 
assessed 
the 
safety, 
tolerability, 
pharmacokinetic, 
and 
pharmacodynamic profile of 3 multiple ascending (14 days) doses (doses 1, 3, and 7.5 mg) 
of MIN-117 in healthy male subjects.  A total of 50 subjects participated in the study with 
29 subjects exposed to MIN-117, 12 to placebo, and 9 to escitalopram (positive control). 
Study MIN-117C01:  assessed the efficacy of MIN-117 0.5 and 2.5 mg compared to 
placebo in reducing the symptoms of a major depressive episode as measured by the change 
from Baseline in the MADRS total score over 6 weeks of treatment in a randomized, 
double-blind study.  The study also assessed the efficacy of MIN-117 using CGI-S, CGI-I, 
HAM-A, A-SEX, cognitive testing, sleep parameters,and the safety of tolerability of MIN-
117 as compared to placebo over a 6-week dusration of daily dosing.  A total of 84 patients 
participated in the study with 42 patients exposed to MIN-117 (21 patients each to 0.5 mg 
and 2.5 mg doses), 20 to placebo, and 20 to 20 mg of paroxetine (positive control).   
Study MIN-117C02:  assessed the effect of food on the PK of a single MIN-117 dose in 
Healthy male and female subjects in a randomized, open-label, 2-way, crossover study.  A 
total of 30 subjects completed both periods of the study and received a single 2.5 mg dose 
under both fasted and fed conditions.  The study is currently ongoing. 
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1.4.2. 
Efficacy 
The primary efficacy endpoint of the MIN-117C01 study was change from Baseline to 
Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS). MIN-117 treatment 
resulted in a reduction of depression severity as measured by MADRS total score change 
compared to Baseline, and showed a dose-dependent reduction in MADRS total score 
values at the end of the treatment phase as compared to placebo. 
For the secondary efficacy analyses, MIN-117 had no effect on Clinical Global 
Impression—Severity Scale (CGI-S) and Clinical Global Impression—Improvement Scale 
(CGI-I) scores. MIN-117 treatment resulted in an improvement in Arizona Sexal 
Experience (A-SEX) scores after 4 weeks of treatment, which continued until the end of 
the 6-weeks treatment phase. Cognition assessed by the Digit Symbol Substitution Test 
(DSST) and Digit Span Backwards task was improved after MIN-117 treatment. No clear 
trend was observed for the comparison of the MIN-117 groups with placebo for the Tower 
of London Test. 
Exploratory efficacy analyses on MADRS responder rates found all odds ratios (ORs) >1 
for the MIN-117 dose groups as compared to placebo, with the largest OR at Week 4 for 
the 2.5 mg dose group. Concerning the influence of MIN-117 on sleep architecture and 
continuity, sleep parameter analysis showed only a minimal influence of MIN-117 
treatment compared to placebo, in contrast to known effects of antidepressants like 
paroxetine where, after treatment, a number of sleep parameters deteriorated. An MDD 
treatment effect as measured by HAM-A scores was seen: after MIN-117 treatment, a trend 
of reduction in anxiety scores was seen starting at Week 2 compared to placebo treatment. 
Safety 
1.4.3. 
Safety  
Healthy Subjects  
Overall, single MIN-117 doses up to 15 mg and repeated MIN-117 doses up to 7.5 mg were 
well tolerated. No dose-limiting adverse events were reported. At this time, the most 
commonly reported adverse drug reactions (ADRs) related to MIN-117 include insomnia, 
somnolence, diarrhea, and nervousness.  
In Study Wf-516-E01, no significant changes in laboratory tests, physical and neurological 
examinations, vital signs, or electrocardiogram (ECG) parameters (12-lead or 24-hour 
Holter) were observed.  In particular, no symptomatic postural hypotension or clinically 
relevant increase in QTc duration was reported.  No clinically significant prolonged QTc 
value was observed around Tmax, in any subject and at any dose. 
 
Of the 34 reported treatment emergent adverse events (TEAEs), 17 events occurred in the 
placebo group and 17 events occurred in the MIN-117 group.  The body systems most 
frequently affected were the nervous system and the musculoskeletal and connective tissue 
body systems.  These TEAEs were mild (11) or moderate (22) in severity. One vasovagal 
malaise was severe in intensity.  
 
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The most common TEAEs were 4 episodes of somnolence (1, placebo; 3, MIN-117 
2.5 mg), and 4 episodes of back pain (1, placebo; 3, MIN-117 15 mg).  Two vasovagal 
malaise cases were reported: one was moderate (MIN-117 15 mg) and one was severe 
(placebo) in intensity, both were considered not related to study drug.  
Six events were considered by the investigator to be related to study drug including 2 events 
occurring in the placebo group: headache (1, placebo 1; 1, MIN-117 2.5 mg) and 
somnolence (1, placebo; 3 MIN-117 2.5 mg). 
One serious adverse event was reported in the Wf-516-E01 study. The subject (MIN-117 
15.0 mg group) presented with an acute paranoid psychosis 61 days post-dosing that 
required hospitalization and treatment with neuroleptics. This event occurred further to the 
End of Study (EOS) visit. According to the subject’s relatives, sleep disorders and mild 
changes in his behavior were already noticed before he entered the study. This event was 
considered as severe in intensity and not related to study drug.  
The maximum tolerated dose could not be established in this study as the highest dose was 
well tolerated. 
In the SON-117-C01 study, 132 TEAEs were reported (40 with placebo, 40 with MIN-117 
1 mg, 22 with MIN-117 3 mg and 30 with MIN-117 7.5 mg). The body systems most 
frequently affected were the Nervous system (36), Skin and subcutaneous system (26), and 
Gastrointestinal system (23). The most frequently reported TEAEs were headache (15 
episodes: 7 with placebo, 1 with MIN-117 1 mg, 2 with MIN-117 3 mg and 5 with MIN-117 
7.5 mg dose) and insomnia (10 episodes; 5 with placebo, 2 with 1 mg dose, 1 with 3 mg 
dose and 2 with 7.5 mg dose). All TEAEs were mild or moderate in intensity. Only 1 TEAE 
was rated as severe (fatigue, MIN-117 7.5 mg). 
Among the reported TEAE, 62 were considered related to the study drug: 22 with placebo 
(66,7% of the subjects) and 40 with MIN-117: 22 with MIN-117 1 mg (60% of the 
subjects); 8 with MIN-117 3 mg (40% of the subjects) and 10 with MIN-117 7.5 mg (44% 
of the subjects). 
The most frequently reported ADRs were insomnia (9 episodes: 5 with placebo,1 with 
MIN-117 1 mg; 1 with MIN-117 3 mg and 2 with MIN-117 7.5 mg), headache (6 episodes: 
5 with placebo and 1 with MIN-117 1 mg) and diarrhea (5 episodes: 2 with placebo, 2 with 
MIN-117 1 mg and 1 with MIN-117 7.5 mg). 
Of note, in the SON-117-C01 study, escitalopram was administered as a positive control to 
9 subjects. In this group, 28 ADRs were reported (88,9% of the subjects). The most 
frequently reported ADRs were asthenia (5 episodes) and headache (3 episodes). 
Results on the SSRI withdrawal scale indicated that there were no more self-perceived 
adverse events with MIN-117 than with placebo or escitalopram. 
No significant biological abnormalities were evidently related to MIN-117. 
Repeated doses of MIN-117 induced no clinically relevant changes in blood pressure. All 
mean values of supine systolic and diastolic blood pressure as well as heart rate were within 
the normal range. There was a trend toward a slight decrease in supine DBP with MIN-117 
3 mg (Day 1, Day 14 and Day 18) when compared to placebo. The incidence of abnormal 
orthostatic tests was also higher with MIN-117 3 mg, although none of them were 
symptomatic. Heart rate tended to increase following MIN-117 3 mg administration. This 
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increase was observed on Day 1 starting at H4 with a maximum at H12 (MIN-117 3 mg: 
+15.6 ± 7.00; placebo: + 1.083 ± 7.192). A similar pattern was observed on Day 8 (max at 
H6) and Day 14 (max at H12). An increase in heart rate was also observed after MIN-117 
7.5 mg but this effect was less marked when compared to the 3 mg dose. 
All mean ECG parameters were in the normal ranges. As for vital signs, an increase in heart 
rate (and concomitant decrease in RR interval) was observed in the MIN-117 3 and 7.5 mg 
dose groups. However, all those changes were considered as clinically not relevant. With 
regards to QTcB, the mean changes from Baseline were mainly negative for placebo and 
MIN-117 1 mg.  They were mainly positive for MIN-117 3 and 7.5 mg.  It could be 
explained by the concomitant increase in heart rate. Given the study design and the high 
inter-subject variability, these changes were judged not clinically relevant.  Only a few 
subjects reported QTcB values over 450 msec: 1 episode in one subject with placebo 
(476 msec Day 3 predose); two episodes in two subjects with MIN-117 1 mg (451 msec 
Day 1 T+2H and 460 msec Day 5 T+3H) and one episode in one subject with MIN-117 
3 mg (453 msec Day 11 predose).  No QTcB value over 480 msec was reported. 
No SAEs were reported in this study. 
The maximum tolerated dose could not be established in this study as the highest dose was 
well tolerated. 
Patients with MDD 
A total of 44 patients (53.7%) experienced TEAEs, with the highest percentage in the 
paroxetine 20 mg group (65.0%, 13 patients) and the lowest in the placebo group (45.0%, 
9 patients). All TEAEs were mild or moderate in intensity, with the exception of 2 severe 
events of nausea (MIN-117 2.5 mg: 1; paroxetine 20 mg: 1). The events of nausea were 
considered possibly/probably related (MIN-117 2.5 mg) and definitively related 
(paroxetine 20 mg) to study medication. 40.2% of patients experienced TEAEs that were 
considered to be related to the double-blind study medication by the investigator. For 6 
patients (7.3%), TEAEs were deemed to be definitively related. Overall, 2 patients were 
withdrawn from the study due to adverse events occurrence (both of whom were 
randomized to the paroxetine 20 mg group): one female patient with severe nausea (non-
serious, definitely related to the study medication) and one female patient with moderate 
transaminases increased (considered as an adverse event as it occurred before the start of 
the study medication) and moderate blood alkaline phosphatase increased (TEAE). Both 
events were considered unrelated to study medication.   
The highest frequencies of TEAEs were reported in the system organ classes Nervous 
system disorders (19.5% of patients), Investigations (17.1%), Gastrointestinal disorders 
(12.2%), and Infections and infestations (11.0%). The most commonly reported TEAE was 
nausea (9.8%, 8 patients). Dizziness as well as headache were reported for 7 (8.5%) 
patients, and upper respiratory tract infection was reported for 4 (4.9%) patients. The 
remainder of reported TEAEs occurred in ≤ 3 (≤ 3.7%) patients. 
In general, Sheehan-Suicide Tracking Scale scores were low for all treatment groups 
throughout the study and no consistent pattern of change was observed. 
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1.5. 
Overall Rationale for the Study  
Major depressive disorder (MDD) is a common, severe, chronic and often life-threatening 
illness. It is now the third leading cause of disability worldwide (WHO 2006). It is a 
heterogeneous disorder, with a variable course. The prevalence of the disorder is 
approximately 10% in men and 20% in women. It is associated with high morbidity with 
significant deleterious health risk and high risk for mortality. Suicide is estimated to be the 
cause of death in up to ~10-15% of individuals with MDD (Belmaker 2008). 
Despite important advances in the treatment of depression, many with this illness remain 
inadequately treated. Although options for pharmacologic treatment for depression have 
grown over the past decades, the current armamentarium of antidepressants continues to 
have limitations in both efficacy and tolerability. With the first antidepressant, 
approximately 60 to 70%, and with 2 consecutive antidepressants 30 to 40%, of subjects 
treated for Major Depression do not achieve sufficient control of their symptoms 
(Trivedi 2009; CHMP 2013).  
There is a clear need to develop novel and improved therapeutics for major depression that 
can improve on tolerability and efficacy. The unique mechanism of action, good 
tolerability, and good efficacy based on animal models of depression make MIN-117 an 
attractive compound to test for efficacy in major depression. 
The combination of the different pharmacological activities of MIN-117 (please refer to 
Investigator’s Brochure and information given above) confers to this molecule a unique 
efficacy profile, which might address particularly some of the major unmet medical needs 
and shortcomings of existing therapies, like delayed onset of mood improvement, cognitive 
impairment and sexual dysfunction.  
In terms of speeding up onset of improving mood, both the effect of MIN-117 on the 
5-HT1a auto-receptor seems key as well as the effect on the DAT as described below.  
A published Cochrane review (Geddes 2003) reviewed 98 randomized controlled trials 
comparing the efficacy of selective serotonin reuptake inhibitors (SSRIs) with other classes 
of antidepressants. Analysis of efficacy was based upon 5044 subjects treated with SSRIs 
or related drugs and 4510 subjects treated with an alternative antidepressant. Overall, no 
clinically significant difference between SSRIs and tricyclic antidepressants were reported. 
Treatment decisions need to be based on considerations of relative subject acceptability, 
toxicity, and cost (Geddes 2003).  Although the pharmacological activity of these drugs is 
rapid, there is a certain delay in the onset of clinical improvement in the depressive 
symptoms of subjects. 
SSRIs inhibit the serotonin reuptake system (Hyttel 1994), which leads to an increase in 
extracellular serotonin. Higher levels of serotonin in the synaptic cleft lead to an activation 
of somatodendritic 5-HT1A autoreceptors, which in turn results in reduced serotonergic 
neuron firing activity (Scuvee-Moreau 1979) and reduced extracellular serotonin in the 
forebrain (Romero 1994).  This initial inhibition of serotonin synaptic release mediated by 
presynaptic 5 HT1A receptors could contribute to the delayed onset of action of SSRIs 
(which are gradually down regulated and desensitized during continuing treatment). 
Therefore, the additional administration of 5-HT1A auto-receptor antagonists), would be 
expected to prevent the negative feedback caused by the initial decrease in the firing rate; 
this may accelerate and enhance the therapeutic efficacy of SSRIs (Artigas 1993; Savitz 
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2009).  More recently, interest has turned to the role of DA in depression. This is based on 
a wide body of preclinical data, the postulation that loss of interest and pleasure (anhedonia) 
are the core symptoms of depression and that all other depressive symptoms are causally 
related, and clinical evidence identifying low concentrations of homovanillic acid (HVA, a 
metabolite of DA) in the cerebrospinal fluid (CSF) and plasma of depressed patients 
(Lambert 2000).  
Furthermore, data from clinical studies have shown that DA agonists, such as 
bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties. Amineptine, 
a TCA-derivative that predominantly inhibits DA re-uptake and has minimal noradrenergic 
and serotonergic activity has also been shown to possess antidepressant activity (Boyer 
1999).  However, amineptine is no longer available as a treatment for depression, and thus, 
MIN-117 might be an alternative treatment.  Indeed, MIN-117 was found to be active in 
the CMS model of depression.  The magnitude of action of the most active doses (0.001 
and 1.0 mg/kg) was comparable of that of imipramine.  The onset of action of these doses 
was clearly faster than that of imipramine (after the first week of treatment with MIN-117). 
In terms of cognitive improvement, preclinical data obtained on a novel object recognition 
test indicates that compared to imipramine, MIN-117 is restoring cognitive skills in 
experimental conditions after repeated stress.  As found in the Novel Object Recognition 
test (NOR), MIN-117 prevented the stressed animals from CMS-induced deficit in working 
memory at the lowest doses of 0.001, 0.01 and 0.1 mg/kg, while the highest dose of 
1.0 mg/kg was ineffective against the CMS-induced deficit in the NOR (see Investigator’s 
Brochure).  Motivation, psychomotor speed, concentration, and the ability to experience 
pleasure are all linked in that they are regulated in part by DA – containing circuits in the 
CNS and impairment of these functions are prominent features of depression. Although, 
some other pharmacological targets on which MIN-117 is binding, it seems that the DAT 
activity might be the main driver of the beneficial effect of the drug on vigilance, attention 
and as a consequence cognition (Dunlop 2007). 
In terms of sexual function, MIN-117 might also exhibit a potent pharmacological profile.  
A preclinical study exploring this function in rats and comparing MIN-117 to paroxetine 
clearly demonstrated a preserved sexual function unlike paroxetine, which induced its 
known impairments (see the Investigator’s Brochure). In terms of underlying 
pharmacological pathways, mostly 5-HT1a binding of MIN-117, might be responsible for 
this preserved function.  As proposed by Baldwin and colleagues (2013), future 
management options may be extended through the development of new antidepressant 
treatments with a lower risk of causing sexual problems.  These could include compounds 
with effects on the 5-HT1a receptor or with noradrenaline reuptake inhibitor properties.  
At present, the evidence relating to the effects of drugs acting on the 5-HT1a receptor is 
intriguing.  The partial agonist, buspirone, has been used to reduce sexual dysfunction 
associated with SSRIs, and the partial agonist, gepirone, improves sexual functioning in 
depressed men, independent of antidepressant or anxiolytic effects.  The novel 
antidepressant drug vilazodone, which has both SSRI and 5-HT1a partial agonist 
properties, appears to have a low incidence of adverse effects on sexual functioning, as 
does the “multimodal” compound vortioxetine, whose pharmacological properties include 
full agonism at the 5-HT1a receptor. 
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While existing therapies for this disease are available, their effectiveness is limited due to 
unacceptable side effects, varying and different levels of efficacy for individual subjects 
requiring physicians to test, check, and alter doses, or change medication during treatment 
(Rush 2006).  As such, the need for new drugs that are equally or more efficacious with 
better safety profile to address unmet medical needs exists, and MIN-117 is one such 
candidate. 
Finally, because MIN-117 has shown, in addition to all the key pharmacological targets 
highlighted above, clear SSRI activity and treatment effect with moderate effect size on 
both depression and anxiety, it is therefore justified to test in a larger pool of depressed 
patients due to the potential AD and anxiolytic effect.   
2. 
OBJECTIVES 
Primary 
To evaluate the efficacy of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 compared with 
placebo in reducing the symptoms of major depression measured by the change in 
Montgomery-Asberg Depression Rating Scale (MADRS) total score over 6 weeks of 
treatment in adult patients with MDD. 
Secondary 
1. To assess the change from Baseline of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 
compared with placebo over 6 weeks of treatment on: 
 The symptoms of anxiety using the HAM-A. 
 The severity of illness and improvement using the CGI-S and CGI-I. 
2. To evaluate the safety of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 compared with 
placebo over 6 weeks of treatment in adult patients with MDD. 
Exploratory 
1. To assess the change from Baseline of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 
compared with placebo over 6 weeks of treatment on: 
 Commonly associated symptoms of MDD by using the IDS-SR30. 
 The ability to experience hedonic capacity by using the SHAPS. 
 Cognitive function as measured by DSST. 
 Perception of stress using the PSS. 
 Sexual functioning by using the A-SEX. 
 Sleep parameters as assessed by Somno-Art methodology (at select sites). 
 Neurotrophic/inflammatory factors. 
2. To explore the PK of MIN-117 
 and assess the PK/PD relationship. 
Hypothesis  
The primary hypothesis is that at least 1 dose of MIN-117 will be superior to placebo on 
the change from Baseline in the MADRS total score at the end of 6 weeks of treatment. 
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3. 
OVERVIEW OF STUDY DESIGN 
This is a 6-week, 3-arm, randomized, double-blind, placebo- controlled study to investigate 
the safety and efficacy of MIN-117 in male and female patients with MDD, aged 18 to 65.  
Approximately 324 patients will be randomly assigned to 1 of 3 treatment arms, including 
placebo, 5.0 mg MIN-117, or 2.5 mg MIN-117, in a 2:1:1 ratio (i.e., approximately 
162 patients in the placebo group and approximately 81 patients in each of the MIN-117 
treatment groups). 
The study design has 3 phases:  a screening phase of up to 3 weeks (including washout), a 
6-week double-blind treatment phase, and a post-study follow-up visit, occurring 
approximately 2 weeks after completing the double-blind treatment phase.  
Screening Phase: Patients with an acute exacerbation of a major depressive episode will be 
screened for this study. Screening will include informed consent (for the overall study as 
well as for optional pharmacogenomic research), evaluation for eligibility in the study, and 
assessment of medical history .  Patients must meet Diagnostic and Statistical Manual of 
Mental Disorders-Fifth Edition (DSM-5) diagnostic criteria for moderate to severe MDD, 
with anxious distress and without psychotic features.  The diagnosis should be confirmed 
by the SCID-5.   Patients will undergo additional physical and psychiatric evaluations, as 
well as safety evaluations.  If patients give informed consent to participate and meet all 
study entry criteria at Screening, they will be tapered off their current psychotropic 
medications.  Patients will be free of any psychotropic medications for a period of 1 week 
(or 2 weeks for MAO inhibitor, 4 weeks for fluoxetine) prior to randomization.  
Double-blind Treatment Phase: After at least 1-week of psychotropic drug-free period, 
patients will undergo evaluation for eligibility, and if they still meet the study entry criteria, 
they will be randomly assigned in a 2:1:1 ratio to receive placebo, 5.0 mg MIN-117, or 
2.5 mg MIN-117, respectively, once daily for 6 weeks.  Clinic visits will occur at Visits 2, 
3, 4, and 5/Early Withdrawal (Weeks 1, 2, 4, and 6, respectively). 
Post-Study Visit: At the end of the study, patients will be evaluated for safety/tolerability 
at the Post-Study Visit, approximately 2 weeks after completing the Double-blind 
Treatment Phase.  Any patient who terminates from the study early will undergo the Early 
Withdrawal visit procedures and will have a Post-Study Visit within approximately 2 
weeks. 
 
 
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Safety will be assessed by monitoring adverse events, clinical laboratory tests (including 
hematology, serum chemistry, urinalysis, lipid profile, and pregnancy tests), vital sign 
assessments, physical and neurologic examinations, and ECGs.  Suicidal ideation/behavior 
will be assessed using the C-SSRS. 
3.1. 
Study Design Rationale 
A placebo control will be used to establish the frequency and magnitude of changes in 
clinical endpoints that may occur in the absence of active treatment.  
Randomization will be used to minimize bias in the assignment of patients to treatment 
groups, to increase the likelihood that known and unknown patient attributes 
(e.g., demographic and Baseline characteristics) are evenly balanced across treatment 
groups, and to enhance the validity of statistical comparisons across treatment groups.  
Blinded treatment will be used to reduce potential bias during data collection and evaluation 
of clinical endpoints. 
Study Population 
The study population will consist of adult men and women with a diagnosis of moderate or 
severe MDD [i.e., met DSM-5 criteria for diagnosis of moderate or severe major depression 
with anxious distress and without psychotic features at Screening based on clinical 
assessment and on the SCID-5 (DSM-5 codes: 296.32, 296.33; ICD-10 codes: F33.1, 
F33.2)].  Patients should have at least one previous episode of depression prior to the one 
qualifying them for this study.  
To minimize rating inflation, patients will qualify for the study by their own self ratings of 
their severity of depression by using the IDS-SR30.  Additional safeguards such as utilizing 
the Massachusetts General Hospital Clinical Trials Network Institute to conduct the 
“SAFER” interviews will be utilized (see Inclusion Criterion # 5).  The SAFER inventory 
helps to facilitate identification of the valid patient for clinical trials.  The inventory 
addresses specific elements adapted from the SAFER criteria that comprise a valid 
symptom and one SAFER element (face validity) that considers the entire symptom cluster 
as a valid nosological entity.  Such criteria seek to confirm that identified patients have 
acute symptoms that reflect the current state of illness and that these symptoms can be 
reliably assessed with validated measurement tools.  Beyond mere presence or absence, 
valid patients must have relevant symptoms that are pervasive, persistent (and not 
fluctuating over a defined period of time), and pathological in nature (Targum 2008). 
Length of Study Phases and Periods 
In any clinical study there is always some risk to removing current psychotropic 
medications and starting an investigational compound. All patients will undergo a 
Screening period including a washout period and a drug-free period of at least 7 days prior 
to randomization. Most patients will tolerate this washout period well without significant 
symptoms and can remain as outpatients with appropriate clinical monitoring and rescue 
medications. Only patients who have not had sufficient clinical benefit from their current 
psychotropic medication will be included in the study. Patients who are benefitting from 
their current psychotropic medications at the time of Screening will not be included in the 
study.  
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Tapering and discontinuation of the previous psychotropic medications will allow for the 
study drug to be assessed for efficacy and safety as monotherapy instead of an add-on 
therapy. 
The 6-week duration of the double-blind study is adequate to assess the potential efficacy 
of MIN-117 in the treatment of MDD.  
Dosage Selection and Interval 
Clinical studies with MIN-117 have been shown the drug to be well tolerated at up to 
7.5 mg/day for up to 14 days, and at up to 2.5 mg for 6 weeks.  The selected doses (5.0 mg 
and 2.5 mg) are considered to be pharmacologically potent to show antidepressant effect as 
doses as low as 0.001 and 1.0 mg/kg were found to be effective in the CMS model of 
depression in mice.  A once daily dosing interval is customary in depression trials and the 
PK properties of MIN-117 support such dosing interval without undue accumulation.  
Choice of Efficacy Measurements 
Mood and Anxiety 
The MADRS was designed for use in subjects with MDD to measure the overall severity 
of depressive symptoms. The scale has been validated, is reliable and is acceptable to 
regulatory health authorities as a primary scale to determine efficacy in major depression. 
The CGI will provide an overall clinician-determined summary measure that takes into 
account all available information, including knowledge of the subject’s history, 
psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the 
subject’s ability to function. The CGI comprises two companion one-item measures 
evaluating the following: severity of psychopathology (CGI-S) from 1 to 7 and change from 
the initiation of treatment on a similar seven-point scale (CGI-I). 
Hamilton Anxiety Scale (HAM-A) measures the severity of a subject's anxiety, based on 
14 parameters, including anxious mood, tension, fears, insomnia, somatic complaints and 
behavior at the interview. The subject is asked to rate the gravity of each item using a 
5-level scale – from 0 to 4, with 4 being the most severe – and afterwards, the results are 
collated and tabulated to determine the severity of anxiety. 
Stress and Anhedonia 
MIN-117 pharmacological profile and hypothesized mechanism of action suggest it will 
have beneficial effect on the perceived levels of stress and hedonic capacity.  To that end, 
the PSS and SHAPS scales will be used in an exploratory fashion to help validate such 
potential benefit. 
Sleep 
Sleep dysfunction, manifesting as too much or too little sleep, can be an indicator of 
depression. In addition, sleep dysfunction can be a side effect of antidepressant 
medications. Sleep-related adverse effects range from somnolence to insomnia, and from 
interrupted sleep to lack of restful, refreshing sleep. The consequences of sleep dysfunction 
may extend to daytime functioning and health-related quality of life. (Devine 2005).  
To date, numerous studies have explored the effects of antidepressants on sleep but less 
research has focused on the use of sleep-electroencephalogram (EEG) parameters as 
biomarkers for the therapeutic effects of antidepressant medication.  In a prospective case-
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control study with a relatively large sample size, abnormal sleep-EEG profiles were 
associated with poor cognitive behavioral therapy response (Thase 1996). Two commonly 
reported biomarkers for therapeutic response are (i) a pretreatment elevated rapid eye 
movement (REM) disinhibition and (ii) an initial tonic REM suppression measured at 
beginning of treatment. Furthermore, recorded sleep EEGs at Day 7 and at Day 42 of 
treatment with paroxetine and tianeptine show that REM density served as a predictor of 
paroxetine treatment response: changes in REM density showed an inverse correlation with 
changes in HAM-D scores (Murk 2003). In summary, most studies point toward REM 
disinhibition before treatment and REM suppression at treatment initiation as predictors for 
better antidepressant treatment outcome. 
Sexual Functioning 
Another common side effect of certain antidepressant medications is sexual dysfunction; 
sexual dysfunction can also be a symptom of depression. Sexual dysfunction can occur in 
any one or more phases of the sexual cycle, including desire, arousal, orgasm and resolution 
(Derogatis 2008). The Arizona Sexual Experiences Scale (A-SEX) addresses the areas of 
sexual functioning most commonly impaired by psychotropic drugs while being brief, easy 
to understand and less intrusive than other sexual functioning measures. It will be used in 
this study to explore the effect of MIN-117 on sexual dysfunction.  
Neurotrophic/Inflammatory Markers  
Several studies have suggested that major depression is associated with reduced 
neurotrophic and elevated inflammatory markers.  Depressed subjects who respond to 
antidepressant treatment show quantitative reversal in these markers. Exploratory 
assessment of these factors is included as potential biomarkers to predict response, subject 
to confirmation in larger studies. 
Cognition 
Cognitive impairments are now widely acknowledged as an important aspect of MDD, and 
the DSM-5 lists impairment in cognition (i.e., diminished ability to think or concentrate or 
indecisiveness) as a criterion item in the diagnosis of a major depressive episode.  Although 
executive function and memory seem to be particularly impaired in patients with MDD, 
other domains can be affected including processing speed (Keefe 2014).  In the present 
study, DSST (processing speed) will be performed. 
4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation in 
this study: 
1. Patients must be able to read and understand the consent forms, complete study-related 
procedures, and communicate with the study staff.  
2. Patients must have provided written consent to participate in the study and understand 
that they are free to withdraw from the study at any time. 
3. Patients must have signed the informed consent form for pharmacogenomic research 
indicating willingness to participate in the pharmacogenomic component of the study 
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in order to participate in the optional pharmacogenomic component of this study. 
Refusal to consent for this component does not exclude a patient from participation in 
the clinical study. 
4. Patients must be aged 18 to 65 years, inclusive, at Screening (Visit 1). 
5. Meet DSM-5 criteria for diagnosis of moderate or severea major depression with 
anxious distress and without psychotic features at Screening based on clinical 
assessment and on the SCID-5 (DSM-5 codes: 296.32, 296.33; ICD-10 codes: F33.1, 
F33.2).  Their major depressive episode must be deemed "valid" using the 
Massachusetts General Hospital (MGH) SAFERb criteria interview administered by 
remote, independent raters. 
6. Subjects must be within a body mass index (BMI) of  18 to < 35 kg/m2 [BMI = weight 
(kg)/height (m)2] at Screening (Visit 1). 
7. Subjects have a history of at least one previous episode of depression prior to the current 
episode.  
8. Patient must have been treated with an antidepressant administered at an adequate dose 
and duration in the past for the treatment of Major Depression.  An adequate treatment 
is defined as an antidepressant treatment for at least 4 weeks at at least the minimum 
therapeutic dose, for any particular antidepressant. 
9. Current major depressive episode of at least 4 weeks in duration. 
10. At Screening (Visit 1) and Baseline (Visit 2), patients must have a score  40 on the 
patient rated IDS-SR30. 
11. At Screening (Visit 1) and Baseline (Visit 2), patients must have a score  18 on 
HAM-A.  
12. At Screening (Visit 1) and Baseline (Visit 2), patients must have a score  4 on the 
investigator-rated CGI-S. 
13. Patients must be outpatients at the time of randomization (Baseline [Day 1]).  
14. Patients must be in good general health prior to study participation with no clinically 
relevant abnormalities as assessed by the investigator and determined by: medical 
history, physical examination, vital signs, blood chemistry, hematology, urinalysis, and 
electrocardiogram (ECG). 
15. If female, the patient must: 
a. be post-menopausal, or 
b. have had a hysterectomy or tubal ligation or be otherwise incapable of 
pregnancy, or 
                                               
a  Several symptoms in excess of those required to make the diagnosis of MDD AND symptoms markedly 
interfere with occupational functioning or with usual social activities or relationships with others. 
b The acronym SAFER stands for interview’s attention to the following criteria: State versus trait; 
Assessability; Face validity; Ecological validity; and Rule of three Ps [pervasive, persistent, and 
pathological]. 
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c. must agree to consistent use of 2 methods of contraception for the duration of 
the study and until 90 days after the last dose of study medication.  One of which 
must be a highly effective method defined as one that results in a low failure 
rate (i.e. less than 1% per year) when used consistently and correctly.  The 
following highly effective contraception methods acceptable for this study are 
hormonal contraception (oral or parenteral hormonal contraceptive) or 
placement of an intrauterine device. The following methods can be used as a 
second form of contraception during the study: Barrier methods for female 
patients include their partner’s use of a condom or the subject’s use of an 
occlusive cap (diaphragm or cervical/ vault caps) with spermicidal foam, gel, 
film, cream or suppository. 
16.  If male with partner of childbearing potential, must be willing to use one barrier 
method of contraception with his partner throughout the study (a condom or his 
partner’s use of an occlusive cap [diaphragm or cervical/ vault caps]).  His partner must 
also be using a highly effective method of birth control defined as one that results in a 
low failure rate (i.e. less than 1% per year) when used consistently and correctly such 
as sterilization, implants, injectables, combined oral contraceptives, and intrauterine 
devices for up to 90 days after the last dose of study treatment. The patient must agree 
to inform the investigator if his partner becomes pregnant during the course of the study.  
17. Male patients who have been sterilized or have partners of non-childbearing potential 
(including homosexual men) are required to use one barrier method of contraception. 
This is to prevent unintended exposure of the partner to the study drug via seminal fluid 
(for male subjects, this must be a condom or their partner's use of an occlusive cap 
[diaphragm or cervical/vault caps].  
18. Female patients of childbearing potential must have a negative serum pregnancy test at 
Screening (Visit 1) and negative serum and urine pregnancy test at Baseline (Visit 2). 
4.2. 
Exclusion Criteria 
Potential patients who meet any of the following criteria will be excluded from participating 
in the study: 
1. A DSM-5 diagnosis of current (active): panic disorder, obsessive compulsive disorder 
(OCD), post-traumatic stress disorder (PTSD), anorexia nervosa, or bulimia nervosa. 
2. History or current diagnosis of a psychotic disorder, bipolar disorder, mental 
retardation, or borderline personality disorders, mood disorder with postpartum onset, 
somatoform disorders, fibromyalgia, or idiopathic medical conditions. 
3. At significant clinical risk for suicidal or violent behavior. 
4. History of treatment within last 6 months with electroconvulsive therapy (ECT), Vagus 
Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), or Transcranial Magnetic 
Stimulation (TMS). 
5. Potential patient who in the opinion of the investigator should not discontinue, or 
participate in washout of a prohibited concomitant medication. 
6. Potential patient who demonstrate a greater than 25% decrease in depressive symptoms 
as reflected by the IDS-SR30 total score from Screening visit to Baseline visit. 
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7. Active cardiovascular disease (including but not limited to: atrial fibrillation or flutter, 
second and third-degree atrioventricular heart block, resting supraventricular 
tachycardia >100 beats per minute, unstable ischemic heart disease, valvular 
abnormality, sick sinus syndrome or other condition requiring pacemaker) or diastolic 
blood pressure > 105 mmHg. 
8. Any serious, untreated, or unstable illnesses, such as: liver or renal insufficiency. 
9. Any significant pulmonary, endocrine, or metabolic disturbances. 
10. Documented disease of the central nervous system that could interfere with the study 
assessments (including but not limited to: stroke, tumor, multiple sclerosis, Parkinson’s 
disease, Alzheimer’s disease, Huntington’s disease, seizure disorder requiring current 
anti-convulsants, traumatic brain injury or trauma, and neurosyphilis. 
11. Hypothyroidism or hyperthyroidism, unless stabilized by appropriate medication for at 
least 3 months prior to Screening (a normal thyroid-stimulating hormone [TSH] is 
required prior to randomization at Baseline).  
12. Any medical condition that can potentially alter oral enteral absorption (e.g., 
gastrectomy), metabolism (e.g., liver failure), or excretion (e.g., renal failure) of the 
study drug. 
13. History of alcohol or substance use disorders (except nicotine and caffeine) meeting 
DSM-5 criteria within 1-year prior to Screening visit. 
14. Positive alcohol and urine drug screen for opiates, cocaine, barbiturates, 
tetrahydrocannabinol, methadone, tricyclic antidepressants, benzodiazepines, and 
amphetamine/methamphetamine at Screening or Baseline. Patients with positive testing 
at Screening due to prescribed benzodiazepines, tricyclic antidepressants, barbiturates 
or opiates are accepted but must test negative at Baseline (Visit 2). 
15. Male patients who have pregnant partners. 
16. Female patients who are breast-feeding. 
17. Received an experimental drug or used an experimental medical device within 60 days 
before the planned start of treatment (Day 1) or have participated in 2 or more clinical 
trials in the previous 2 years. 
18. QTcF interval at Screening or Baseline greater than 450 msec for males and 470 msec 
for females.  
19. Patients requiring treatment with drugs likely to prolong QT. 
20. Patients with known hypersensitivity to MIN-117 or placebo or their excipients (refer 
to section 13.1 p. 64 of the protocol). 
21. Positive hepatitis B surface antigen, or hepatitis C antibody or Human 
Immunodeficiency Virus (HIV) 1 and 2 antibodies at Screening. 
22. Employees of the investigator or study center, when the employee has direct 
involvement in the proposed study or other studies under the direction of that 
investigator or study center; also family members of the employee or the investigator. 
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4.3. 
Prior and Concomitant Therapy  
4.3.1. 
Prior Therapy 
Any medication (including, but not limited to, over-the-counter medicines such as aspirin, 
antacids, vitamins, mineral supplements, and herbal preparations) that the patient is 
receiving at the time of Screening, or receives during the study, must be recorded on the 
appropriate eCRF along with the reason for use, dates of administration, and dosages. 
 Women must remain on a highly effective method of birth control (see Section 4.1, 
Inclusion Criteria). 
 Patients must not use antidepressant within 1 week of the time they will take their 
first dose of study medication, or MAO inhibitor medications within 2 weeks, or 
fluoxetine (Prozac) within 4 weeks of the time they will take their first dose of study 
medication (i.e., 5 half-lives of the antidepressant). 
 Patients must not use other prescription medication within 7 days (or per study 
physician’s recommendation) prior to Baseline (Day 1) visit except those allowed  
in Attachment 1 (Allowed and Prohibited Concomitant Medications).  An exception 
is that women using hormone replacement therapy or hormonal contraception who 
have been using it continuously for at least 30 days before dosing may take the 
medication. 
 
Other exceptions justified by the patient’s medical condition could be allowed after 
the Sponsor’s Responsible Medical Officer approval ( refer to Section 4.3.2). 
 Patients must not use herbal medications (e.g., St. John’s Wort, ephedra, ginkgo, 
ginseng, and kava kava) within 7 days prior to Baseline visit or during the study. 
Information on the dose, date of last administration, length of time on medication and 
reason for stopping or changing the medication will be collected in the source documents 
and appropriate eCRF pages.  
4.3.2. 
Concomitant Therapy 
All medications except study drug, administered to a patient during the study, should be 
documented in the eCRF as concomitant medications.  
In general, concomitant medications with primary CNS activity, as well as CYP 2C8 and 
CYP 3A4/5 inhibitors, CYP 2C8 and CYP 3A4/5 inducers, and concomitant medications 
metabolized through CYP 2C9 are not allowed in this study (refer to Attachment 1).  
As the list of prohibited/allowed concomitant medications (Attachment 1) is not exhaustive, 
other concomitant medications justified by the patient’s medical condition could be allowed 
on a case by case basis after Sponsor’s Responsible Medical Officer approval.  
As a general rule: 
 
 Patients must not use psychotropic drugs other than the study medications at any 
time during the study. For a complete list of prohibited therapies, please refer to 
Attachment 1.  
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 Patients must be strongly discouraged from using alcohol or illicit substances 
during the entire study.  
 Ongoing psychological treatment (eg, Cognitive Behavior Therapy, Interpersonal 
Psychotherapy, Psychodynamic Psychotherapy, etc.) if it started > 3 months prior 
to the double-blind treatment phase, if the investigator deems the psychological 
treatment to continue during the study. 
Patients should be discontinued from the study if any prohibited medications are used 
during the study (the Sponsor’s Responsible Medical Officer can allow exceptions). 
4.3.3. 
Contraception 
Patients who are sexually active must use, with their partner, 2 approved methods of highly 
effective contraception from the time of study drug administration until 90 days after the 
last dose of study drug.  
Two or more of the following methods are acceptable and must include at least 1 barrier 
method: 
 Surgical sterilization (i.e., bilateral tubal ligation/salpingectomy, hysterectomy for 
female patients or partners; vasectomy for male patients or partners). 
 Placement of an intrauterine device or intrauterine system. 
 Hormonal contraception (implantable, patch, oral, injectable). 
 Barrier methods (for male patients, this must be a condom or their partner’s use of an 
occlusive cap [diaphragm or cervical/vault caps]; for female patients, either their 
partner’s use of a condom or the patient’s use of an occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal foam/gel/film/cream/suppository). 
Male patients who have been sterilized or have partners of non-childbearing potential 
(including homosexual men) are required to use one barrier method of contraception 
(condom). This is to prevent unintended exposure of the partner to the study drug via 
seminal fluid. 
Female patients who are not of childbearing potential, i.e., women who are post-
menopausal (defined as spontaneous amenorrhea for at least 1 year or spontaneous 
amenorrhea for at least 6 months confirmed by an follicle stimulating hormone [FSH] result 
of ≥ 40 IU/mL) or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy), are not required to use any contraception during this study. 
Alternatively, true abstinence is acceptable when it is in line with the patient’s preferred 
and usual lifestyle. If a patient is usually not sexually active but becomes active, they, with 
their partner, must comply with the contraceptive requirements detailed above. 
4.3.4. 
Exposure to Partners During the Study 
As there is a significant risk of drug exposure through the ejaculate (which also applies to 
vasectomized males) that might be harmful to the sexual partners, including pregnant 
partners, of male patients, barrier contraception should be used throughout the study and 
for 90 days after the last day of study drug administration. 
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4.3.5. 
Sperm Donation 
Male patients should not donate sperm for the duration of the study and for at least 90 days 
after the last day of study drug administration. 
4.3.6. 
Pregnancy 
Patients will be instructed that if they/their partner become pregnant during the study, the 
pregnancy should be reported to the investigator. The investigator should also be notified 
of pregnancy occurring during the study but confirmed after completion of the study. In the 
event that a patient/patient’s partner is subsequently found to be pregnant after the patient 
is included in the study, then consent will be sought from the partner and, if granted, any 
pregnancy will be followed and the status of mother and/or child will be reported to the 
sponsor after delivery. Any patient reporting a pregnancy during the study will be 
withdrawn from the study.  
Men who plan to father a child or to donate sperm within 90 days after last study drug 
administration (Day 43 or early withdrawal) are not allowed to participate in the study. 
Woman who are currently pregnant or nursing, or are planning to conceive a child within 
90 days after the last study drug administration (Day 43 or early withdrawal) are not 
allowed to participate in the study. 
5. 
TREATMENT ALLOCATION AND BLINDING 
5.1. 
Randomization 
Central randomization will be implemented in this study. Patients will be randomized to 
1 of 3 treatment arms, based on a computer-generated randomization schedule prepared by 
or under the supervision of the sponsor before the study. The randomization will be 
balanced by using permuted blocks. The Interactive Web Response System (IWRS) will 
assign a unique treatment code, which will dictate the treatment assignment and matching 
study drug kit for the patient. 
Approximately 324 eligible patients will be randomized in a 2:1:1 ratio to the following 
groups: 
 Placebo 
 5.0 mg MIN-117   
 2.5 mg MIN-117  
The investigator will not be provided with randomization codes. The codes will be 
maintained within the IWRS, which has the functionality to allow the investigator to break 
the blind for an individual patient, if needed. 
5.2. 
Blinding 
Under normal circumstances, the blind should not be broken until all patients have 
completed the study and the database is locked.  Otherwise, the blind should be broken only 
if specific emergency treatment/course of action would be dictated by knowing the 
treatment the patient is receiving.  In such cases, the investigator may in an emergency 
determine the identity of the treatment by IWRS.  Telephone contact with the sponsor or 
its designee will be available 24 hours per day, 7 days per week.   
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In the event the blind is broken, the sponsor must be informed as soon as possible. The date, 
time, and reason for the unblinding must be documented by the investigator in the 
appropriate section of the electronic case report form (eCRF), and in the source document. 
The documentation received from the IWRS indicating the code break must be retained 
with the patient’s source documents in a secure manner (e.g., sealed envelope) so as not to 
unblind the treatment assignment to the study site, sponsor/contract research organization 
(CRO) personnel. The investigator is also advised not to reveal the study treatment 
assignment to the study site or sponsor personnel. 
6. 
DOSAGE AND ADMINISTRATION 
On Day 1 (Visit 2) of the double-blind treatment phase, patients will be randomized to 
receive placebo, 5.0 mg MIN-117, or 2.5 mg MIN-117, PO, once daily for 6 weeks (Table 
1).   
Study drugs will be packaged using a double-dummy, double-blind design.  The study 
drugs will be packaged in individual patient kits containing 6 weekly blisters, with each 
blister containing medication sufficient for 8 days (1 week of treatment and 1 day of 
overage).  Medications blisters will be dispensed to the patients at Visit 2 (3 blisters), Visit 
3 (2 blisters), and Visit 4 (1 blister) to ensure intra-visit daily dosing, including the allowed 
visit windows (±3 days), are covered.  Daily dose will consist of 2 capsules containing the 
intended dose (MIN-117 or Placebo).  MIN-117 capsules are available in 2.5 mg strength.  
Table 1:  Characteristics of the Treatment and Dosage  
Treatment 
Capsule Strength / Number 
 
Total Number of Capsules 
No. of  
MIN 2.5 mg 
capsules
No. of MIN-117 
placebo 
capsules
 
During  
Study   
Participation
Total 
Capsules 
Dispensed
5.0 mg MIN-117 
2 
- 
 
84 
96 
2.5 mg MIN-117 
1 
1 
 
84 
96 
Placebo 
- 
2 
 
84 
96 
Placebo and MIN-117 capsules are identically matched in appearance. 
The study drug should be administered in a single dose in the morning at approximately 
the same time each day with or without food per patient’s food intake habit. Capsules 
should be swallowed whole with water and not divided, crushed, chewed, or placed in 
water. 
7. 
TREATMENT COMPLIANCE 
The investigator or designated study center personnel will maintain a log of all study drug 
dispensed and returned during the study. Study drug supplies for each patient will be 
inventoried and accounted for throughout the study to verify the patient’s compliance with 
the dosage regimen.  Patients will be counseled regarding compliance at every visit.   
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8. 
STUDY EVALUATIONS 
8.1. 
Study Procedures 
8.1.1. 
Overview 
The Time and Events Schedule that follows the Synopsis summarizes the frequency and 
timing of efficacy, PK, PD, and safety measurements applicable to this study. 
With the exception of fasting safety laboratory and pre-dose PK blood draws, all visit-
specific efficacy assessments during any study visit should be conducted first, before other 
scheduled tests, procedures, or medical consultations planned for the patients at any 
specific visit. 
A serum pregnancy test is required at Screening, Baseline, and the post-study follow-up 
visit for all women of childbearing potential.  Additional urine pregnancy tests may be 
performed, as determined necessary by the investigator or required by local regulation, to 
establish the absence of pregnancy throughout the study.   
During the study, including the end-of-study visit, the total blood volume to be collected 
from each patient will be 136.5 mL (Table 2).  
These estimates are for required blood samples and do not include additional blood samples 
that may be collected at the investigator’s discretion for drug level monitoring or other 
clinical laboratory tests deemed necessary for appropriate patient care in case of occurrence 
of adverse events.  
Table 2:  Estimated Blood Volume Drawn 
Type of Sample 
Volume per 
Sample 
(mL) 
No. of 
Samples 
per Patient 
Total 
Volume of 
Blood  
(mL)a 
Safety
Hematology
3.5
4
14
Chemistry
5.0
4
20
TSH and Serologyb
8.5
1
8.5
PK
6
9
54
PD
15
2
30
Pharmacogenomic
10
1
10
Total blood volume drawn 
 
 
136.5 
a Calculated as number of samples multiplied by amount of blood per sample. 
b Includes HBsAg, anti-HCV, and anti-HIV.
8.1.2. 
Screening Period (Visit 1) 
At the Screening visit, a signed informed consent form for study participation will be 
obtained.  Informed consent must be freely given by the patient and documented by 
signature before any procedures are performed.  The inclusion and exclusion criteria will 
be reviewed to verify the patient’s eligibility, and Screening procedures will be performed 
as detailed in the Time and Events Schedule.   
Patients must meet the DSM-5 diagnostic criteria for moderate to severe MDD, without 
psychotic features. The diagnosis should be confirmed by using the SCID-5.  If patients 
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give informed consent to participate and meet all study entry criteria at Screening, they will 
be tapered off their current psychotropic medications.  Patients will be free of any 
psychotropic medications for a period of 1 week or 2 weeks for MAO inhibitors (including 
reversible inhibitors of monoamine oxidase A), and up to 4 weeks for fluoxetine (i.e., a 
minimum of 5 half-lives of the drug).  This visit may be extended to 4 weeks on a case-by-
cases basis after consultation with the sponsor. 
8.1.3. 
Double-Blind Treatment Phase 
8.1.3.1. 
Visits 2 (Baseline Visit /Randomization) 3, 4, and 5/Early 
Withdrawal (Weeks 1, 2, 4, and 6) – Double-Blind Phase 
Patients will undergo 2 consecutive nights of sleep assessments using Somno-Art on the 
evenings of Day -1, and Day 1.  Sleep recording will be done in outpatient settings at select 
sites.  On the morning of Day 1, all inclusion and exclusion criteria will be verified, 
including all efficacy and safety assessments as per the Time and Events Schedule, and 
eligible patients will be randomized to 1 of 3 treatment groups: placebo, 5.0 mg MIN-117, 
or 2.5 mg MIN-117, to receive the first dose of study treatment.  Pharmacokinetic blood 
samples will be drawn within 1 hour before and 2-4 hours after dosing.   
Refer to the Time and Events Schedule for evaluations and procedures to be performed 
during the double-blind treatment phase. 
If patients terminate from the study early, they will undergo the Visit 5/Early Withdrawal 
Visit. 
8.1.3.2. 
Visit 6 (Post-Study Follow-up; Week 8 or 2 Weeks after 
Early Withdrawal)  
At the end of the study, patients will be evaluated for safety/tolerability at the Post-Study 
Visit, approximately 2 weeks after completing the double-blind treatment phase.  Any 
patient who terminates from the study early will have a Post-Study Follow-up Visit 
approximately 2 weeks following Early Withdrawal.  If any of the laboratory results 
indicate an abnormality that warrants repeating the test, the patient should be fasting for the 
repeat assessment.  Also, patients with ongoing adverse events at the time of the follow-up 
visit will be followed until all significant changes have resolved or become medically 
stable. 
8.2. 
Efficacy 
8.2.1. 
Efficacy Evaluations 
Efficacy will be evaluated based on the change from Baseline in the MADRS total score 
after 6 weeks of treatment or at Early Withdrawal. In addition, other efficacy evaluations 
will be based on the change from Baseline in the CGI-S, HAM-A total score, A-SEX, DSST 
score, IDS-SR30, SHAPS, and PSS, and observed CGI-I score.  Sleep parameters as 
assessed by Somno-Art (at select sites) will also be used to evaluate efficacy at specific 
time points as outlined in the Time and Events Schedule. 
Every effort should be made to ensure that all clinician-reported objective measurements 
are completed by the same individual who made the initial Baseline determinations. 
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The Montgomery-Asberg Depression Rating Scale (MADRS) – The MADRS is a 
physician-rated scale designed to measure depression severity and detects changes due to 
antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item 
not present or normal) to 6 (severe or continuous presence of the symptoms), for a total 
score of 60 (Attachment 2).  Higher scores represent a more severe condition.  The MADRS 
evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, 
lassitude, interest level, pessimistic thoughts, and suicidal thoughts.  The test exhibits high 
inter-rater reliability and its capacity to differentiate between responders and 
non-responders to antidepressant treatment has been shown to be comparable to the 
Hamilton Rating Scale for Depression.   
Hamilton Anxiety Scale (HAM-A) – HAM-A is composed of 14 items, each defined by a 
series of symptoms (Attachment 3).  The subject is asked to rate the gravity of each item 
using a 5-level scale – from 0 to 4, where 0 being not present and 4 being severe – and 
afterwards, the results are collated and tabulated to determine the severity of anxiety.  
Clinical Global Impression- Severity and Improvement (CGI-S and CGI-I) – The CGI-S is 
a physician-rated scale that is designed to rate the severity of the subject’s illness at the 
time of assessment, relative to the clinician's past experience with subjects who have the 
same diagnosis and improvement with treatment. Considering total clinical experience, a 
subject is assessed on severity of mental illness at the time of rating according to: normal 
(not at all ill)=1; borderline mentally ill=2; mildly ill=3; moderately ill=4; markedly ill=5; 
severely ill=6; or extremely ill=7.  The CGI-I is a 7-point scale that requires the clinician 
to assess how much the subject’s illness has improved or worsened relative to a Baseline 
state at the beginning of the intervention and rated as: 1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, 
very much worse.  
See Attachment 4 and Attachment 5 for an example of these scales. 
Inventory of Depressive Symptoms - Subject-Rated – IDS-SR30 – The 30-item IDS 
(Attachment 6; Rush 1996) is designed to assess the severity of depressive symptoms.  The 
IDS is available in the clinician (IDS-C) and self-rated versions (IDS-SR).  The IDS assess 
all the criterion symptom domains designated by the American Psychiatry Association 
DSM-5 to diagnose a major depressive episode.  This assessment can be used to screen for 
depression, although it has been used predominantly as measures of symptom severity, and 
is sensitive to change, with medications, psychotherapy, or somatic treatments, making it 
useful for both research and clinical purposes.  The psychometric properties of the IDS 
have been established in various study samples.  The IDS requires minimal training to 
administer and should be completed in one sitting, and rates symptoms for the prior seven 
days. 
The IDS-SR30 is scored by summing responses to 28 of the 30 items to obtain a total score 
ranging from 0 to 84.  Either appetite increase or decrease, but not both, and weight increase 
or decrease, but not both, are used to calculate the total score.  Higher scores indicate 
increase in severity of depression. 
Snaith-Hamilton Pleasure Scale (SHAPS) – The 14-item SHAPS is a self-administered 
instrument that is used to measure hedonic capacity (Snaith, 1993).  The SHAPS has 
excellent internal consistency, with construct validity, and is unidimensional in assessing 
hedonic capacity among adult outpatients with major depressive disorder (Attachment 7).  
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The pattern of the SHAPS mean scores is consistent with the scoring direction on the 
pleasure/enjoyment item of the IDS (Clinician-administered, sub-item 21); that is, those 
who rarely or are unable to derive pleasure from activities (as coded/scored on IDS sub-
item 21) also have higher levels of anhedonia or lower levels of hedonic capacity (as 
measured via the SHAPS).  The SHAPS is not influenced by age, gender, race, education, 
duration of the current depressive episode, length of illness, or first versus recurrent episode 
of depression. Each of the items has a set of four response categories--Definitely Agree, 
Agree, Disagree, and Strongly Disagree, with either of the Disagree responses receiving a 
score of 1 and either of the Agree responses receiving a score of 0.  Thus, the SHAPS is  
scored as the sum of the 14 items so that total scores ranged from 0 to 14.  A higher total 
SHAPS score indicated higher levels of present state of anhedonia. 
Perceived Stress Scale – PSS – The PSS is the most widely used psychological instrument 
for measuring the perception of stress (Attachment 8).  It is a measure of the degree to 
which situations in one’s life are appraised as stressful.  Items were designed to tap how 
unpredictable, uncontrollable, and overloaded respondents find their lives.  The scale also 
includes a number of direct queries about current levels of experienced stress.   Moreover, 
the questions are of a general nature and hence are relatively free of content specific to any 
sub-population group.  The questions in the PSS ask about feelings and thoughts during the 
last month.  In each case, respondents are asked how often they felt a certain way (Cohen 
1983). 
The Arizona Sexual Experience Scale (A-SEX) – The A-SEX scale is a subject-completed 
scale designed to measure five specific areas that are the core elements of sexual function 
(Attachment 9).  The self-reported 5-item scale has male and female specific versions and 
has been commonly used in clinical studies of depression.  The items are answered on 6-
point Likert scales, ranging from hyperfunction (1) to hypofunction (6).  The recall period 
is the past week.  The total A-SEX score is calculated by adding scores of the five items.  
Each response option for each item is assigned a score from 1-6 (e.g., 1=extremely strong 
to 6=none), with the total score ranging on a scale from 5 to 30.  Lower scores reflect higher 
sexual functioning.  A total A-SEX score of > 19 indicates sexual dysfunction.  
Digit Symbol Substitution Test (DSST) – The DSST will be used to evaluate cognition.  
The DSST is a neuropsychological test sensitive to brain damage, dementia, age, and 
depression. It consists of digit-symbol pairs (e.g., 1/-,2/┴ ... 7/Λ,8/X,9/=) followed by a list 
of digits.  Under each digit the subject should write down the corresponding symbol as fast 
as possible.  The number of correct symbols within the allowed time (e.g., 90 or 120 sec) 
is measured. 
See Attachment 10 for an example of this test. 
Somno-Art – Somno-Art is a new methodology to score sleep.  The device is worn on the 
non-dominant forearm and records the cardiac cycle by photoplethysmography, while body 
movements are recorded by the integrated actimetry.  The actimetry is measured through 
the vector magnitude of accelerations obtained every second in the three dimensions of the 
space 
The  cardiac and actimetry data are sampled and stored at 1 Hz.  The data are then post-
processed in 1-second average “.srt” files that are used for sleep analysis using the Somno-
Art methodology. 
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The following sleep parameters will then be extracted: 
Sleep Onset Latency (SOL): elapsed time between light out time and the first occurrence of 
any sleep stage other than stage W. 
REM sleep Latency (REML): elapsed time between sleep onset and the first occurrence of 
REM sleep. 
Wake After Sleep Onset (WASO): cumulative time of wake episodes occurring between 
sleep onset and light on time. 
Time spent in each sleep stage: cumulative time spent in each sleep stages (N1, N2, N3 or 
REM sleep) between sleep onset and light on time. 
Total Sleep Time (TST): cumulative time spent in N1, N2, N3 and REM sleep from sleep 
onset to light on time. 
Sleep Efficiency Index (SEI): ratio between total sleep time divided by time in bed. 
Number of awakenings (NAW): number of wake episodes exceeding 15 seconds, between 
sleep onset and light on time. 
Number of Sleep Cycles (NSC): a sleep cycle was defined as the elapsed time between sleep 
onset and the end of the first REM sleep phase (1st cycle) or the end of one REM sleep 
phase to the end of the following REM sleep phase (2nd and following cycles).  A REM 
sleep phase can be constituted by several REM sleep episodes.  Two successive REM sleep 
episodes were considered as parts of the same REM sleep phase when they were separated 
by less than 20 min of any other sleep stage. 
8.2.2. 
Efficacy Criteria 
The primary efficacy endpoint will be the change in MADRS total score from Baseline 
(i.e., the start of double-blind treatment) to the end of the double-blind treatment period 
(i.e., Week 6). The primary comparisons will be between each MIN-117 dose group 
(5.0 mg and 2.5 mg) and the placebo group. 
The key secondary endpoint will be the change from Baseline in HAM-A, and it will be 
evaluated similar to the primary efficacy endpoint.   Change from Baseline in CGI-S and 
observed CGI-I scores will also be evaluated as measures of the clinical meaningfulness of 
the changes in the objective measures of depression and anxiety.  The primary comparisons 
will be between each MIN-117 dose groups (5.0 mg and 2.5 mg) and the placebo group. 
The change from Baseline for the remaining efficacy endpoints will be analysed similarly 
to primary endpoint. 
Time to onset of antidepressant effect will include criteria of sustained pre-defined decrease 
in depressive symptomatology and will be analysed using conditional survival analysis. 
In order to establish the clinical relevance of the primary analysis results, the rate of 
responders defined as a MADRS score of ≥ 50%, will be calculated at each assessment 
between Week 1 and Week 6 and the 95% confidence interval for the odds ratio of  
MIN-117 versus placebo computed using a logistic regression model. 
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Time to clinical response (first assessment with a ≥ 50% improvement from Baseline in 
total MADRS score scale) will be analysed using a survival analysis method assuming 
proportional hazard.  Time to ≥ 30% will also be explored. 
The rate of early and sustained full responders (≥ 50% improvement from Baseline in total 
MADRS score and a CGI-I score ≤ 2 at every time points) and the rate of remission in 
MADRS (defined as a score < 12) will be analysed using the same method as for the clinical 
response.  The rate of early and sustained response based on ≥ 30% will also be explored. 
The following efficacy evaluations will be performed at the scheduled visits according to 
the time points provided in the Time and Events Schedule in the following order and in the 
morning (between 8:00 a.m. to 1:00 p.m.) during the 6-week, double-blind treatment phase, 
as applicable: 
 MADRS 
 CGI-S 
 CGI-I 
 HAM-A 
 IDS-SR30 
 SHAPS 
 PSS 
 A-SEX 
 DSST 
8.3. 
Pharmacokinetic Evaluations  
8.3.1. 
Sample Collection and Handling 
Blood samples (6 mL) will be collected for assessing the plasma concentration of MIN-117 
 during the Double-blind Treatment Period at Visits 2, 3, 4, and 5, 
at pre-dose (within 1 hour from dosing) and approximately 2 to 4 hours post-dose 
(approximate time of maximum plasma concentration for MIN-117).  Additionally one 
sample will be collected at the post-study follow-up visit (Visit 6). 
The actual time and date of the blood draw and actual date and time of the last study drug 
administration prior to collection of the PK sample must be accurately recorded on eCRF.  
8.3.2. 
Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of MIN-117 
 
 using validated, specific, and sensitive liquid chromatography-mass 
spectrometry (LC-MS/MS) methods under the supervision of the sponsor’s bioanalytical 
facility or designee. 
Plasma samples will be disposed after the clinical study report is finalized. 
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review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the adverse event section of the eCRF. The following 
tests will be performed: 
 Urinalysis  
Dipstick 
Sediment (if dipstick result is abnormal) 
- specific gravity
- RBC
- pH
- white blood cell (WBC)
- glucose
- epithelial cells
- protein
- crystals
- blood
- casts
- ketones
- bacteria
- bilirubin
- urobilinogen
- nitrite
- leukocyte esterase
 
If dipstick result is abnormal, the sediment will be examined microscopically. 
 Serum Pregnancy Testing for women of childbearing potential: at Screening,  Baseline 
(Visit 2) and Post study Visit (Visit 6). . 
 Urine Pregnancy Testing for women of childbearing potential only: at Baseline (Visit 
2), Visits 4, 5 and 6.  
If results of the pregnancy test(s) are positive, the patient will be excluded or withdrawn 
from the study. Of note, at Baseline (Visit 2), both a urine and a serum pregnancy test will 
be performed.  Enrollment will be based on the result of the urine test performed locally in 
 Hematology: 
 
- hemoglobin
- platelet count
- hematocrit
- red blood cell (RBC) count
- white blood cell (WBC) count 
with differential
 
 Serum Chemistry: 
 
- sodium
- lactic acid dehydrogenase (LDH)
- potassium
- uric acid
- chloride
- calcium
- blood urea nitrogen (BUN)
- phosphorous (inorganic)
- creatinine
- albumin
- glucose (fasting)
- total protein
- AST
- cholesterol (total)
- ALT
- triglycerides
- total bilirubin
- high density lipoprotein (HDL)
- alkaline phosphatase
- low density lipoprotein (LDL)
- gamma-glutamyl transferase (GGT)
-  creatine phosphokinase (CPK)   
- thyroid-stimulating hormone (TSH)
 
 (at Screening only) 
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order not to postpone the randomization.  Nevertheless, this urine pregnancy test will have 
to be confirmed by the serum pregnancy test assessed centrally.  Should there be a 
discrepancy in the results, the result of serum test will prevail.  
 Serology (HBsAg, HCV antibody, and HIV antibodies 1 and 2). 
 Urine Drug Screen and Urine Alcohol: Potential patients will be tested for drugs of 
abuse (cocaine, methadone, amphetamines, cannabinoids, opiates, benzodiazepines, 
barbiturates, tricyclic antidepressants) and alcohol according to the Time and Events 
Schedule. If the results of the urine drug screen (except for prescription 
benzodiazepines, prescription barbiturates, prescription tricyclic antidepressants or 
prescription opiates at Screening) or the urine alcohol test are positive at Screening or 
Baseline, the patient will not be enrolled.  If the screen is positive for cannabinoids, 
they will be excluded. 
Electrocardiogram (ECG)  
Triplicate ECGs will be performed according to the Time and Events Schedule. The visits, 
three 12-lead ECGs will be recorded at least 1 minute apart within 5 minutes after the 
patient is supine for at least 10 minutes.  ECG assessments during the double-blind phase 
should occur prior to the post-dose PK sample. 
Twelve-lead ECGs will be recorded at a paper speed of 25 mm per second until 4 regular 
consecutive complexes are available.  
The following intervals will be assesed: RR, PR, QRS, and QT. Electrocardiogram 
monitoring will include the evaluation of lengthening of the QTc interval using QTcF. 
Vital Signs  
Vital signs will include oral/aural temperature, respiratory rate, pulse, and blood pressure. 
Three consecutive blood pressure and pulse readings will be taken at each visit. Blood 
pressure and pulse should be taken in the arm with the highest pressure, using the same arm 
for each reading and for all visits.  An appropriately sized arm cuff will be used, and the 
size of the cuff should remain constant for all visits. 
Blood pressure and pulse will be taken after the patient has been resting quietly in supine 
position for 5 minutes.  Vital signs assessments during the double-blind phase should occur 
prior to the post-dose PK sample, and after the ECG assessments. 
Physical Examination 
Physical examinations, height, and weight will be performed at the times specified in the 
Time and Events Schedule. 
Any abnormalities present at Baseline, or subsequent changes, will be documented in the 
appropriate sections of the CRF. Any clinically significant abnormalities persisting at the 
end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Emergence of suicidal ideation will be assessed using the C-SSRS, a prospective rating 
scale that tracks both treatment-emergent suicidal ideation and behaviors, and will be 
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performed at the times specified in the Time and Events Schedule.  The C-SSRS has been 
used frequently in clinical studies, is a standard measure for suicidal ideation assessment, 
and its use is in accordance with FDA guidance.  
See Attachment 11 for an example of this scale. 
9. 
PATIENT COMPLETION/WITHDRAWAL 
9.1. 
Completion 
A patient will be considered to have completed the study if he or she has completed 
assessments at Week 6 of the double-blind treatment phase. Patients who prematurely 
discontinue study treatment for any reason before completion of the double-blind treatment 
phase will not be considered to have completed the study. The investigational drug will not 
be available after the completion of the study. 
9.2. 
Withdrawal from the Study and Replacement. 
The patients have the right to withdraw from the study at any time for any reason, without 
the need to justify. 
A patient will be withdrawn from the study for any of the following reasons: 
 Patient withdraws consent. 
 Lost to follow-up. 
 Termination of the study. 
 The investigator believes that for safety reasons (e.g., adverse event) it is in the best 
interest of the patient to stop treatment. 
 The patient becomes pregnant.  
 Failure to use an acceptable method of birth control.  
 Significant deviation from the protocol.  
 Occurrence of a treatment-related serious adverse event. 
 Concurrent illness and requirement of a prohibited medication. 
 The patient meets one of the following .stopping criteria: 
o Patient with significant increase in ALT [i.e., > 5 upper limit of normal (ULN)]. 
o Patient with abnormal laboratory results with simultaneous increases of total 
bilirubin (> 2 ULN), ALT (> 3 ULN) and alkaline phosphatases (< 1.5 ULN). 
o Patient with sustained mean QTcF (calculated using Fridericia’s formula) value 
> 500 msec (confirmed by a second ECG under strict resting position and at 
minimum at ½ hour distant from the first measurement). 
o Patient with sustained increase of more than 60 msec in the mean QTcF compared 
to Baseline (confirmed by a second ECG under strict resting conditions). 
If a patient discontinues treatment before the double-blind phase ends, attempts to obtain 
end-of-treatment and follow-up assessments must be made.  In case a patient is lost to 
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follow-up, every possible effort must be made by the study site personnel to contact the 
patient and determine the reason for discontinuation/withdrawal.  The measures taken to 
follow-up must be documented.  When a patient withdraws before completing the study, 
the reason for withdrawal is to be documented in the eCRF and in the source document.  
Study drug assigned to the withdrawn patient may not be assigned to another patient.  
Patients who withdraw will not be replaced. 
10. 
STATISTICAL METHODS  
10.1. 
Sample Size Determination 
The sample size for this study is based on the assumption of a treatment difference of at 
least 4 points in the mean change from Baseline to end point in MADRS total score between 
any MIN-117 dose group and placebo. A standard deviation of 9 in the change in MADRS 
total score from Baseline is used. Using the Bonferroni multiplicity adjustment for multiple 
comparisons of 2 MIN-117 dose groups with placebo and assuming an allocation of 2:1:1 
for placebo and the 2 MIN-117 doses, 146 patients in the placebo group and 73 patients in 
each MIN-117 dose group are required to detect the treatment difference of 4 points with a 
power of 80% at an overall 2-sided significance level of 0.05. When adjusted for a rate of 
10% of patients who will not have either Baseline or post-Baseline efficacy assessments, 
the required number of patients becomes 162 for the placebo group and 81 for each of the 
two MIN-117 dose groups. Therefore, the total number of patients across the 3 treatment 
groups will be 324. 
10.2. 
Data Set 
One analysis set  is included in this study, the Intent-to-Treat (ITT) analysis set.  The ITT 
analysis set will consist of all patients as all randomized patients who receive at least 1 dose 
of study drug during the 6-week double-blind period. This analysis set will be used for 
efficacy and safety analyses of the 6-week double-blind period.  Analyses of change from 
Baseline will include only patients who have both Baseline and post-Baseline data during 
the 6-week double-blind treatment period. 
Details about the analysis of the efficacy analyses will be explained in the Statistical 
Analysis Plan (SAP). 
10.3. 
Patient Information 
For all patients who received at least one dose of study drug, descriptive statistics by dose 
group and also totaled over all dose groups will be provided for age, body mass index, 
weight in kilograms, and height in centimeters. Gender will be tabulated by dose group and 
overall. The BMI will be calculated and presented using the following formula: BMI = 
(weight in kg/height in meters2). 
The number and percentage of patients who complete the double-blind treatment period 
and of patients who prematurely discontinue during the same period will be presented for 
each treatment arm and pooled across treatment arms for the ITT analysis set. The reasons 
for premature discontinuation from the double-blind treatment period as recorded on the 
termination pages of the eCRFs will be summarized (number and percentage) by treatment 
arm for the ITT analysis set. The percentage of premature discontinuations will be 
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compared overall and for each discontinuation reason between treatment groups using the 
Fisher exact test. 
The number and percent of patients with a current or historical presence of abnormal 
finding in medical history will be summarized by dose group and totaled over all dose 
groups. 
10.4. 
Extent of Exposure and Treatment Compliance 
Investigational Product 
Exposure to double-blind treatment for the ITT analysis set during the double-blind 
treatment period will be summarized for treatment duration, calculated as the number of 
days from the date of the first dose of double-blind treatment taken to the date of the last 
dose taken, inclusive, for the double-blind treatment period.  Descriptive statistics will be 
presented by treatment group. 
Prior and Concomitant Medications 
Prior medications are defined as any medication taken before the date of the first dose of 
double-blind treatment. Concomitant medications are defined as any medication taken on 
or after the date of the first dose of double-blind treatment. 
Both prior medication use and concomitant medication use (during the double-blind 
treatment period) will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and will be presented in data listings, and only concomitant medication will 
be summarized by the number and proportion of patients in each treatment arm receiving 
each medication within each therapeutic class for the ITT analysis set. Multiple medication 
use by a patient will only be counted once.  
Measurement of Treatment Compliance 
Dosing compliance for a specified period is defined as the total number of tablets actually 
taken by a patient during that period divided by the number of tablets prescribed during the 
same period multiplied by 100. The total number of tablets actually taken will be calculated 
from the study medication record. The number of tablets prescribed for a specific treatment 
period will be calculated by multiplying the number of days in that period by the number 
of tablets prescribed per day. Descriptive statistics for treatment compliance will be 
presented by treatment arm for each period between 2 consecutive visits when medication 
dispensation occurred, as well as for the entire double-blind treatment period. 
10.5. 
Efficacy Analyses  
Primary Estimand 
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 3 components: 
Population:  patients with a pre-defined minimum threshold and fluctuation of depressive 
symptoms as captured by IDS-SR30 score. 
Endpoint:  change in MADRS total score from Baseline to the end of Week 6. 
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Measure of Intervention:  the effect of the initially randomized treatment that would have 
been observed had all patients remained on their treatment throughout the double-blind 
phase. 
The primary efficacy analysis will be based on the ITT Population.  Baseline for efficacy 
is defined as values recorded at Visit 2 (Baseline).   
Analyses of change from Baseline will include only patients who have both Baseline and 
post-Baseline data during the 6-week double-blind period. 
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance.  All confidence intervals will be 2-sided 95% confidence intervals, unless 
stated otherwise.  
Additionally, by-visit analyses will be done for all efficacy parameters using the MMRM 
and last observation carried forward (LOCF) approaches (described in Section 10.5.1), 
unless stated otherwise.  
10.5.1. 
Primary Endpoint 
The primary efficacy endpoint will be the change in the MADRS total score from Baseline 
to Week 6.  This endpoint will be analyzed using MMRM with treatment arm 5.0 mg MIN-
117 dose, 2.5 mg MIN-117 dose, placebo), pooled study center (by country or region based 
on enrollment), visit, and treatment arm-by-visit interaction as fixed effects, patient nested 
in treatment as random effect, and Baseline total MADRS score as covariate.  An 
unstructured covariance matrix will be used to model the covariance of within-patient 
scores.  The Kenward-Roger approximation (Kenward 1997) will be used to estimate 
denominator degrees of freedom.  In this analysis in which the MMRM is fitted to all post-
Baseline data, patients in the ITT analysis set who do not have complete data will still 
contribute to the estimates at Week 6, but will have less weight in the analysis than those 
patients with complete data (i.e., only the observed cases without imputation of missing 
values will be used in this analysis).  Comparisons against placebo will be performed using 
the appropriate contrasts from this model at Week 6.  An analysis of observed scores 
available at each visit will also be performed. 
The adjustment for multiplicity within the family of primary hypotheses will utilize the 
conventional Hochberg procedure for the purpose of reporting of results.  This procedure 
will allow the null hypothesis of no treatment difference for both the 5.0 mg and 2.5 mg 
doses versus placebo to be rejected if largest p-value of comparing either of these 2 doses 
versus placebo is at or below 0.050.  Otherwise, the lowest of these 2 p-values must be at 
or below 0.025 to allow for rejecting the null hypothesis for the representative dose. 
The overall type I error rate for testing the 2 MIN-117 doses versus placebo for the primary 
and the key secondary endpoint will be controlled at the 2-sided 0.05 level.  The primary 
family of hypotheses (corresponding to the primary endpoint) and the secondary family of 
hypotheses (corresponding to the key secondary endpoint, the change from Baseline in 
HAM-A total score) will be tested in a sequential manner with suitable adjustment for 
multiplicity within the family of primary hypotheses and within the family of the secondary 
hypotheses such that a MIN-117 dose versus placebo null hypothesis contrast testing within 
the secondary family can be evaluated only when the same null hypothesis contrast in the 
primary family was rejected. 
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Sensitivity analyses of the primary endpoint will also be performed and will be detailed 
further in the statistical analysis plan. These will include an ANCOVA model with factors 
for treatment and region and Baseline MADRS total score as a covariate. In this analysis, 
patients without a MADRS total score at Week 6 will have an earlier post-Baseline score 
imputed using the last-observation-carried-forward (LOCF) method. Other sensitivity 
analyses may also be performed to investigate the robustness of treatment estimates to the 
observed pattern of, and/or reason for, early withdrawals. 
10.5.2. 
Secondary and Exploratory Endpoints 
The change from Baseline in CGI-S and observed CGI-I scores will be analyzed by means 
of an ANCOVA of ranked data, with treatment (MIN-117 doses and placebo) as a factor, 
and Baseline CGI-S value as a covariate. 
Change from Baseline for efficacy parameters, HAM-A, IDS-SR30, SHAPS, DSST, PSS, 
A-SEX, and sleep parameters will be analyzed using the same MMRM model and weighted 
combination test procedure as described above. 
10.5.3. 
Additional Efficacy Analyses 
 The rate of responders defined as a decrease in MADRS score of ≥ 50%, will be 
calculated at each assessment between Week 1 and Week 6 and will be analyzed using 
a logistic regression model with the treatment group and the corresponding Baseline 
score as explanatory variable for the LOCF approach only. 
 Time to clinical response (first assessment with a ≥ 50% improvement from Baseline 
in total MADRS score scale, and ≥ 30% improvement from Baseline in total MADRS 
score scale) will be analyzed using cox-regression model with treatment group and the 
corresponding Baseline score as covariate.   
 The rate of early responders (≥ 50% improvement from Baseline in total MADRS score 
and a CGI-I score ≤ 2 at each post-Baseline visit) will be analyzed using a logistic 
regression model with the treatment group and the corresponding Baseline score as 
explanatory variable for the LOCF approach only.  Early responders defined using ≥ 
30% improvement from Baseline in total MADRS score and a CGI-I score ≤ 2 at each 
post-Baseline visit will also be analyzed.   
 The rate of sustained full responders (≥ 50% improvement from Baseline in total 
MADRS score at every time points and a CGI-I score ≤ 2 at every post-Baseline visit, 
once achieved) using a logistic regression model with the treatment group and the 
corresponding Baseline score as explanatory variable for the LOCF approach only.  
Sustained full responders defined using ≥ 30% improvement from Baseline in total 
MADRS score at every time points and a CGI-I score ≤ 2 at every post-Baseline visit, 
once achieved, will also be analyzed. 
 The rate of remission in MADRS (defined as a score < 12) will be analyzed using a 
logistic regression model with the treatment group and the corresponding Baseline 
score as explanatory variable for the LOCF approach only. 
 Changes from Baseline in single MADRS rating scale items and for core mood items 
(items 1 & 2 combined) will be analyzed using an ANCOVA of ranked data, with 
treatment as a factor, and Baseline value as a covariate. 
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10.6. 
Interim Analysis 
No interim analyses are planned for this study.  
10.7. 
Pharmacokinetics  
Individual plasma levels of MIN-117 
, will be tabulated with the 
corresponding time related to study drug administration. Descriptive statistics will be 
summarized for MIN-117
 
Population pharmacokinetic analysis of plasma concentration-time data of MIN-117 
 
 will be performed using nonlinear mixed-effects modeling. Data may be 
combined with those of a selection of Phase 1 studies to support a relevant structural model.  
Available patient characteristics (demographics, laboratory variables, genotypes, etc.) will 
be tested as potential covariates affecting pharmacokinetic parameters.  Details will be 
given in a population pharmacokinetic analysis plan and results of the population 
pharmacokinetic analysis will be presented in a separate report. 
10.8. 
Safety Analyses 
All patients randomized to treatment who receive at least one dose of double-blind study 
drug will be included in the safety analyses. Summary statistics will be provided for all 
safety data using appropriate descriptive statistics adverse events, C-SSRS, laboratory tests, 
ECGs, and vital signs. 
10.8.1. 
Adverse Events 
The original terms used in the eCRFs by investigators to identify adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reported 
adverse events with onset during the 6-week double-blind period (i.e., treatment-emergent 
adverse events or TEAE) will be included in the analysis. For each adverse event, the 
percentage of patients who experienced at least one occurrence of the given event will be 
summarized by treatment group.  
Special attention will be given to those patients who died, or who discontinued treatment 
due to an adverse event, or who experienced a severe or a serious adverse event 
(e.g., summaries, listings, and narrative preparation may be provided, as appropriate). 
A TEAE that occurs > 14 days after the date of the last dose of double-blind treatment will 
not be summarized.  
10.8.2. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test.  Reference ranges and 
markedly abnormal results (specified in the SAP) will be used in the summary of laboratory 
data.  Descriptive statistics will be calculated for each laboratory analyte at Baseline and at 
each scheduled time point.  Changes from Baseline results will be presented in pre- versus 
post-treatment cross tabulations (with classes for below, within, and above normal ranges).  
A listing of patients with any laboratory results outside the reference ranges will be 
provided.  A listing of patients with any markedly abnormal laboratory results will also be 
provided. 
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10.8.3. 
Vital Signs 
Descriptive statistics of body temperature, pulse, respiratory rate, and blood pressure 
(systolic and diastolic) values and changes from Baseline will be summarized at each 
scheduled time point. The percentage of patients with values beyond clinically important 
limits will be summarized. Clinically important limits will be defined in the SAP. 
10.8.4. 
Electrocardiogram (ECG) 
The effects on cardiovascular variables will be evaluated by means of descriptive statistics 
and frequency tabulations.  These tables will include observed values and changes from 
Baseline values (the pre-dose ECG will be used as Baseline) to allow detection of clinically 
relevant changes in individuals. 
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, 
QT interval, and QTc interval corrected for heart rate using QTcF.  QTcF values will be 
tabulated for their absolute values and also tabulated relative to Baseline measurements in 
order to detect individual QTcF changes (ICH-E14 2005).   
Descriptive statistics of QTcF intervals and changes from Baseline will be summarized at 
each scheduled time point. The percent of patients with QTc interval > 450 msec, > 480 
msec, or > 500 msec will be summarized as will the percent of patients with QTcF interval 
increases from Baseline of 30  to 60 msec or > 60 msec. 
All important abnormalities in ECG waveform that are changes from the Baseline readings 
will be reported (e.g., changes in T-wave morphology or the occurrence of U-waves). 
10.8.5. 
Physical Examination 
Physical examination abnormalities will be listed. 
10.8.6. 
Other Safety Parameters 
Observed and changes from Baseline in heart rate will be summarized in tabular format 
showing descriptive statistics. 
10.8.6.1. 
Columbia Suicide Severity Rating Scale (C-SSRS)  
Results from the C-SSRS will be tabulated by treatment. 
11. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of patients, investigators, and the sponsor, and are 
mandated by regulatory agencies worldwide.  
11.1. 
Definitions 
11.1.1. 
Adverse Event Definitions and Classifications 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study patient 
administered a medicinal (investigational or non-investigational) product. An adverse event 
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does not necessarily have a causal relationship with the treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational or 
non-investigational) product, whether or not related to that medicinal (investigational or 
non-investigational) product. (Definition per International Conference on Harmonisation 
[ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the Baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 
Note: The sponsor collects adverse events starting with the signing of the informed consent 
form (refer to Section 11.3.1, all Adverse Events for time of last adverse event recording). 
Serious Adverse Event 
An SAE is defined as any AE that results in any of the following: 
 Death:  The patient died as the result of the event. 
 Life-threatening event:  Any AE that places the patient, in the view of the 
Investigator or Sponsor, at immediate risk of death from the AE as it occurred, 
i.e., does not include an AE that had it occurred in a more severe form, might have 
caused death. 
 Required or prolonged inpatient hospitalization:  The AE resulted in 
hospitalization or prolonged an existing hospitalization.  Since hospitalization may be 
part of the study, only hospitalizations that are longer than expected based on 
Investigator judgment, will be considered prolonged hospitalizations. 
 Persistent or significant disability/incapacity:  An AE that results in a substantial 
disruption of a person’s ability to conduct normal life functions. 
 Congenital anomaly/birth defect:  A congenital anomaly/birth defect that occurs in 
the offspring of a patient exposed to the IP. 
 Important medical events:  An AE that may not result in death, be life-threatening, 
or require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in situations other than those listed above.  For example, 
important medical events may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the outcomes listed in the definition above (e.g., suspected transmission of an infectious 
agent by a medicinal product is considered a serious adverse event).  Any adverse event is 
considered a serious adverse event if it is associated with clinical signs or symptoms judged 
by the investigator to have a significant clinical impact. 
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Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An unlisted AE, the nature or severity of which is not consistent with the applicable product 
reference safety information.  For an investigational product, the expectedness of an AE 
will be determined by whether or not it is listed in the Investigator's Brochure.   
Adverse Event Associated With the Use of the Drug 
An adverse event is considered associated with the use of the drug if the attribution is 
possible, probable, or definite as per the definitions listed in Section 11.1.2. 
11.1.2. 
Attribution Definitions 
Every effort should be made by the investigator to try to explain each AE and assess its 
relationship, if any, to the study drug. The temporal relationship of the event to study drug 
administration should be considered in the causality assessment (i.e., if the event starts soon 
after study drug administration and resolves when the study drug is stopped). 
Causality should be assessed using the following categories 
Unrelated: An adverse event that is not related to the use of the drug. 
Possibly/probably related: An adverse event that might be due to the use of the drug. An 
alternative explanation, e.g., concomitant drug(s), concomitant disease(s), is inconclusive 
or unlikely.  The relationship in time is reasonable; therefore, the causal relationship cannot 
be excluded. 
Definitely: An adverse event that cannot be reasonably explained by an alternative 
explanation, e.g., concomitant drug(s), concomitant disease(s). The relationship in time is 
very suggestive. 
11.1.3. 
Severity Criteria  
An assessment of severity grade will be made using the following general categorical 
descriptors: 
Mild: Awareness of symptoms that are easily tolerated causing minimal discomfort and 
not interfering with everyday activities. 
Moderate: Sufficient discomfort is present to cause interference with normal activity. 
Severe: Extreme distress causing significant impairment of functioning or incapacitation.  
Prevents normal everyday activities. 
The investigator should use clinical judgment in assessing the intensity of events not 
directly experienced by the patient (e.g., laboratory abnormalities).  
11.1.4. 
Action Taken and Outcome  
For all AEs reported, the following will also be specified: 
 Actions taken: none, medication required, tests required, hospitalization required or 
prolonged, treatment unblinded, study drug withdrawn/interrupted, other-specify   
 Outcome and date of outcome according to the following definitions: 
 Recovered/resolved 
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 Recovering/resolving 
 Not recovered/not resolved 
 Recovered with sequelae/resolved with sequelae 
 Fatal 
 Unknown 
 Seriousness: yes or no (criteria for SAE see above) 
11.2. 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting 
and/or safety evaluation include, but are not limited to: 
 
Overdose of a sponsor study drug. 
 
Suspected abuse/misuse of a sponsor study drug, defined as 3 x daily dose within any 
24-hour period. 
 
Accidental or occupational exposure to a sponsor study drug. 
 
Medication error involving a sponsor product (with or without patient/patient exposure 
to the sponsor study drug, e.g., name confusion). 
 
Exposure to a sponsor study drug during pregnancy or breastfeeding. 
Special reporting situations should be recorded in the eCRF.  Any special reporting 
situation that meets the criteria of a SAE should be recorded on the SAE page of the eCRF. 
11.3. 
Procedures 
11.3.1. 
All Adverse Events 
All AEs, whether serious or non-serious, will be reported from the time a signed and dated 
informed consent form is obtained until completion of the last study-related procedure (may 
include contact for follow-up of safety).  Serious adverse events, including those 
spontaneously reported to the investigator within 30 days after the last dose of study drug, 
must be reported using the Serious Adverse Event Form.  The sponsor will evaluate any 
safety information that is spontaneously reported by an investigator beyond the time frame 
specified in the protocol. 
All events that meet the definition of a serious adverse event will be reported as serious 
adverse events, regardless of whether they are protocol-specific assessments.  
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, 
must be recorded using medical terminology in the source document and the eCRF.  
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as “upper respiratory infection”).  Investigators must record in the eCRF 
their opinion concerning the relationship of the AE to study therapy.  All measures required 
for adverse event management must be recorded in the source document and reported 
according to sponsor instructions. 
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The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory 
authorities.  The sponsor will also report to the investigator all SAEs that are unlisted 
(unexpected) and associated with the use of the drug.  The investigator (or sponsor where 
required) 
must 
report 
these 
events 
to 
the 
appropriate 
Independent 
Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.  
Patients (or their designees, if appropriate) must be provided with a “study card” indicating 
the name of the investigational study drug, the study number, the investigator’s name, a 
24-hour emergency contact number, and, if applicable, excluded concomitant medications. 
11.3.2. 
Serious Adverse Events 
All SAEs occurring during the study must be reported by the investigational staff within 
24 hours of their knowledge of the event.  The following contact information must be used: 
Email:  
 
In the unlikely event that the email address results in a delivery failure, one of the following 
backup fax numbers must be used: 
For US cases: 
 
For Europe/Rest of the world cases: 
 
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse 
Event Form, which must be completed and signed by a member of the investigational staff, 
and transmitted to the sponsor within 24 hours.  The initial and follow-up reports of a SAE 
should be made by email. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient’s participation in the study, must be followed until any of the 
following occurs: 
 The event resolves. 
 The event stabilizes. 
 The event returns to Baseline, if a Baseline value is available. 
 The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct. 
 It becomes unlikely that any additional information can be obtained (patient or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts). 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during 
the course of a patient’s participation in a clinical study must be reported as a SAE, except 
hospitalizations for the following: 
 Social reasons in absence of an adverse event. 
 Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). 
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Suspected transmission of an infectious agent by a medicinal product should be reported as 
a SAE.  
 The cause of death of a patient in the study within 30 days of the last dose of study 
drug, whether or not the event is expected or associated with the study drug, is 
considered a SAE.  
11.3.3. 
Pregnancy 
All initial reports of pregnancy must be reported to the sponsor by the investigational staff 
within 24 hours of their knowledge of the event using the appropriate pregnancy 
notification form. Abnormal pregnancy outcomes are considered serious adverse events 
and must be reported using the Serious Adverse Event Form. Any patient who becomes 
pregnant during the study must be promptly withdrawn from the study. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
patients included in the study will be reported by the investigational staff within 24 hours 
of their knowledge of the event using the appropriate pregnancy notification form. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required. 
11.4. 
Contacting Sponsor Regarding Safety  
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding safety issues or questions regarding the study are listed on the Contact 
Information page(s), which will be provided as a separate document. 
12. 
PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related 
to manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, 
quality, durability, and reliability of a product, including its labeling or package integrity.  
PQCs may have an impact on the safety and efficacy of the product.  Timely, accurate, and 
complete reporting and analysis of PQC information from clinical studies are crucial for 
the protection of patients, investigators, and the sponsor, and are mandated by regulatory 
agencies worldwide.  The sponsor has established procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of PQC information; all clinical 
studies conducted by the sponsor or its affiliates will be conducted in accordance with those 
procedures. 
12.1. 
Procedures 
All initial PQCs must be reported to the sponsor by the investigational staff as soon as 
possible after being made aware of the event. 
If the defect is combined with a serious adverse event, the investigational staff must report 
the PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 11.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor. 
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12.2. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding product quality issues are listed on the Contact Information page(s), 
which will be provided as a separate document. 
13. 
STUDY DRUG INFORMATION 
13.1. 
Physical Description of Study Drug(s) 
MIN-117 will be available in capsules of 2.5 mg strength.  
 
 
  All excipients of 
the MIN-117 capsules are derived from sources that are in compliance with Committee for 
Proprietary Medicinal Products guidelines on minimizing the risk of transmitting animal 
spongiform encephalopathy agents via medicinal products.  
 
 
  Certificate of Analysis and 
TSE/BSE statement of the batch to be used in the proposed clinical trial are checked and 
accepted according to the regulatory requirements.   
MIN-117 placebo will be 
 made of white hard gelatin containing 
silicified microcrystalline cellulose and vegetable magnesium stearate.  All excipients of 
the MIN-117 placebo capsules are derived from sources that are in compliance with 
Committee for Proprietary Medicinal Products guidelines on minimizing the risk of 
transmitting animal spongiform encephalopathy agents via medicinal products.  
 
 
  Certificate of Analysis and TSE/BSE statement of 
the batch to be used in the proposed clinical trial are checked and accepted according to the 
regulatory requirements. 
13.2. 
Packaging 
The study drug will be packaged in individual patient kits containing sufficient medication 
with overage for each intra-visit duration.  
13.3. 
Labeling 
Each kit containing study drug will have a product and study-specific label containing 
information that meets the applicable regulatory requirements.  The study dispensing labels 
will contain dosing instructions, quantity of product dispensed, and spaces to record subject 
number, visit number, date dispensed, and investigator’s name/site number.  
13.4. 
Preparation, Handling, and Storage  
All study drugs must be stored in a controlled environment at room temperature (i.e.,  
 from 15 to 25 oC).   
13.5. 
Drug Accountability 
The investigator is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study.  The dispensing of study drug to the 
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patient, and the return of study drug from the patient (if applicable), must be documented 
on the drug accountability form.  Patients must be instructed to return all original 
containers, whether empty or containing study drug.  Study drug returned by study patients 
will be stored and disposed of according to the sponsor’s instructions.  Site staff must not 
combine contents of the study drug containers. 
Study drug must be handled in strict accordance with the protocol and the container label 
and will be stored in a limited access area or in a locked cabinet under appropriate 
environmental conditions.  Unused study drug, and study drug returned by the patient 
(if applicable), must be available for verification by the sponsor’s site monitor during 
on-site monitoring visits.  The return to the sponsor of unused study drug, or used returned 
study drug for destruction, will be documented on the Drug Return Form.  When the site is 
an authorized destruction unit and study drug supplies are destroyed on site, this must also 
be documented on the Drug Return Form. 
Study drug should be dispensed under the supervision of the investigator, a qualified 
member of the investigational staff, or by a hospital/clinic pharmacist.  Study drug will be 
supplied only to patients participating in the study.  Returned study drug must not be 
dispensed again, even to the same patient. Returned study drug may not be relabeled or 
reassigned for use by other patients.  The investigator agrees neither to dispense the study 
drug from, nor store it at, any site other than the study sites agreed upon with the sponsor. 
14. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
 eCRF and infrastructure 
 Forms and questionnaires for special assessments 
 Pharmacokinetic blood sampling supplies 
 PD blood sampling supplies 
 Safety laboratory sampling supplies 
 Patient education material 
 Somno-Art device 
 ECG device 
 Patient trial card indicating the IMP, the study number, the investigator's name and an 
emergency telephone number providing 24-hour service.  
15. 
ETHICAL ASPECTS 
15.1. 
Study-Specific Design Considerations 
Clinical Trial in Major Depressive Disorder 
Major depression is a serious and common illness that can run a chronic course and is 
associated with both frequent morbidity and high mortality (WHO 2006). There is a clear 
need to develop novel and improved therapeutics for major depressive disorders. 
MIN-117 has shown antidepressant-like effects in animal models and has unique 
mechanism of action and good tolerability. These characteristics make MIN-117 an 
attractive compound to test for efficacy in major depression.  
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Selection of Patients 
The primary aim of the study is to evaluate the efficacy, safety and tolerability of MIN-117 
for the treatment of patients MDD.  Thus, the study cannot be completed in healthy subjects.  
Patients selected in the study will have adequate capacity to give consent for participation 
in the study. 
Justification for Using Placebo 
Assessing the potential efficacy of a new compound for the treatment of patients with MDD 
requires adequate and well-controlled clinical studies.  For a new compound this can be 
achieved either through a placebo-controlled study or through a study comparing it to an 
active comparator through a non-inferiority design.  For non-inferiority studies, previous 
placebo-controlled studies have to show consistently the superiority of the active standard 
drug to placebo. A large proportion of studies with antidepressant fail even with previously 
proven antidepressant, making assay sensitivity difficult to establish and thus, a 
non-inferiority design invalid (Laughren 2001). Therefore, randomized, controlled studies 
that rely on comparison with the standard of care drug(s) alone may generate unreliable 
results with limited assay sensitivity.  
Though some continue to consider it unethical to do placebo-controlled studies due to the 
potential risk of irreversible harm (Rothman 1994), the use of a placebo-controlled study 
design remains the gold standard for assessment of efficacy of new compound to allow for 
scientifically meaningful results.  Placebo-controlled studies in major depressive disorders 
are ethically and scientifically justifiable (Temple 2000; Laughren 2001). 
Precautions to Ensure Patient Safety in the Study  
Patients may participate in the study only if they have adequate capacity to give consent 
and after fully understanding the potential risks and giving an informed consent. Patients 
may discontinue the study at any time.  The probability of receiving placebo and the concept 
of random assignment will be explained to the patient.  The duration of the study is short, 
minimizing the time on placebo.  Potential disadvantages and adverse events of 
participating in the study and alternative treatment options will be discussed. Patients at 
high risk of suicide will be excluded from participating.  Patients who do not respond during 
the study may drop out during the study and clinical care will be arranged between the 
study investigator and their physician. 
Compensation for any study requirements or procedure will be fair per local standards and 
approved by the participating sites EC in order to not offer any undue incentive to 
participate in the study. 
Specific entry criteria, including exclusion of patients with clinically apparent liver disease, 
hepatic insufficiency, and other medically unstable systemic diseases, and significantly 
abnormal ALT, bilirubin, hematology, or other test results at Screening or Baseline, will 
further ensure the appropriate selection and safety of patients who enter the study.  During 
the study, patients who are unable to tolerate study drug will be discontinued from the 
study.  Only patients who have not adequately responded to their antidepressant where a 
clinician would consider changing it for lack of response or poor tolerability in addition to 
meeting the severity criteria for the study will be enrolled. 
Only highly qualified and experienced investigators will be participating in the study. 
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15.2. 
Regulatory Ethics Compliance 
15.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and 
applicable regulatory and country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the rights, 
safety, and well-being of study patients are protected, consistent with the principles that 
originated in the Declaration of Helsinki and that the clinical study data are credible. 
15.2.2. 
Independent Ethics Committee or Institutional Review 
Board (IEC/IRB)  
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents: 
 Final protocol and, if applicable, amendments 
 Sponsor-approved informed consent form (and any other written materials to be 
provided to the patients) 
 Investigator’s Brochure (or equivalent information) and amendments 
 Sponsor-approved patient recruiting materials 
 Information on compensation for study-related injuries or payment to patients for 
participation in the study, if applicable 
 Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by IEC/IRB) 
 Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for patients 
 Any other documents that the IEC/IRB requests to fulfill its obligation. 
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any), the informed consent form, applicable recruiting materials, 
and patient compensation programs, and the sponsor has received a copy of this approval. 
This approval letter must be dated and must clearly identify the IEC/IRB and the documents 
being approved. 
During the study the investigator (or sponsor where required) will send the following 
documents and updates to the IEC/IRB for their review and approval, where appropriate:  
 Protocol amendments 
 Revision(s) to informed consent form and any other written materials to be provided to 
patients 
 If applicable, new or revised patient recruiting materials approved by the sponsor 
 Revisions to compensation for study-related injuries or payment to patients for 
participation in the study, if applicable 
 Investigator’s Brochure amendments or new edition(s) 
 Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB 
(at least annually) 
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 Reports of adverse events that are serious, unexpected, and related with the 
investigational drug 
 New information that may adversely affect the safety of the patients or the conduct of 
the study 
 Deviations from or changes to the protocol to eliminate immediate hazards to the 
patients 
 Report of deaths of patients under the investigator's care 
 Notification if a new investigator is responsible for the study at the site 
 Annual Safety Report and Line Listings, where applicable 
 Any other requirements of the IEC/IRB. 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for patients, data or trial conduct), the amendment and applicable informed 
consent form revisions must be submitted promptly to the IEC/IRB for review and approval 
before implementation of the change(s).  
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion. 
15.2.3. 
Informed Consent 
Each patient must give written consent according to local requirements after the nature of 
the study has been fully explained.  The consent form must be signed before performance 
of any study-related activity. The consent form that is used must be approved by both the 
sponsor and by the reviewing IEC/IRB.  The informed consent should be in accordance 
with principles that originated in the Declaration of Helsinki, current ICH and GCP 
guidelines, applicable regulatory requirements, and sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the 
investigational staff must explain to potential patients (or their legal representatives) the 
aims, methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail.  Patients will be informed that their 
participation is voluntary and that they may withdraw consent to participate at any time.  
They will be informed that choosing not to participate will not affect the care the patient 
will receive for the treatment of his or her disease.  Patients will be told that alternative 
treatments are available if they refuse to take part and that such refusal will not prejudice 
future treatment.  Finally, they will be told that the investigator will maintain a patient 
identification register for the purposes of long-term follow-up if needed and that their 
records may be accessed by health authorities and authorized sponsor staff without 
violating their confidentiality, to the extent permitted by the applicable law(s) or 
regulations.  By signing the informed consent form the patient (or legal representative) is 
authorizing such access, and agrees to allow his or her study physician to re-contact the 
patient for the purpose of obtaining consent for additional safety evaluations, if needed, or 
to obtain information about his or her survival status. 
The patient will be given sufficient time to read the informed consent form and the 
opportunity to ask questions.  After this explanation and before entry into the study, consent 
should be appropriately recorded by means of the patient’s personally dated signature.  
After having obtained the consent, a copy of the informed consent form must be given to 
the patient. 
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If the patient is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) 
and should personally date and sign the informed consent form after the oral consent of the 
patient is obtained. 
15.2.4. 
Privacy of Personal Data 
The collection and processing of personal data from patients enrolled in this study will be 
limited to those data that are necessary to investigate the efficacy, safety, quality, and utility 
of the investigational study drug(s) used in this study. 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations.  Appropriate technical and organizational measures to protect the personal data 
against unauthorized disclosures or access, accidental or unlawful destruction, or accidental 
loss or alteration must be put in place. Sponsor personnel whose responsibilities require 
access to personal data agree to keep the identity of study patients confidential. 
The informed consent obtained from the patient (or legal representative) includes explicit 
consent for the processing of personal data and for the investigator to allow direct access 
to his or her original medical records for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection.  This consent also addresses the transfer of the data to other 
entities and to other countries. 
The patient has the right to request through the investigator access to his or her personal 
data and the right to request rectification of any data that are not correct or complete.  
Reasonable steps will be taken to respond to such a request, taking into consideration the 
nature of the request, the conditions of the study, and the applicable laws and regulations. 
15.2.5. 
Country Selection 
This study is being conducted in United States of America and select European countries.  
16. 
ADMINISTRATIVE REQUIREMENTS 
16.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal 
amendment.  All protocol amendments must be issued by the sponsor, and signed and dated 
by the investigator.  Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-
acceptance, except when necessary to eliminate immediate hazards to the patients, in which 
case the amendment must be promptly submitted to the IEC/IRB and relevant competent 
authority.  Documentation of amendment approval by the investigator and IEC/IRB must 
be provided to the sponsor or its designee.   
During the course of the study, in situations where a departure from the protocol is 
unavoidable, the investigator or other physician in attendance will contact the appropriate 
sponsor representative (see Contact Information pages provided separately).  Except in 
emergency situations, this contact should be made before implementing any departure from 
the protocol.  In all cases, contact with the sponsor must be made as soon as possible to 
discuss the situation and agree on an appropriate course of action.  The data recorded in the 
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CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it. 
16.2. 
Regulatory Documentation 
16.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory 
authorities in each respective country, as applicable.  A study may not be initiated until all 
local regulatory requirements are met. 
16.2.2. 
Required Pre-study Documentation 
The following documents must be provided to the sponsor before shipment of study drug 
to the investigational site: 
 Protocol and amendment(s), if any, signed and dated by the investigator. 
 A copy of the dated and signed written IEC/IRB approval of the protocol, amendments, 
informed consent form, any recruiting materials, and if applicable, patient 
compensation programs. This approval must clearly identify the specific protocol by 
title and number and must be signed by the chairman or authorized designee. 
 Name and address of the IEC/IRB including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and 
the applicable laws and regulations.  If accompanied by a letter of explanation, or 
equivalent, from the IEC/IRB, a general statement may be substituted for this list.  If 
an investigator or a member of the investigational staff is a member of the IEC/IRB, 
documentation must be obtained to state that this person did not participate in the 
deliberations or in the vote/opinion of the study. 
 Regulatory authority approval or notification, if applicable. 
 Documentation of investigator qualifications (e.g., curriculum vitae). 
 Completed investigator financial disclosure form from the investigator, where required. 
 Signed and dated clinical trial agreement, which includes the financial agreement. 
 Any other documentation required by local regulations. 
The following documents must be provided to the sponsor before enrollment of the first 
patient: 
 Documentation of subinvestigator qualifications (e.g., curriculum vitae). 
 Name and address of the laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests. 
 Laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(e.g., accreditation/license), if applicable. 
16.3. 
Patient Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a patient identification and enrollment log to permit 
easy identification of each patient during and after the study. This document will be 
reviewed by the sponsor site contact for completeness. 
The patient identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file.  To ensure patient confidentiality, no copy will be 
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made. All reports and communications relating to the study will identify patients by initials 
and assigned number only. 
The investigator must also complete a patient-screening log, which reports on all patients 
who were seen to determine eligibility for inclusion in the study. 
16.4. 
Source Documentation 
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: patient identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy 
parameters as required by the protocol; record of all adverse events; and follow-up of 
adverse events; concomitant medication; drug receipt/dispensing/return records; study drug 
administration information; and date of study completion, and reason for early 
discontinuation of study drug or withdrawal from the study, if applicable.  
It is recommended that the author of an entry in the source documents be identifiable. 
At a minimum, the type and level of detail of source data available for a study patient should 
be consistent with that commonly recorded at the site as a basis for standard medical care.  
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document). 
16.5. 
Case Report Form Completion 
Case report forms are provided in electronic format for each patient who is enrolled in this 
study.   
Data must be entered into eCRFs in English.  The investigator must verify that all data 
entries in the eCRFs are accurate and correct.  All eCRF entries, corrections, and alterations 
must be made by the investigator or other authorized study-site personnel. 
16.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified investigators and appropriate study centers, review of protocol procedures with 
the investigator and associated personnel before the study, and periodic monitoring visits 
by the sponsor.  Written instructions will be provided for collection, preparation, and 
shipment of blood, plasma, and urine samples.  
Guidelines for eCRF completion will be provided and reviewed with study personnel 
before the start of the study.  
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring 
visits and after transmission to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate.  After entry of the data into the clinical study 
database they will be verified for accuracy.  
16.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all 
CRFs and all source documents that support the data collected from each patient, as well 
as all study documents as specified in ICH/GCP Section 8, Essential Documents for the 
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Conduct of a Clinical Trial, and all study documents as specified by the applicable 
regulatory requirement(s). The investigator/institution will take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor.  It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be 
retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. The sponsor must be notified in writing of the name and 
address of the new custodian. Under no circumstance shall the investigator relocate or 
dispose of any study documents before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review 
any documentation relating to this study, the investigator must permit access to such 
reports. 
16.8. 
Monitoring 
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor 
will record dates of the visits in a study center visit log that will be kept at the site.  The 
first post-initiation visit will be made as soon as possible after enrollment has begun.  At 
these visits, the monitor will compare the data entered into the eCRFs with the hospital or 
clinic records (source documents).  The nature and location of all source documents will be 
identified to ensure that all sources of original data required to complete the eCRF are 
known to the sponsor and investigational staff and are accessible for verification by the 
sponsor site contact.  If electronic records are maintained at the investigational site, the 
method of verification must be discussed with the investigational staff.  
Direct access to source documentation (medical records) must be allowed for the purpose 
of verifying that the data recorded in the eCRF are consistent with the original source data.  
Findings from this review of eCRF and source documents will be discussed with the 
investigational staff.   The sponsor expects that, during monitoring visits, the relevant 
investigational staff will be available, the source documentation will be accessible, and a 
suitable environment will be provided for review of study-related documents.  The monitor 
will meet with the investigator on a regular basis during the study to provide feedback on 
the study conduct. 
16.9. 
Study Completion/Termination 
16.9.1. 
Study Completion 
The study is considered completed with the last visit of the last patient participating in the 
study.  The final data from the investigational site will be sent to the sponsor (or designee) 
after completion of the final patient visit at that site.  Investigational sites will be closed 
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upon study completion.  An investigational site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been 
performed. 
16.9.2. 
Study Termination 
The sponsor reserves the right to close the investigational site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Investigational sites will be closed 
upon study termination. An investigational site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been 
performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended closure. 
Reasons for the early closure of an investigational site by the sponsor or investigator may 
include but are not limited to: 
 Failure of the investigator to comply with the protocol, the sponsor’s procedures, or 
GCP guidelines 
 Inadequate recruitment of patients by the investigator 
 Discontinuation of further drug development. 
16.10. 
On-Site Audits 
Representatives of the sponsor’s clinical quality assurance department may visit the site at 
any time during or after completion of the study to conduct an audit of the study in 
compliance with regulatory guidelines and company policy.  These audits will require 
access to all study records, including source documents, for inspection and comparison with 
the eCRF.  Patient privacy must, however, be respected.  The investigator and staff are 
responsible for being present and available for consultation during routinely scheduled site 
audit visits conducted by the sponsor or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either 
as part of a national GCP compliance program or to review the results of this study in 
support of a regulatory submission.  The investigator should immediately notify the sponsor 
if they have been contacted by a regulatory agency concerning an upcoming inspection. 
16.11. 
Use of Information and Publication 
All information, including but not limited to information regarding MIN-117 or the 
sponsor’s operations (e.g., patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the sponsor to the 
investigator and not previously published, and any data generated as a result of this study, 
are considered confidential and remain the sole property of the sponsor.  The investigator 
agrees to maintain this information in confidence and use this information only to 
accomplish this study, and will not use it for other purposes without the sponsor’s prior 
written consent. 
The investigator understands that the information developed in the clinical study will be 
used by the sponsor in connection with the continued development of MIN-117, and thus 
may be disclosed as required to other clinical investigators or regulatory agencies.  To 
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permit the information derived from the clinical studies to be used, the investigator is 
obligated to provide the sponsor with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report (CSR) generated by the 
sponsor and will contain CRF data from all investigational sites that participated in the 
study.  Recruitment performance or specific expertise related to the nature and the key 
assessment parameters of the study will be used to determine a coordinating investigator, 
if needed.   Any work created in connection with performance of the study and contained 
in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner 
of copyright in such work.  
The sponsor shall have the right to publish such data and information without approval 
from the investigator.  If an investigator wishes to publish information from the study, a 
copy of the manuscript must be provided to the sponsor for review at least 60 days before 
submission for publication or presentation.  Expedited reviews will be arranged for 
abstracts, poster presentations, or other materials. If requested by the sponsor in writing, 
the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application.  In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator.  The 
sponsor will not mandate modifications to scientific content and does not have the right to 
suppress information.   
For multicenter study designs and substudy approaches, results may need to be published 
in a given sequence (e.g., substudies) should not generally be published before the primary 
endpoints of a study have been published.  Similarly, investigators will recognize the 
integrity of a multicenter study by not publishing data derived from the individual site until 
the combined results from the completed study have been published in full, within 
12 months after conclusion, abandonment, or termination of the study at all sites, or the 
sponsor confirms there will be no multicenter study publication.  Authorship of publications 
resulting from this study will be based on the guidelines on authorship, such as those 
described in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 
which state that the named authors must have made a significant contribution to the design 
of the study or analysis and interpretation of the data, provided critical review of the paper, 
and given final approval of the final version. 
16.12. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and/or disclose the existence of and the results of clinical studies 
as required by law. 
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17. 
REFERENCES 
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Belmaker RH, Agam G. (2008). Major depressive disorder. N Engl J Med., 358(1), 55-68.  
Boyer P, Lecrubier Y, Stalla-Bourdillon A, Fleurot O. (1999).  Amisulpride versus 
amineptine and placebo for the treatment of dysthymia. Neuropsychobiology, 39, 25–32. 
Cohen S, Kamarck T, and Mermelstein R. (1983).  A global measure of perceived stress.  
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Derogatis LR. (2008).  Assessment of Sexual Function/Dysfunction via Patient Reported 
Outcomes. International Journal of Impotence Research, 20, 35-44.  
Devine EB, Hakim Z, Green J. (2005).  A Systematic Review of Patient-Reported Outcome 
Instruments Measuring Sleep Dysfunction in Adults. Pharmacoeconomics, 23(9), 889 912.  
Dunlop BW and CB Nemeroff. (2007).  The role of dopamine in the pathophysiology of 
depression. Arch. Gen. Psychiatry. 64, 327-337. 
Geddes JR, Freemanatle N, Mason J, Eccles. MP, and Boynton. J. (2003).  Selective 
Serotonin Reuptake Inhibitors (SSRIs) For Depression.  The Cochrane Library, Issue 1.  
Guideline on clinical investigation of medicinal products in the treatment of depression. 
EMA/CHMP/185423/2010 Rev 2. 
International Conference on Harmonisation Tripartite Guideline. The clinical evaluation of 
the QT/QTc interval prolongation and proarrhythmic potential for non-anti-arrhythmic 
drugs.  E14. 12 May 2005. 
Hyttel J. (1994). Pharmacological characterization of selective serotonin reuptake 
inhibitors (SSRIs). Int. Clin. Psychopharmacol., 9 (Suppl 1), 19-26.  
Keefe RS, McClintock SM, Roth RM, Doraiswamy PM, Tiger S, Madhoo M. (2014).  
Cognitive effects of pharmacotherapy for major depressive disorder: A systematic review. 
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Kenward, MG and Roger, JH. (1997). Small Sample Inference for Fixed Effects from 
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Kessler RC, Bromet EJ. (2013).  The epidemiology of depression across cultures. Annu 
Rev Public Health. 34, 119-138. 
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. (2008).  
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Lambert G, Johansson M, Agren H, Friberg P. (2000).  Reduced brain norepinephrine and 
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Laughren TP. (2001). The scientific and ethical basis for placebo-controlled trials in 
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Evaluation of outcomes with citalopram for depression using measurement-based care in 
STAR*D: implications for clinical practice. Am J Psychiatry., 163(1), 28-40. 
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World 
Health 
Organization. 
(2006). 
 
The 
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World 
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(fact 
sheets). 
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2015. 
http://www.who.int/mediacentre/factsheets/fs369/en/. Accessed 30 October 2015. 
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ATTACHMENT 1:  ALLOWED/PROHIBITED CONCOMITANT MEDICATIONS 
The list is not exhaustive; other concomitant medications could be allowed after Sponsor’s Responsible 
Medical Officer approval – As a general rule, CYP 2C8 and CYP3A4/5 inducers and inhibitors as well as 
drugs metabolized through CYP2C9 are always prohibited.  
 
 
Drug Class 
As 
Needed
Chronic 
Use 
 
Comments 
Analgesics 
Y 
N 
Non-opiate analgesics only.  
Anorexics 
N 
N 
 
Antacids 
Y 
N 
 
Antianginal Agents 
N 
N 
 
Antiarrhythmics 
N 
N 
 
Antiasthma Agents 
Y 
Y 
Inhaled agents only. 
Antibiotics 
Y 
N 
 
Anticholinergics 
N 
N 
 
Anticoagulants 
N 
Y (1) 
Aspirin (max. 325 mg/day) is allowed as chronic anti-
platelet treatment. 
Anticonvulsants 
N 
N 
 
Antidepressants 
N 
N 
 
Antidiarrheal 
Preparations 
Y 
N 
 
Antifungal Agents: 
 
 
 
 
Systemic 
N 
N 
 
 
Topical 
Y 
Y 
 
Antihistamines 
Y 
N 
 Allegra, Claritin, and Zyrtec are allowed. 
Antihypertensives 
N 
 Y (1) 
Telmisartan, ramipril, atenolol are allowed  
Anti-inflammatory 
Drugs 
N 
N  
 
Antinauseants 
Y 
N 
 
Antineoplastics 
N 
N 
 
Antiobesity 
N 
N 
 
Antipsychotics 
N 
N 
 
Anxiolytics 
N 
N 
 
Cough/Cold 
Preparations 
Y 
N 
Use of cough and cold preparations containing 
pseudoephedrine or phenylpropanolamine is not 
permitted. Decongestants containing narcotics are not 
permitted. 
Diuretics 
Y 
 Y (1) 
Amiloride and hydrochlorothiazide are allowed  
H2-Blockers 
Y 
N 
 
Hormones 
N 
Y 
Only thyroid hormone replacement, oral contraceptives 
and estrogen replacement therapy are allowed. 
Hypoglycemic 
Agents 
N 
Y (1) 
Metformine is allowed   
Hypolipidemics 
N 
 Y (1) 
Rosuvastatin is allowed  
Insulin 
N 
N 
 
Benign Prostatic 
Hypertrophy  
N 
Y(1) 
Finasteride, dutasteride are allowed  
Muscle Relaxants 
N 
N 
 
Psychotropic drugs 
not otherwise 
specified (including 
herbal products) 
N 
N 
No drugs with psychomotor effects or with anxiolytic, 
stimulant, antipsychotic, or sedative properties are 
allowed. 
Sedatives/Hypnotics
N 
N 
 
(1) Allowed for some specific medications. Please contact the Medical Monitor as needed. 
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ATTACHMENT 2: MONTGOMERY-ASBERG DEPRESSION RATING SCALE 
(MADRS) 
 
The rating should be based on a clinical interview moving from broadly phrased questions 
about symptoms to more detailed ones, which allow a precise rating of severity.  The rater 
must decide whether the rating lies on the defined scale steps (0, 2, 4, 6) or between them 
(1, 3, 5) and then report the appropriate number.  The items should be rated with regards to 
the patient has done over the past week. 
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ATTACHMENT 4: CLINICAL GLOBAL IMPRESSION – SEVERITY RATING 
(CGI-S) 
 
Severity of illness 
Considering your total clinical experience with this particular patient, how mentally ill is the patient at this 
time?  
0 = Not assessed 
1 = Normal, not at all ill 
2 = Borderline mentally ill 
3 = Mildly ill 
4 = Moderately ill 
5 = Markedly ill 
6 = Severely ill 
7 = Among the most extremely ill patients 
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ATTACHMENT 5: CLINICAL GLOBAL IMPRESSION – IMPROVEMENT 
RATING (CGI-I) 
Global Improvement: Rate total improvement whether or not, in your judgment, it is due entirely to drug 
treatment. 
Compared to the patient’s condition at admission to the study, how much has this patient changed?  
0 = Not assessed 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very  
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ATTACHMENT 6: INVENTORY OF DEPRESSIVE SYMPTOMS - SUBJECT-
RATED (IDS-SR30) 
 
 
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ATTACHMENT 8: PERCEIVED STRESS SCALE (PSS) 
 
 
 
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ATTACHMENT 9: ARIZONA SEXUAL EXPERIENCES SCALE (A-SEX) 
 
 
 
 
 
 
 
 
 
 
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ATTACHMENT 10: DIGIT SYMBOL SUBSTITUTION TEST (DSST) 
Sample Sheet 
 
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ATTACHMENT 11: COLUMBIA SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
 
 
 
 
 
 
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its 
administration. The questions contained in the Columbia-Suicide Severity Rating Scale 
are suggested probes. Ultimately, the determination of the presence of suicidal ideation or 
behavior depends on the judgment of the individual administering the scale. 
 
 
 
 
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INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the 
time designated. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the study drug, the conduct of the 
study, and the obligations of confidentiality. 
Coordinating Investigator (where required): 
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator: 
Name (typed or printed):
Institution and Address:
Telephone Number:
 
 
Signature:
 
 
 
Date:
 
(Day Month Year)
Sponsor’s Responsible Medical Officer: 
    
 
Signature:
 
Date:   20 November 2018 
Note 
If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be 
required. 
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Statistical Analysis Plan                                                                                                             Final Version  
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL................................ 2 
1. 
INTRODUCTION ................................................................................................... 5 
1.1. 
Study Overview ................................................................................................................. 5 
1.2. 
Time and Events Schedule .................................................................................................. 6 
1.3. 
Glossary of Abbreviation .................................................................................................... 8 
2. 
OBJECTIVES ........................................................................................................ 10 
3. 
GENERAL STATISTICAL CONSIDERATIONS .............................................. 10 
3.1. 
Sample Size and Power .................................................................................................... 10 
3.2. 
Randomization and Blinding ............................................................................................ 11 
3.3. 
Handling of Data ............................................................................................................. 12 
3.3.1. 
Strata and Covariates ..................................................................................................... 12 
3.3.2. 
Examination of Patient Subsets ....................................................................................... 12 
3.3.3. 
Multiple Testing and Comparisons................................................................................... 12 
3.3.4. 
Missing Data and Outliers .............................................................................................. 12 
3.3.5. 
Imputation of Incomplete Dates ....................................................................................... 13 
3.3.6. 
Imputation of Alphanumeric Data .................................................................................... 13 
3.3.7. 
Presentations by Time Point ............................................................................................ 13 
3.3.8. 
Definitions and Terminology .......................................................................................... 14 
3.4. 
Timing of Analysis ........................................................................................................... 16 
4. 
ANALYSIS POPULATIONS ................................................................................ 17 
4.1. 
Intent to Treat Population ................................................................................................ 17 
4.2. 
Safety Population ............................................................................................................. 17 
5. 
STATISTICAL METHODS .................................................................................. 17 
5.1. 
Patient Disposition, Demographic and Baseline Characteristics .......................................... 17 
5.2. 
Efficacy Analysis ............................................................................................................. 18 
5.2.1. 
Primary Estimand .......................................................................................................... 18 
5.2.2. 
Primary Efficacy Analysis .............................................................................................. 19 
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5.2.3. 
Key Secondary Estimand ................................................................................................ 20 
5.2.4. 
Key Secondary Efficacy Analysis .................................................................................... 20 
5.2.5. 
Additional Secondary and Exploratory Endpoints .............................................................. 21 
5.2.6. 
Secondary and Exploratory Analyses ............................................................................... 22 
5.3. 
Pharmacokinetic Analyses ................................................................................................ 24 
5.4. 
Safety Analyses ................................................................................................................ 24 
5.4.1. 
Adverse Events ............................................................................................................. 24 
5.4.2. 
Clinical Laboratory Assessments ..................................................................................... 25 
5.4.3. 
Concomitant Medications ............................................................................................... 26 
5.4.4. 
Other Safety Analyses .................................................................................................... 26 
6. 
PROTOCOL VIOLATIONS ................................................................................. 28 
7. 
CHANGES IN THE PLANNED ANALYSES ...................................................... 28 
8. 
PROGRAMMING CONVENTIONS ................................................................... 29 
9. 
PROPOSED TABLES, LISTINGS, AND FIGURES ........................................... 31 
 
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1. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the 
summary and analysis of data from Protocol MIN-117C03.  Background information is 
provided for the overall study design and objectives.  The reader is referred to the study 
protocol and case report forms (CRFs) for details of study conduct and data collection. 
1.1. 
STUDY OVERVIEW 
Protocol MIN-117C03 is a 6-week, 3-arm, randomized, double-blind, placebo- controlled 
study to investigate the safety and efficacy of MIN-117 in male and female patients with 
Major Depressive Disorder (MDD), aged 18 to 65. Approximately 324 patients will be 
randomly assigned to 1 of 3 treatment arms, including placebo, 5.0 mg MIN-117, or 2.5 mg 
MIN-117, in a 2:1:1 ratio.  
The study design has 3 phases: a screening phase of up to 3 weeks (including washout), a 6-
week double-blind treatment phase, and a post-study follow-up visit, occurring 
approximately 2 weeks after completing the double-blind treatment phase. 
Screening Phase: Patients with an acute exacerbation of a major depressive episode will be 
screened for this study. Screening will include informed consent (for the overall study as 
well as for optional pharmacogenomic research), evaluation for eligibility in the study, and 
assessment of medical history.  Patients must meet Diagnostic and Statistical Manual of 
Mental Disorders-Fifth Edition (DSM-5) diagnostic criteria for moderate to severe MDD, 
with anxious distress and without psychotic features.  The diagnosis should be confirmed by 
the Structured clinical interview for DSM-5 (SCID-5).  Patients will undergo additional 
physical and psychiatric evaluations, as well as safety evaluations.  If patients give informed 
consent to participate and meet all study entry criteria at Screening, they will be tapered off 
their current psychotropic medications.  Patients will be free of any psychotropic 
medications for a period of 1 week [or 2 weeks for a monoamine oxidase (MAO) inhibitor, 
4 weeks for fluoxetine] prior to randomization.  
Double-blind Treatment Phase: After at least 1-week of psychotropic drug-free period, 
patients will undergo evaluation for eligibility, and if they still meet the study entry criteria, 
they will be randomly assigned in a 2:1:1 ratio to receive placebo, 5.0 mg MIN-117, or 
2.5 mg MIN-117, respectively, once daily for 6 weeks. Clinic visits will occur at Visits 2, 3, 
4, and 5/Early Withdrawal (Weeks 1, 2, 4, and 6, respectively). 
Post-Study Visit: At the end of the study, patients will be evaluated for safety/tolerability at 
the Post-Study Visit, approximately 2 weeks after completing the Double-blind Treatment 
Phase.  Any patient who terminates from the study early will undergo the Early Withdrawal 
visit procedures and will have a Post-Study Visit within approximately 2 weeks. 
 
 
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1.2. TIME AND EVENTS SCHEDULE 
Procedures and Evaluations 
Screening 
Baseline 
Double-Blind Phase 
Post Study 
Follow-Up 
Visit#a 
1 
2 
3 
4 
5 / EWb 
6 
Week 
-3 
1 
2 
4 
6 
8 
Day 
-21 to -1 
1 
15 
29 
43 
57 
Screening/Administrative  
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Pharmacogenomic informed consentc 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Medical history, SCID-5, MGH-
SAFER 
X 
 
 
 
 
 
Prior medications 
X 
X 
 
 
 
 
Preplanned surgery/procedures 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Pregnancy testd 
X 
X 
 
X 
X 
X 
Alcohol and Drug Screen 
X 
X 
 
 
 
 
TSH, serology 
X 
 
 
 
 
 
Taper of psychotropic drugs 
Xe 
Xe 
 
 
 
 
Randomization 
 
Xf 
 
 
 
 
Study Drug 
 
 
 
 
 
 
Administer/Dispense study drug 
 
X 
X 
X 
Xg 
 
Study drug accountability 
 
 
X 
X 
X 
 
Pharmacokinetics 
 
 
 
 
 
 
Blood sample collectionh 
 
X 
X 
X 
X 
X 
Pharmacodynamics 
 
 
 
 
 
 
Blood sample collection 
 
X 
 
 
X 
 
Pharmacogenomics 
 
 
 
 
 
 
Blood sample collection 
 
Xi 
 
 
 
 
Efficacy 
 
 
 
 
 
 
Investigator-Rated: MADRS, HAM-
A, CGI-S 
X 
X 
X 
X 
X 
 
Investigator-Rated: CGI-I 
 
 
X 
X 
X 
 
Investigator-Rated: DSST 
 
X 
X 
X 
X 
 
Subject-Rated: SHAPS, A-SEX 
X 
X 
X 
X 
X 
 
Subject-Rated: IDS-SR30 
X 
X 
 
 
X 
 
Subject-Rated: PSS 
 
X 
 
 
X 
 
Sleep recording (Somno-Art) j 
X 
X 
 
 
X 
 
Safety 
 
 
 
 
 
 
Physical examination  
X 
X 
 
 
X 
X 
12-Lead ECG (triplicate) k 
X 
X 
 
X 
X 
X 
Vital signs, temperature, weightl 
X 
X 
X 
X 
X 
X 
Clinical laboratory testsm 
X 
X 
 
 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
Adverse Events  
Continuous 
Concomitant therapy 
Continuous 
 
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Abbreviations: A-SEX = Arizona Sexual Experiences Scale; CGI-I = Clinical Global Impression of Improvement Scale; CGI-S = Clinical 
Global Impression of Severity Scale; C-SSRS = Columbia Suicide Severity Rating Scale; DSST = digit symbol substitution test; HAM-A = 
Hamilton anxiety scale; IDS-SR30 = Inventory of Depressive Symptoms – Subject-Related; MADRS = Montgomery-Asberg Depression 
Rating Scale; PSS = Perceived Stress Scale; SCID-5 = Structured clinical interview for DSM-5; SHAPS = Snaith-Hamilton Pleasure Scale. 
aVisits 3 to 6 may occur within a ±3-day window relative to Baseline (Visit 2). Visit 2 may occur within a +7 day window relative to Visit 
1 (i.e., the screening period may be extended to 28 days) upon Sponsor’s decision. 
bVisit 5 represents the end-of-treatment or early withdrawal (EW) visit, and patients who discontinue the study prematurely should undergo 
all assessments indicated for this visit. 
cTo participate in the optional pharmacogenomic component of this study, patients must sign the pharmacogenomic informed consent form, 
indicating their willingness to participate. 
dFor all women of childbearing potential, serum pregnancy testing will be performed at Screening (Visit 1), Baseline (Visit 2), and post 
study visit. Urine pregnancy testing will be performed at Baseline (Visit 2), and Visits 4, 5, and 6. 
eAfter meeting eligibility criteria during their Screening visit, patients will taper off their current psychotropic medications. Patients will be 
free of any psychotropic medications for a period of 1 week (or 2 weeks for MAO inhibitor, 4 weeks for fluoxetine) prior to randomization. 
fAll procedures (except dispensing of study medication) should be completed on Day 1 before randomization. 
g Only drug administration at Visit 5. 
h Samples will be obtained within 1 hour prior to dosing and approximately 2 to 4 hours after dosing (the approximate time of maximum 
plasma concentration for MIN-117) on Visits 2, 3, 4, and 5. Additionally, 1 sample will be taken on Visit 6. 
i A 10-mL blood sample will be collected only from patients who give informed consent for the pharmacogenomic component of this study. 
A sample collected at a later time point does not constitute a protocol violation and would not require protocol amendment. 
j Sleep recording by using Somno-Art for 1 night after Screening, 1 night before dosing, and 1 night after dosing on Visit 2 and Visit 5. 
k Triplicate ECGs to be performed at least 1 minute apart within 5 minutes, while the patient is supine for ≥ 10 minutes. 
l Patients will be weighed clothed (lightly) and without shoes. 
m Clinical laboratory tests will include hematology, serum chemistry (including serum lipid profile, and fasting blood glucose), and 
urinalysis. Patients must fast for 8 hours before the blood sample is taken. 
 
 
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1.3. 
GLOSSARY OF ABBREVIATION 
AE 
 
Adverse event 
ANCOVA 
Analysis of covariance 
A-SEX 
Arizona Sexual Experiences Scale 
BMI 
 
Body mass index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CGI-I  
Clinical Global Impression – Improvement Rating 
CGI-S  
Clinical Global Impression – Severity Rating 
CMH  
Cochran-Mantel-Haenszel 
CRF 
 
Case Report Form 
CRO  
Contract Research Organization 
CS 
 
Clinically Significant 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition 
DSST  
Digital Symbol Substitution Test 
ECG  
Electrocardiogram 
eCRF  
Electronic Case Report Form 
HAM-A 
Hamilton Anxiety Scale 
IDS-SR30 
Inventory of Depressive Symptoms – Subject Rated 
IWRS  
Interactive Web Response System 
ITT 
 
Intent to Treat 
KR 
 
Kenward-Roger 
LOCF  
Last Observation Carried Forward 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MAO  
Monoamine oxidase 
MDD  
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects Model Repeated Measurement 
PCS 
 
Potentially Clinically Significant 
PD 
 
Pharmacodynamic 
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PK 
 
Pharmacokinetic 
PSS 
 
Perceived Stress Scale 
QTc 
 
QT interval value corrected for heart rate 
QTcF  
QT interval value corrected for heart rate using Fridericia’s formula 
SAE 
 
Serious adverse event 
SAF 
 
Safety set 
SCID-5 
Structured clinical interview for DSM-5 
SD 
 
Standard Deviation 
SHAPS 
Snaith-Hamilton Pleasure Scale 
TE 
 
Treatment-emergent 
TEAE  
Treatment-emergent adverse event 
WHO  
World Health Organization 
 
 
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2. 
OBJECTIVES 
Primary Objective: 
• To evaluate the efficacy of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 compared 
with placebo in reducing the symptoms of major depression measured by the change 
in Montgomery-Asberg Depression Rating Scale (MADRS) total score over 6 weeks 
of treatment in adult patients with MDD. 
Secondary Objectives: 
1. To assess the change from Baseline of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 
compared with placebo over 6 weeks of treatment on: 
• The symptoms of anxiety using the HAM-A (key secondary).  
• The severity of illness and improvement using the Clinical Global Impression – 
Severity Rating (CGI-S) and Clinical Global Impression – Improvement Rating 
(CGI-I). 
2. To evaluate the safety of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 compared with 
placebo over 6 weeks of treatment in adult patients with MDD. 
Exploratory Objectives: 
1. To assess the change from Baseline of 2 fixed doses (5.0 mg or 2.5 mg) of MIN-117 
compared with placebo over 6 weeks of treatment on: 
• Commonly associated symptoms of MDD by using the Inventory of Depressive 
Symptoms – Subject Rated (IDS-SR30). 
• The ability to experience hedonic capacity by using the Snaith-Hamilton Pleasure 
Scale (SHAPS). 
• Cognitive function as measured by Digital Symbol Substitution Test (DSST). 
• Perception of stress using the Perceived Stress Scale (PSS). 
• Sexual functioning by using the Arizona Sexual Experiences Scale (A-SEX). 
• Sleep parameters as assessed by Somno-Art methodology (at select sites). 
• Neurotrophic/inflammatory factors. 
2. To explore the pharmacokinetics (PK) of MIN-117 
 and assess the 
PK/pharmacodynamics (PD) relationship. 
3. 
GENERAL STATISTICAL CONSIDERATIONS 
3.1. 
SAMPLE SIZE AND POWER 
The sample size for this study is based on the assumption of a treatment difference of at least 
4 points in the mean change from Baseline to to endpoint in MADRS total score between 
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any MIN-117 dose group and placebo. A standard deviation of 9 in the change in MADRS 
total score from Baseline is used. Using the Bonferroni multiplicity adjustment for multiple 
comparisons of 2 MIN-117 dose groups with placebo and assuming an allocation of 2:1:1 
for placebo and the 2 MIN-117 doses, 146 patients in the placebo group and 73 patients in 
each MIN-117 dose group are required to detect the treatment difference of 4 points with a 
power of 80% at an overall 2-sided significance level of 0.05. When adjusted for a rate of 
10% of patients who will not have either Baseline or post-Baseline efficacy assessments, the 
required number of patients becomes 162 for the placebo group and 81 for each of the 2 
MIN-117 dose groups. Therefore, the total number of patients across the 3 treatment groups 
will be 324. 
3.2. 
RANDOMIZATION AND BLINDING 
Central randomization will be implemented in this study. Patients will be randomized to 1 
of 3 treatment arms, based on a computer-generated randomization schedule prepared by or 
under the supervision of Minerva before the study. The randomization will be balanced by 
using permuted blocks. The Interactive Web Response System (IWRS) will assign a unique 
treatment code, which will dictate the treatment assignment and matching study drug kit for 
the patient.  
Approximately 324 eligible patients will be randomized in a 2:1:1 ratio to the following 
groups: 
• Placebo 
• 5.0 mg MIN-117   
• 2.5 mg MIN-117  
The investigator will not be provided with randomization codes. The codes will be 
maintained within the IWRS, which has the functionality to allow the investigator to break 
the blind for an individual patient, if needed. 
Under normal circumstances, the blind should not be broken until all patients have 
completed the study and the database is locked. Otherwise, the blind should be broken only 
if specific emergency treatment/course of action would be dictated by knowing the treatment 
the patient is receiving. In such cases, the investigator may in an emergency determine the 
identity of the treatment by IWRS.  
In the event the blind is broken, then sponsor must be informed as soon as possible. The 
date, time, and reason for the unblinding must be documented by the investigator in the 
appropriate section of the electronic case report form (eCRF), and in the source document. 
The documentation received from the IWRS indicating the code break must be retained with 
the patient’s source documents in a secure manner (e.g., sealed envelope) so as not to unblind 
the treatment assignment to the study site, sponsor/contract research organization (CRO) 
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personnel. The investigator is also advised not to reveal the study treatment assignment to 
the study site or sponsor personnel. 
3.3. 
HANDLING OF DATA 
3.3.1. Strata and Covariates 
The primary efficacy analysis and corresponding sensitivity analyses will have Baseline 
MADRS as a covariate. Similarly, secondary endpoints and select additional efficacy 
analyses will contain covariates of their respective Baseline values. 
3.3.2. Examination of Patient Subsets 
Select efficacy analyses will be presented by region, which will consist of the following 
grouping:  
• US and Finland combined 
• All other countries 
3.3.3. Multiple Testing and Comparisons  
The adjustment for multiplicity within the family of primary hypotheses will utilize the 
Hochberg procedure for the purpose of reporting of results. The procedure will allow the 
null hypothesis of no treatment difference for both the 5.0 mg and 2.5 mg doses versus 
placebo to be rejected if the largest p-value of comparing either of these 2 doses versus 
placebo is at or below 0.05. Otherwise, the lowest of these 2 p-values must be at or below 
0.025 to allow for rejecting the null hypothesis for the representative dose. 
The overall type I error rate for testing the 2 MIN-117 doses versus placebo for the primary 
and the key secondary endpoints will be controlled at the 2-sided 0.05 level. The primary 
family of hypotheses (corresponding to the primary endpoint) and the secondary family 
hypotheses (corresponding to the key secondary endpoint, the change from Baseline in 
HAM-A total score) will be tested in a sequential manner with suitable adjustment for 
multiplicity within the family of primary hypotheses and within the family of the secondary 
hypotheses such that a MIN-117 dose versus placebo null hypothesis contrast testing within 
the secondary family can be evaluated only when the same null hypothesis contrast in the 
primary family was rejected (the truncated Hochberg procedure). 
3.3.4. 
Missing Data and Outliers 
Every effort will be made to obtain required data at each scheduled evaluation from all 
patients who have been treated. Imputation of incomplete dates is detailed in Section 3.3.5.  
As part of sensitivity analyses on the primary and key secondary endpoint, patients who are 
missing MADRS and HAM-A scores, respectively, will have this value imputed using the 
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last-observation-carried-forward (LOCF) method and multiple imputation. An additional 
sensitivity analysis will impute scores missing due to early study discontinuation using the 
mean score of the placebo group. Additionally, the LOCF method may be used to impute 
missing MADRS and CGI-I values for the analyses of secondary and exploratory endpoints. 
Only post-Baseline scores will be eligible to be carried forward for this imputation. The 
primary analysis will use observed data without imputation.  
3.3.5. Imputation of Incomplete Dates 
An incomplete date is any date for which either the day, month, or year is unknown, but all 
three fields are not unknown.  An incomplete date occurs when the exact date an event 
occurred or ended cannot be obtained from a patient.  For many of the analyses, a complete 
date is necessary in order to determine if the event should be included in the analysis (i.e., if 
the event is treatment-emergent) or to establish the duration of an event.  In such cases, 
incomplete dates will be imputed. 
In an effort to minimize bias, the project statistician will impute dates in a systematic but 
reasonable manner. If the month/year is the same as the Day 1 month/year then the date will 
be set to the date of Day 1.  In other cases, missing days will be imputed as the day 
component of Day 1; missing months/years will be imputed as the month/year of Day 1. If 
this method of imputation produces and invalid date, the last date of the month will be used.  
3.3.6. 
Imputation of Alphanumeric Data 
Should there be instances where laboratory data are recorded as for example, “<0.1” or 
“>10”, the data will be imputed for the purpose of quantitative summaries.  The data will 
appear in data listings unchanged.   
For incorporation in quantitative summaries, the following imputation rules will be 
employed: 
The limit of quantitation will be increased by one level of precision in the direction of the 
symbol that precedes the value.  For example, “< 0.1” will be imputed to “0.09”, while 
“>0.1” will be imputed to “0.11”, and “>10” will be imputed to “10.1”.  Value reported as 
“≤” or “≥” will be imputed similarly. For example, “≤ 0.1” will be imputed to “0.09”. 
3.3.7. 
Presentations by Time Point 
Nominal Time Points as obtained from the CRF or laboratory will be utilized for summary 
displays. If assessments are collected multiple times within a given nominal time point, the 
result closest to the scheduled time will be used for summary presentations.  If two 
measurements have the same distance to the expected time, the earlier value will be used. If 
a scheduled assessment and an Unscheduled or Early Termination assessment are collected 
on the same day, the scheduled assessment will be used for summary presentations, unless 
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otherwise indicated by the sponsor. Unscheduled and Early Termination assessments will be 
windowed to a study visit using the analysis window described below in case the scheduled 
visit was not performed. All assessments will be presented in the listings. 
Visit 
Target 
Day 
Window 
Days 
3: Week 2 
15 
9 - 22 
4: Week 4 
29 
23 - 36 
5: Week 6 
43 
37 - 50  
6: Follow-Up 57 
51 - 64 
   
3.3.8. Definitions and Terminology  
Baseline Value 
Baseline will be defined as the last valid evaluation done before the study drug 
administration on Day 1.  
Day 1  
Day 1 is the earliest day that study drug is first initiated. 
Study Day  
Study Day is defined relative to Baseline (Day 1). Thus, the study day of an event is 
calculated as: 
For events occurring on or after Day 1, Study Day = event date – date of 
Day 1+ 1. 
For events occurring prior to Day 1, Study Day = event date – dated of 
Day 1 
Study Visit  
Study Visit is the nominal visit as recorded on the CRF. 
Last Dose of Study Drug 
Last Dose of Study Drug is defined as the last date that the patient received study drug as 
determined by last date of dosing as recorded on the Study Drug Administration and 
Accountability CRF for Visit 5/Early Termination. 
Days on Treatment 
Days on treatment will be calculated as the number of days from the date of first dose to the 
date of last dose, inclusive. 
 
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Treatment Compliance 
Treatment compliance during a specified period of time is defined as the total number of 
tablets taken by a patient during that time divided by the number of tablets prescribed during 
that time, multiplied by 100. The number of tablets prescribed during a specified period of 
time will be calculated as the number of days in that timeframe multiplied by the number of 
tablets prescribed per day. 
Change from Baseline  
Change from baseline for a given endpoint is defined as the Study Visit X value minus the 
Baseline Value. 
MADRS Response 
MADRS response is defined as a decrease from Baseline in MADRS total score of ≥ 50%. 
Time to ≥ 50% MADRS Improvement (Days) 
Time to ≥ 50% MADRS improvement is defined as the time, in days, from initiation of study 
treatment to the first observed ≥ 50% decrease from Baseline in MADRS total score. Any 
patient who does not experience a ≥ 50% decrease from Baseline in MADRS total score 
during the study will have their time to ≥ 50% MADRS improvement censored at the time 
of his or her last non-missing MADRS assessment. 
Time to ≥ 30% MADRS Improvement (Days) 
Time to ≥ 30% MADRS improvement is defined as the time, in days, from initiation of study 
treatment to the first observed ≥ 30% decrease from Baseline in MADRS total score. Any 
patient who does not experience a ≥ 30% decrease from Baseline in MADRS total score 
during the study will have their time to ≥ 30% MADRS improvement censored at the time 
of his or her last non-missing MADRS assessment. 
Early Response 
Early response is defined as experiencing a ≥ 50% decrease from Baseline in MADRS total 
score along with a CGI-I score ≤ 2 at any post-Baseline visit.  
Additionally, the same analysis will be repeated using ≥ 30% decrease from Baseline in 
MADRS total score along with a CGI-I score ≤ 2 at any post-Baseline visit. 
Sustained Response 
Sustained response is defined as experiencing a ≥ 50% decrease from Baseline in MADRS 
total score along with a CGI-I score ≤ 2 at Week 2 or Week 4 that continues to Week 6. 
Additionally, the same analysis will be repeated using ≥ 30% decrease from Baseline in 
MADRS total score along with a CGI-I score ≤ 2 at Week 2 or Week 4 that continues to 
Week 6. 
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Remission in MADRS (sustained or occasional) 
Remission in MADRS is defined as a MADRS total score < 12. 
MADRS Core Mood Items 
MADRS core mood items are defined as a combination of the first two items on the MADRS 
questionnaire, Apparent Sadness and Reported Sadness. 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study patient administered 
a medicinal (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) 
product.  
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the Baseline condition, or abnormal results of diagnostic procedures, including laboratory 
test abnormalities. 
All adverse events will be recorded on the Adverse Event CRF. 
Treatment-emergent Adverse Event  
Any recorded Adverse Event that occurs on or after the initiation of study treatment is 
considered treatment-emergent (TE).  Additionally, it is assumed that an Adverse Event 
which was reported to have started on Day 1 without an associated onset time may have 
occurred after the initiation study treatment.  Hence, Adverse Events occurring on Day 1 
without an onset time are assumed to be TE. 
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of study 
treatment.  This definition includes medications started prior to the initiation of study 
treatment, but continuing concomitantly with study treatment. 
Prior Medications 
Prior medications are those medications taken and completed prior to the initiation of study 
treatment.  
3.4. 
TIMING OF ANALYSIS 
A final analysis will be conducted once the last patient completes or discontinues the study, 
and the resulting clinical database has been cleaned, quality checked, the final database lock 
has occurred, and the treatments are unblinded. 
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4. 
ANALYSIS POPULATIONS 
The populations for analysis will include the intent to treat population (ITT), and the safety 
population (SAF).  
4.1. 
INTENT TO TREAT POPULATION  
The ITT population is defined as all randomized patients who receive at least 1 dose of study 
drug. Patients in this population will be analyzed according to the treatment to which they 
were randomized, regardless of what treatment they received. All efficacy analyses will be 
based on this population and treatment assignment. 
4.2. 
SAFETY POPULATION  
The SAF is the population of all patients who receive at least 1 dose of study treatment. 
Patients in this population will be analyzed according to the treatment they received, 
regardless of which treatment they were randomly assigned. All safety and tolerability 
analyses will be based on this population and treatment assignment. 
5. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study, with 
hypothesis testing performed for selected endpoints. Unless stated otherwise, the term 
“descriptive statistics” refers to number of patients (n), mean, median, standard deviation 
(SD), minimum, and maximum for continuous data and frequencies and percentages for 
categorical data.  All data collected during the study will be included in data listings. Unless 
otherwise noted, the data will be sorted by treatment group, patient number, and by date 
within each patient number.   
The term ‘treatment group’ refers to the three treatment arms of this study: Placebo, 2.5 mg 
MIN-117, and 5.0 mg MIN-117.  
All statistical testing will be two-sided and will be performed using a significance (alpha) 
level of 0.050 unless stated otherwise, as described in section 3.3.3.  
The statistical analyses will be conducted with the SAS® System version 9.4 or higher. All 
analyses will be patient to formal verification procedures.  Specifically, results will be 
verified utilizing independent programming prior to issuance of the draft statistical report.  
All documents will be verified by the lead statistician to ensure accuracy and consistency of 
analyses. 
5.1. 
PATIENT 
DISPOSITION, 
DEMOGRAPHIC 
AND 
BASELINE 
CHARACTERISTICS  
Patient disposition will be presented for all patients. The number of patients who meet all 
eligibility criteria will be presented, as well as the number of patients included in the ITT, 
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and safety populations. The number of patients who completed all study treatment and 
discontinued from the study will be provided. The reasons for early discontinuation at any 
point also will be presented by treatment group. The proportion of premature 
discontinuations will be compared between treatment groups using the Fisher exact test. 
Similarly, the percentages for each discontinuation reason will be compared between 
treatment groups using the Fisher exact test.  Additionally, the number of days on study will 
be summarized for all treated patients. 
Demographic data and baseline characteristics including age, weight, height, body mass 
index (BMI), gender, and race will be summarized using descriptive statistics for the safety 
population, and will be presented by treatment group, combined MIN-117 doses, and overall. 
The number and percent of patients with a current or historical presence of abnormal finding 
in medical history will be summarized by treatment group and overall. This information will 
be reviewed for baseline differences, but no statistical testing will be performed. 
Baseline disease characteristics, including MADRS, HAM-A, IDS-SR30, CGI-S, SHAPS, 
DSST, PSS, and A-SEX scores at Baseline will be summarized using descriptive statistics 
for the safety population, and will be presented by treatment group, combined MIN-117 
doses, and overall. 
Additionally, study treatment exposure and treatment compliance will be summarized by 
treatment group. The number of days on study treatment will be summarized for all treated 
patients. Treatment compliance over the treatment period will be similarly summarized by 
treatment group. Additionally, treatment compliance between consecutive visits will be 
summarized by visit and treatment group.  
5.2. 
EFFICACY ANALYSIS 
5.2.1. 
Primary Estimand 
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following components: 
Population: patients with a pre-defined minimum threshold and fluctuation of depressive 
symptoms as captured by IDS-SR30 score before randomization. 
Endpoint: change in MADRS total score from Baseline to the end of Week 6. 
Measure of Intervention: the effect of the initially randomized treatment that would have 
been observed had all patients remained on their treatment throughout the double-blind 
phase. 
Intercurrent events: early study discontinuation for any reason. 
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Summary measure: difference in treatment means. 
5.2.2. 
Primary Efficacy Analysis 
MADRS total score values and change from Baseline will be summarized by treatment group 
and study visit. Change from Baseline in MADRS total score will be analyzed using a mixed-
effect model repeated measurement (MMRM) with fixed effects for treatment group 
(placebo, 2.5 mg MIN-117, and 5.0 mg MIN-117), region, visit, and treatment group-by-
visit interaction, a random effect for patient within treatment group, and Baseline MADRS 
total score as a covariate. An unstructured covariance matrix will be used to model the 
covariance of within-patient scores. The Kenward-Roger (KR) approximation will be used 
to estimate denominator degrees of freedom. Comparisons against placebo will be performed 
using the appropriate contrasts from this model at Week 6.  
As a sensitivity analysis of the primary endpoint, change from Baseline to Week 6 in 
MADRS total score will additionally be analyzed using an analysis of covariance 
(ANCOVA) model with factors for treatment and region and Baseline MADRS score as a 
covariate. This analysis will be repeated for change from Baseline to Week 2 and 4 as well. 
For this analysis, patients missing MADRS total score at any visit will have this value 
imputed using the LOCF method.  
An additional sensitivity analysis of the primary endpoint will be performed to determine 
the impact of how data missing due to early discontinuation for any reason is handled. This 
analysis will use the same ANCOVA model described above. This analysis will be repeated 
for change from Baseline to Week 2 and 4 as well. For this analysis, any MADRS total 
scores that are missing due to early discontinuation of a subject will be imputed using the 
value of the mean MADRS total score in the placebo group at that timepoint. All missing 
MADRS total scores that are not due to early discontinuation will be imputed using the 
LOCF method. 
A final sensitivity analysis of the primary endpoint will be performed using the same 
ANCOVA model described above, wherein all missing MADRS total scores will be imputed 
using multiple imputation. Missing values will be imputed using the following auxiliary 
information: treatment, Baseline MADRS total score, region, sex, Baseline age, and visit. 
Treatment, Baseline MADRS total score, region, sex, Baseline age, and visit are included as 
auxiliary information because it is believed that subjects with similar values for each of these 
parameters would respond similarly. A total of 10 imputations will be performed. The least 
square (LS) Mean, standard error (SE), LS Mean difference and p-value from the PROC 
MIANALYZE will be presented. Additionally, the range of p-values from all 10 imputations 
will be presented.      
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5.2.3. 
Key Secondary Estimand 
The key secondary estimand is defined by the following components: 
Population: patients with a pre-defined minimum threshold and fluctuation of depressive 
symptoms as captured by IDS-SR30 score before randomization. 
Endpoint: change in HAM-A total score from Baseline to the end of Week 6. 
Measure of Intervention: the effect of the initially randomized treatment that would have 
been observed had all patients remained on their treatment throughout the double-blind 
phase. 
Intercurrent events: early study discontinuation for any reason. 
Summary measure: difference in treatment means. 
5.2.4. 
Key Secondary Efficacy Analysis 
HAM-A total score and change from Baseline will be summarized by treatment group and 
study visit. Change from Baseline in HAM-A total score will be analyzed using an MMRM 
model with fixed effects for treatment group, region, visit, and treatment group-by-visit 
interaction, a random effect for patient within treatment group, and Baseline HAM-A total 
score as a covariate. Comparisons against placebo will be performed using the appropriate 
contrasts from this model at Week 6. 
As a sensitivity analysis of the primary endpoint, change from Baseline to Week 6 in HAM-
A total score will additionally be analyzed using an ANCOVA model with factors for 
treatment and region and Baseline HAM-A score as a covariate. This analysis will be 
repeated for change from Baseline to Week 2 and 4 as well. For this analysis, patients 
missing HAM-A total score at any visit will have this value imputed using the LOCF 
method.  
An additional sensitivity analysis of the primary endpoint will be performed to determine 
the impact of how data missing due to early discontinuation for any reason is handled. This 
analysis will use the same ANCOVA model described above. This analysis will be repeated 
for change from Baseline to Week 2 and 4 as well For this analysis, any HAM-A total scores 
that are missing due to early discontinuation of a subject will be imputed using the value of 
the mean HAM-A total score in the placebo group at that timepoint. All missing HAM-A 
total scores that are not due to early discontinuation will be imputed using the LOCF method. 
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A final sensitivity analysis of the key secondary endpoint will be performed using the same 
ANCOVA model described above, wherein all missing HAM-A total scores will be imputed 
using multiple imputation. Missing values will be imputed using the following auxiliary 
information: treatment, Baseline HAM-A total score, region, sex, Baseline age, and visit. 
Treatment, Baseline HAM-A total score, region, sex, Baseline age, and visit are included as 
auxiliary information because it is believed that subjects with similar values for each of these 
parameters would respond similarly. A total of 10 imputations will be performed. The least 
square (LS) Mean, standard error (SE), LS Mean difference and p-value from the PROC 
MIANALYZE will be presented. Additionally, the range of p-values from all 10 imputations 
will be presented. 
5.2.5. 
Additional Secondary and Exploratory Endpoints 
Other secondary and exploratory endpoints include 
• Change from Baseline in CGI-S score 
• Observed CGI-I score 
• Change from Baseline in IDS-SR30 
• Change from Baseline in SHAPS 
• Change from Baseline in DSST 
• Change from Baseline in PSS 
• Change from Baseline in A-SEX 
• Rate of MADRS responders 
• Time to ≥ 50% MADRS improvement 
• Time to ≥ 30% MADRS improvement 
• Rate of early responders 
• Rate of sustained responders 
• Rate of remission in MADRS 
• Changes from Baseline in single MADRS rating scale items 
• Changes from Baseline in MADRS core mood items 
• Change from Baseline in sleep onset latency 
• Change from Baseline in REM sleep latency 
• Change from Baseline in wake after sleep onset 
• Change from Baseline in time spent in each sleep stage 
• Change from Baseline in total sleep time 
• Change from Baseline in sleep efficiency index 
• Change from Baseline in number of awakenings 
• Change from Baseline in number of sleep cycles 
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5.2.6. 
Secondary and Exploratory Analyses 
CGI-S scores and change from Baseline will be summarized by treatment group and study 
visit. Differences between treatment groups in change from Baseline at Week 6 will be 
analyzed by means of an ANCOVA model run on ranked change, with treatment group as a 
factor and Baseline CGI-S value as a covariate.  
CGI-I scores will be summarized by treatment group and study visit. Differences between 
treatment groups in CGI-I score at Week 6 will be analyzed by means of an ANCOVA model 
run on ranked score, with treatment group as a factor and Baseline CGI-S value as a 
covariate. 
IDS-SR30 total score and change from Baseline will be summarized by treatment group and 
study visit. Change from Baseline in IDS-SR30 total score will be analyzed using an MMRM 
model with fixed effects for treatment group, region, visit, and treatment group-by-visit 
interaction, a random effect for patient within treatment group, and Baseline IDS-SR30 total 
score as a covariate. Comparisons against placebo will be performed using the appropriate 
contrasts from this model at Week 6. 
SHAPS total score and change from Baseline will be summarized by treatment group and 
study visit. Change from Baseline in SHAPS total score will be analyzed using an MMRM 
model with fixed effects for treatment group, region, visit, and treatment group-by-visit 
interaction, a random effect for patient within treatment group, and Baseline SHAPS total 
score as a covariate. Comparisons against placebo will be performed using the appropriate 
contrasts from this model at Week 6. 
DSST score and change from Baseline will be summarized by treatment group and study 
visit. Change from Baseline in DSST score will be analyzed using an MMRM model with 
fixed effects for treatment group, region, visit, and treatment group-by-visit interaction, a 
random effect for patient within treatment group, and Baseline DSST score as a covariate. 
Comparisons against placebo will be performed using the appropriate contrasts from this 
model at Week 6. 
PSS total score and change from Baseline will be summarized by treatment group and study 
visit. Change from Baseline in PSS total score will be analyzed using an MMRM model with 
fixed effects for treatment group, region, visit, and treatment group-by-visit interaction, a 
random effect for patient within treatment group, and Baseline PSS total score as a covariate. 
Comparisons against placebo will be performed using the appropriate contrasts from this 
model at Week 6. 
A-SEX total score and change from Baseline will be summarized by treatment group and 
study visit. Change from Baseline in A-SEX total score will be analyzed using an MMRM 
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model with fixed effects for treatment group, region, visit, and treatment group-by-visit 
interaction, a random effect for patient within treatment group, and Baseline A-SEX total 
score as a covariate. Comparisons against placebo will be performed using the appropriate 
contrasts from this model at Week 6. 
The rate of responders will be presented by treatment group and study visit. Treatment 
differences in responder rate at Week 6 will be analyzed using a logistic regression model 
with factors for treatment group and Baseline MADRS total score. Any patients who are 
missing Week 6 MADRS total score will have this value imputed using LOCF for this 
analysis. 
Time to ≥ 50% MADRS improvement will be summarized by treatment group using the 
Kaplan-Meier method. Treatment differences in time to ≥ 50% MADRS improvement will 
be analyzed using a Cox-regression model with treatment group and Baseline MADRS total 
score as a covariate. If a patient does not experience ≥ 50% improvement during the duration 
of the study, his or her time to ≥ 50% MADRS improvement will be censored at the time of 
their last non-missing MADRS assessment. 
Time to ≥ 30% MADRS improvement will be summarized by treatment group using the 
Kaplan-Meier method. Treatment differences in time to ≥ 30% MADRS improvement will 
be analyzed using a Cox-regression model with treatment group and Baseline MADRS total 
score as a covariate. If a patient does not experience ≥ 30% improvement during the duration 
of the study, his or her time to ≥ 30% MADRS improvement will be censored at the time of 
their last non-missing MADRS assessment. 
The rate of early responders (≥ 50% and ≥ 30% MADRS) will be presented by treatment 
group and study visit. Treatment differences in responder rate will be analyzed using a 
logistic regression model with factors for treatment group and Baseline MADRS total score. 
Any missing MADRS and CGI-I scores will be imputed using LOCF for this analysis.  
The rate of sustained responders (≥ 50% and ≥ 30% MADRS) will be presented by treatment 
group. Treatment differences in responder rate will be analyzed using a logistic regression 
model with factors for treatment group and Baseline MADRS total score Any missing 
MADRS and CGI-I scores will be imputed using LOCF for this analysis. 
The rate of remission in MADRS will be presented by treatment group. Treatment 
differences in remission rate will be analyzed using a logistic regression model with factors 
for treatment group and Baseline MADRS total score.  
Single MADRS rating scale items and their change from Baseline will be summarized by 
treatment group and study visit. Differences between treatment groups in change from 
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Baseline to Week 6 will be analyzed using an ANCOVA of ranked data, with treatment 
group as a factor and Baseline rating value as a covariate. 
MADRS core mood items and their change from Baseline will be summarized by treatment 
group and study visit. Differences between treatment groups in change from Baseline to 
Week 6 will be analyzed using an ANCOVA of ranked data, with treatment group as a factor 
and Baseline rating value as a covariate. 
All changes in sleep parameters will be analyzed using an MMRM model with fixed effects 
for treatment group, region, visit, and treatment group-by-visit interaction, a random effect 
for patient within treatment group, and Baseline sleep parameter as covariate. Comparisons 
against placebo will be performed using the appropriate contrasts from this model at Week 
6. 
If the data is not amenable to analysis by logistic regression for any of the responder 
endpoints included in this section, then comparisons between treatment groups may be 
performed using Cochran-Mantel-Haenszel (CMH) testing instead. 
5.3. 
PHARMACOKINETIC ANALYSES 
The primary objective of the PK statistical analysis will be to estimate the relative 
bioavailability of MIN-117 and the effect of MIN-117 dose. Details of this analysis can be 
found in the PK Analysis Plan. 
5.4. 
SAFETY ANALYSES 
5.4.1. 
Adverse Events 
Adverse events will be mapped to a Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.0 preferred term and system organ classification.  If a patient 
experiences multiple events that map to a single preferred term, the greatest severity grade 
and strongest investigator assessment of relation to study medication will be assigned to the 
preferred term for the appropriate summaries.  Should an event have a missing severity or 
relationship, it will be classified as having the highest severity and/or strongest relationship 
to study medication.  
The occurrence of TE adverse events (TEAEs) will be summarized by treatment group using 
preferred terms, system organ classifications, and severity.  Separate summaries of TE 
serious adverse events (SAE), TEAE related to study treatment, TEAE leading to 
discontinuation of study treatment, and TE fatal adverse events will be generated.  All 
adverse events reported will be listed for individual patients showing both verbatim and 
preferred terms, as well as system organ class. All adverse events that occurred prior to the 
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initiation of study treatment will be excluded from the tables but will be included in the 
listings. Any TEAE occurring after the End of Study visit will not be summarized. 
Missing onset dates will be imputed as previously outlined in Section 3.3.5 as required to 
determine TE events. Adverse events occurring on Day 1 with missing onset times will be 
assumed to be TE. 
5.4.2. Clinical Laboratory Assessments 
Descriptive summaries of selected (quantitative) clinical laboratory results and change from 
baseline will be presented by treatment group and visit. Laboratory abnormalities will be 
determined using pre-defined normal ranges. The number and percentage of patients 
experiencing TE clinically significant (CS) laboratory abnormalities as reported by the 
central laboratory, and potentially clinically significant (PCS) abnormalities for select 
parameters per the table below will be summarized by treatment group. Additionally, shifts 
in Laboratory values with reference to the normal range from Study Baseline to Week 6 will 
be summarized by treatment group.  
Listings will be provided for patients with any laboratory results outside the reference 
ranges, as well as for patients with any CS and PCS (select parameters) laboratory results. 
 
 Criteria for Potentially Clinically Significant Laboratory Tests 
Laboratory Parameter 
SI Units Conversion 
Factora 
Traditional 
 Units 
PCS Criteriab 
Low Values 
PCS Criteriab 
High Values 
Hematology 
Hemoglobin           F 
g/L 
0.1 
g/dL 
< 100 
— 
Male 
 
 
 
< 120 
 
Hematocrit             F 
ratio 
100 
% 
≤ 32% and 
≥3%  decrease 
from baseline 
— 
Male
 
 
 
≤ 37% and 
≥3%  decrease 
from baseline 
 
White cell count 
109/L 
1 
103/µL 
≤ 2.5 
≥ 15 
Eosinophils 
absolute cell count 
109/L 
1 
103/µL 
— 
≥ 1.50  
Neutrophils 
absolute cell count 
109/L 
1 
103/µL 
≤ 1.50 
≥ 12.0 
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Lymphocyte 
absolute cell count 
109/L 
1 
103/µL 
≤ 0.8 
≥ 4.0 
Platelet count 
109/L 
1 
103/µL 
≤ 75 
≥ 700 
Chemistry 
Albumin 
g/L 
0.1 
g/dL 
< 28 
— 
Alkaline phosphatase 
U/L 
1 
U/L 
— 
≥ 2 × UNL 
ALT 
U/L 
1 
U/L 
— 
≥ 3 × UNL 
AST 
U/L 
1 
U/L 
— 
≥ 3 × UNL 
Blood urea nitrogen 
mmol/L 
2.8011 
mg/dL 
— 
> 1.4 × UNL 
Calcium 
mmol/L 
4.008 
mg/dL 
< 1.97 
> 2.77 
 
 
 
 
 
 
Cholesterol 
mmol/L 
38.6698 
mg/dL 
— 
> 7.75  
Creatinine 
µmol/L 
0.0113 
mg/dL 
— 
> 1.4 × UNL 
Glucose, fasting 
mmol/L 
18.015 
mg/dL 
< 3.0 
> 7.6 × UNL 
Potassium 
mmol/L 
1 
mEq/L 
< 3.3 
> 5.5 
Sodium 
mmol/L 
1 
mEq/L 
< 130 
> 150 
Total bilirubin 
µmol/L 
0.0585 
mg/dL 
— 
> 1.5 × UNL 
 
 
 
 
 
 
Urinalysis 
Protein 
— 
— 
— 
— 
≥ 2 + 
Glucose 
— 
— 
— 
— 
≥ 1 + 
a 
Conversion factor is the multiplication factor to convert from SI units to traditional units.  
b  Criteria refer to SI units. 
LNL = lower normal limit of laboratory reference range; PCS = potentially clinically significant; SI = Le 
Système 
International d'Unités (International System of Units); UNL = upper normal limit of laboratory 
reference range. 
5.4.3. Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) dictionary version March 2018. Prior and concomitant medications will be presented 
in a data listing. Concomitant medications will additionally be summarized by treatment 
group.  
5.4.4. Other Safety Analyses 
Descriptive summaries of vital signs data including body temperature, pulse, respiratory rate, 
and blood pressure (systolic and diastolic) and respective changes from Baseline, will be 
presented by time point and treatment group. The number and percentage of patients with 
PCS vital signs per the table below, as determined in the eCRF, occurring post-baseline will 
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also be summarized by time point and treatment group. All vital signs will be listed with 
clinically significant values flagged, as well as for patients with any PCS results.  
CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT VITAL SIGNS 
Parameter 
Flag 
Criteria 
Observed Value 
Systolic blood pressure 
(mm Hg)  
High 
≥ 150 
Low 
≤ 90 
Diastolic blood pressure 
(mm Hg)  
High 
≥ 100 
Low 
≤ 50 
Pulse rate (bpm) 
High 
≥ 110 
Low 
≤ 50 
Temperature (oC) 
 
High 
≥ 38 
Low 
< 35 
Electrocardiogram (ECG) variables and their change from baseline will be summarized with 
descriptive statistics by time point and treatment group. ECG variables will include heart 
rate, PR interval, QRS interval, QT interval, and QTc interval corrected for heart rate using 
QTcF. QTcF values will also be tabulated for their absolute values and tabulated relative to 
baseline measurements in order to detect individual QTcF changes. Additionally, the number 
and percentage of patients with PCS values defined in the table below  
Use header of the convention table for all relevant safety parameters. 
 
 
Criteria for Potentially Clinically Significant ECG Parameters 
Parameter 
Flag 
Criteria 
Observed Value 
Change from Baseline or 
Observed Value 
Heart Rate (bpm) 
High 
> 110 
 
Low 
≤ 50 
 
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QTcFa Interval (msec) 
High Male 
> 450 
30-60, > 60, > 500 
High Female 
> 470 
QRS Interval (msec) 
High 
> 120 
 
PR Interval (msec) 
High 
> 220 
 
 a QTc interval (Fridericia’s) is derived as: QTcF=QT Interval (msec) / (RR (msec)/1000)(1/3)  
For these summaries, worst-case assignments will be made to ensure patients with such 
values are not counted more than once.  For example, a patient with QTcF interval > 500 
msec will count once in the > 500 msec category and will not appear in the > 450 or > 480 
msec categories.  Similar conventions will be used for the 30 to 60 and > 60 msec categories. 
All ECG analyses will be based on the average of triplicate measurements. 
Important abnormalities in ECG waveform that are changes from Baseline readings will also 
be reported in a listing. All ECG will be listed with clinically significant values flagged, as 
well as for patients with any PCS results. 
All physical examination results will be listed.  
Results from the Columbia-Suicide Severity Rating Scale (C-SSRS) will be summarized by 
visit and treatment group. All C-SSRS results will also be reported in a listing. 
6. 
PROTOCOL VIOLATIONS 
Possible protocol deviations will be identified and displayed in a data listing and sorted by 
patient and study day (where applicable).  The following deviations may be identified as 
protocol deviations from the database: 
• Violations of inclusion/exclusion criteria 
• Non-compliance with MIN-117 
7. 
CHANGES IN THE PLANNED ANALYSES 
No deviations in the conduct of the study or the planned analysis are anticipated.  Should 
any deviations from the analyses specified in the authorized statistical analysis plan arise, 
such deviations will be documented in the final clinical study report. 
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8. 
PROGRAMMING CONVENTIONS 
• Page orientation, margins, and fonts: Summary tables, listings, and figures will appear 
in landscape orientation.  There should be a minimum of a 1.25” boundary on the upper 
(bound) edge, and a minimum of a 1.0” boundary on the remaining three edges.  Output 
should be printed in Courier New with a point size of 8.  Titles may be printed using a 
larger font (e.g., Arial point size 10). 
• Identification of analysis population: Every summary table and figure should clearly 
specify the analysis population being summarized.  Listings will be prepared for all 
patients. 
• Group headers: In the summary tables, the group headers will identify the summary 
group and the sample size for the indicated analysis population.  Of note, the header’s 
sample size does not necessarily equal the number of patients actually summarized 
within any given summary module; some patients in the analysis population may have 
missing values and thus may not be summarized. 
• Suppression of percentages corresponding to null categories: When count data are 
presented as category frequencies and corresponding percentages, the percent should be 
suppressed when the count is zero in order to draw attention to the non-zero counts. 
• Presentation of sample sizes: Summary modules should indicate, in one way or another, 
the number of patients actually contributing to the summary statistics presented in any 
given summary module.  As mentioned above, this may be less than the number of 
patients in the analysis population due to missing data. 
♦ In the quantitative modules describing continuous variables (and thus presenting 
sample size, means, and standard deviations), the sample size should be the number 
of non-missing observations.  The number of missing observations, if any, will be 
noted. 
♦ For categorical variables that are presented in frequency tables, the module should 
present the total count in addition to the count in each category.  Percentages should 
be calculated using this total as the denominator, and the percentage corresponding 
to the sum itself (that is, 100%) should be presented so as to indicate clearly to a 
reviewer the method of calculation.  The number of missing observations, if any, will 
be noted. 
• Sorting: Listings will be sorted by treatment group, patient number and date, if 
applicable.  If a listing is sorted in a different manner, a footnote will indicate as such.  
• General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures.  No intermediate 
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rounding will be performed on derived variables.  The standard rounding practice of 
rounding numbers ending in 0-4 down and numbers ending in 5-9 up will be employed.   
• The presentation of numerical values will adhere to the following guidelines:  
♦ Raw measurements will be reported to the number of significant digits as captured 
electronically or on the CRFs.   
♦ Standard deviations will be reported to one decimal place beyond the number of 
decimal places the original parameter is presented. 
♦ Means will be reported to the same number of significant digits as the parameter.  
• Dates will be formatted as DDMMMYYYY.  Partial dates will be presented on data 
listings as recorded on CRFs. 
♦ Time will be presented according to the 24-hour clock (HH:MM). 
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9. 
PROPOSED TABLES, LISTINGS, AND FIGURES 
Summary Tables 
 
Accountability and Baseline Characteristics 
14.1.1 
          Final Patient Disposition, All Enrolled Patients 
14.1.2.1            Demographics, Safety Population 
14.1.2.2           Baseline Disease Characteristics, Safety Population 
14.1.3 
          Drug Exposure and Compliance, Safety Population 
14.1.4 
          Concomitant Medications by ATC Classification and Preferred Term, Safety 
Population 
Efficacy 
14.2.1.1.1  
Summary of MADRS Total Score by Visit, ITT Population 
14.2.1.1.2  
Summary of MADRS Total Score by Visit – Sensitivity with LOCF, ITT 
Population 
14.2.1.1.3  
Summary of MADRS Total Score by Visit – Sensitivity with LOCF and Placebo 
Average, ITT Population 
14.2.1.1.4  
Summary of MADRS Total Score  – Sensitivity with Multiple Imputation, ITT 
Population 
14.2.2.1.1  
Summary of HAM-A Score by Visit, ITT Population 
14.2.2.1.2  
Summary of HAM-A Score by Visit – Sensitivity with LOCF, ITT Population 
14.2.2.1.3  
Summary of HAM-A Score by Visit – Sensitivity with LOCF and Placebo 
Average, ITT Population 
14.2.2.1.4  
Summary of HAM-A Score– Sensitivity with Multiple Imputation, ITT Population 
14.2.2.2  
Summary of CGI-S and CGI-I Score by Visit, ITT Population 
14.2.2.3  
Summary of IDS-SR30 Score by Visit, ITT Population 
 
14.2.2.4  
Summary of SHAPS Score by Visit, ITT Population 
14.2.2.5  
Summary of DSST Score by Visit, ITT Population 
14.2.2.6  
Summary of PSS Score by Visit, ITT Population 
14.2.2.7  
Summary of A-SEX Score by Visit, ITT Population 
14.2.3.1  
MADRS Response by Visit, ITT Population 
14.2.3.2  
Remission and Sustained Response in MADRS, ITT Population 
14.2.3.3  
Time to MADRS Improvement, ITT Population 
14.2.3.4  
Summary of Single MADRS Rating Scale Items by Visit, ITT Population 
14.2.3.5  
Summary of MADRS Core Mood Items by Visit, ITT Population 
14.2.4.1  
Summary of Sleep Parameters by Visit, ITT Population 
 
Safety 
14.3.1.1             Overall Summary of Treatment-Emergent Adverse Events, Safety Population 
14.3.1.2             Treatment-Emergent Adverse Events by System Organ Classification, Preferred 
Term and Maximum Severity, Safety Population 
14.3.1.3             Treatment-Emergent Adverse Events Related to Study Treatment by System Organ 
Classification, Preferred Term and Maximum Severity, Safety Population 
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14.3.1.4             Treatment-Emergent Adverse Events Leading to Discontinuation of Study 
Treatment by System Organ Classification, Preferred Term and Maximum 
Severity, Safety Population 
14.3.1.5             Treatment-Emergent Fatal Adverse Events by System Organ Classification and 
Preferred Term, Safety Population 
14.3.2.1             Treatment-Emergent Serious Adverse Events by System Organ Classification and 
Preferred Term, Safety Population 
14.3.4.1 
Clinical Laboratory Hematology Parameters by Time Point, Safety Population 
14.3.4.2 
Clinical Laboratory Chemistry Parameters by Time Point, Safety Population 
14.3.4.3.1 
Clinically Significant Laboratory Values, Safety Population 
14.3.4.3.2 
Clinically Significant and Potentially Clinically Significant Laboratory Values, 
Safety Population 
14.3.4.4            Clinical Laboratory Parameter Shifts from Study Baseline to Week 6, Safety 
Population 
14.3.5.1 
Vital Signs by Time Point, Safety Population 
14.3.5.2.1 
Patients with Clinically Significant Vital Signs Occurring Post-Baseline, Safety 
Population 
14.3.5.2.2 
Patients with Clinically Significant or Potentially Clinically Significant Vital Signs 
Occurring Post-Baseline, Safety Population 
14.3.5.3.1  
12-Lead ECG Assessments by Time Point, Safety Population 
14.3.5.3.2 
Summary of QTcF (msec) Categories, Safety Population 
14.3.5.4 
Patients with Significant ECG Abnormalities Occurring Post-Baseline, Safety 
Population 
14.3.6.1 
Summary of C-SSRS by Visit, Safety Population 
 
 
Data Listings 
 
16.2.1                Patient Disposition 
16.2.2.1 
Protocol Deviations 
16.2.2.2 
Inclusion/Exclusion Criteria 
16.2.4.1             Demographics 
16.2.4.2             Medical and Surgical History 
16.2.5.1             Study Drug Administration 
16.2.5.2             Prior and Concomitant Medications 
16.2.5.3.1          Pharmacokinetic Plasma Concentrations 
16.2.6.1             MADRS Rating Scale 
16.2.6.2             CGI-S and CGI-I Questionnaires 
16.2.6.3             HAM-A Questionnaires 
16.2.6.4             IDS-SR30 Questionnaires 
16.2.6.5             SHAPS Questionnaires 
16.2.6.6             DSST Questionnaires 
16.2.6.7             PSS Questionnaires 
16.2.6.8             A-SEX Questionnaires 
16.2.6.9             C-SSRS Questionnaires 
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16.2.6.10           Somno-Art Sleep Parameters 
16.2.7                Adverse Events 
16.2.8.1.1          Laboratory Data – Chemistry 
16.2.8.1.2          Laboratory Data – Hematology 
16.2.8.1.3          Laboratory Data – Urinalysis 
16.2.8.1.4          Laboratory Data – Other  
16.2.8.1.5          Laboratory Results Outside Reference Range 
16.2.8.1.6          Potentially Clinically Significant Laboratory Results 
16.2.8.2.1          Vital Signs 
16.2.8.2.2          Weight, Height and BMI 
16.2.8.3             Physical Examinations 
16.2.8.4            12-Lead ECG Findings 
 
 
Figures 
 
14.2.1.1.5 
Change from Baseline in MADRS by Visit, ITT Population 
14.2.2.1.5 
Change from Baseline in HAM-A by Visit, ITT Population 
14.2.3.6 
Change from Baseline in Single MADRS Rating Scale Items by Visit, ITT 
Population 
14.2.3.7 
Time to ≥ 50% MADRS Improvement, ITT Population 
14.2.3.8 
Time to ≥ 30% MADRS Improvement, ITT Population 
 
 
 
 
 
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