Clinical trial NCT03051256
Conditions: Depressive Disorder, Major Depressive Disorder, Treatment-Resistant
Keywords: REL-1017 d-Methadone Methadone Depression Refractory Depression Antidepressant Adjunctive Treatment NMDA Receptor Antagonist Excitatory Amino Acid Antagonist Glutamate Antagonist
Sponsor: Relmada Therapeutics, Inc.
Start date: 2018-05-11; Completion date: 2019-09-30
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This a Phase 2a, multicenter, randomized, double-blind, placebo controlled 3 arm study to assess the safety and tolerability of multiple oral doses of REL-1017 25 mg and 50 mg as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD). The patients will be adults with MDD who are diagnosed with a current MDE who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication. This population will provide the opportunity to compare the safety and efficacy effects of treatment with an approved antidepressant in conjunction with REL-1017 versus the effects of an antidepressant alone. This study includes in-patient and out-patient periods.

Detailed description:
Currently available medications have proven to be useful for the treatment of depression, but also have limitations including low response rates, a significant number of treatment resistant patients, and time-lag for response, which emphasizes a major unmet need for more efficacious and faster-acting antidepressants. Recent studies have demonstrated that ketamine, a non-competitive glutamate-N-methyl-D-Aspartate (NMDA) receptor antagonist, produces rapid onset (2 hours) and long-lasting (7 days) antidepressant actions in treatment resistant patients. This rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, represents a significant finding in the field of depression.

Racemic methadone, the 50/50 combination of d-methadone and l-methadone, has been in widespread use for decades and has been studied extensively. Methadone is currently approved for use in the management of severe pain, detoxification treatment of opioid addiction, and maintenance treatment of opioid addiction.

The results of a study evaluating the receptor binding profiles of racemic methadone and its stereoisomers suggest that d-methadone does not essentially contribute to the opioid effect of racemic methadone and that it has a 10 times lower affinity for the mu1, mu2, and delta opioid receptors compared to l-methadone. Racemic methadone and its d- and l isomers exhibit similar affinities for the non-competitive binding site of the NMDA receptor and are non-competitive NMDA receptor antagonists.

In the forced swim test, a rodent behavioral model of antidepressant activity, both ketamine and d-methadone at all doses tested significantly decreased the immobility of the rats compared to the vehicle suggesting antidepressant like activity. Neither drug increased spontaneous locomotor activity.

Relmada has conducted 2 clinical studies to identify the dose levels of REL-1017 (d-methadone) that have little to no opioid effects and that are expected to possess NMDA antagonistic properties for the evaluation of oral REL-1017 in the treatment of MDD and neuropathic pain conditions. Initial Phase 1 single ascending dose and multiple ascending dose clinical studies of REL-1017 were designed to evaluate the safety and tolerance of the pure d methadone isomer in healthy opioid-naïve subjects and identify a safe and potentially effective dose range in this population. These studies showed that REL-1017 was safe and well-tolerated at single oral doses up to 150 mg (maximum tolerated dose) and up to 75 mg administered once daily for 10 days in healthy opioid-naïve subjects.

The pre-clinical and previous clinical experience with REL-1017 (d-methadone) provided the basis for the initiation of the present study, which will extend the evaluation of the safety, tolerability, and PK of REL-1017 at 2 doses with repeated administration to depressed patients. Since REL-1017 is proposed for use as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD), the patients will be male adults with MDD who are diagnosed with a current depressive episode who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication.

Based on the safety data from Protocol REL-1017-111, single doses of 5 mg, 20 mg, 60 mg, 100 mg, and 150 mg of REL-1017 or placebo were well tolerated. The results of Protocol REL-1017-112 evaluated 10 days of dosing with 25 mg, 50 mg and 75 mg of REL-1017 or placebo, and no impact on safety was observed. In spite of the confirmed dose proportionality, the comparison of concentration and exposure between the 50 mg and 75 mg REL-1017 treatment groups demonstrated only slight differences. Consequently, 25 mg and 50 mg doses were chosen for administration in Protocol REL-1017-202 as single daily doses over a period of 7 days.

Thus, as a single isomer of racemic methadone, d-methadone has been shown to possess NMDA antagonist properties with virtually no opioid activity or ketamine-like toxicities at the expected therapeutic doses.

In this study, adult male patients with MDD who are diagnosed with a current MDE and who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication will be randomized to study drug in a 1:1:1 ratio. Approximately 15 patients each will receive REL-1017 25 mg, REL-1017 50 mg, or placebo once daily for 7 days. Endpoints include assessments of safety, tolerability, efficacy and pharmacokinetics of REL-1017. Patients will be required to stay in the clinic for 10 days and will then be followed as an outpatient for 12 additional days.

Arms: arm 1: REL-1017 75 mg of powder in 100 mL of Ocean Spray® Diet Cranberry Juice daily on Day 1, 25 mg of powder in 100 mL Ocean Spray® Diet Cranberry Juice daily on Day 2-7. arm 2: REL-1017 100 mg of powder in 100 mL of Ocean Spray® Diet Cranberry Juice daily on Day 1, 50 mg of powder in 100 mL Ocean Spray® Diet Cranberry Juice daily on Day 2-7. arm 3: 100 mL Ocean Spray® Diet Cranberry Juice will be administered as a single oral dose daily for 7 days.
Interventions: intervention 1: REL-1017 intervention 2: Placebo
Intervention descriptions: intervention 1: REL-1017 will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study. intervention 2: Placebo will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 1 of 165 
 
 
 
 
 
 
 
 
Clinical Study Protocol REL-1017-202 
 
 
 
 
 
A Phase 2a, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, 3-Arm Study to Assess the Safety, Tolerability, 
PK Profile, and Symptom Response of a 7-Day Dosing with 
REL-1017 25 mg QD and 50 mg QD as Adjunctive Therapy in the 
Treatment of Patients Diagnosed with Major Depressive Disorder 
 
 
 
Protocol Amendment 5, Version: 6.0, 07-Mar-2019 
 
 


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 2 of 165 
 
 
 
Short Title 
Safety, Tolerability, PK Profile, and Symptom Response of a 
7-Day Dosing with 25 mg QD and 50 mg QD of REL-1017 in 
MDD 
Protocol Number 
REL-1017-202 
Syneos Health 
Project Number 
1008945 
Phase 
Phase 2a 
Sponsor 
Sergio Traversa 
Chief Executive Officer 
Relmada Therapeutics 
880 Third Avenue, 12th Floor 
New York, NY 10022 
Work: 212-547-9591  
st@relmada.com 
Test Product 
REL-1017 (d-Methadone) 25 mg and 50 mg 
Dose/Route of 
Administration 
REL-1017 25 mg or 50 mg powder dissolved in 100 mL Ocean 
Spray® Diet Cranberry Juice administered orally 
Medical Monitor 
Morgan Kearney, MD 
Syneos Health, Inc. 
3201 Beechleaf Court, Suite 600 
Raleigh, NC, USA 27604 
24-Hr Contact Phone Numbers: 
Office: 919-257-6801 
Mobile: 919-397-0174 
Protocol Date 
13-Dec-2016 (Version 1.0) 
Amendment 1 
19-Jan-2017 (Version 2.1) 
Amendment 2 
29-Jan-2018 (Version: 3.0) 
Amendment 3 
05-Apr-2018 (Version 4.0) 
Amendment 4 
19-Nov-2018 (Version 5.0) 
Amendment 5 
07-Mar-2019 (Version 6.0) 
 
 
 
 


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 3 of 165 
 
CONFIDENTIALITY STATEMENT 
This protocol contains information that is confidential and proprietary to Relmada Therapeutics, 
Inc. This information is being provided to you for conducting a clinical study for Relmada 
Therapeutics, Inc. You may disclose the contents of this protocol to study personnel under your 
supervision who need to know the contents for this purpose, as well as to your Institutional 
Review Board(s) or Ethics Committee(s), subject to the following condition: The contents of this 
protocol may not be disclosed to any person or entity without the prior written permission of 
Relmada Therapeutics, Inc., and may not be used for any purpose other than the conduct of this 
study. The foregoing shall not apply to disclosure required by governmental regulations or laws; 
however, you will give prompt notice to Relmada Therapeutics, Inc., of any such disclosure. 
Any supplemental information that may be added to this document is also confidential and 
proprietary to Relmada Therapeutics, Inc., and must be kept in confidence in the same manner as 
the contents of this protocol. 
Any person who receives this protocol without due authorization from Relmada Therapeutics, 
Inc., is requested to return it to Relmada Therapeutics, Inc., or to promptly destroy it. 
 
 


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 4 of 165 
 
PROTOCOL SYNOPSIS 
 
Title of Study: 
Protocol REL-1017-202: 
A Phase 2a, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, 3-Arm Study to Assess the Safety, Tolerability, 
PK Profile, and Symptom Response of a 7-Day Dosing with 
REL-1017 25 mg QD and 50 mg QD as Adjunctive Therapy in the 
Treatment of Patients Diagnosed with Major Depressive Disorder 
Sponsor: 
Relmada Therapeutics, Inc. (Relmada) 
Phase of 
Development: 
Phase 2a 
Clinical Study 
Objectives: 
Primary Objective: 
• To assess the safety and tolerability of 25 mg and 50 mg of 
REL-1017 (d-methadone) compared to Placebo as adjunctive 
treatment in patients with major depressive disorder (MDD) 
Secondary Objectives: 
• To characterize the pharmacokinetic (PK) profile of 25 mg and 
50 mg of REL-1017 (d-methadone) as adjunctive treatment in 
patients with MDD 
• To explore the efficacy of 25 mg and 50 mg of REL-1017 
(d-methadone) as adjunctive treatment in patients with MDD 
Endpoints: 
Safety and Tolerability: 
The following assessments will be conducted to measure safety and 
tolerability throughout the study: 
• Adverse Events (AEs) 
• Vital Signs 
• Weight 
• Physical Examination 
• Clinical Laboratory Parameters (chemistry, hematology, and 
urinalysis) 
• Electrocardiogram (ECG) parameters 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Clinician Administered Dissociative States Scale (CADSS) 
• Clinical Opiate Withdrawal Scale (COWS) 
• 4-Item Positive Symptom Rating Scale (PSRS) 
 


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
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Endpoints 
(Continued): 
Pharmacokinetics: 
The PK profile of REL-1017 25 mg and 50 mg will be evaluated on 
Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data 
allow: 
• Maximum observed plasma concentration (Cmax) 
• Time to maximum observed plasma concentration (Tmax) 
• Area under the plasma concentration-time curve from time zero 
until the dosing interval of 24 hours (AUCtau) 
• Area under the plasma concentration-time curve from time zero 
until the last quantifiable time point (AUC0-last) on Day 7 
• Area under the plasma concentration-time curve from time zero 
to infinity (AUC0-inf) 
• Apparent termination elimination rate constant (λz) 
• Apparent terminal elimination half-life (t½) 
• Attainment of steady state 
• Steady state clearance (CSS/F) 
• Volume of distribution at steady state (VSS/F) 
• Accumulation ratios based on minimum observed plasma 
concentration (Cmin), Cmax, and AUCtau 
Efficacy: 
The following assessments will be conducted to evaluate efficacy: 
• Change from Baseline (Day 1) to the End of the Dosing Period 
(EDP, Day 7) on the Montgomery-Asberg Depression Rating 
Scale (MADRS) 
• Change from Baseline (Day 1) to EDP (Day 7) on the Symptoms 
of Depression Questionnaire (SDQ)  
• Change from Baseline (Day 1) to EDP (Day 7) on the Clinical 
Global Impressions of Severity (CGI-S) scale. 
• Change from Baseline (Day 2) to EDP (Day 7) on The Clinical 
Global Impressions of Improvement (CGI-I) scale will be 
measured at pre-dose on Day 2, post-dose on Day 4 and Day 7 
within 3 hours of dosing, and on Day 14. 
The timing of each assessment is detailed in the Time and Events 
Schedule (Table 1). 
Study Design: 
A Phase 2a, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, 3-Arm Study to Assess the Safety, Tolerability, 
PK Profile, and Symptom Response of a 7-Day Dosing with 
REL-1017 25 mg QD and 50 mg QD as Adjunctive Therapy in the 
Treatment of Patients Diagnosed with MDD 
Investigational 
Product: 
REL-1017 (d-Methadone) 25 mg, 50 mg, 75 mg and 100 mg Powder 
Formulation 


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
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Study Drug, Dose 
Schedule, and Mode 
of Administration: 
REL-1017 consists of d-methadone hydrochloride (HCl) in a 
powder formulation. The following doses will be used in the study: 
• REL-1017 75 mg QD Day 1, 25 mg REL-1017 QD Day 2-7 
• REL-1017 100 mg QD Day 1, 50 mg REL-1017 QD Day 2-7 
• Placebo (Ocean Spray® Diet Cranberry Juice) 
REL-1017 will be provided as a powder and prepared as a solution 
with Ocean Spray® Diet Cranberry Juice on site to obtain a final 
volume of 100 mL for dosing. 
Patients will continue to take the same, stabilized antidepressant 
medication that they were taking at Screening throughout the course 
of the study, and the supply of medication during the confined study 
period will be arranged and assured by the Investigator. 
An unblinded pharmacist will assign study drug to patients according 
to randomized treatment codes provided by the Interactive Web 
Response System (IWRS). The randomization code used in the IWRS 
will be prepared by a statistician who is not working as a statistician 
on the study in any other capacity. The study drug solution or Placebo 
will be prepared within 3 hours of administration in blinded 
containers, and then will be dispensed to blinded study staff for 
administration to the patients. 
After drinking the 100 mL of study drug, 25 mL of non-carbonated 
water will be added to the study drug container and gently swirled. 
The patient will drink this rinse volume followed by 125 mL of 
non-carbonated water to drink immediately thereafter. 
All dosing must be completed within 5 minutes. 
Dosing will take place once daily in the morning after an overnight 
fast of at least 8 hours. 
Study Population 
and Duration of 
Participation 
Adult patients with MDD who are diagnosed with a current major 
depressive episode (MDE) and who have experienced an inadequate 
response to 1 to 3 courses of treatment with an adequate dose and 
duration (as defined by the Antidepressant Treatment Response 
Questionnaire [ATRQ]) of an antidepressant medication for the 
current episode will be randomized to study drug in a 1:1:1 ratio.  
Approximately 120 patients will be screened, and approximately 
60 qualified patients will be randomized to study drug in a 1:1:1 
ratio (approximately 20 patients per arm). Each patient will 
participate for up to 51 days (30 days Screening, 7 days treatment, 
and 14 days of observation and follow-up). 
Sample Size 
Considerations: 
As this is a Phase 2a study, formal sample size calculations are not 
applicable. The study will not be powered for signal detection. 


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
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Inclusion Criteria: 
To enroll in the clinical study, patients must meet the following 
inclusion criteria: 
1. Males and females between 18 and 65 years of age, inclusive. 
2. Diagnosed with recurrent MDD as defined by the Diagnostic and 
Statistical Manual, Fifth Edition (DSM-5), and confirmed by the 
Mini International Neuropsychiatric Interview, Version 7.0.2 
(MINI). 
3. Diagnosed with a current MDE lasting 8 weeks to 
36 months as defined by the DSM-5 and confirmed by the 
MINI. 
4. Treated with an adequate dosage of a selective serotonin 
reuptake inhibitor (SSRI), serotonin and norepinephrine 
reuptake inhibitor (SNRI), or bupropion during the current 
MDE for at least 8 weeks prior to Screening with the same, 
adequate dosage for the last 4 weeks. Minimum adequate 
doses are defined in the ATRQ. The maximum dose 
allowed for paroxetine is 40 mg QD, for fluoxetine is 
60 mg QD, and for sertraline is 200 mg QD. 
5. Have experienced an inadequate response to 1 to 3 courses of 
treatment with an antidepressant medication in the current episode, 
defined as <50% improvement with an antidepressant medication 
at doses listed on the SAFER Interview (Criteria: State versus trait; 
Assessability; Face validity; Ecological validity; and Rule of three 
Ps [pervasive, persistent, and pathological). 
6. Hamilton Depression Rating Scale-17 (HAM-D-17) ≥19 at 
Screening and Check-in (Day -1). 
7. Body Mass Index (BMI) between 18.0 and 35.0 kg/m
2, inclusive, 
and a minimum weight of 50.0 kg. 
8. Per the Investigator’s judgment, able to meet all study 
requirements, including the confined/inpatient portion of the 
study, adherence with both approved antidepressant therapy and 
study drug regimen, and completion of all assessments and all 
scheduled visits. 
9. Male and female patients of reproductive potential must be 
using and willing to continue using medically acceptable 
contraception, as specified in the protocol, from Screening and 
for at least 2 months after the last study drug administration. 
Female patients must have a negative pregnancy test, and must 
not be lactating. 
10. Must be able to read, speak, and understand English and must 
provide written informed consent prior to the initiation of any 
protocol-specific procedures. 


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Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
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Exclusion Criteria: 
1. History or presence of clinically significant abnormality as 
assessed by physical examination, medical history, 12-lead ECG, 
vital signs, or laboratory values, which in the opinion of the 
Investigator would jeopardize the safety of the patient or the 
validity of the study results, including torsades de pointes, any 
bradyarrhythmias, or uncompensated heart failure. 
2. Chronic use of prescribed opioids (i.e., >120 days in a 6-month 
period) up to 6 months prior to Screening or any recreational use 
of opioids. 
3. Evidence of clinically significant hepatic or renal 
impairment, including alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) >1.5 x upper limit of 
normal (ULN), bilirubin >1 x ULN, or endocrine laboratory 
values (including clinically significant thyroid parameters, 
i.e., thyroid stimulating hormone [TSH], triiodothyronine 
[T3], and thyroxine [T4]). 
4. History or family history of sudden unexplained death or 
long QT syndrome (measure of the time between the start of 
the Q wave and the end of the T wave in the heart’s electrical 
cycle). 
5. An average QTcF ≥450 msec or an average QRS interval 
≥120 msec from the 12-lead ECGs performed at Screening.  
6. History of clinically diagnosed hypotension requiring treatment. 
7. History or presence of any condition in which an opioid is 
contraindicated (e.g., significant respiratory depression, acute or 
severe bronchial asthma or hypercarbia, bronchitis, or has/is 
suspected of having paralytic ileus). 
8. No more than 3 prescribed doses of an opioid within the 6 months 
prior to Screening and no use at all within the last month. 
9. Use of an antipsychotic, anticonvulsant, or mood stabilizer, 
regardless of indication, within the 3 months prior to Screening. 
10. History of allergy or hypersensitivity to methadone or related 
drugs (e.g., opioids). 
11. Positive test for hepatitis B or human immunodeficiency virus 
(HIV). Patients with a positive hepatitis C test may be considered 
for inclusion with approval from the Medical Monitor. 
12. Any current and primary psychiatric disorder, as defined as a 
condition that is the primary focus of distress and/or treatment, 
other than MDD. 
13. Any lifetime history of bipolar I or II disorder, any psychotic 
disorder, post-traumatic stress disorder, borderline personality 
disorder, antisocial personality disorder, obsessive compulsive 
disorder, eating disorder, intellectual disability, or pervasive 
developmental disorder. 
 


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
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Exclusion Criteria 
(Continued): 
14. History in the past 12 months of a primary diagnosis of anxiety 
disorder or panic disorder not related to the current MDE.  
15. Current diagnosis of alcohol or substance use disorder, as defined 
by DSM-5, at Screening or within the 12 months prior to 
Screening. Patients with the following diagnoses within the past 
12 months, however, may be included at the Investigator’s 
discretion: mild alcohol use disorder, mild cannabis use disorder, 
and any severity tobacco use disorder.  
16. A confirmed positive result on the urine drug/alcohol screen at 
Screening or Check-in. If the urine drug/alcohol screen is positive 
at Screening, retesting or rescreening may be scheduled with prior 
approval from the Medical Monitor. 
17. Patients who, in the Investigator’s judgment, are at significant risk 
for suicide. A patient with a C-SSRS ideation score of 4 or 5 within 
the last 6 months or any suicide attempt within the past year must 
be excluded, as should a patient with an ideation score of 4 or 5 or 
any suicide attempt at the Check-in or Baseline Visit. 
18. Patients with a 20% improvement between Screening and 
Check-in (Day -1) on the HAM-D-17.  
19. Patients who did not safely discontinue prohibited medications. 
20. Patients receiving new onset psychotherapy (individual, group, 
marriage, or family therapy) within 2 months prior to Screening or 
plans to start at any time during participation in the study. 
21. Patients who have received electroconvulsive therapy (ECT), 
repetitive transcranial magnetic stimulation (rTMS), or vagus nerve 
stimulation (VNS) or who have participated in a ketamine study 
within the last 6 months. 
22. Patients with any clinically significant neurological, hepatic, renal, 
metabolic, hematological, immunological, cardiovascular, 
pulmonary, chronic pain, or gastrointestinal disorder. Medical 
conditions that are minor or well-controlled may be permitted if 
they will not increase the safety risk to the patient or compromise 
interpretation of the safety or efficacy endpoints. 
23. Patients taking fluvoxamine or St. John’s Wort. 
24. Patients who have participated in a clinical study with an 
investigational medication in the past 6 months, or who have 
participated in more than 4 clinical studies with investigational 
medications in the past 2 years. 


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
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Procedures: 
Screening: 
After the Informed Consent Form (ICF) is signed, a Screening number 
will be assigned to the patient, and an outpatient Screening Visit will 
be conducted during which the patient will undergo an interview and 
medical assessments to determine eligibility for study participation. 
Patients who meet all the screening entry criteria will be scheduled for 
admission to the clinical research unit (CRU). 
The patient’s eligibility assessment will be reviewed by an external 
medical team based on key protocol inclusion and exclusion criteria 
to promote appropriate patient enrollment and data quality. Sites 
should submit specific Screening information (detailed in the in the 
Massachusetts General Hospital Clinical Trials Network and 
Institute [MGH CTNI] manual) within 72 hours after the Screening 
Visit for review by the external medical team prior to proceeding to 
Check-in. Subjects who are deemed eligible by the Principal 
Investigator and confirmed by the Medical Monitor will undergo the 
SAFER Interview by clinicians at the MGH CTNI. 
To ensure that appropriate subjects are entered into the study, a 
remote interview will be conducted by MGH CTNI raters. The 
assessments administered will be the SAFER Interview, which will 
include the HAM-D17, and the MGH ATRQ. The interview will be 
performed remotely by the MGH CTNI rater, and the subject will be 
contacted at his or her home or other off-site location after the 
Screening Visit, during which call the above assessments will be 
performed. Sites will be notified of the results within 24 hours of the 
interview. Only subjects whose eligibility will be confirmed by the 
SAFER Interview will be allowed to proceed in the study.   
Check-in (Day -1): 
Inpatient admission may occur up to 30 days after the Screening Visit 
as soon as it is determined that patients meet all screening criteria. 
Upon Check-in, patients will undergo further medical and psychiatric 
Screening according to the Time and Events Schedule (Table 1) to 
ensure they continue to qualify for participation in the study. 
Baseline (Day 1): 
Assessments will be conducted according to the Time and Events 
Schedule (Table 1). The Baseline criteria checklist must be completed 
on Day 1, prior to randomization, to determine if the patient is still 
eligible for participation in the study. Any patient who does not meet 
full Screening and Baseline entry criteria must be discontinued from 
the study and will be considered a screen failure. Patients who meet full 
Screening and Baseline entry criteria will be randomized and assigned 
a Patient Identification (ID) Number. 
 
Procedures 
(Continued): 
Dosing Period (Day 1 to Day 7): 


Clinical Study Protocol Amendment 5 
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Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
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The dosing period will begin on Day 1 and continue through the last 
dose of study drug on Day 7 (EDP). Study drug will be administered in 
the morning. The patient’s prescribed antidepressant will be administered 
by site personnel while the patient is confined to the study unit. 
Assessments during the dosing period will include measures of safety 
and tolerability, PK, and efficacy. For patients who discontinue study 
drug prior to Day 7, all EDP assessments should be completed according 
to the Time and Events Schedule (Table 1), provided informed consent 
has not been withdrawn. 
24-Hour Post-Dose Assessments (Day 8): 
On Day 8, patients will be evaluated 24 hours after the final dose of 
study drug on Day 7 according to the Time and Events Schedule 
(Table 1). 
Discharge (Day 9): 
Following the last dose of study drug, each patient (including those 
who discontinue from the study drug prior to Day 7) is to remain in the 
inpatient facility for at least 2 additional days of safety and efficacy 
monitoring. The assessments to be conducted prior to Discharge are 
listed in the Time and Events Schedule (Table 1). 
Outpatient Observation Period (Day 10 to Day 14): 
The End of the Observation Period (EOP) will occur on Day 14 when 
the EOP interview will be conducted in person to assess psychiatric 
symptoms and safety endpoints, including medical conditions, new 
medications, and newly emergent AEs as listed in the Time and 
Events Schedule (Table 1). Samples will be drawn for PK analysis. 
For patients who discontinue study drug prior to Day 7, the EOP 
interview will occur 7 days after their last dose of study drug. (The 
window for the EOP visit is ± 3 days.) 
Follow-Up Period (Day 15 to Day 21): 
Follow-up interviews will be conducted with all patients (including 
those who discontinue from the study drug prior to Day 7) 14 days 
after their last dose of study drug. (The visit window is ± 3 days). In 
the Follow-Up interview (Day 21), C-SSRS, AEs, and concomitant 
medications will be recorded (Table 1). This interview may be 
conducted by telephone. During the Follow-Up Period, safety 
evaluations should be conducted, at the discretion of the Investigator, 
to evaluate any unresolved abnormal treatment-emergent findings. 
 


Clinical Study Protocol Amendment 5 
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Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
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Procedures 
(Continued): 
Safety: 
Adverse events will be listed and summarized by treatment group. All 
AEs reported in this study will be coded using the current Medical 
Dictionary for Regulatory Activities (MedDRA) Version 16.0 or higher. 
The overall incidences of AEs and serious AEs (SAEs) in system-
organ-class and preferred term will be tabulated by treatment group. In 
addition, incidence rates (frequencies and percentages) will be broken 
down by intensities and relationship to treatment with REL-1017. 
Changes from Check-in (Day -1) in vital signs, ECGs, weight, body 
temperature, and clinical laboratory tests will be derived by treatment 
group. Any clinically significant abnormalities will be followed until 
resolution or stabilization. 
Statistical Data 
Analysis: 
Safety: 
Safety and tolerability parameters will be listed by treatment and patient 
and displayed in summary tables using descriptive statistics. 
The number and percentage of patients with treatment-emergent AEs 
will be summarized by system organ-class, preferred term, and 
treatment and for each treatment by maximum severity and relationship 
to study treatment. 
Descriptive statistics for vital signs, weight, and oral body temperature 
will be calculated and presented for each time point by treatment 
(absolute values and change from Baseline). 
Absolute values, change from Check-in (Day -1) in 12-lead ECG results 
and QT/QTcF categories will be summarized using descriptive 
statistics; frequencies (numbers and percentages) will be calculated for 
the overall evaluation by scheduled time and treatment. 
Laboratory data will be summarized by the type of laboratory test and 
scheduled visit. Descriptive statistics will be calculated and presented 
for each time point by treatment (absolute values and change from 
Check-in [Day -1]). Descriptive statistics and the number of patients 
with laboratory test results below, within, and above normal ranges will 
be tabulated by scheduled time. 
Medical history and physical examination abnormalities will be listed. 
Concomitant medication data will also be listed. 
Pharmacokinetics: 
The pharmacokinetic (PK) parameters for REL-1017 determined by 
non-compartmental analysis will be summarized. Graphs of the 
concentration (original and log transformed) versus time will be 
generated. Descriptive statistics, including number of patients, mean, 
standard deviation (SD), coefficient of variation (CV), median, 
minimum, and maximum will be calculated by time point for 
REL-1017 25 mg and 50 mg.  


Clinical Study Protocol Amendment 5 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 13 of 165 
 
Statistical Data 
Analysis 
(Continued): 
Pharmacokinetics (Continued): 
Concentrations below the limit of quantification (BLQ) will be set to 
zero for the generation of summary statistics for concentrations and the 
generation of mean concentration time plots. 
For the calculation of the PK parameters, concentration-time data will 
be treated as follows: BLQ concentrations prior to the first quantifiable 
concentration will be set to zero; BLQ concentrations after the first 
quantifiable concentration will be treated as missing; and pre-dose 
sampling times relative to dosing will be set to zero. 
Descriptive statistics, including number of patients, mean, SD, 
geometric mean, geometric CV, minimum, maximum, and median will 
be calculated for all REL-1017 PK parameters except Tmax or t½. The 
Tmax data will be summarized with number of patients, minimum, 
maximum, and median. The t½ data will be summarized with number of 
patients, mean, SD, minimum, maximum, and median. 
Efficacy: 
The depressive symptom changes associated with 7 days of daily 
dosing with REL-1017 25 mg and 50 mg will be measured using the 
MADRS, SDQ, and CGI-S. The MADRS, SDQ, and CGI-S will be 
conducted pre-dose at Baseline (Day 1) and on Day 2; post-dose on 
Day 4 and Day 7 within 3 hours of dosing; and at EOP (Day 14). The 
CGI-I will be measured at pre-dose on Day 2, post-dose on Day 4 and 
Day 7 within 3 hours of dosing, and on Day 14. 
The change from Baseline in each parameter on Day 7 will be 
compared among treatment groups (Placebo, REL-1017 25 mg, and 
REL-1017 50 mg) using a MMRM (Mixed Model of Repeated 
Measurement) with treatment group, stratification (concomitant 
antidepressant drug) factor, visit (Day 2, Day 4, and Day 7), 
interaction between treatment and visit as independent variables, and 
Baseline endpoint as a covariate. Least square (LS) means with 
standard errors (SEs), differences in LS means with standard errors 
(SEs), 90% confidence intervals (Cis) for the difference in LS means, 
and corresponding P-values will be presented. 
Actual values, absolute change, and percent change from Baseline will 
be summarized by treatment and all visits. 
The assumptions of normality may be evaluated using the 
Shapiro-Wilks test. If the assumptions of normality are not satisfied, the 
ranked change and ranked Baseline may replace the change and 
Baseline in the above mixed model as a sensitivity analysis. 
 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 14 of 165 
 
Table 1 
Time and Events Schedule 
Visit 
Screening 
Check-In 
Baseline 
EDP 
Discharge 
EOP 
FU 
Assessment Daya 
-30 to -2 
-1 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
14 
21 
Informed Consent 
X 
Medical History  
X 
X 
Xb 
Xb 
Psychiatric History 
X 
Medication History 
X 
Demographics and Height 
X 
Inclusion/Exclusion Review 
X 
X 
MINI 
X 
ATRQ 
X 
X 
HAM-D-17 
X 
X 
SAFER Interview 
X 
 
Physical Examination 
X 
X 
X 
X 
Vital Signs and Pulse Oximetryc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and Oral Body Temperature 
X 
X 
X 
X 
BMI 
X 
 
 
 
ECGd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/Biochemistry/Urinalysise 
X 
X 
Xe 
 
 
 
 
 
Xe 
 
 
X 
Hepatitis B, Hepatitis C, and HIV 
X 
 
 
 
 
Thyroid Panel - TSH, T3, and T4 
X 
 
 
 
 
Drug Screen (urine)f 
X 
X 
 
 
 
Breath Alcoholg 
X 
X 
 
 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
Study Restrictions Reviewh 
X 
 
 
 
 
 
 
 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 15 of 165 
 
Visit 
Screening 
Check-In 
Baseline 
EDP 
Discharge 
EOP 
FU 
Assessment Daya 
-30 to -2 
-1 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
14 
21 
Inpatient Unit Confinement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medicationsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Sample for DNA Extractionj 
X 
 
 
 
 
 
 
 
 
 
MADRSk 
X 
X 
X 
X 
X 
SDQk 
X 
X 
X 
X 
X 
CGI-Sk 
X 
X 
X 
X 
X 
CGI-Ik 
 
X 
X 
X 
 
X 
CADSSl 
X 
 
 
X 
X 
 
4-Item PSRSl 
X 
 
 
X 
X 
 
Randomization 
X 
PK Blood Samplingm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test for Females 
X 
X 
 
 
 
 
 
 
 
X 
X 
Serum FSH Test for Females 
X 
 
 
 
 
 
 
 
Study Drug Dosing QD 
X 
X 
X 
X 
X 
X 
X 
COWS 
 
 
 
 
 
 
 
X 
X 
X 
Telephone Follow-Up Call 
X 
Abbreviations: 4-Item PSRS = 4-Item Positive Symptom Rating Scale; AE = adverse event; ATRQ = Antidepressant Treatment Response Questionnaire; 
BMI = Body Mass Index; BP = Blood Pressure;; CADSS = Clinician Administered Dissociative States Scale; CGI-I = Clinical Global Impressions of 
Improvement; CGI-S = Clinical Global Impressions of Severity; COWS = Clinical Opiate Withdrawal Scale; CRU = Clinical Research Unit; C-
SSRS = Columbia-Suicide Severity Rating Scale; CTNI = Clinical Trials Network and Institute; DNA = deoxyribonucleic acid; ECG = Electrocardiogram; 
EDP = End of the Dosing Period; EOP = End of the Observation Period (Day 14 ± 3 days); FSH = follicle stimulating hormone; FU = Follow-Up Visit (Day 
21 ± 3 days); HAM-D-17 = Hamilton Rating Scale for Depression; HIV = Human Immunodeficiency Virus; HR = Heart Rate; MADRS = Montgomery-
Asberg Depression Rating Scale; MGH = Massachusetts General Hospital; MINI = Mini International Neuropsychiatric Interview, Version 7.0.2; 
PK = Pharmacokinetics; QD = Quaque Die (Once Daily); RR = Respiratory Rate; SOP = Standard Operating Procedure; SDQ = Symptoms of Depression 
Questionnaire; SAFER = State versus trait; Assessability; Face validity; Ecological validity; and Rule of three Ps [pervasive, persistent, and pathological). 
a All Baseline/Day 1 assessments and activities will be done pre-dose, unless otherwise specified. 
b Review of Medical History for Status of Intercurrent Illnesses. 
c Vital signs include blood pressure (BP), heart rate (HR), pulse oximetry, and respiratory rate (RR) measured after the patient has been resting in a supine or 
semi- supine position for at least 3 minutes. Measurement of orthostatic BP should follow measurement of supine or semi-supine BP with patients asked to 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 16 of 165 
 
stand for 3 minutes before measurement of orthostatic BP. From Day 2 through Day 7, vital signs will be measured once before the dose of study drug. Vital 
signs will be measured once on Day 8, Day 9 prior to Discharge and Day 14. 
d On Day 1 and Day 2, an ECG will be done 1 hour pre-dose and 2 hours, 4 hours, 6 hours, and 8 hours post-dose. From Day 3 through EDP (Day 7), an ECG 
will be done 2 hours after the dose of study drug. An ECG will also be done on Day 8, prior to Discharge on Day 9, and at EOP (Day 14). 
e Testosterone levels will be assayed for male patients on Day 1 and Day 7. 
f Urine drug screen tests for tetrahydrocannabinol, opiates (including oxycodone), amphetamines, cocaine, and benzodiazepines. 
g Patients will be asked to abstain from alcohol for 24 hours prior to Screening, 24 hours prior to Check-in to the CRU, while in the CRU, and 24 hours prior 
to the Day 14 visit. 
h Sites should submit specific Screening information (detailed in the MGH CTNI manual) within 72 hours after the Screening Visit for review by the external 
medical team prior to proceeding to Check-in. 
i The patient’s prescribed antidepressant will be administered by site personnel while the patient is confined to the study unit. 
j A whole blood sample for DNA isolation will be collected from all patients in this study for potential pharmacogenetic analysis of genes that may affect the 
PK of d-methadone. Pharmacogenetic analysis will be performed only in cases where patients exhibit abnormal PK results. This analysis will be restricted to 
the evaluation of genes that may be involved in the PK of d-methadone (e.g., drug metabolism, disposition, elimination). One 4 mL whole blood sample for 
DNA isolation will be collected on Day 1 from each patient. Samples will be collected and shipped according to the site’s standard operating procedures 
(SOPs) and instructions from the Sponsor and/or pharmacogenetic laboratory. The samples will be stored in a secure space with adequate measures to protect 
patient confidentiality. The samples will be retained while research on d-methadone (REL-1017) continues, but not longer than 20 years. 
k MADRS, SDQ, and CGI-S will be conducted pre-dose on Day 1 and Day 2; post-dose on Day 4 and Day 7 within 3 hours of dosing; and on Day 14. The 
CGI-I will be conducted at pre-dose on Day 2; post-dose on Day 4 and Day 7 within 3 hours of dosing; and on Day 14. 
l 4-Item PSRS and CADSS will be measured at 30 to 60 minutes pre-dose on Day 1, 2 hours post-dose on Day 1, 2 hours post-dose on Day 7, and prior to 
Discharge on Day 9. 
m A safety catheter will be placed before dosing on Day 1 until the 12-hour post-dose sample has been collected in case a rescue medication is required. PK 
sampling will be done on Day 1 at 1 hour pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. On Day 2 through Day 7, sampling will be done 1 hour pre-
dose. On Day 8, sampling will be done approximately 24 hours after the last dose of study drug (on Day 7). On Day 9, sampling will be done approximately 
48 hours after the last dose (on Day 7). Sampling will also be done on Day 14 at 7 days (± 3 days) (approximately 168 hours) after the last dose of study drug 
(on Day 7). 
 
 
 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 17 of 165 
 
SPONSOR APPROVAL PAGE 
A Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study to 
Assess the Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing with 
REL-1017 25 mg QD and 50 mg QD as Adjunctive Therapy in the Treatment of Patients 
Diagnosed with Major Depressive Disorder 
 
 
Version: 6.0 
Date: 07-Mar-2019 
 
Relmada Therapeutics, Inc. 
 
 
 
 
 
 
                                                   07 March 2019 
 
 
Ottavio V. Vitolo, MD, MMSc  
SVP, Head of R&D and Chief Medical Officer 
Relmada Therapeutics, Inc. 
 
Date 
 
 
 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 18 of 165 
 
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study to 
Assess the Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing with 
REL-1017 25 mg QD and 50 mg QD as Adjunctive Therapy in the Treatment of Patients 
Diagnosed with Major Depressive Disorder 
I agree, as an Investigator conducting this study: 
• To assume responsibility for the proper conduct of the study at this site. 
• To conduct the study in compliance with this protocol, with any future amendments, and 
with any other written study conduct procedures provided, reviewed, and approved by 
Relmada Therapeutics, Inc. 
• Not to implement any deviations from or changes to this protocol without agreement from 
the Sponsor and prior review and written approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard to the patients/subjects or 
for administrative aspects of the study (where permitted by all applicable regulatory 
requirements). 
• That I am thoroughly familiar with the appropriate use of the investigational drug, as 
described in this protocol, and any other information provided by the Sponsor including, 
but not limited to, the current Investigator’s Brochure or equivalent document provided by 
Relmada Therapeutics, Inc. 
• That I am aware of, and will comply with, Good Clinical Practice (GCP) and all applicable 
regulatory requirements, including the regulations governing the use of controlled 
substances. 
• To ensure that all persons assisting me with the study are adequately informed about the 
investigational drug and that they are qualified to perform their study-related duties and 
functions as described in this protocol. 
• That I have been informed that certain regulatory authorities require the Sponsor to obtain 
and supply details about the qualified Investigator’s ownership interest in the Sponsor or 
the study drug and more generally about his/her financial ties with the Sponsor. Relmada 
Therapeutics, Inc., will obtain and disclose any relevant information in this regard solely 
for complying with regulatory requirements. 
Hence, I: 
• Agree to supply Relmada Therapeutics, Inc., with all information regarding ownership 
interest and financial ties with Relmada Therapeutics, Inc. (including those of my spouse 
and dependent children); 
• Agree to promptly update this information if any relevant changes occur during the study 
and for 1 year following completion of the study; and 
• Agree that Relmada Therapeutics, Inc., may disclose this information about such 
ownership interests and financial ties to regulatory authorities. 
 
Principal Investigator’s Name 
(please print) 
Signature 
Date (dd-mmm-yyyy) 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 19 of 165 
 
TABLE OF CONTENTS 
1 
STUDY BACKGROUND ............................................................................................. 28 
1.1 Pre-Clinical Data ............................................................................................................... 30 
1.1.1 In Vitro .................................................................................................................. 30 
1.1.2 In Vivo .................................................................................................................. 31 
1.2 Previous Human Experience ............................................................................................. 32 
1.2.1 Results from Clinical Study REL-1017-111 ......................................................... 32 
1.2.2 Results from Clinical Study REL-1017-112 ......................................................... 33 
1.3 Study Rationale ................................................................................................................. 34 
1.3.1 Role of NMDA Receptors in Neuronal Plasticity and Depression ....................... 34 
1.3.2 NMDA Antagonist Activity of d-Methadone ........................................................ 35 
1.3.3 Effect of d-Methadone in the Forced Swim and Spontaneous Locomotor Tests .. 36 
1.3.4 Rationale for Protocol REL-1017-202 .................................................................. 36 
2 
STUDY OBJECTIVES ................................................................................................. 38 
2.1 Primary Objective ............................................................................................................. 38 
2.2 Secondary Objectives ....................................................................................................... 38 
2.2.1 Pharmacokinetics: ................................................................................................. 38 
2.2.2 Efficacy: ................................................................................................................ 39 
3 
INVESTIGATIONAL PLAN ....................................................................................... 40 
3.1 Study Design ..................................................................................................................... 40 
3.2 Study Procedures ............................................................................................................... 40 
3.3 Discussion of Study Design .............................................................................................. 43 
4 
STUDY POPULATION ................................................................................................ 44 
4.1 Number of Patients ........................................................................................................... 44 
4.2 Inclusion Criteria .............................................................................................................. 44 
4.3 Exclusion Criteria ............................................................................................................. 45 
4.4 Study Restrictions ............................................................................................................. 47 
4.4.1 Prohibited Medications ......................................................................................... 47 
4.4.2 Contraceptive Precautions .................................................................................... 48 
4.4.3 Dietary and Other Restrictions ............................................................................. 49 
4.5 Patient Discontinuation/Withdrawal Criteria .................................................................... 49 
4.6 Rater Qualifications .......................................................................................................... 50 
5 
STUDY DRUG INFORMATION ................................................................................. 52 
5.1 Study Drug Administration ............................................................................................... 52 
5.2 Study Drug Identification ................................................................................................. 52 
5.2.1 Packaging and Labeling ........................................................................................ 53 
5.2.2 Handling, Storage, and Accountability ................................................................. 53 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 20 of 165 
 
5.2.3 Dispensing ............................................................................................................ 54 
5.3 Method of Assigning Patients to Treatment Groups ........................................................ 54 
5.4 Selection of Doses ............................................................................................................ 55 
5.5 Blinding and Unblinding Procedures ................................................................................ 56 
5.6 Treatment Phase ................................................................................................................ 56 
5.7 Treatment Compliance ...................................................................................................... 56 
6 
STUDY PROCEDURES AND ASSESSMENTS ......................................................... 57 
6.1 Study Procedures ............................................................................................................... 57 
6.1.1 Screening (Day -30 to Day -2) .............................................................................. 57 
6.1.2 Check-In (Day -1) ................................................................................................. 57 
6.1.3 Baseline (Day 1) ................................................................................................... 57 
6.1.4 Dosing Period (Day 1 to Day 7) ........................................................................... 57 
6.1.5 24-Hour Post-Dose Assessments (Day 8) ............................................................. 57 
6.1.6 Discharge (Day 9) ................................................................................................. 58 
6.1.7 Outpatient Observation Period (Day 10 to Day 14) ............................................. 58 
6.1.8 Follow-Up Period (Day 15 to Day 21) ................................................................. 58 
6.2 Safety Assessments ........................................................................................................... 58 
6.2.1 Vital Signs ............................................................................................................ 58 
6.2.2 Weight and Body Temperature ............................................................................. 58 
6.2.3 Physical Examination ........................................................................................... 59 
6.2.4 12-Lead Electrocardiograms (EGCs) ................................................................... 59 
6.2.5 Clinical Laboratory Assessments ......................................................................... 59 
6.2.5.1 Clinical Chemistry ................................................................................. 59 
6.2.5.2 Hematology ............................................................................................ 60 
6.2.5.3 Urinalysis ............................................................................................... 60 
6.2.5.4 Thyroid Panel ......................................................................................... 60 
6.2.5.5 Viral Screen ........................................................................................... 60 
6.2.5.6 Breath Alcohol ....................................................................................... 60 
6.2.5.7 Drugs of Abuse Screen .......................................................................... 60 
6.2.5.8 Pregnancy Testing .................................................................................. 60 
6.2.6 Other Safety Assessments ..................................................................................... 60 
6.2.6.1 Clinical Administered Dissociative States Scale (CADSS) .................. 60 
6.2.6.2 Columbia-Suicide Severity Rating Scale (C-SSRS) .............................. 61 
6.2.6.3 The Clinical Opiate Withdrawal Scale (COWS) ................................... 61 
6.2.6.4 4-Item Positive Symptom Rating Scale (4-Item PSRS) ........................ 61 
6.3 Pharmacokinetic Assessments .......................................................................................... 61 
6.4 Efficacy Assessments ........................................................................................................ 62 
6.4.1 Primary Efficacy Measure .................................................................................... 62 
6.4.2 Secondary Efficacy Measures ............................................................................... 62 
6.4.2.1 Symptoms of Depression Questionnaire (SDQ) .................................... 62 
6.4.2.2 Clinical Global Impressions (CGI) Scale .............................................. 62 
6.5 Pharmacogenetic Analysis ................................................................................................ 62 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 21 of 165 
 
6.6 Appropriateness of Measures ........................................................................................... 63 
6.6.1 Baseline Measurements ........................................................................................ 63 
6.6.1.1 Mini International Neuropsychiatric Interview ..................................... 63 
6.6.1.2 Antidepressant Treatment Response Questionnaire .............................. 63 
6.6.1.3 Hamilton Depression Rating Scale (HAM-D-17) ................................. 63 
6.6.2 Efficacy Measurements ........................................................................................ 63 
6.6.2.1 Montgomery-Asberg Depression Rating Scale (MADRS) ................... 63 
6.6.2.2 Clinical Global Impressions (CGI) Scale .............................................. 63 
6.6.3 Other Safety Measurements .................................................................................. 64 
6.6.3.1 Columbia-Suicide Severity Rating Scale (C-SSRS) .............................. 64 
6.6.3.2 Clinician Administered Dissociative States Scale (CADSS) ................ 64 
6.6.3.3 Clinical Opiate Withdrawal Scale (COWS) .......................................... 64 
6.6.3.4 4-Item Positive Symptom Rating Scale (4-Item PSRS) ........................ 64 
6.6.4 Pharmacokinetic (PK) Assessments ..................................................................... 65 
7 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .................................... 66 
7.1 Definitions ........................................................................................................................ 66 
7.1.1 Adverse Events ..................................................................................................... 66 
7.1.2 Serious Adverse Events and Serious Unexpected Adverse Events ...................... 66 
7.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments ............... 67 
7.1.4 Other Adverse Events of Interest .......................................................................... 67 
7.2 Evaluation of Adverse Events and Serious Adverse Events ............................................ 68 
7.2.1 Classification of Adverse Event Intensity ............................................................ 68 
7.2.2 Classification of Adverse Event Causality ........................................................... 68 
7.2.3 Classification of Adverse Event Outcome ............................................................ 70 
7.3 Reporting Procedures ........................................................................................................ 70 
7.3.1 Serious Adverse Events and Serious Unexpected Adverse Events ...................... 70 
7.3.2 Any Adverse Event ............................................................................................... 71 
7.3.3 Pregnancy ............................................................................................................. 71 
7.4 Follow-Up of Adverse Events and Serious Adverse Events ............................................ 71 
8 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................. 73 
8.1 Statistical and Analytical Plans ........................................................................................ 73 
8.1.1 Analysis Populations ............................................................................................ 73 
8.1.2 General Statistical Considerations ........................................................................ 73 
8.1.3 Endpoint Definitions ............................................................................................. 73 
8.1.3.1 Primary Endpoint: Safety and Tolerability of REL-1017 ...................... 73 
8.1.3.2 Secondary Objective: Pharmacokinetic Profile of REL-1017 ............... 74 
8.1.3.3 Secondary Objectives: Efficacy of REL-1017 ....................................... 74 
8.1.4 Planned Analyses .................................................................................................. 75 
8.1.4.1 Analysis of Safety Assessments ............................................................ 75 
8.1.4.2 Adverse Events ...................................................................................... 75 
8.1.4.3 Other Safety Assessments ...................................................................... 75 
8.1.4.4 Analysis of Pharmacokinetics ................................................................ 76 
8.1.4.5 Analysis of Efficacy Assessments ......................................................... 77 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 22 of 165 
 
8.1.5 Demographics and Other Baseline Characteristics ............................................... 77 
8.1.6 Interim Analyses ................................................................................................... 78 
8.1.7 Missing Data ......................................................................................................... 78 
8.2 Determination of Sample Size .......................................................................................... 78 
9 
STUDY ADMINISTRATION ...................................................................................... 80 
9.1 Data Collection and Electronic Data Capture ................................................................... 80 
9.2 Regulatory and Ethical Considerations ............................................................................. 80 
9.2.1 Ethical Conduct of the Study ................................................................................ 80 
9.2.2 Regulatory Authority Approval ............................................................................ 80 
9.2.3 Ethics Approval .................................................................................................... 80 
9.2.4 Patient Informed Consent ..................................................................................... 81 
9.2.5 Principal Investigator Reporting Requirements .................................................... 81 
9.3 Privacy .............................................................................................................................. 81 
9.3.1 Patient Identifiers .................................................................................................. 81 
9.3.2 Purpose of Collecting Personal Information and Use ........................................... 82 
9.3.3 Access and Disclosure of Personal Information ................................................... 82 
9.3.4 Release of Patient Information ............................................................................. 82 
9.3.5 Consent for Collection, Access, Use and Disclosure of Patient Information ....... 82 
9.4 Study Monitoring .............................................................................................................. 83 
9.4.1 Quality Control by Syneos Health ........................................................................ 83 
9.4.2 Study Monitoring by Sponsor and/or Third Party ................................................ 83 
9.4.3 Principal Investigator’s Data Responsibility ........................................................ 84 
9.5 Data Quality Assurance .................................................................................................... 84 
9.6 Study and Site Closure ...................................................................................................... 84 
9.7 Records Retention ............................................................................................................. 85 
10 
REFERENCES .............................................................................................................. 86 
11 
APPENDICES ............................................................................................................... 90 
11.1 Amount of Blood Drawn per Study Period ...................................................................... 90 
11.2 SAFER Interview .............................................................................................................. 91 
11.3 Columbia-Suicide Severity Rating Scale (C-SSRS) ......................................................... 93 
11.4 Clinician Administered Dissociative States Scale (CADSS) ........................................... 99 
11.5 Clinical Opiate Withdrawal Scale (COWS) ................................................................... 104 
11.6 4-Item Positive Symptom Rating Scale (4-Item PSRS) ................................................. 105 
11.7 Antidepressant Treatment Response Questionnaire (ATRQ) ......................................... 105 
11.8 Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale 
(SIGMA) ......................................................................................................................... 109 
11.9 Symptoms of Depression Questionnaire (SDQ) ............................................................. 118 
11.10 
Clinical Global Impressions (CGI) Scale ........................................................... 128 
11.11 
Structured Interview Guide for the Hamilton Depression Rating Scale-17 Item 


Clinical Study Protocol Amendment 5 
 
REL-1017-202 
Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
  
Version: 6.0, 07-Mar-2019 
Confidential 
Page 23 of 165 
 
(SIGH-D) ........................................................................................................................ 130 
11.12 
Amendment 2: Table of Changes ....................................................................... 138 
11.13 
Amendment 3: Table of Changes ....................................................................... 149 
11.14 
Amendment 4: Table of Changes ....................................................................... 159 
11.15 
Amendment 5: Table of Changes ....................................................................... 164 
 
 
Table of Tables 
Table 1 
Time and Events Schedule ...................................................................................... 14 
Table 2 
Relmada Study: Effects of Test Articles on NR1/NR2A and NR1/NR2B Glutamate 
Receptors Expressed in Mammalian Cells (Antagonist Mode) .............................. 35 
Table 3 
Time from Discontinuation of Prohibited Medications, Supplements, and Other 
Substances ............................................................................................................... 48 
Table 4 
Classification of Adverse Event Intensity ............................................................... 68 
Table 5 
Classification of Adverse Event Causality .............................................................. 68 
Table 6 
Classification of Adverse Event Outcomes ............................................................. 70 
 
Table of Figures 
Figure 1: Non-parametric Superimposition PK Profile for Once Daily Loading Dose of 75 mg and 
Maintenance Doses of 25 mg for 6 Days ................................................................ 30 
Figure 2: Flow Chart of Study Design ........................................................................................... 42 
  
 


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ACRONYMS AND ABBREVIATIONS 
 
4-Item PSRS 
4-Item Positive Symptom Rating Scale 
ADT 
Antidepressant Therapy 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AMPA 
α-Amino-3-Hydroxy-5-Methylisoxazolepropionate 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATRQ 
Antidepressant Treatment Response Questionnaire 
AUC 
Area under the Plasma Concentration-Time Curve 
AUC0-inf 
Area under the Plasma Concentration-Time Curve from Time Zero to 
Infinity 
AUC0-last 
Area under the Plasma Concentration-Time Curve from Time Zero until the 
Last Quantifiable Time Point 
AUCtau 
Area under the Plasma Concentration-Time Curve from Time Zero until the 
Dosing Interval of 24 Hours (AUC0-24) 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
BP 
Blood Pressure (Systolic and Diastolic) 
BPM 
Beats per minute 
CADSS 
Clinician Administered Dissociative States Scale 
CGI 
Clinical Global Impressions 
CGI-S 
Clinical Global Impressions of Severity 
CGI-I 
Clinical Global Impressions of Improvement 
CGS-19755 
Selfotel, NMDA Receptor Antagonist 
CL/F 
Apparent Clearance/Bioavailable Fraction Absorbed 
Cmax 
Maximum Observed Plasma Concentration 
Cmin 
Minimum Observed Plasma Concentration 
CNS 
Central Nervous System 
COWS 
Clinical Opiate Withdrawal Scale 
CRU 
Clinical Research Unit 
Css 
Concentration at Steady State 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSS/F 
Steady State Clearance 
CTNI 
Clinical Trials Network and Institute 
CV 
Coefficient of Variation 
 
CYP 
Cytochrome 
DNA 
Deoxyribonucleic Acid 


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DSM-5 
Diagnostic and Statistical Manual, Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECT 
Electroconvulsive Therapy 
EDC 
Electronic Data Capture 
EDP 
End of the Dosing Period (Day 7) 
EDTA 
Ethylene Diamine Tetra-acetic Acid 
EOP 
End of the Observation Period (Day 14) 
EW 
Early Withdrawal 
FDA 
United States Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GluR1 
Glutamate Receptor 1 
HAM-D-17 
Hamilton Depression Rating Scale 
HCl 
Hydrochloride 
hERG 
Human Ether-A-Go-Go-Related Gene 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ID 
Identification 
IKr 
Delayed Rectifier Current Channel 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
Ki 
Thermodynamic Inhibition Constant 
λz 
Apparent Termination Elimination Rate Constant 
LD50 
Half Maximum Lethal Dose 
LS 
Least Square Means 
MAD 
Multiple Ascending Dose 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MAOI 
Monoamine Oxidase Inhibitor 
MDD 
Major Depressive Disorder 
MDE 
Major Depressive Episode 
MedDRA 
Medical Dictionary for Regulatory Activities (Version 16.0 or Higher) 
MGH 
Massachusetts General Hospital 
mGlu2/3 
Metabotropic Glutamate (mGlu) Receptors 


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MINI 
Mini International Neuropsychiatric Interview, Version 7.0.2 
MK-801 
Dizocilpine, NMDA Receptor Antagonist 
MTD 
Maximum Tolerated Dose 
mTORC1 
Rapamycin Complex 1 
NMDA 
N-methyl-D-aspartate 
PD 
Pharmacodynamic(s) 
PFC 
Prefrontal Cortex 
PK 
Pharmacokinetic(s) 
PSD95 
Postsynaptic Density Protein 95 
QD 
Quaque Die (Once Daily) 
QT 
Measure of the Time between the Start of the Q Wave and the 
End of the T Wave in the Heart’s Electrical Cycle 
QTc 
Corrected QT 
QTcF 
QT Interval with Fridericia's Correction 
RBC 
Red Blood Cell (Count) 
REL-1017 
d-Methadone (Dextromethadone) Hydrochloride 
Relmada 
Relmada Therapeutics, Inc. 
RR 
Respiratory Rate 
rTMS 
Repetitive Transcranial Magnetic Stimulation 
SAD 
Single Ascending Dose 
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 
SD 
Standard Deviation 
SDQ 
Symptoms of Depression Questionnaire 
SIGH-D 
Structured Interview Guide for the HAM-D-17 
SIGMA 
Structured Interview Guide for the MADRS 
SMS 
Scheduled Measurement System 
SNRI 
Serotonin and Norepinephrine Reuptake Inhibitor 
SOP 
Standard Operating Procedure 
SSRI 
Selective Serotonin Reuptake Inhibitor 
Syneos Health 
Syneos Health, Inc. (formerly INC Research, Inc. [Contract Research 
Organization]) 
t½ 
Apparent Terminal Elimination Half-Life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time to Maximum Observed Plasma Concentration 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 


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VAS 
Visual Analogue Scale 
VNS 
Vagus Nerve Stimulation 
VSS/F 
Volume of Distribution at Steady State 
WBC 
White Blood Cell (Count) 
WHO 
World Health Organization 
 
 


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1 STUDY BACKGROUND 
Among mental and behavioral disorders, unipolar depression is by far the most common with 
12-month global prevalence rates averaging approximately 5.5%.1 The global burden of disease 
for patients with major depressive disorder (MDD) is ranked as second only to chronic lower 
back pain, and is associated with an estimated 54,700 years lived with disability per 
1000 persons.2 Of note, the World Health Organization (WHO) predicts that by 2030 unipolar 
depressive disorder will account for 6.2% of the total disability adjusted life years lost due to all 
diseases worldwide. Approximately 70% of patients do not fully remit symptomatically after a 
full course of monotherapy antidepressant treatment,3 and up to 85% of patients will relapse at 
least once.4 
Other disadvantages of available treatments include the slow onset of action and side effects that 
compromise patient compliance,5 all of which translate to a clear unmet need for medications 
that can enhance the efficacy of existing antidepressants, regardless of whether they are 
efficacious alone. It is hypothesized that augmenting established antidepressant therapies (ADTs) 
with medications that modulate alternate neurotransmitter systems may enhance the efficacy of 
current treatment and increase the likelihood of response. To date, three second generation 
antipsychotics (aripiprazole, quetiapine extended release, and brexpiprazole) have been approved 
as adjunctive therapy to antidepressants for the treatment of MDD, but no adjunctive medication 
from an alternate pharmacological class is currently approved by the United States Food and 
Drug Administration (FDA). 
d-Methadone (dextromethadone) is a non-competitive N-methyl-D-aspartate (NMDA) receptor 
antagonist that binds to the dizocilpine (MK-801) binding site of the receptor with an affinity 
comparable to that of well-established NMDA receptor antagonists.6 In experimental studies, 
d-methadone was found to block morphine tolerance and NMDA-induced hyperalgesia. In the 
rat formalin test, d-methadone was also found to be anti-nociceptive,7 which was not blocked by 
naloxone and was the result of NMDA receptor antagonistic activity. 
There have been a limited number of studies evaluating the d-methadone stereoisomer. The 
predominant use of d-methadone is in the racemic form of methadone (referred to as racemic 
methadone in this protocol), which is a 50/50 mix of l-methadone and d-methadone. Although 
both d-methadone and l-methadone bind to the MK-801–labeled, non-competitive site of the 
NMDA receptor,5 only l-methadone binds to opioid receptors with high affinity.8 Unlike 
d-methadone in racemic methadone, l-methadone is primarily responsible for opioid effects. 
Therefore, treatment with d-methadone at doses equivalent to the racemic methadone is expected 
to result in NMDA antagonism with fewer expected clinical opioid effects. 
The drug substance, d-methadone hydrochloride (HCl), is manufactured by Mallinckrodt 
Pharmaceuticals, St. Louis, MO. Relmada Therapeutics, Inc., (Relmada) is developing 
REL-1017, a formulation of d-methadone HCl that is administered orally. 
Relmada has conducted clinical studies to identify the dose levels of d-methadone that have little 


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to no opioid effects and that are expected to possess NMDA antagonistic properties for the 
evaluation of oral REL-1017 in the treatment of MDD and neuropathic pain conditions. Initial 
Phase 1 single ascending dose (SAD)9 and multiple ascending dose (MAD)10 clinical studies of 
REL-1017 were designed to evaluate the safety and tolerance of the pure d-methadone isomer in 
healthy opioid-naïve subjects and identify a safe and potentially effective dose range in this 
population. These studies showed that REL-1017 was safe and well tolerated at single oral doses 
up to 150 mg (maximum tolerated dose [MTD]) in healthy opioid-naïve subjects. In addition, 
there were no events of respiratory depression or QT prolongation (measure of the time between 
the start of the Q wave and the end of the T wave in the heart’s electrical cycle) at all doses 
tested up to 200 mg. 
In the multiple ascending dose (MAD) study, Cmax demonstrated a progressive increase from 
one dose to the next due to drug accumulation. The area under the plasma concentration-time 
curve from time zero until the dosing interval of 24 hours (AUC0-24) (AUCtau) values also 
demonstrated a large accumulation over the 10 days of dosing. Steady state was achieved by 
dose 7 for the 25 mg and 50 mg REL-1017 dose levels and by dose 6 for the 75-mg dose level. 
Dose proportionality between the 25 mg, 50 mg, and 75 mg dose levels was demonstrated for the 
single-dose parameters Cmax and AUCtau and for steady state parameters Cmax, AUCtau, and 
concentration at steady state (Css). Despite the confirmed dose proportionality, the comparison 
of concentration and exposure between the 50 mg and 75 mg REL-1017 treatment groups 
demonstrated only slight differences. The subjective pharmacodynamic (PD) effects of 
REL-1017, as assessed by the Bond-Lader Visual Analogue Scale (VAS), were minimal. The 
objective measure of PD effects, pupillometry, showed a dose response for the 75 mg REL-1017 
group. The multiple doses of REL-1017 administered in this study appeared to be safe with no 
indication of respiratory depression, clinically significant QT interval with Fridericia's correction 
(QTcF) prolongation, or opioid withdrawal. 
The safety and pharmacokinetic (PK) data from these initial studies were used to select the doses 
of REL-1017 that will be evaluated in this study, REL-1017-202. Additionally, the preclinical 
data for the forced swim test in rats were used to identify efficacious doses for MDD. On the 
forced swim test, d-methadone at the dose of 10 mg/kg shows equivalent antidepressant activity 
on the parameter “Frequency of behavior – Immobility” as that of ketamine at the dose of 
10 mg/kg. The 20 and 40 mg/kg d-methadone subcutaneous doses decreased immobility even 
further, but their effects were not significantly different from each other. 
The human efficacious AUC for ketamine is 635 ng*hr/mL with the ratio 6.5 to the AUC 
exhibiting efficacy in the mouse forced swim test.11 Comparison of rat PK data and PK data in 
healthy human volunteers using the conversion ratio for ketamine and other anti-depressant 
drugs provided information about d-methadone exposure in humans to target. The predicted 
AUCtau for d-methadone antidepressant activity in humans with the 10 mg/kg dose is in the range 
of 4000 to 5000 ng*hr/mL and 10,000 to 13,500 ng*hr/mL, based on the ketamine and other 
anti-depressant equivalent conversion ratio of 6.5 or 17.88, respectively. The AUCtau was 
approximately 4500 ng*hr/mL (range of 2000 to 7000 ng*hr/mL) after the oral administration of 


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25 mg d-methadone in healthy subjects and was approximately 10,000 ng*hr/mL (range of 4000 
to 17,000 ng*hr/mL) after the oral administration of 50 mg d-methadone. This approach, despite 
its limitations, supports that the dose range selected for this study should demonstrate 
antidepressant activity in the targeted population. 
The nonparametric superimposition of data from the d-methadone MAD study in healthy 
volunteers was used to model different dosing regimens using loading doses of 25, 50, 75, and 
100 mg with a maintenance dose of 25 mg. The extrapolations demonstrated that the best 
combination to reach steady state sooner was a 75 mg loading dose followed by daily doses of 
25 mg and 100 mg loading doses followed by daily doses of 50 mg. The loading dose of >75 mg 
was shown to be safe both as a single dose and multiple doses in healthy volunteers (Figure 1). 
Figure 1: Non-parametric Superimposition PK Profile for Once Daily Loading Dose of 75 mg 
and Maintenance Doses of 25 mg for 6 Days 
 
 
The intent of this study is to assess the safety and tolerance of daily dosing for 7 days with 2 dose 
strengths of the pure REL-1017 isomer as adjunctive therapy in adult patients with MDD who 
are diagnosed with a current major depressive episode (MDE) and who have experienced an 
inadequate response to 1 to 3 courses of treatment with an adequate dose and duration (as 
defined by the ATRQ) of an antidepressant medication for the current episode; these patients will 
be randomized to study drug in a 1:1:1 ratio. 
 
1.1 
Pre-Clinical Data 
1.1.1 In Vitro 
The NMDA receptor binding properties of d-methadone have been characterized and compared 
to other NMDA receptor antagonists.6,12 Racemic methadone and its d- and l-isomers exhibit low 
micromolar affinities for the [3H]MK-801–labeled non-competitive site of the NMDA receptor in 


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both rat forebrain and spinal cord synaptic membranes. The thermodynamic inhibition constant 
(Ki) values and displacement curves are similar to dextromethorphan, an established NMDA 
receptor antagonist. They lack affinity at the [3H]CGS-19755 (selfotel)–labeled competitive site 
of the NMDA receptor.13 Therefore, racemic methadone and its d- and l-isomers differ from 
morphine, hydromorphone, and naltrexone in that they have non-competitive antagonist activity 
at the NMDA receptor. 
The affinity of racemic methadone as well as its pure stereoisomers for various subtypes of 
NMDA receptor channels expressed in Xenopus oocytes14 demonstrates that the affinities for 
channel subtypes vary between the d- and l-isomer. The clinical relevance of these preferences is 
unknown. 
The literature demonstrates a high affinity of d-methadone for the NMDA receptor, which 
provides the basis for its antinociceptive effects via a central glutamatergic system. At the same 
time, in vitro data demonstrate that the affinity of d-methadone for the mu1, mu2, and delta 
opioid receptors is 10 to 30 times lower compared to l-methadone.8,13 
In vitro studies on the binding of d-methadone to the cardiac potassium channel human 
ether-a-go-go-related gene (hERG) and inhibition of the delayed rectifier current channel (IKr) 
are used to predict the possibility of corrected QT (QTc) prolongation and other cardiac issues. 
The Fridericia formula will be used for QTc. d-Methadone inhibits the hERG current in oocyte 
models to the same extent as l-methadone, although at lower concentrations. The half maximal 
inhibitory concentration (IC50) of d- and l-methadone was 0.10±0.01 and 0.27±0.01 mM, 
respectively.15 In HEK293 cells consistently expressing hERG, the current inhibition by d-
methadone was approximately 65%, while it was 40% by l-methadone. In general, l-methadone 
blocked IhERG significantly less potently than d-methadone, whereas the racemic methadone 
block was intermediate. The obtained IC50 values were as follows: racemic methadone 3 µM; d-
methadone 2 µM; l-methadone 7 µM.16 
Based on tests with racemic methadone, positive results have been seen in multiple in vivo 
assays, e.g., the mouse dominant lethal assay and the mammalian spermatogonial chromosome 
aberration test. For additional data from in vitro studies of d-methadone, please see the 
Investigator’s Brochure. 
1.1.2 In Vivo 
The in vivo studies of methadone have mostly involved the racemic mixture, which includes d- 
and l-methadone acting as an NMDA receptor antagonist and l-methadone acting as an opioid 
receptor agonist. Thus, in terms of safety and tolerance, the expected side effects of d-methadone 
alone could be expected to be of the same nature or less compared to racemic methadone, 
especially in terms of opioid-related effects. Some NMDA receptor antagonists have been shown 
to produce neurotoxic effects in animals. 
Based on racemic methadone, positive tests were seen in multiple assays (the in vivo mouse 
dominant lethal assay, the in vivo mammalian spermatogonial chromosome aberration test, in the 


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E. coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation 
assays). No effect on respiratory parameters was observed in guinea pigs, while the locomotor 
activity was comparable to that of l-methadone or racemic methadone.17 
There were no significant differences in PK parameters when beagles were administered a single 
0.25 mg/kg intravenous (IV) dose of either isomer or 0.5 mg/kg of racemic methadone.18 
After IV administration in mice, the isomers of methadone demonstrated a slightly higher half 
maximum lethal dose (LD50) than the racemic mix.19 
Intrathecal infusions of d-methadone in dogs demonstrated effects such as marked hind limb or 
whole-body hypertonicity, paralysis, marked sedation, agitation and/or spontaneous vocalization, 
extreme sensitivity to light touch applied to the flank (allodynia), and/or marked ataxia at higher 
doses.20,21 
In a developmental toxicity study, pregnant CDÒ rats (Charles River Laboratories) were given 
daily oral gavage administration of 0 (vehicle), 10, 20, and 40 mg/kg d-methadone hydrochloride 
on GD 6 through GD 17. No test article-related effects were observed on maternal survival, 
clinical findings, ovarian and uterine parameters (mean number of corpora lutea, implantation 
sites, viable fetuses/litter size, resorptions, and pre- and postimplantation loss), or macroscopic 
findings at any dose level evaluated. Test article-related, but non-adverse, effects on maternal 
body weight and/or body weight change were observed at 10, 20, and 40 mg/kg/day and on food 
consumption at 40 mg/kg/day. No test article-related effects were observed on fetal sex ratios; 
body weights; or external, visceral, or skeletal examinations.  
No developmental toxicity was observed at any dose level tested. The no-observed-adverse-
effect level (NOAEL) for both maternal and developmental toxicity was set to be 40 mg/kg/day. 
Based on a 60-kg human body weight and conversion of rat to human dose based on body 
surface area, the human equivalent dose (HED) was determined to be 387 mg. The dose provides 
approximately 15.48-fold and 7.74-fold safety margins when compared to the 25 mg and 50 mg 
doses of REL-1017-202. The safety margins calculations were based on the on the FDA 
Guidance “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics 
in Adult Healthy Volunteers”.22  
The genotoxic effects of d-methadone are unknown. 
1.2 
Previous Human Experience 
Relmada has completed two studies of the safety, tolerability, and PK of REL-1017 (d-methadone). 
1.2.1 Results from Clinical Study REL-1017-111 
Study REL-1017-111 was “A Phase 1 Study to Investigate the Safety, Tolerability, and 
Pharmacokinetic Profile of Single Ascending Doses of d-Methadone in Healthy Subjects.” It was 
a double-blind, randomized, placebo-controlled study in sequential arms. Safety and PK for 
REL-1017 (d-methadone) oral administration were determined in ascending dose arms from 
5 mg to 200 mg. Pharmacokinetic parameters were calculated for all dose levels, although some 
individual results had to be excluded due to emesis or statistical analysis criteria. 


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Pharmacogenomics analysis was performed for subjects exhibiting either fast or slow 
metabolism of REL-1017. Overall, there were minimal subjective PD effects of REL-1017 up to 
150 mg, as assessed by the Bond-Lader VAS. For additional information, please reference the 
Investigator’s Brochure. 
The overall conclusions drawn from Clinical Study REL-1017-111 were: 
• The MTD for oral REL-1017 in healthy opiate-naive subjects was determined to be 150 mg. 
• The PK analysis revealed high variability of the REL-1017 parameters, including Cmax, time 
to maximum observed plasma concentration (Tmax), area under the plasma 
concentration-time curve from time zero to infinity (AUC0-inf), apparent terminal elimination 
half-life (t½), and apparent clearance/bioavailable fraction absorbed (CL/F). 
• Statistical models demonstrated linear proportionality of Cmax and AUC0-inf versus dose, 
although the result was not statistically significant. 
• In general, there were no specific trends observed for Tmax or t½ of REL-1017. 
• The subjective PD effects of REL-1017 up to 150 mg were minimal. 
• The objective measure of PD effects, pupillometry, showed a dose response with greater 
pupil constriction in the higher dose groups. 
• The single doses of REL-1017 administered in this study appeared to be safe with no 
indication of respiratory depression or clinically significant QTcF prolongation. In terms of 
tolerability, nausea and vomiting become potential adverse events (AEs) with higher doses. 
1.2.2 Results from Clinical Study REL-1017-112 
Study REL-1017-112 was “A Phase 1 Study to Investigate the Safety, Tolerability, and 
Pharmacokinetic Profile of Multiple Ascending Doses of d-Methadone in Healthy Subjects.” It 
was a double-blind, randomized, Placebo-controlled study in sequential arms. There were 
8 subjects randomized into 3 arms of 25 mg, 50 mg, and 75 mg REL-1017. In each arm, 
2 subjects were dosed with Placebo and 6 subjects with a powder formulation of REL-1017. 
Doses were administered from Day 1 to Day 10. (For additional information, please reference the 
Investigator’s Brochure.) 
The overall conclusions drawn from Clinical Study REL-1017-112 were: 
• Cmax demonstrated a progressive increase from one dose to the next due to drug 
accumulation. AUCtau values also demonstrated a large accumulation over the 10 days of 
dosing. 
• Steady state was achieved by Dose 7 for the 25 mg and 50 mg REL-1017 dose levels and by 
Dose 6 for the 75 mg dose level. 
• Dose proportionality between the 25 mg, 50 mg, and 75 mg dose levels was demonstrated for 
the single-dose parameters Cmax and AUCtau and for steady state parameters Cmax, AUCtau, 


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and Css. 
• Despite the confirmed dose proportionality, the comparison of concentration and exposure 
between the 50 mg and 75 mg REL-1017 treatment groups demonstrated only slight 
differences. 
• The subjective PD effects of REL-1017, as assessed by the Bond-Lader VAS, were minimal. 
The objective measure of PD effects, pupillometry, showed a dose response for the 75 mg 
REL-1017 group. 
• The multiple doses of REL-1017 administered in this study appeared to be safe with no 
indication of respiratory depression, clinically significant QTcF prolongation, or opioid 
withdrawal. 
1.3 
Study Rationale 
1.3.1 Role of NMDA Receptors in Neuronal Plasticity and Depression 
Currently available medications have proven to be useful for the treatment of depression, but 
also have serious limitations. These include low response rates, a significant number of 
treatment-resistant patients, and time-lag for response, which emphasizes a major unmet need for 
more efficacious and faster-acting antidepressants. Recent studies have demonstrated that 
ketamine, a non-competitive glutamate-NMDA receptor antagonist, produces rapid onset 
(2 hours) and long-lasting (7 days) antidepressant actions in treatment-resistant patients. This 
rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, 
represents a significant finding in the field of depression. 
The molecular and cellular mechanisms underlying the actions of ketamine are more complicated 
than simple antagonism of the NMDA receptor. NMDA receptor blockade results in a nearly 
immediate (30 minutes) stimulation of the mammalian target of rapamycin complex 1 
(mTORC1), which underlies the rapid behavioral responses to ketamine.22 mTORC1 has been 
linked to the regulation of synaptic plasticity. A role for protein synthesis-dependent plasticity in 
the actions of ketamine is supported by studies demonstrating that ketamine increases synaptic 
protein levels (postsynaptic density protein 95 [PSD95], glutamate receptor 1 [GluR1]) and 
synaptogenesis (spine number and function) in rat prefrontal cortex (PFC), and produces rapid 
antidepressant behavioral responses. Moreover, these effects of ketamine are blocked by the 
selective mTORC1 inhibitor rapamycin. Studies have found that metabotropic glutamate 
receptor (mGlu2/3) antagonists23 and another class of rapid acting antidepressant, the muscarinic 
receptor antagonist scopolamine, also increases mTORC1 signaling and synaptogenesis in the 
PFC.24 Other studies have demonstrated that GLYX-13, a putative NMDA receptor modulator 
with glycine-site partial agonist/antagonist properties, also increases mTORC1 signaling, levels 
of synaptic proteins, and spine-synapse number and function in the PFC.25 
GluA1 and α-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) receptors are also 
implicated in the antidepressant effect of ketamine. The antidepressant actions of NMDA 
antagonists are blocked by pretreatment with an AMPA receptor antagonist.23,24,25,26 These 


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findings represent a fundamental shift in our understanding of the mechanisms underlying the 
rapid actions of NMDA receptor blockade and identify several novel therapeutic targets for 
treatment-resistant depression.27,28 
1.3.2 NMDA Antagonist Activity of d-Methadone 
Racemic methadone, the 50/50 combination of d-methadone and l-methadone, has been in 
widespread use for decades and has been studied extensively. Methadone is currently approved 
for use in the management of severe pain, detoxification treatment of opioid addiction, and 
maintenance treatment of opioid addiction. 
The results of a study evaluating the receptor binding profiles of methadone, its stereoisomers, 
and morphine suggest that d-methadone does not essentially contribute to the opioid effect of 
racemic methadone and that it has a 10 times lower affinity for the mu1, mu2, and delta receptor 
compared to l-methadone.8 
In another study, racemic methadone and its stereoisomers were evaluated in competition binding 
assays. Racemic methadone and its d- and l-isomers exhibited low micromolar affinities for the 
[3H]MK-801-labeled non-competitive site of the NMDA receptor in both rat forebrain and 
spinal cord synaptic membranes, with thermodynamic inhibition constant (Ki) values and 
displacement curves similar to those of dextromethorphan, an established NMDA receptor 
antagonist. They lacked affinity at the [3H]CGS-19755-labeled competitive site of the NMDA 
receptor.13 
Relmada examined the antagonist effects of racemic methadone, d-methadone, racemic 
ketamine, and [S]-ketamine on the electrophysiological response of human cloned NMDA 
NR1/NR2a and NR1/NR2b receptors expressed in HEK293 cells. The results demonstrated 
approximately equivalent antagonism of peak current for all compounds in the low µM range 
(Table 2). 
Table 2 
Relmada Study: Effects of Test Articles on NR1/NR2A and NR1/NR2B Glutamate 
Receptors Expressed in Mammalian Cells (Antagonist Mode) 
NR1/NR2A 
NR1/NR2B 
IC50 
Hill Slope 
IC50 
Hill Slope 
Memantine 
5.00 
1.08 
1.46 
-1.62 
Racemic Ketamine 
8.07 
1.55 
2.69 
-1.01 
S-(+)-Ketamine 
7.56 
0.86 
3.28 
-0.85 
Racemic Methadone 
11.12 
0.96 
9.94 
-0.76 
d-Methadone 
13.49 
1.16 
11.12 
-0.87 
Abbreviations: IC50 = half maximal inhibitory concentration; ID = identification. Note: Data are on 
file at Relmada. 


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1.3.3 Effect of d-Methadone in the Forced Swim and Spontaneous Locomotor Tests 
When rats are forced to swim in a small cylinder from which no escape is possible, they readily 
adopt a characteristic immobile posture and make no further attempts to escape except for small 
movements needed to prevent them from drowning. The immobility induced by the procedure 
can be reversed or largely decreased by a wide variety of antidepressants, suggesting that this test 
is sensitive to an antidepressant-like effect. However, since this test will also pick up many false 
positives (e.g., psychostimulants and antihistaminergics), locomotor activity was also performed 
to rule out hyperactivity. 
All rats were exposed to a swim test (“habituation”) prior to compound administration. This 
pre-administration swim test consisted of one 15-minute session which was followed 24 hours 
later by a 5-minute experimental test. Immobility, climbing, and swimming behaviors were 
recorded every 5 seconds for a total of 60 counts per subject. 
Rats were administered vehicle, ketamine, or d-methadone on Day 1 (after habituation; 24 hours 
prior to the forced swim testing). The test and the analysis of the video files were performed by 
an observer blind to the treatment. 
At all doses tested, d-methadone significantly decreased the immobility of the rats compared to 
the vehicle suggesting antidepressant-like activity. In addition, the effect of d-methadone 
(20 mg/kg and 40 mg/kg) on immobility was larger than the effect seen with ketamine 
(10 mg/kg). It should be noted that the effects of d-methadone (10 mg/kg, 20 mg/kg, and 
40 mg/kg) in the forced swim test were not confounded by any changes in the locomotor activity 
of the rats.28 
1.3.4 Rationale for Protocol REL-1017-202 
In summary, preclinical and clinical data suggest that low doses of NMDA receptor antagonists 
such as ketamine initiate brain plasticity processes and increase prefrontal connectivity, reversing 
the potential effects of chronic stress and depression. The elucidation of these processes, 
however, has been derived from animal research. There remains a need for research with 
depressed human subjects to determine if these putative mechanisms of action involving the 
NMDA receptor and downstream pathways mediate ketamine’s antidepressant effects in 
depressed patients. 
The pre-clinical and previous clinical experience with REL-1017 (d-methadone) provided the 
basis for the initiation of the present study, which will extend the evaluation of the safety, 
tolerability, and PK of REL-1017 at 2 doses with repeated administration to humans. Since 
REL-1017 is proposed for use as adjunctive therapy in the treatment of patients diagnosed with 
MDD, the patients will be adults with MDD who are diagnosed with a current MDE and who 
have experienced an inadequate response to 1 to 3 courses of treatment with an adequate dose 
and duration (as defined by the Antidepressant Treatment Response Questionnaire [ATRQ]) of 
an antidepressant medication for the current episode will be randomized to study drug in a 1:1:1 
ratio. This population will provide the opportunity to compare the safety and efficacy effects of 
treatment with an antidepressant plus REL-1017 versus the effects of an antidepressant alone. 


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2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is safety: 
Safety objectives will assess the safety and tolerability of 25 mg and 50 mg of REL-1017 
(d-methadone) compared to Placebo as adjunctive treatment in patients with MDD. The following 
assessments will be conducted to measure safety and tolerability throughout the study: 
• AEs 
• Vital signs 
• Weight 
• Physical examination 
• Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• Electrocardiogram (ECG) parameters 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Clinician Administered Dissociative States Scale (CADSS) 
• Clinical Opiate Withdrawal Scale (COWS) 
• 4-Item Positive Symptom Rating Scale (4-Item PSRS) 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
2.2.1 Pharmacokinetics:  
The PK objective will characterize the PK profile of 25 mg and 50 mg of REL-1017 (d-methadone) 
as adjunctive treatment in patients with MDD. The PK profile of REL-1017 25 mg and 50 mg will 
be evaluated on Day 1 through Day 7, Day 8, Day 9, and Day 14 where the data allow: 
• Maximum observed plasma concentration (Cmax) 
• Time to maximum observed plasma concentration (Tmax) 
• Area under the plasma concentration-time curve from time zero until the dosing 
interval of 24 hours (AUCtau) 
• Area under the plasma concentration-time curve from time zero until the last 
quantifiable time point (AUC0-last) on Day 7 
• Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) 
• Apparent termination elimination rate constant (λz) 
• Apparent terminal elimination half-life (t½) 


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• Attainment of steady state 
• Steady state clearance (CSS/F) 
• Volume of distribution at steady state (VSS/F) 
• Accumulation ratios based on minimum observed plasma concentration (Cmin), Cmax, and 
AUCtau 
2.2.2 Efficacy:  
The efficacy of 7 days of daily dosing with REL-1017 25 mg and 50 mg will be measured with the 
following efficacy endpoints: 
• Change from Baseline (Day 1) to End of the Dosing Period (EDP, Day 7) on the 
Montgomery-Asberg Depression Rating Scale (MADRS) with measurements 
made pre-dose on Day 1 and Day 2; post-dose on Day 4 and Day 7 within 
3 hours of dosing; and on Day 14; 
• Change from Baseline (Day 1) to EDP (Day 7) on the Symptoms of Depression 
Questionnaire (SDQ) with measurements made pre-dose on Day 1 and Day 2; 
post-dose on Day 4 and Day 7 within 3 hours of dosing; and on Day 14; and, 
• Change from Baseline (Day 1) to EDP (Day 7) on the Clinical Global 
Impressions of Severity (CGI-S) with measurements made pre-dose on Day 1 and 
Day 2; post-dose on Day 4 and Day 7 within 3 hours of dosing; and on Day 14. 
• Evaluation of Clinical Global Impressions of Improvement (CGI-I) total score on 
Day 7 (post-dose), as well as CGI-I scores on Days 2 (pre-dose), 4 (post-dose), 
and 14. 


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3 INVESTIGATIONAL PLAN 
3.1 
Study Design 
This a Phase 2a, multicenter, randomized, double-blind, Placebo-controlled 3-arm study to assess 
the safety and tolerability of multiple oral doses of REL-1017 25 mg and 50 mg as adjunctive 
therapy in the treatment of patients diagnosed with MDD. The patients will be adults with MDD 
who are diagnosed with a current MDE who have experienced an inadequate response to 1 to 
3 courses of treatment with an antidepressant medication. This population will provide the 
opportunity to compare the safety and efficacy of REL-1017 with SSRIs, SNRIs, or bupropion 
versus an antidepressant with Placebo. 
The study will be conducted at approximately 10 sites in the United States. 
Approximately 60 qualified patients will be randomized to 25 mg or 50 mg of REL-1017 or 
Placebo with approximately 20 patients per treatment group. REL-1017 will be provided as a 
powder and will be prepared as a solution with Ocean Spray® Diet Cranberry Juice on site to 
obtain a final volume of 100 mL for dosing. 
An unblinded pharmacist will assign study drug patients according to randomized treatment 
codes provided by a statistician who is not working as a statistician on the study in any other 
capacity. The study drug solution will be prepared within 3 hours of administration in blinded 
containers, and then will be dispensed to blinded study staff for administration to the patients. 
The administration of study drug must be observed by a staff member. After drinking the 
100 mL of study drug, 25 mL of non-carbonated water will be added to the study drug container 
and gently swirled. The patient will drink this rinse volume followed by 125 mL of 
non-carbonated water to drink immediately thereafter. All dosing must be completed within 
5 minutes. 
Dosing will take place once daily in the morning after an overnight fast. 
3.2 
Study Procedures 
The overall duration of the study will be up to 51 days per patient. All patients will be admitted 
to the clinical research unit (CRU) for a period of approximately 10 days during which they will 
receive daily doses of REL-1017 or Placebo for 7 consecutive days. The Screening Visit will 
assess patient eligibility to participate in the study and will occur between Day -30 and Day -2. 
Patients will be admitted the day prior to receiving the study drug (Day -1) and will remain in the 
CRU under clinical supervision for at least 48 hours after the last dose is received on Day 7. 
Patients will be discharged on Day 9, but return to the CRU 7 days after their last dose of study 
drug for follow-up evaluations. The study personnel will telephone each patient 14 days after the 
last dose of study drug and conduct a Follow-Up interview to assess the patient’s condition. 
The patient’s eligibility assessment will be reviewed by an external medical team based on key 
protocol inclusion and exclusion criteria to promote appropriate patient enrollment and data 
quality. Sites should submit specific Screening information (detailed in the Massachusetts 
Clinical Trials Network and Institute [MGH CTNI] manual) within 72 hours after the Screening 


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Visit for review by the external medical team prior to proceeding to Check-in. Subjects who are 
deemed eligible by the Principal Investigator and confirmed by the Medical Monitor will 
undergo the SAFER Interview30 by clinicians at the MGH CTNI. To ensure that appropriate 
subjects are entered into the study, a remote interview will be conducted by MGH CTNI raters. 
The assessments administered will be the SAFER Interview, which will include the HAM-D17, 
and the MGH ATRQ. The interview will be performed remotely by the MGH CTNI rater, and 
the subject will be contacted at his or her home or other off-site location after the Screening 
Visit, during which call the above assessments will be performed. Sites will be notified of the 
results within 24 hours of the interview. Only subjects whose eligibility will be confirmed by the 
SAFER Interview will be allowed to proceed in the study. 
The study design is summarized in Figure 2. Study assessments will be performed at the visits 
and time points outlined in the Time and Events Schedule (Table 1). 
Approximately 60 qualified patients will be randomized to study drug in a 1:1:1 ratio. Arm 1 will 
consist of approximately 20 patients who will receive REL-1017 25 mg. Arm 2 will consist of 
approximately 20 patients who will receive REL-1017 50 mg. Arm 3 will consist of 
approximately 20 patients who will receive Placebo. REL-1017 will be provided as a powder and 
prepared as a solution with Ocean Spray® Diet Cranberry Juice on site to obtain a final volume 
of 100 mL for dosing. The study drugs will consist of the following: 
• Arm 1: REL-1017 (d-methadone) 75 mg of powder in 100 mL of Ocean Spray® Diet 
Cranberry Juice QD on Day 1, 25 mg of powder in 100 mL Ocean Spray® Diet Cranberry 
Juice QD on Day 2-7. 
• Arm 2: REL-1017 (d-methadone) 100 mg of powder in 100 mL of Ocean Spray® Diet 
Cranberry Juice QD on Day 1, 50 mg of powder in 100 mL Ocean Spray® Diet Cranberry 
Juice QD on Day 2-7. 
• Arm 3: Placebo = 100 mL Ocean Spray® Diet Cranberry Juice. 
 


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Figure 2: Flow Chart of Study Design 
 
 


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3.3 
Discussion of Study Design 
Adult patients with MDD who are diagnosed with a current MDE and who have experienced an 
inadequate response to 1 to 3 courses of treatment with an adequate dose and duration (as 
defined by the ATRQ) of an antidepressant medication for the current episode will be 
randomized to study drug in a 1:1:1 ratio. This population will provide the opportunity to 
compare the safety and efficacy of REL-1017 with SSRIs, SNRIs, or bupropion versus an 
antidepressant with Placebo. 
The randomized, double-blind, Placebo-controlled study is a scientifically valid design for an 
early Phase 2 study, and the Patient Identification (ID) Numbers are appropriate for the 
exploratory nature of this study. 
The timing of the continuous monitoring and confinement are based on the clinical information 
of the respiratory depression and other effects as described above (see Section 1). 


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4 STUDY POPULATION 
4.1 
Number of Patients 
Adult patients with MDD who are diagnosed with a current MDE and who have experienced an 
inadequate response to 1 to 3 courses of treatment with an adequate dose and duration (as 
defined by the ATRQ) of an antidepressant medication for the current episode will be 
randomized to study drug in a 1:1:1 ratio. Approximately 20 patients each will receive 
REL-1017 75 mg/REL-1017 25 mg, REL-1017 100 mg/REL-1017 50 mg, or Placebo. 
Investigators should strive to evenly distribute the choice of ADTs at their respective sites among 
different ADTs. No more than 2 out of every 6 patients at an investigational site should be 
assigned to any 1 ADT without permission by the Medical Monitor. 
Approximately 120 patients will be screened, and approximately 60 qualified patients will be 
randomized to study drug in a 1:1:1 ratio (approximately 20 patients per arm). Each patient will 
participate for up to 51 days (30 days Screening, 7 days treatment, and 14 days of observation 
and follow-up). 
4.2 
Inclusion Criteria 
Patients will be considered eligible to participate in this study if each of the following inclusion 
criteria is satisfied at Screening: 
1. Males and females between 18 and 65 years of age, inclusive. 
2. Diagnosed with recurrent MDD as defined by the Diagnostic and Statistical Manual, Fifth 
Edition (DSM-5), and confirmed by the Mini International Neuropsychiatric Interview, 
Version 7.0.2 (MINI). 
3. Diagnosed with a current MDE lasting 8 weeks to 36 months as defined by the DSM-5 and 
confirmed by the MINI. 
4. Treated with an adequate dosage of a selective serotonin reuptake inhibitor (SSRI), 
serotonin and norepinephrine reuptake inhibitor (SNRI), or bupropion during the current 
MDE for at least 8 weeks prior to Screening with the same, adequate dosage for the last 
4 weeks. Minimum adequate doses are defined in the (ATRQ). The maximum dose allowed 
for paroxetine is 40 mg QD, for fluoxetine is 60 mg QD, and for sertraline is 200 mg QD. 
5. Have experienced an inadequate response to 1 to 3 courses of treatment with an 
antidepressant medication in the current episode, as defined as <50% improvement with an 
antidepressant medication at doses listed on the SAFER Interview (Criteria: State versus 
trait; Assessability; Face validity; Ecological validity; and Rule of three Ps [pervasive, 
persistent, and pathological]). 
6. Hamilton Depression Rating Scale-17 (HAM-D-17) ≥19 at Screening and Check-in 
(Day -1). 
7. Body Mass Index (BMI) between 18.0 and 35.0 kg/m2, inclusive, and a minimum weight of 
50.0 kg. 


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8. Per the Investigator’s judgment, able to meet all study requirements, including the 
confined/inpatient portion of the study, adherence with both approved ADT and study drug 
regimen, and completion of all assessments and all scheduled visits. 
9. Male and female patients of reproductive potential must be using and willing to continue 
using medically acceptable contraception, as specified in Section 4.4.2, from Screening and 
for at least 2 months after the last study drug administration. Female patients must have a 
negative pregnancy test, and must not be lactating. 
10. Must be able to read, speak, and understand English and must provide written informed 
consent prior to the initiation of any protocol-specific procedures. 
4.3 
Exclusion Criteria 
Patients will not be considered eligible to participate in this study if any one of the following 
exclusion criteria is satisfied at Screening: 
1. 
History or presence of clinically significant abnormality as assessed by physical 
examination, medical history, 12-lead ECG, vital signs, or laboratory values, which in the 
opinion of the Investigator would jeopardize the safety of the patient or the validity of the 
study results, including torsades de pointes, any bradyarrhythmias, or uncompensated 
heart failure. 
2. 
Chronic use of prescribed opioids (i.e., >120 days in a 6-month period) up to 6 months 
prior to Screening or any recreational use of opioids. 
3. 
Evidence of clinically significant hepatic or renal impairment, including alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 x upper limit of normal 
(ULN), bilirubin >1 x ULN, or endocrine laboratory values (including clinically 
significant thyroid parameters, i.e., thyroid stimulating hormone [TSH], triiodothyronine 
[T3], and thyroxine [T4]). 
4. 
History or family history of sudden unexplained death or long QT syndrome (measure of 
the time between the start of the Q wave and the end of the T wave in the heart’s 
electrical cycle). 
5. 
An average QTcF ≥450 msec or an average QRS interval ≥120 msec from the 12-lead 
ECGs performed at Screening. 
6. 
History of clinically diagnosed hypotension requiring treatment. 
7. 
History or presence of any condition in which an opioid is contraindicated (e.g., 
significant respiratory depression, acute or severe bronchial asthma or hypercarbia, 
bronchitis, or has/is suspected of having paralytic ileus). 
8. 
No more than 3 prescribed doses of an opioid within the 6 months prior to Screening and 
no use at all within the last month. 
9. 
Use of an antipsychotic, anticonvulsant, or mood stabilizer, regardless of indication, 
within the 3 months prior to Screening. 


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10. 
History of allergy or hypersensitivity to methadone or related drugs (e.g., opioids). 
11. 
Positive test for hepatitis B or human immunodeficiency virus (HIV). Patients with a 
positive hepatitis C test may be considered for inclusion with approval from the Medical 
Monitor. 
12. 
Any current and primary psychiatric disorder, as defined as a condition that is the primary 
focus of distress and/or treatment, other than MDD. 
13. 
Any lifetime history of bipolar I or II disorder, any psychotic disorder, post-traumatic 
stress disorder, borderline personality disorder, antisocial personality disorder, obsessive 
compulsive disorder, eating disorder, intellectual disability, or pervasive developmental 
disorder. 
14. 
History in the past 12 months of a primary diagnosis of anxiety disorder or panic disorder 
not related to the current MDE. 
15. 
Current diagnosis of alcohol or substance use disorder, as defined by DSM-5, at 
Screening or within the 12 months prior to Screening. Patients with the following 
diagnoses within the past 12 months, however, may be included at the Investigator’s 
discretion: mild alcohol use disorder, mild cannabis use disorder, and any severity 
tobacco use disorder. 
16. 
A confirmed positive result on the urine drug/alcohol screen at Screening or Check-in. If 
the urine drug/alcohol screen is positive at Screening, retesting or rescreening may be 
scheduled with prior approval from the Medical Monitor. 
17. 
Patients who, in the Investigator’s judgment, are at significant risk for suicide. A patient 
with a Columbia-Suicide Severity Rating Scale (C-SSRS) ideation score of 4 or 5 within 
the last 6 months or any suicide attempt within the past year must be excluded, as should 
a patient with an ideation score of 4 or 5 or any suicide attempt at the Check-in or 
Baseline Visit. 
18. 
Patients with a 20% improvement between Screening and Check-in (Day -1) on the 
HAM-D-17. 
19. 
Patients who did not safely discontinue medications prohibited in Section 4.4.1.  
20. 
Patients receiving new onset psychotherapy (individual, group, marriage, or family 
therapy) within 2 months prior to Screening or plans to start at any time during 
participation in the study. 
21. 
Patients who have received electroconvulsive therapy (ECT), repetitive transcranial 
magnetic stimulation (rTMS), or vagus nerve stimulation (VNS) or who have participated 
in a ketamine study within the last 6 months. 
22. 
Patients with any clinically significant neurological, hepatic, renal, metabolic, 
hematological, immunological, cardiovascular, pulmonary, chronic pain, or 
gastrointestinal disorder. Medical conditions that are minor or well-controlled may be 


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permitted if they will not increase the safety risk to the patient or compromise 
interpretation of the safety or efficacy endpoints. 
23. 
Patients taking fluvoxamine or St. John’s Wort. 
24. 
Patients who have participated in a clinical study with an investigational medication in 
the past 6 months, or who have participated in more than 4 clinical studies with 
investigational medications in the past 2 years. 
4.4 
Study Restrictions 
4.4.1 Prohibited Medications 
All patients must have discontinued all prohibited medications prior to the Screening period to 
meet the protocol requirements. Table 3 provides the required duration of time to discontinuation 
period for selected prohibited medications. All other prohibited medications should be stopped 
prior to Check-in at the CRU. Benzodiazepines and non-benzodiazepine sleep aids taken as 
scheduled medications and at stable doses not higher than that in the FDA-approved label for at 
least 30 days prior to the Check-in are allowed in the study. Any questions regarding these 
medications should be directed to the Study Medical Monitor. Initiation of these medications 
during the study is not allowed. 
Any medication taken consistently by the patient for 30 days prior to Screening and that is not a 
prohibited medication may be continued during the study if appropriately documented and 
captured in the electronic Case Report Form (eCRF). All medications taken within 6 months 
prior to Screening must be noted on the eCRF. 
The Investigators and their designees are obliged to ensure the well-being of all patients during 
this study. If medical intervention is required during the study, no medication or treatment will 
be withheld from a patient; and the Investigator will ensure proper documentation is kept in the 
eCRF. Due to each subject’s clinical condition being unique, there is no specific rescue plan or 
rescue therapy recommended for subjects. If a subject experiences a clinical condition, the 
Investigator should use clinical judgment and knowledge of the subject’s specific condition to 
institute the best treatment for that subject. 
All medications taken by patients after Screening until the completion of the final Follow-Up 
Visit or the Early Withdrawal (EW) Visit will be documented as concomitant medications. The 
reported concomitant medications will be reviewed and evaluated by the Investigator to 
determine if they affect a patient’s eligibility or continued participation in the study. 


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Table 3 
Time from Discontinuation of Prohibited Medications, Supplements, and Other 
Substances 
 
Prohibited Medications, Supplements, and Other 
Substances 
Time from Discontinuation to 
Check-In1 
Monoamine oxidase inhibitors (MAOIs) 
90 days 
Tricyclic antidepressants and atypical antidepressants 
90 days 
PRN Benzodiazepines 
30 days 
All other psychotropic medications except for those 
allowed in the study  
90 days 
Herbal drugs/dietary supplements for depression, 
anxiety, or insomnia 
30 days 
PRN = As Needed. 
1 The Medical Monitor should be contacted for any questions regarding the potential for pharmacological interactions 
with concomitant medications used by patients during the study. These include off-label use of medications for 
depression. 
 
The use of the following medications is prohibited during the study: 
1. Antidepressants other than the approved, stable dose started prior to the study; the 
maximum allowed dose for paroxetine is 40 mg QD, for fluoxetine is 60 mg QD, and 
for sertraline is 200 mg QD. 
2. Antipsychotics 
3. Antiepileptic drugs 
4. Benzodiazepines and hypnotics used as needed or above the approved doses 
5. Stimulants 
6. Opioid analgesics 
7. Nutritional supplements and non-prescription based herbal preparations with central 
nervous system (CNS) effects 
8. Barbiturates 
4.4.2 Contraceptive Precautions 
For men with female sexual partners of childbearing potential, examples of medically acceptable 
forms of contraception include vasectomy, or male condom for patients plus an additional 
method of contraception for their female partners. For vasectomized men, original documents 
obtained after vasectomy or a note from the family physician is required to confirm sterility. In 
the absence of such documents, it will be assumed that the patient is of childbearing potential, 
and the patient will be advised to use the medically acceptable birth control methods. 
Men must also abstain from sperm donation from Screening until at least 2 months after the last 
study drug administration. 
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post menopause) must agree to use 2 methods of contraception through the end of the study and 
until at least 2 months after the last study drug administration. Surgical sterilization is defined as 
removal of the uterus and/or both ovaries. Acceptable forms of contraception for female patients 
include: 
• Intrauterine device (IUD) 
• Bilateral tubal ligation, bilateral salpingectomy, or bilateral tubal occlusive procedure  
• Hormonal contraceptives (e.g., oral, patch, or injectable) 
• A double-barrier protection method (e.g., condom, sponge, or vaginal diaphragm with 
spermicide cream, foam, or gel) 
Women must also abstain from egg donation from Screening until at least 2 months after the last 
study drug administration. 
4.4.3 Dietary and Other Restrictions 
During the inpatient period for the study, patients will receive a standard diet. No additional food 
or beverages may be consumed while patients are staying in the CRU. Meals will be served at 
specific times after the completion of any scheduled assessments. 
Aside from the inclusion and exclusion criteria listed in Section 4.2 and Section 4.3, respectively, 
the patient must agree to abide by each of the following restrictions for the specified time: 
• Patients will be asked to abstain from alcohol for 24 hours prior to Screening, 24 hours 
prior to Check-in to the CRU, while in the CRU, and 24 hours prior to the Day 14 visit. 
• Patients will be required to abstain from recreational drug use throughout the study, from 
Screening until after the Day 21 Follow-Up telephone call. Abstinence from drug use will 
be confirmed with urine drug screens at Screening and Check-in, and patients will be 
reminded to adhere to restrictions throughout the study. 
• Dosing will occur in the morning following an overnight fast of at least 8 hours. 
• Patients will be required to abstain from blood donation during the study and for 30 days 
following the last study visit. A copy of the Informed Consent Form (ICF) with the study 
restrictions will be provided to each patient. Patients will be reminded by phone calls prior 
to study visits to adhere to study restrictions as described in the ICF. 
• Patients will be required to follow the ICF and the clinic code of conduct. 
4.5 
Patient Discontinuation/Withdrawal Criteria 
Any patient who voluntarily withdraws consent or is discontinued (e.g., because of an AE) from 
the study prior to completion will be considered as withdrawn from the study. Patients may be 
discontinued from the study for any reason including any of the following circumstances: 
• Occurrence of intolerable AE, as assessed by the Investigator or designee. 
• Clinically significant abnormality on vital signs, electrocardiogram (ECG), clinical 


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laboratory, or physical examination evaluations, as assessed by the Investigator or 
designee. 
• Subjects with a QTcF ≥500 msec or ≥60 msec above the patient’s Baseline value will 
discontinue study medication and be re-assessed. The ECG should be repeated until values 
return below 500 msec, or ≥60 msec above Baseline. These findings will be reviewed by a 
cardiologist. Any additional intervention for the safety of the subject should be discussed 
with the Study Medical Monitor and Sponsor.  
• ALT or AST ≥2 x ULN. 
• Withdrawal of consent. 
• Lost to follow-up. 
• Administrative reasons (e.g., Sponsor decision). 
• Major violation of the protocol. 
• If in the opinion of the qualified Investigator, it is in the best interest of the patient. 
• Non-compliance with study requirements and restrictions. 
• Use of a concomitant medication that, in the opinion of the Investigator or designee, could 
interfere with the study procedures or data integrity or compromise the safety of the patient. 
• Positive breath alcohol test at Check-in to the CRU. 
• Termination of the study. 
When an event such as a family emergency, a transient intercurrent illness (e.g., a cold) unrelated 
to study drug, or a remediable act of non-compliance prevents a patient from Check-in to the 
CRU, but the patient wishes to continue in the study, with the agreement of the Investigator, the 
research site staff may attempt to reschedule the Check-in and retain the patient in the study. 
If a patient is prematurely discontinued from participation in the study for any reason after study 
drug administration, the Investigator or designee must make every effort to perform the 
assessments scheduled for the Day 14 visit (7 days after the last dose of study drug). The reason 
for withdrawal will be recorded in the eCRF and the patient’s source medical record. 
In the event of a patient discontinuation following dosing, PK and safety assessments may 
continue at the discretion of the Investigator based on the time points outlined in the Time and 
Events Schedule (Table 1). 
Patients who are randomized, but not dosed, may be replaced. Patients who receive at least one 
dose of study drug, but are withdrawn prior to study completion, will not be replaced. 
4.6 
Rater Qualifications  
Raters must demonstrate sufficient assessment experience as well as appropriate educational 
background and indication experience.  


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Raters performing the clinical assessments will require training and approval by the Sponsor 
designated vendor prior to rating in this study. 
The vendors designated by the Sponsor will conduct rater qualification and will provide 
documentation about each rater’s certification and/or training.  
If possible, each subject will be interviewed and assessed throughout the study by the same rater.   
 
 


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5 STUDY DRUG INFORMATION 
5.1 
Study Drug Administration 
The study drug will be administered as a single oral dose. Patients will receive one of the 
following: 
Day 1 Dosing 
• Arm 1: 75 mg REL-1017 powder prepared as a solution with Ocean Spray® Diet Cranberry 
Juice on site to obtain a final volume of 100 mL for dosing 
• Arm 2: 100 mg REL-1017 powder prepared as a solution with Ocean Spray® Diet 
Cranberry Juice on site to obtain a final volume of 100 mL for dosing 
• Arm 3: 100 mL of Ocean Spray® Diet Cranberry juice (Placebo). 
Day 2-6 Dosing 
• Arm 1: 25 mg REL-1017 powder prepared as a solution with Ocean Spray® Diet Cranberry 
Juice on site to obtain a final volume of 100 mL for dosing; 
• Arm 2: 50 mg REL-1017 powder prepared as a solution with Ocean Spray® Diet Cranberry 
Juice on site to obtain a final volume of 100 mL for dosing; or, 
• Arm 3: 100 mL of Ocean Spray® Diet Cranberry juice (Placebo). 
The administration of study drug must be observed by a staff member. After drinking the 
100 mL of study drug, 25 mL of non-carbonated water will be added to the study drug container 
and gently swirled. The patient will drink this rinse volume followed by 125 mL of 
non-carbonated water to drink immediately thereafter. All dosing must be completed within 
5 minutes. 
Dosing will take place once daily in the morning after an overnight fast (at least 8 hours). 
5.2 
Study Drug Identification 
The investigational product, REL-1017, is composed of d-methadone HCl as a powder and 
prepared as a solution with Ocean Spray® Diet Cranberry Juice on site to obtain a final volume 
of 100 mL for dosing. The drug product will be supplied by the Sponsor. The study drug will be 
administered as a solution of 25 mg, 50 mg, 75 mg or 100 mg REL-1017, based on 
randomization prepared in Ocean Spray® Diet Cranberry Juice with a final volume of 100 mL 
Patients will continue to take the same, stabilized antidepressant medication that they were 
taking at Screening throughout the course of the study, and the supply of medication during the 
confined study period will be arranged and assured by the Investigator. 
An unblinded pharmacist will assign study drug to patients according to randomized treatment 
codes provided by the Interactive Web Response System (IWRS). The randomization code used 
in the IWRS will be prepared by a statistician who is not working as a statistician on the study in 
any other capacity. The study drug solution will be prepared within 3 hours of administration in 


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blinded containers, and then will be dispensed to blinded study staff for administration to the 
patients. 
After drinking the 100 mL of study drug, 25 mL of non-carbonated water will be added to the 
study drug container and gently swirled. The patient will drink this rinse volume followed by 
125mL of non-carbonated water to drink immediately thereafter. 
All dosing must be completed within 5 minutes. 
Dosing will take place once daily in the morning after an overnight fast of at least 8 hours. 
5.2.1 Packaging and Labeling 
Each container of study drug will be clearly labeled with study-specific information meeting all 
the applicable regulatory requirements. 
Clinical study drug supply labels will bear the following information: 
• Statement indicating that the drug is an investigational drug. 
• Name, number, or identifying mark of the drug. 
• Re-test date of the drug. 
• Recommended storage conditions of the drug. 
• Lot number of the drug. 
• Name and address of the Sponsor. 
• Protocol code or study ID. 
• Quantity of drug per container. 
The pharmacy staff at each site will record the following information for the Ocean Spray® Diet 
Cranberry Juice that is used for Placebo and to dissolve the REL-1017 for administration during 
the clinical study: 
• Type of container, e.g., plastic bottle, aluminum can. 
• Size of container. 
• Name and address of the manufacturer/distributor. 
• Lot number. 
• Expiration/use buy/sell by/best if used by date. 
5.2.2 Handling, Storage, and Accountability 
All study drug will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions supplied to the research site and its designated 
pharmacy, the site’s standard operating procedures (SOPs), and applicable regulations 
(Guidelines for Temperature Control of Drug Products during Storage and Transportation, 
GUIDE-0069). Appropriate storage temperature and transportation conditions will be maintained 


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for the study drug from the point of manufacture up to delivery of the study drug. 
Upon receipt by the study site, the bulk study drugs will be promptly transferred to the 
appropriate environmentally controlled storage area. The research pharmacy staff will examine 
the shipment and temperature monitoring devices (if applicable) to verify that the bulk study 
drugs were received in acceptable condition. Once inspected, the bulk study drugs will be stored 
in a restricted access, secured area with access limited to authorized research site staff, under 
physical conditions consistent with the investigational product’s specific requirements. After 
study drug is dispensed to patients, the remaining bulk study drug will be returned to storage in a 
restricted access, secured area under physical conditions consistent with the investigational 
product’s specific requirements. 
The research site’s pharmacist or delegate is responsible for ensuring that all bulk study drug 
received at the site is inventoried and accounted for throughout the study, according to applicable 
regulations. All containers of dispensed study drug that have been provided to the patients will 
be returned to the pharmacy, and any volume of unused study drug will be recorded. Dispensed 
study drugs that have not been used will not be provided to patients again (even to the same 
patient), nor relabeled or reassigned for use by other patients. Study drugs that have been 
dispensed, but not used, will be stored and disposed of according to the Sponsor’s instructions. 
The contents of dispensed study drug containers will not be combined. Unused bulk study drugs 
and dispensed study drugs will be available for verification by the Sponsor’s site monitor. 
5.2.3 Dispensing 
The study drug will be dissolved in Ocean Spray® Diet Cranberry Juice. Details regarding the 
preparation and administration of the study drug will be outlined in the pharmacy manual. The 
study drug solution will be prepared within 3 hours of administration. Only eligible patients 
participating in the study will receive the study drug. Only authorized research site staff may 
supply or administer the study drug. 
5.3 
Method of Assigning Patients to Treatment Groups 
Randomization will be used to avoid bias in the assignment of patients to treatment, to increase 
the likelihood that known and unknown patient attributes (e.g., demographics and Baseline 
characteristics) are evenly balanced between treatment groups, and to enhance the validity of 
statistical comparisons between treatment groups. 
Each potential patient will be assigned a unique number in the Screening process (Patient ID 
Number). This number will be used to identify the patient throughout the study. Patients who are 
randomized will be assigned a unique randomization number. Once any patient number is 
assigned, it cannot be reassigned to any other patient. 
All randomization codes will be generated by the designated unblinded statistician at Syneos 
Health, Inc., (formerly INC Research, Inc.) before the start of the study. The treatment 
assignment for each subject will be assigned through the IWRS in a 1:1:1 ratio (REL-1017 
25 mg, REL-1017 50 mg, or Placebo). Stratified randomization will be used to achieve a 
reasonable balance of patients taking cytochrome (CYP) 2B6 inhibitor ADTs versus patients who 


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take non-CYP2B6 inhibitors within the three treatment groups. A randomization list will be 
computer-generated for each of the two strata using random permuted blocks (first strata: 
patients receiving concomitant ADTs that are cytochrome CYP2B6 inhibitors: paroxetine, 
fluoxetine, sertraline; second strata: patients receiving concomitant ADTs that are not CYP2B6 
inhibitors). The goal of stratified randomization is to end the study with a similar number of 
patients taking CYP2B6 inhibitors in each study treatment group (e.g., if 15 patients are 
randomized who are taking ADTs with CYP2B6 inhibitor activity, then approximately 5 will be 
in the REL-1017 25 mg group, 5 will be in the REL-1017 50 mg group, and 5 will be in the 
Placebo group). Stratification will allow for subgroup exploratory analyses to be interpreted 
more easily after the study is complete and unblinded. 
If applicable, replacement patients for patients who withdraw prior to dosing will receive the 
same treatment allocation as those whom they replace. 
5.4 
Selection of Doses 
Since extensive clinical experience is available for racemic methadone and some clinical 
experience for d-methadone,31,32,33 the 25 mg and 50 mg doses are selected based on the 
comparative characteristics of racemic methadone and available data with d-methadone in 
healthy patients. 
The following rationale was applied. In recent studies in healthy patients, an oral dose of at least 
0.2 g/kg (10 mg to 20 mg) or 8 mg to 15 mg was well tolerated and provided information on the 
PK of individual isomers and the interaction with other CYP3A4 substrate drugs.34 Moreover, in 
the study of REL-1017 alone in opiate-naive patients, a dose as high as 150 mg was tested with 
no severe adverse reactions. Due to differences in the pharmacologic activity of the methadone 
enantiomers, the same incidence and severity of opioid-related AEs observed with racemic 
methadone are not anticipated to occur with the administration of d-methadone. 
Based on the safety data from Protocol REL-1017-111, single doses of 5 mg, 20 mg, 60 mg, 
100 mg, and 150 mg of REL-1017 or Placebo were well tolerated. The results of Protocol 
REL-1017-112 evaluated 10 days of dosing with as high as 75 mg, and no impact on safety was 
observed. Regardless of the confirmed dose proportionality, the comparison of concentration and 
exposure between the 50 mg and 75 mg REL-1017 treatment groups demonstrated only slight 
differences. Consequently, 25 mg and 50 mg doses were chosen for administration in Protocol 
REL-1017-202 as daily doses over a period of 7 days. 
To reach steady state more quickly for REL-1017 25 mg and REL-1017 75 mg dosing arms, a 
loading dose on Day 1 was added to each dosing arm, REL-1017 75 mg on Day 1 followed by 
25 mg REL-1017 on Day 2-7; 100 mg REL-1017 on Day 1 followed by 50 mg REL-1017 on 
Day 2-7. 
PK/PD modelling, based on the demonstrated AUCtau of d-methadone in pre-clinical and clinical 
studies and on the AUCtau of ketamine at doses that provide antidepressant efficacy, supports the 
conclusion that d-methadone 25 mg and 50 mg QD are the predicted efficacious doses. 


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5.5 
 Blinding and Unblinding Procedures 
The REL-1017 powder will be dissolved in a strong-tasting juice/drink (Ocean Spray® Diet 
Cranberry Juice) to mask the taste of the d-methadone. This will help to maintain the blind. Also, 
patients who are randomized to receive Placebo will receive an equivalent volume of Ocean 
Spray® Diet Cranberry Juice. 
5.6 
Treatment Phase 
The only persons with access to the blinding schema during the treatment phase will be the 
designated pharmacy personnel who are responsible for the dispensing of study drug, the 
compliance auditor(s) who verify conformity to study procedures, and the unblinded statisticians 
who generate the code. Under normal circumstances, the blind will not be broken until all 
patients have completed treatment. Blinded dosing information will be broken only in an 
emergency where knowledge of the dosing information could impact further treatment decisions 
or aid in the emergency treatment of a patient. Individual code breaks will result in the 
withdrawal of the patient from the study. The date, time, and reason for the unblinding will be 
documented in the appropriate section of the eCRF and in the source documents. 
5.7 
Treatment Compliance 
Study drugs, including the patient’s current ADT, will be administered under the supervision of 
study personnel, and treatment compliance will be verified accordingly. 
 
 


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6 STUDY PROCEDURES AND ASSESSMENTS 
All study assessments will be performed at the visits and time points outlined in the Time and 
Events Schedule (Table 1). 
The pre-dose period on Day 1 will be considered time zero. Other logistical considerations (e.g., 
sequence of events, assessment windows) will be outlined in study-specific procedures. 
Post-Screening psychiatric scales will be administered using the timeframe since the last 
administration of the scale. 
6.1 
Study Procedures 
6.1.1 Screening (Day -30 to Day -2) 
After the ICF is signed, a Screening number will be assigned to the patient, and an outpatient 
Screening Visit will be conducted during which the patient will undergo an interview and 
medical assessments to determine eligibility for study participation. Patients who meet all the 
Screening entry criteria will be scheduled for admission to the inpatient facility. 
6.1.2 Check-In (Day -1) 
Inpatient admission may occur up to 30 days after the Screening Visit as soon as it is determined 
that patients meet all Screening criteria. Upon Check-in, patients will undergo further medical 
and psychiatric Screening according to the Time and Events Schedule (Table 1) to ensure they 
continue to qualify for participation in the study. The patient’s prescribed antidepressant will be 
administered by site personnel while the patient is confined to the study unit. 
6.1.3 Baseline (Day 1) 
Assessments will be conducted according to the Time and Events Schedule (Table 1). The 
Baseline criteria checklist must be completed on Day 1, prior to randomization, to determine if 
the patient is still eligible for participation in the study. Any patient who does not meet full 
Screening and Baseline entry criteria must be discontinued from the study and will be considered 
a screen failure. Patients who meet full Screening and Baseline entry criteria will be randomized 
and assigned a Patient ID Number. 
6.1.4 Dosing Period (Day 1 to Day 7) 
The dosing period will begin on Day 1 and continue through the last dose of study drug on Day 7 
(End of the Dosing Period [EDP]). Study drug will be administered in the morning. Assessments 
during the dosing period will include measures of safety and tolerability, PK, and efficacy. For 
patients who discontinue study drug prior to Day 7, all EDP assessments should be completed 
according to the Time and Events Schedule (Table 1) provided informed consent has not been 
withdrawn. 
6.1.5 24-Hour Post-Dose Assessments (Day 8) 
On Day 8, patients will be evaluated 24 hours after the final dose of study drug on Day 7 
according to the Time and Events Schedule (Table 1). Blood samples will also be drawn for PK 
analysis approximately 24 hours after the last dose of study drug. 


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6.1.6 Discharge (Day 9) 
Following the last dose of study drug, each patient (including those who discontinue from the 
study drug prior to Day 7) is to remain in the inpatient facility for at least 2 additional days of 
safety and efficacy monitoring. The assessments to be conducted prior to Discharge on Day 9 are 
listed in the Time and Events Schedule (Table 1). Blood samples will also be drawn for PK 
analysis prior to Discharge on Day 9. 
6.1.7 Outpatient Observation Period (Day 10 to Day 14) 
The End of the Observation Period (EOP) will occur on Day 14 when the EOP interview will be 
conducted in person to assess psychiatric symptoms and safety endpoints, including medical 
conditions, new medications, and newly emergent AEs as listed in the Time and Events Schedule 
(Table 1). A confirmatory pregnancy test will be administered. Blood samples will also be drawn 
for PK analysis approximately168 hours after the last dose of study drug. For patients who 
discontinue study drug prior to Day 7, the EOP interview will occur 7 days after their last dose of 
study drug. (The window for the EOP visit is ± 3 days.) 
6.1.8 Follow-Up Period (Day 15 to Day 21) 
Follow-up interviews will be conducted with all patients (including those who discontinue from 
the study drug prior to Day 7) 14 days after their last dose of study drug. (The visit window is 
± 3 days). In the Follow-Up interview (Day 21), C-SSRS, AEs, and medications will be recorded 
(Table 1). This interview may be conducted by telephone. A confirmatory pregnancy test will be 
administered if the visit is conducted at the site. During the Follow-Up Period, safety evaluations 
should be conducted, at the discretion of the Investigator, to evaluate any unresolved abnormal 
treatment-emergent findings. 
6.2 
Safety Assessments 
Safety assessments will be performed at the time points indicated in the Time and Events 
Schedule (Table 1). 
6.2.1 Vital Signs 
Routine vital sign parameters will be measured at Screening and Check-in (Day -1), pre-dose and 
1 hour post-dose on Day 1, pre-dose on Day 2 through Day 7, once on Day 8, prior to Discharge 
on Day 9 and on Day 14. Vital signs should be measured after the patient has been in a supine or 
semi-supine position for at least 3 minutes. Vital signs will include blood pressure (BP, systolic 
and diastolic, mmHg), heart rate (HR, pulse rate [bpm]), pulse oximetry, and respiratory rate 
(RR, breaths/minute). Measurement of orthostatic BP should follow measurement of supine or 
semi-supine BP. Patients should be asked to stand for 3 minutes before measurement of 
orthostatic BP. The BP cuff should be kept in place between supine and orthostatic BP 
measurements. Blood pressure should be recorded to the nearest 2 mmHg mark on the 
manometer or to the nearest whole number on an automatic device. 
6.2.2 Weight and Body Temperature 
Weight and oral body temperature (°C) will be recorded at Screening, Check-in (Day -1), EDP 
(Day 7), and EOP (Day 14). 


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6.2.3 Physical Examination 
The physical examination, assessing the patient’s overall health and physical condition, will be 
performed at Screening, Check-in (Day -1); Day 7 and prior to Discharge (Day 9). The patient’s 
BMI will be calculated at Screening. Height will be recorded at Screening only. 
6.2.4 12-Lead Electrocardiograms (EGCs) 
12-Lead ECGs will be performed at Screening; at Check-in (Day -1); 1 hour pre-dose and 
2 hours, 4 hours, 6 hours, and 8 hours post-dose on Day 1 and Day 2; daily 2 hours post-dose on 
Day 3 through EDP (Day 7); on Day 8; prior to Discharge on Day 9; and at EOP (Day 14). 
Electrocardiograms will be performed in triplicate at each time point (e.g., 3 separate 10-second 
ECG recordings collected at intervals of approximately 1 minute apart, but within 5 minutes). 
Electrocardiograms will be performed with the electrodes positioned on the torso after the patient 
has been resting in a supine or semi-supine position for at least 3 minutes. The ECG will 
electronically measure and calculate ventricular HR and the PR, QRS, measure of the time 
between the start of the Q wave and the end of the T wave in the heart’s electrical cycle (QT), 
and QTc intervals. The Fridericia formula will be used for QTc. Triplicate ECGs will be 
averaged in the database for data analysis. 
ECGs will be submitted electronically to central ECG reading center for evaluation of subject for 
entry into the study. The Investigator will make a final judgment on whether to include the 
subject’s ECGs meets the entry criteria for the study. 
At the discretion of the Investigator, a standard 12-lead ECG with conventional lead placement 
may be performed at any time during the study (e.g., in case potential ischemia or any cardiac 
abnormality is observed). 
6.2.5 Clinical Laboratory Assessments 
Clinical laboratory tests (chemistry, hematology, and urinalysis) will be conducted at Screening, 
Check-in (Day -1), EDP (Day 7), and EOP (Day 14) unless otherwise noted. Blood and urine 
samples will be collected, processed, and shipped according to the research site’s SOPs and 
instructions from the safety laboratory. All laboratory safety data will be reviewed by the 
Investigator or designee for clinical significance. 
Blood volumes required per draw, laboratory test, and study phase are available in 
Appendix 11.1. Additional laboratory samples may be taken at the discretion of the Investigator 
or designee (e.g., if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure safety). 
6.2.5.1 Clinical Chemistry 
Quantitative analysis will be performed for the following analytes: alkaline phosphatase, 
albumin, calcium, chloride, creatinine, random glucose, potassium, magnesium, ALT, AST, 
gamma-glutamyl transferase (GGT), lactate dehydrogenase, sodium, total bilirubin, urea, and 
testosterone. 


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6.2.5.2 Hematology 
A peripheral blood smear will be performed to assess blood cell morphology. Quantitative 
analysis will be performed for at least the following analytes: hemoglobin, hematocrit, red blood 
cell count (RBC), white blood cell (WBC) count, WBC differential (absolute counts), and 
numerical platelet count. 
6.2.5.3 Urinalysis 
Qualitative or quantitative analysis will be performed for the following analytes, as appropriate: 
specific gravity, pH, ketones, glucose, nitrite, blood, leukocyte esterase, protein, urobilinogen, 
and bilirubin. If nitrite, blood, or protein tests are positive, a microscopic examination will be 
performed. 
6.2.5.4 Thyroid Panel 
A thyroid panel will be evaluated at Screening to identify patients with clinically significant 
abnormal laboratory results for TSH, T3, and T4. 
6.2.5.5 Viral Screen 
Serology will screen for hepatitis B, hepatitis C, and HIV at Screening. Patients with negative 
viral serology tests for hepatitis B and HIV will be eligible for the study. Positive hepatitis C 
values will be reviewed for eligibility on a case by case basis by the Medical Director. Positive 
results will be managed according to local regulatory requirements and the site’s SOPs. 
6.2.5.6 Breath Alcohol 
Breath alcohol testing will be performed according to the site’s SOPs at Screening, Check-in 
(Day -1), and Day 14. If there is any doubt or concern regarding alcohol use, research site staff 
may request a breath test for alcohol measures at any time during the study. 
6.2.5.7 Drugs of Abuse Screen 
A urine drug test will be conducted at Screening and Check-in. The urine drug screen will test 
for following drugs of abuse: tetrahydrocannabinol, opiates (including oxycodone), 
amphetamines, cocaine, and benzodiazepines. 
6.2.5.8 Pregnancy Testing 
A urine pregnancy test and a serum follicle stimulating hormone (FSH) test will be administered to 
all female patients at Screening (Day -30 to Day -2). Negative test results are required for enrollment 
in the study. Another negative urine pregnancy test will be required at Check-in (Day -1) for 
confirmation. Additional confirmatory pregnancy tests will be administered at the End of the 
Observation Period Visit (Day 14 ± 3 days and Follow-Up Visit (Day 21 ± 3 days). 
6.2.6 Other Safety Assessments 
6.2.6.1 Clinical Administered Dissociative States Scale (CADSS) 
The Clinical Administered Dissociative States Scale (CADSS) will be measured at 30 to 
60 minutes pre-dose on Day 1, 2 hours post-dose on Day 1, 2 hours post-dose on Day 7, and 
prior to Discharge on Day 9. 


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6.2.6.2 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be measured at Screening and Check-in (Day -1); at pre-dose on Day 1 and 
Day 2; and on Day 8, Day 9, EOP (Day 14) and EOS (Day 21).  
6.2.6.3 The Clinical Opiate Withdrawal Scale (COWS) 
The COWS will be measured on Day 8, Day 9, and EOP (Day 14). 
6.2.6.4 4-Item Positive Symptom Rating Scale (4-Item PSRS) 
The 4-Item PSRS will be measured at 30 to 60 minutes pre-dose at Baseline (Day 1), 2 hours 
post-dose on Day 1 (after first dose), 2 hours post-dose on Day 7 (EDP) (after last dose), and 
prior to Discharge on Day 9. 
6.3 
Pharmacokinetic Assessments 
Venous blood samples will be collected daily from Day 1 through Day 7, Day 8, Day 9, and on 
Day 14 at the following time points to determine the plasma concentrations of REL-1017: 
• PK sampling will be done on Day 1 at 1 hour pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours 
post-dose. 
• On Day 2 through Day 7, sampling will be done 1 hour pre-dose. 
• On Day 8, sampling will be done approximately 24 hours after the last dose of study drug 
(on Day 7). 
• On Day 9, sampling will be done approximately 48 hours after the last dose (on Day 7). 
• On Day 14, sampling will be done approximately 168 hours after the last dose (on Day 
7 ± 3 days). 
A safety catheter will be placed before dosing on Day 1 until the 12-hour post-dose sample has 
been collected in the event a rescue medication is required. 
Samples will be collected, processed, and shipped according to the site’s SOPs and instructions 
from the Sponsor or the bioanalytical laboratory. The blood volumes required for PK sampling 
are available in Appendix 11.1. 
The plasma samples will be analyzed by the bioanalytical laboratory using validated methods. 
Plasma samples will be shipped frozen on dry ice from the research site to the bioanalytical 
laboratory. Samples will not be shipped without prior arrangement with the bioanalytical 
laboratory and notification of the Sponsor. 
Drug concentration information that may unblind the study will not be reported to the study site 
or blinded personnel until the study has been unblinded. 


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6.4 
Efficacy Assessments 
Efficacy assessments will be performed at the time points indicated in the Time and Events 
Schedule (Table 1). 
6.4.1 Primary Efficacy Measure 
The Montgomery-Asberg Depression Rating Scale (MADRS) will be measured at pre-dose on 
Day 1 and Day 2; post-dose on Day 4 and Day 7 within 3 hours of dosing; and on Day 14. 
6.4.2 Secondary Efficacy Measures 
6.4.2.1 Symptoms of Depression Questionnaire (SDQ) 
The SDQ is a 44-item, self-report scale designed to measure the severity of symptoms across 
several subtypes of depression. The SDQ was developed to more fully capture the heterogeneity 
of symptom presentations of depressive disorders than current, widely used scales for MDD. The 
SDQ includes items that inquire about an extensive number of depressive symptoms beyond the 
ones included in other commonly used scales such as the Quick Inventory of Depression 
Symptomatology (QIDS).  
The 44 SDQ items are rated on a 6-point scale. Each item is rated based on a subject’s perception 
of what is normal for the individual (score = 2), what is better than normal (score = 1), and what 
is worse than normal (scores = 3–6).  
Items reflect a broad and heterogeneous collection of depression related symptom features. For 
example, Factor 1 (see Appendix 11.9) measures common dimensions of depressive symptoms 
including lassitude, energy, mood, and cognitive, and social functioning (subscale 1). Factor 3 
includes items on outlook on life, pessimism, suicide, self-harm, and worthlessness (subscale 3). 
Factors 4 and 5 measure physiological features of depression, namely sleep difficulties and 
changes in appetite/weight, respectively. Moreover, the SDQ includes several items that inquire 
about anxiety symptoms often present among depressed patients.35 
6.4.2.2 Clinical Global Impressions (CGI) Scale 
The CGI-S will be measured at pre-dose on Day 1 and Day 2; post-dose on Day 4 and Day 7 
within 3 hours of dosing; and on Day 14. The CGI-I will be measured at pre-dose on Day 2, 
post-dose on Day 4 and Day 7 within 3 hours of dosing, and on Day 14. 
6.5 
Pharmacogenetic Analysis 
On Day 1 of dosing, a blood sample for DNA isolation will be collected from all patients in this 
study for potential pharmacogenetic analysis of genes that may affect the PK of d-methadone. 
Pharmacogenetic analysis may be performed in cases where patients experience abnormal PK 
results. This analysis would be restricted to the evaluation of genes that may be involved in the 
PK of d-methadone (e.g., drug metabolism, disposition, elimination). 
One 4 mL whole blood sample for DNA isolation will be collected on Day 1 from each patient 
into an appropriately labeled ethylene diamine tetra-acetic acid (EDTA) tube. The tube will be 
inverted 8 to 10 times to reduce the chance of clot formation. Within 30 minutes of collection, 
the sample will be stored at -20°C or colder until shipped on dry ice sufficient to last during 


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transport. Samples will be collected and shipped according to the site’s SOPs and instructions 
from the Sponsor and/or pharmacogenetic laboratory. 
The samples will be stored in a secure space with adequate measures to protect patient 
confidentiality. The samples will be retained while research on d-methadone (REL-1017) 
continues, but not longer than 20 years. 
6.6 
Appropriateness of Measures 
All safety and efficacy assessments have been well documented and are generally regarded as 
reliable, accurate, and relevant in this patient population. 
6.6.1 Baseline Measurements 
6.6.1.1 Mini International Neuropsychiatric Interview 
The MINI, Version 7.0.2, is a widely used psychiatric structured diagnostic interview instrument 
that can be used to assess the effectiveness of the patient’s prescribed antidepressant medication. 
The interview is brief and only requires “yes” or “no” answers.36 
6.6.1.2 Antidepressant Treatment Response Questionnaire 
The ATRQ examines the efficacy and adequacy of any antidepressant treatment in a step-by-step 
procedure. This widely accepted questionnaire evaluates improvement (0% to 100%) and 
adequacy (adequate duration and dose).37 
6.6.1.3 Hamilton Depression Rating Scale (HAM-D-17) 
The HAM-D-17 has proven useful for many years as a way of determining a patient’s level of 
depression before, during, and after treatment. Many clinicians consider the HAM-D-17 to be the 
gold standard for evaluating the severity of a patient’s depression. In Study REL-1017-202, the 
HAM-D-17 must be administered using the Structured Interview Guide for the Hamilton 
Depression Rating Scale (SIGH-D).38 
6.6.2 Efficacy Measurements 
6.6.2.1 Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS is one of the questionnaires most frequently used in clinical studies to measure 
outcome in antidepressant efficacy studies. This scale exhibits construct validity (internal 
homogeneity) and concurrent validity relative to the HAM-D-17 and the concepts of endogenous 
and non-endogenous depression. The questionnaire includes questions on the following 
symptoms: (1) Apparent sadness; (2) Reported sadness; (3) Inner tension; (4) Reduced sleep; 
(5) Reduced appetite; (6) Concentration difficulties; (7) Lassitude; (8) Inability to feel; 
(9) Pessimistic thoughts; (10) Suicidal thoughts. A higher MADRS score indicates severer 
depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 with 
scores above 34 indicating severe depression. In Study REL-1017-202, the MADRS must be 
administered using the Structured Interview Guide for the MADRS (SIGMA).39, 40,41 
6.6.2.2  Clinical Global Impressions (CGI) Scale 
The CGI-S is a standard method used in clinical studies to quantify and track patient progress 


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and treatment response over time. The scale is composed of 7 ratings: 1 = normal, not at all ill; 
2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 
7 = among the most extremely ill patients. The score ranges from 1 to 7, and a lower CGI-S 
score indicates lower levels of depression.42 
The CGI-I is a standard method used in clinical studies to quantify and track patient change over 
time. The scale is composed of 7 ratings: 1 = very much improved; 2 = much improved; 
3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very 
much worse. The score ranges from 1 to 7, and a lower CGI-I score indicates greater 
improvement in symptoms.42 
6.6.3 Other Safety Measurements 
6.6.3.1 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is routinely used to quantify the severity of suicidal ideation and behavior. Both the 
ideation and behavior subscales are sensitive to change over time. 
The scale identifies behaviors that may be indicative of an individual's intent to commit suicide. 
This measure contains six "yes" or "no" questions in which respondents are asked to indicate 
whether they have experienced several thoughts or feelings relating to suicide over the past 
month. Each question addresses a different component of the respondent's suicide ideation 
severity: (1) Desire to be dead; (2) Suicidal thoughts; (3) Consideration of suicide methods; 
(4) Formed intent to commit suicide; (5) Completed suicide plan; and (6) Initiated suicide plan. 
A higher score indicates a higher intensity of suicidal ideation.43 
At the Screening Visit, the C-SSRS Baseline/Screening version will be administered. At all 
subsequent visits, the C-SSRS Since Last Visit version will be administered. 
6.6.3.2 Clinician Administered Dissociative States Scale (CADSS) 
The CADSS is an instrument for the measurement of present-state dissociative symptoms with 
good interrater reliability and construct validity. The CADSS can discriminate patients with 
dissociative disorders from healthy subjects and patients with other psychiatric disorders. The 
CADSS is a 23-item scale with all items administered to the subject. A higher score indicates a 
higher likelihood of the presence of a dissociative state. Subscales of the CADSS were 
developed to identify amnesia (Items 14 and 15), depersonalization (Items 3 to 7), and de 
realization (Items 1, 2, 8 to 13, and 16 to 19).44 
6.6.3.3 Clinical Opiate Withdrawal Scale (COWS) 
Safety assessments have been included to monitor for any opioid-related effects. The COWS is a 
clinician-administered instrument that rates 11 common opiate withdrawal signs or symptoms. 
The summed score of the 11 items can be used to assess a patient's level of opiate withdrawal 
and to make inferences about their level of physical dependence on opioids.45 
6.6.3.4 4-Item Positive Symptom Rating Scale (4-Item PSRS) 
The 4-Item PSRS was adapted from the Brief Psychiatric Rating Scale developed by Ventura and 
colleagues. It is a clinician-administered scale intended to assess the extent to which a subject is 


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currently experiencing positive psychotic symptoms. The scale assesses paranoia and 
hallucinations as well as some specific issues related to difficulty thinking and having unusual 
thoughts. When administering the scale, the rater enters a number for each of 4 symptom 
constructs with scores that range from 1 (not present) to 7 (extremely severe). Total score on the 
4-Item PSRS can range from 4 to 28. 46,47 
6.6.4 Pharmacokinetic (PK) Assessments 
Standard PK assessments, appropriate for an early Phase 2 study, have been included as outlined 
in Section 6.3. 


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7 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The Investigator or designee and research site staff are responsible for the detection, 
documentation, classification, reporting, and follow-up of events meeting the definition of an AE 
or SAE. Procedures for managing AEs and SAEs are detailed in the research site’s SOPs. 
Spontaneously reported or observed AEs will be recorded throughout the study, and AEs will be 
elicited using a non-leading question at every visit from Screening through the Day 21. 
Follow-Up telephone call will assess the status of any AE ongoing at the time of Discharge and 
record any new AE that has occurred. Regardless of seriousness, intensity, or presumed 
relationship to the study drug, all AEs will be recorded in the source documentation from the 
time of first contact with the patient (e.g., Screening) until the end of the Follow-Up Period of 
the study (Day 21). 
AEs that occur after medical Screening and prior to administration of the first dose of study drug 
will be recorded in the source documentation as Baseline signs and symptoms. All measures 
required for the management of AEs will be recorded in the source documentation. 
7.1 
Definitions 
7.1.1 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and may not necessarily have a causal relationship with 
the administered treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant laboratory abnormality, for example), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, regardless of 
relationship to the medicinal (investigational) product. During the study, an AE can also occur 
outside the time that the investigational product(s) was given (e.g., during the time from 
discontinuation of prohibited medications). 
Pre-existing conditions, diseases, or disorders are not considered AEs unless there is a change in 
intensity, frequency, or quality. 
7.1.2 Serious Adverse Events and Serious Unexpected Adverse Events 
An SAE is any untoward medical occurrence that at any dose 
• Results in death, 
• Is life-threatening (at the time of the event), 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical or 


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surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency in 
the risk information set out in the Investigator’s Brochure or on the label of the drug. 
7.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Abnormal laboratory findings (e.g., from clinical chemistry or hematology tests or urinalysis) or 
other abnormal assessments (e.g., from vital signs, ECGs, C-SSRS, 4-Item PSRS, CADSS, 
COWS) judged as clinically significant by the Investigator or designee will be recorded as AEs 
or SAEs if they meet the definitions provided in Section 7.1.1 and Section 7.1.2. Furthermore, 
abnormal laboratory findings or other abnormal assessments present at Baseline that significantly 
worsen following the start of the study (i.e., become clinically significant) will be reported as 
AEs or SAEs. However, abnormal laboratory findings present at the start of the study that do not 
worsen will not be reported as AEs or SAEs. 
The Investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
7.1.4 Other Adverse Events of Interest 
If other AEs of interest are observed during the study, they will be recorded in the eCRFs and 
analyzed as appropriate in the final clinical study report. Examples of these types of AEs would 
be difficulty breathing, chest pain, or clinically significant bradycardia, tachycardia, or QTcF 
prolongation (≥500 msec or ≥60 msec above the patient’s Baseline value that continuously 
occurs over a period of time). At the discretion of the Investigator, ECGs or other relevant tests 
may be repeated for confirmation of the results. 
If more than one ECG is collected, the mean of the replicate measurements will be reported. If 
any of the 3 individual ECG tracings has a QTcF value ≥500 msec, but the mean of the 
triplicates is not ≥500 msec, the data from the subject’s individual tracing will be described in a 
safety section of the study report to place the ≥500 msec value in appropriate clinical context. 
However, values from individual tracings within triplicate measurements that are ≥500 msec will 
not be included in the categorical analysis unless the average from those triplicate measurements 
is also ≥500 msec. Changes from Baseline will be defined as the change between QTcF 
post-dose from the time-matched average Baseline triplicates on Baseline Day 1 (Visit 2). 
The study drug will be administered under the supervision of study personnel, which should 
eliminate the opportunity for abuse during the course of the study. However, Investigators should 
take note of AEs that might suggest that the study drug has the potential for abuse. For example, 
the occurrence of a euphoria-like response is a key observation in the clinical assessment of 
whether a test drug has abuse potential. 
Examples of Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms that may 
provide abuse-related information about a drug include: 


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• Euphoria-related terms - euphoric mood, elevated mood, feeling abnormal, feeling drunk, 
feeling of relaxation, dizziness, thinking abnormal, hallucination, inappropriate affect 
• Terms indicative of impaired attention, cognition, and mood - somnolence, mood 
disorders, and disturbances 
• Dissociative/psychotic terms - psychosis, aggression, confusion, and disorientation 
• Drug withdrawal syndrome 
7.2 
Evaluation of Adverse Events and Serious Adverse Events 
The Investigator or designee is responsible for making an assessment as to the seriousness, 
intensity, causality, and outcome of an AE. 
7.2.1 Classification of Adverse Event Intensity 
For each recorded AE or SAE, the Investigator or designee must assess the intensity based on the 
following criteria (Table 4). If there is insufficient information to determine intensity, the AE 
must still be reported. 
Table 4 
Classification of Adverse Event Intensity 
Classification 
Definition 
Mild 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living. 
Moderate 
An event that is alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily 
living, causing discomfort, but poses no significant or 
permanent risk of harm to the subject. 
Severe 
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm 
to the subject and hospitalization may be required. 
7.2.2 Classification of Adverse Event Causality 
For each recorded AE or SAE, the Investigator or designee must assess the causality based on 
the following criteria (Table 5) to determine the relationship between the AE and study drug. 
Table 5 
Classification of Adverse Event Causality 
Classification 
Definition 
Unrelated 
The AE or SAE is judged to be clearly and incontrovertibly due only to 
extraneous causes (e.g., disease, environment) and does not meet the 
criteria for study drug relationship listed under probable, possible, or 
unlikely. 


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Classification 
Definition 
Unlikely 
The AE or SAE is unlikely related to the study drug, when the AE or 
SAE: 
• Does not follow a reasonable temporal sequence from 
administration of the study drug. 
• May readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy 
administered to the subject. 
• Does not follow a known pattern of response to the study drug. 
• Does not reappear or worsen when the study drug is 
re-administered. 
Possible 
The AE or SAE is possibly related to the study drug when the 
connection to the study drug appears unlikely but cannot be ruled out 
with certainty. This causal relationship is assigned when the AE or 
SAE: 
• Follows a reasonable temporal sequence from administration of the 
study drug. 
• May have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy 
administered to the subject. 
ll
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d
d d
Probable 
The AE or SAE is probably related to the study drug when the 
connection to study drug can be made with a high degree of certainty. 
This causal relationship is assigned when the AE or SAE: 
• Follows a reasonable temporal sequence from administration of the 
study drug. 
• Cannot be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject. 
• Disappears or decreases upon cessation or reduction in dose (note 
that there are important exceptions when an AE or SAE does not 
disappear upon discontinuation of the study drug, yet drug 
relatedness clearly exists, e.g., bone marrow depression or tardive 
dyskinesias). 
• Follows a known pattern of response to the suspected study drug. 
• Reappears upon re-challenge. 


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Classification 
Definition 
Definite 
The AE or SAE is definitely related to the study drug when the event: 
• Follows a reasonable temporal sequence from administration of the 
study drug. 
• Follows a known pattern of response to the suspected study drug. 
• Is confirmed by improvement on stopping and reappearance of the 
event on repeated exposure to the study drug. 
• Cannot be reasonably explained by the known characteristics of the 
subject’s clinical state. 
7.2.3 Classification of Adverse Event Outcome 
For each recorded AE or SAE, the Investigator or designee must assess the outcome at the time 
of the last observation. The outcome of AEs or SAEs will be documented as outlined in Table 6. 
Table 6 
Classification of Adverse Event Outcomes 
 
Classification 
 Definition 
Fatal 
The subject died. 
Resolved 
The AE or SAE has ended. 
Resolved with Sequelae 
The AE or SAE has ended but changes are noted from 
Baseline. 
Unresolved 
The AE has not ended. 
An AE outcome can only be categorized as unresolved, if 
the AE is: 
• Ongoing at the end of the reporting period (i.e., 14 days 
after the last dose of study drug on Day 7), and the 
Investigator deems that further follow-up is not 
medically required. 
• Lost to follow-up after repeated unsuccessful attempts 
to contact the subject. 
• Ongoing and referred to the subject’s physician or a 
specialist for follow-up. 
7.3 
Reporting Procedures 
7.3.1 Serious Adverse Events and Serious Unexpected Adverse Events 
Any SAE, expected or unexpected, irrespective of relationship to study treatments, including 
death due to any cause, experienced by a study patient will be reported to Relmada, by the 
Investigator or designee within 24 hours of learning of the event. Information regarding the SAE 
will be transmitted to Relmada by fax at 1-888-228-5672. 
The contact information for the Syneos Health safety and pharmacovigilance team and for the 


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Medical Monitor is as follows: 
Name: 
Syneos Health Safety and Pharmacovigilance 
Fax: 
1-877-464-7787 
Email: 
safetyreporting@syneoshealth.com 
Name: 
Morgan Kearney, MD, Associate Medical Director 
Address: 
Syneos Health, Inc. 
3201 Beechleaf Court, Suite 600 
Raleigh, NC, USA 27604 
Phone: 
1-919-257-6801 
Mobile: 
1-919-397-0174 
Email: 
Morgan.Kearney@syneoshealth.com 
Syneos Health assumes responsibility for the appropriate reporting of AEs to the regulatory 
authorities. All SAEs that are unlisted and associated with the use of the study drug will also be 
reported to all Investigators. The Investigator (or Relmada Therapeutics, Inc., where required) 
must report these events to the appropriate IRB that approved the protocol (unless otherwise 
required and documented by the IRB). 
All additional follow-up evaluations for SAEs will be reported to Relmada. 
7.3.2 Any Adverse Event 
Regardless of seriousness, intensity, or presumed relationship to study drug, all AEs will be 
recorded in the source documentation. When the signs and symptoms are due to a common 
etiology, the diagnoses will be recorded whenever possible. In addition, the Investigator must 
record his or her opinion as to the intensity of the AE and whether the AE is related to the study 
drug. All measures required for management of the AE will be recorded in the source 
documentation. 
7.3.3 Pregnancy 
Given that the effects of the study drug on egg and sperm have not been fully elucidated, any 
pregnancy in the patient or partner of a patient participating in the study will be reported to 
Relmada within 24 hours of learning of the event. 
Follow-up information will be obtained where possible (i.e., with the consent of the patient or 
patient’s partner) regarding the course and outcome of the pregnancy, including any post-natal 
sequelae in the infant. 
7.4 
Follow-Up of Adverse Events and Serious Adverse Events 
All unresolved AEs will be followed for up to a minimum of 14 days after the patient’s final 
dose of study drug on Day 7 unless the Investigator’s judgment dictates otherwise, the event has 
resolved or stabilized before Day 21, or the patient is lost to follow-up. 
All AEs that result in discontinuation and all SAEs will be followed until one of the following 
occurs: 
• The event resolves. 


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• The event stabilizes. 
• The event returns to a Baseline value, if a Baseline value is available. 
• The event can be attributed to agent(s) other than the study drug or to factors unrelated to 
study conduct. 
When it becomes unlikely that any additional information can be obtained (e.g., patient or health 
care practitioner refuses to provide additional information, the patient is lost to follow-up), the 
Investigator or designee will ensure that the follow-up includes any pertinent supplemental 
investigations (e.g., laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals) to elucidate the nature and/or causality of the 
AE or SAE. 
Investigators are not obligated to actively seek AEs or SAEs in former study patients that occur 
after the Follow-Up Period. However, if the Investigator or designee learns of any AE or SAE at 
any time after a patient has been discharged from the study and the event is considered as 
reasonably related to the study drug, the Investigator will notify Relmada. 
 
 


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8 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1 
Statistical and Analytical Plans 
8.1.1 Analysis Populations 
The study analysis populations will consist of 
• Randomized population: All patients who are randomized. 
• Safety population: All randomized patients who receive any study treatment (REL-1017 or 
Placebo). 
• Pharmacokinetic population: All patients who receive REL-1017, with at least 1 post-dose 
blood draw to determine plasma concentration of d-methadone. Pharmacokinetic 
parameters will be reported for this population where available. 
• Intent-to-Treat population: All randomized patients who receive any study treatment 
(REL-1017 or Placebo) and have a Baseline and at least 1 post-Baseline efficacy 
measurement (MADRS, SDQ, CGI-S, or CGI-I). 
The details of patient evaluability criteria will be determined prior to study unblinding. 
8.1.2 General Statistical Considerations 
Complete details of the statistical analyses to be performed will be documented in a Statistical 
Analysis Plan (SAP) that will be completed prior to unblinding the study data. This document 
will include more details of the analysis populations, summary strategies, and any amendments to 
the proposed analyses listed here, if necessary. Any changes to the SAP will be outlined in the 
final clinical study report. 
8.1.3 Endpoint Definitions 
8.1.3.1 Primary Endpoint: Safety and Tolerability of REL-1017 
The primary objective is to evaluate the safety and tolerability of 7 days of daily dosing with 
REL-1017 25 mg or 50 mg in patients. The following assessments will be conducted to measure 
safety and tolerability throughout the study:  
• AEs 
• Vital signs 
• Weight 
• Physical examination 
• Clinical laboratory parameters (chemistry, hematology, and urinalysis) 
• Electrocardiogram (ECG) parameters 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Clinician Administered Dissociative States Scale (CADSS) 


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• Clinical Opiate Withdrawal Scale (COWS) 
• 4-Item Positive Symptoms Response Scale (4-Item PSRS) 
8.1.3.2 Secondary Objective: Pharmacokinetic Profile of REL-1017 
A secondary objective is to evaluate the PK profiles of 7 days of daily dosing with REL-1017 
25 mg and 50 mg on Day 1 through Day 7, Day 8, Day 9, and Day 14 where data allow. The 
plasma concentration of d-methadone as a function of time will be analyzed using 
non-compartmental, validated software to estimate the following PK parameters: 
• Maximum observed plasma concentration (Cmax) 
• Time to maximum observed plasma concentration (Tmax) 
• Area under the plasma concentration-time curve from time zero until the dosing interval of 
24 hours (AUCtau) 
• Area under the plasma concentration-time curve from time zero until the last quantifiable 
time point (AUC0-last) 
• Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) 
• Apparent termination elimination rate constant (λz) 
• Apparent terminal elimination half-life (t½) 
• Attainment of steady state 
• Steady state clearance (CSS/F) 
• Volume of distribution at steady state (VSS/F) 
• Accumulation ratios based on minimum observed plasma concentration (Cmin), Cmax, and 
AUCtau 
In addition, other relevant parameters may be calculated. 
8.1.3.3 Secondary Objectives: Efficacy of REL-1017 
The efficacy of 7 days of daily dosing with REL-1017 25 mg and 50 mg as measured by 
the following efficacy endpoints: 
• Change from Baseline (Day 1) to EDP (Day 7) on the MADRS with measurements 
made pre-dose on Day 1 and Day 2; post-dose on Day 4 and Day 7 within 3 hours 
of dosing; and on Day 14; 
• Change from Baseline (Day 1) to EDP (Day 7) on the SDQ with measurements made 
pre-dose on Day 1 and Day 2; post-dose on Day 4 and Day 7 within 3 hours of dosing; and 
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• Change from Baseline (Day 1) to EDP (Day 7) on the CGI-S with measurements made 
pre-dose on Day 1 and Day 2; post-dose on Day 4 and Day 7 within 3 hours of dosing; and 
on Day 14. 
• Evaluation of CGI-I total score on Day 7 (post-dose), as well as CGI-I scores on Days 2 
(pre-dose), 4 (post-dose), and 14. 
8.1.4 Planned Analyses 
All analyses (other than PK parameter calculations) will be performed using SAS Version 9.3 or 
higher, run on the Microsoft Windows Server 2003 R2 operating system. Pharmacokinetic 
parameter calculations will be performed using WinNonlin Version 6.3 or higher, run on the 
Windows XP platform or higher. 
8.1.4.1 Analysis of Safety Assessments 
Safety and tolerability parameters will be listed by treatment and patient and displayed in 
summary tables using descriptive statistics. 
8.1.4.2 Adverse Events 
Original terms used in the eCRFs by Investigators or designees to identify AEs will be coded 
using the MedDRA (Version 16.0 or higher). The number and percentage of patients with 
treatment-emergent AEs will be summarized by system-organ-class, preferred term, and 
treatment and for each treatment by maximum severity and relationship to study treatment. A 
treatment-emergent AE is any that is new in onset or was aggravated in severity or frequency 
following the first dose of study drug (Day 1), up to and including the last visit of the study 
(Day 21). 
8.1.4.3 Other Safety Assessments 
Vital signs will consist of BP (systolic and diastolic), HR, pulse oximetry, and RR. Descriptive 
statistics will be calculated and presented for each time point by treatment (absolute values and 
change from Baseline). Vital signs will be measured after the patient has been resting in a supine 
or semi-supine position for at least 3 minutes. Measurement of orthostatic BP should follow 
measurement of supine or semi-supine BP. Patients should be asked to stand for 3 minutes before 
measurement of orthostatic BP. The BP cuff should be kept in place between supine and 
orthostatic BP measurements. Blood pressure should be recorded to the nearest 2 mmHg mark on 
the manometer or to the nearest whole number on an automatic device. 
Descriptive statistics will be calculated and presented for each time point by treatment (absolute 
values and change from Check-in [Day -1]) for weight and oral body temperature. 
Absolute values, change from Check-in (Day -1) in 12-lead ECG results (average of triplicate 
assessments, where applicable), and QT/QTcF categories per FDA Guidance E14 will be 
summarized using descriptive statistics; frequencies (numbers and percentages) will be 
calculated for the overall evaluation by scheduled time and treatment. Patients must be supine for 
at least 3 minutes before an ECG is recorded, and they must remain supine or semi-supine and 
awake while the ECG is recorded. Overall interpretation and machine read intervals (HR, PR, 


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QRS, QT and QTcF) will be recorded on the ECG eCRF. Clinically significant ECG findings 
that emerge after drug treatment will be recorded on the AE eCRF. 
Laboratory data will be summarized by the type of laboratory test and scheduled visit. 
Descriptive statistics will be calculated and presented for each time point by treatment (absolute 
values and change from Check-in [Day -1]). Descriptive statistics and the number of patients 
with laboratory test results below, within, and above normal ranges will be tabulated by 
scheduled time. Abnormal findings in laboratory data will be listed with a flag for clinical 
significance based on the Investigator judgment. 
Physical examination results will be listed.  
Medical history abnormalities will be coded to MedDRA terms using Version 16.0 or higher. 
Physical examination abnormalities will also be listed. 
The original verbatim terms collected in the eCRF for concomitant medications will be coded 
using the WHO Drug Dictionary into drug class (Anatomical Therapeutic Chemical [ATC] level 
2) and preferred term. These data will be listed. 
8.1.4.4 Analysis of Pharmacokinetics 
Blood samples will be collected for PK analysis on: 
• Day 1 at 1 hour pre-dose (Baseline) and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose; 
• Day 2 through Day 7 at 1 hour pre-dose; 
• On Day 8 at 24 hours after the last dose of study drug (Day 7); 
• On Day 9 at 48 hours after the last dose of study drug (Day 7) prior to Discharge from 
the CRU; and, 
• On Day 14 at approximately 168 hours (± 3 days) after the last dose of study drug on Day 7. 
The PK parameters for REL-1017 determined by non-compartmental analysis will be summarized. 
Graphs of the concentration (original and log transformed) versus time will be generated. 
Descriptive statistics, including number of patients, mean, standard deviation (SD), coefficient of 
variation (CV), median, minimum, and maximum, will be calculated by time point for REL-1017 
25 mg and 50 mg. Concentrations below the limit of quantification (BLQ) will be set to zero for 
the generation of summary statistics for concentrations and the generation of mean 
concentration-time plots. 
For the calculation of the PK parameters, concentration-time data will be treated as follows: BLQ 
concentrations prior to the first quantifiable concentration will be set to zero; BLQ concentrations 
after the first quantifiable concentration will be treated as missing; and pre-dose sampling times 
relative to dosing will be set to zero. Descriptive statistics, including number of patients, mean, 
SD, geometric mean, geometric CV, minimum, maximum, and median will be calculated for all 
REL-1017 PK parameters except Tmax or t½. The Tmax data will be summarized with number of 
patients, minimum, maximum, and median. The t½ data will be summarized with number of 
patients, mean, SD, minimum, maximum, and median. 


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8.1.4.5 Analysis of Efficacy Assessments 
The depressive symptom changes associated with 7 days of daily dosing with REL-1017 25 mg 
and 50 mg will be measured using the MADRS, SDQ, and CGI-S. The MADRS, SDQ, and 
CGI-S will be conducted pre-dose at Baseline (Day 1) and on Day 2; post-dose on Day 4 and 
Day 7 within 3 hours of dosing; and at EOP (Day 14). The CGI-I will be administered pre-dose 
on Day 2; post-dose on Day 4 and Day 7 within 3 hours of dosing; and at EOP (Day 14). 
The change from Baseline in each parameter on Day 7 will be compared among treatment groups 
(Placebo, REL-1017 25 mg, and REL-1017 50 mg) using a mixed model of repeated 
measurement with treatment group, stratification (concomitant antidepressant drug) factor, visit 
(Day 2, Day 4, and Day 7), interaction between treatment and visit as independent variables, and 
Baseline endpoint as a covariate. Least square (LS) means with standard errors, differences in LS 
means with standard errors, 90% confidence intervals for the difference in LS means, and 
corresponding P-values will be presented. 
Actual values, absolute change, and percent change from Baseline will be summarized by 
treatment and all visits. 
The assumptions of normality may be evaluated using the Shapiro-Wilks test. If the assumptions 
of normality are not satisfied, the ranked change and ranked Baseline may replace the change 
and Baseline in the above mixed model as a sensitivity analysis. 
8.1.5 Demographics and Other Baseline Characteristics 
Demographics and Baseline characteristics (age, sex, race, ethnicity, body weight, height, oral 
body temperature, and BMI) will be summarized using descriptive statistics (number of patients, 
mean, SD, median, minimum, and maximum for continuous variables and the proportion of 
patients for categorical variables) for the Safety population. No formal statistical comparison 
between the groups will be performed. Demographics and height will be recorded at Screening 
only. Weight and oral body temperature will also be recorded at Check-in (Day -1), EDP 
(Day 7), and EOP (Day 14). In addition, BMI will be calculated at Screening. 
The patient’s eligibility for participation in the study will be determined with the inclusion and 
exclusion criteria at Screening. The inclusion and exclusion criteria will be reviewed again at 
Check-in (Day -1) when the patient is admitted to the CRU. The study restrictions review will 
also occur at Check-in (Day -1). 
Patients will be confined to the CRU from Check-in (Day -1) through Discharge on Day 9. 
Patients will be administered study drug daily from Day 1 through Day 7. 
Randomization will occur on Day 1 prior to administration of the first dose of study drug. The 
treatment assignment for each patient will be assigned through the IWRS in a 1:1:1 ratio 
(REL-1017 25 mg, REL-1017 50 mg, or Placebo), and the randomization schedule will be 
stratified based on patients receiving concomitant ADTs that are cytochrome (CYP) 2B6 
inhibitors (e.g., paroxetine, fluoxetine) versus those who are not. 
Medical history and psychiatric history will be coded into the most recent version of MedDRA 
available (Version 16.0 or higher). Medical history will be listed by treatment arm and patient at 


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Screening and Check-in (Day -1). Psychiatric history will be listed by treatment arm and patient 
at Screening only. 
Prior and concomitant medications will be assigned a 12-digit code using the most recent version 
of the WHO drug codes available. Prior and concomitant medications will be listed by treatment 
arm and patient. Medication history (prior medications) will be listed at Screening, and 
concomitant medications will be listed at every visit from Check-in (Day -1) through EOP 
(Day 21) and summarized by treatment. 
The effectiveness of the patient’s prescribed antidepressant medication will be assessed using the 
MINI, ATRQ, and HAM-D-17. The MINI will be conducted at Screening only, while the ATRQ 
and HAM-D-17 will be conducted at both Screening and Check-in (Day -1). 
The mental status of patients will be further evaluated with the C-SSRS, CADSS, and COWS. 
The C-SSRS will be conducted at Screening, Check-in (Day -1), Baseline (Day 1, first day of 
dosing), Day 2 (24 hours after first dose), Day 8 (24 hours after last dose), Discharge (Day 9), 
Day 14 (EOP), and Day 21 (Follow-up). The 4-Item PSRS will be measured at 30 to 60 minutes 
pre-dose at Baseline (Day 1), 2 hours post-dose on Day 1 (after first dose), 2 hours post-dose on 
Day 7 (EDP) (after last dose), and prior to Discharge on Day 9. The CADSS will be measured at 
30 to 60 minutes pre-dose at Baseline (Day 1), 2 hours post-dose on Day 1 (after first dose), 2 
hours post-dose on Day 7 (after last dose), and prior to Discharge on Day 9. The COWS will be 
conducted on Day 8 (24 hours after the final dose of study drug), on Day 9 (Discharge), and at 
EOP (Day 14). 
The Investigator or designee will contact each patient by telephone on Day 21 (14 days after the 
last dose of study drug) to assess C-SSRS, ask about AEs and evaluate the patient’s general 
status. 
The number of patients in each of the treatment groups will be presented, in addition to the 
number of patients who complete each visit. The reasons for all post-randomization 
discontinuations will be tabulated and grouped by treatment group and all patients combined. All 
deviations related to study inclusion or exclusion criteria, conduct of the study, patient 
management, or patient assessment will be described. 
8.1.6 Interim Analyses 
No interim analyses are planned for this study. 
8.1.7 Missing Data 
A mixed model of repeated measurement based on missing at random will be used to address 
missing efficacy data (MADRS, SDQ, CGI-S, and CGI-I). Details on the handling of missing 
data and missing values imputation will be provided in the SAP. 
8.2 
Determination of Sample Size 
As this is a Phase 2a study, formal sample size calculations are not applicable. The study will not 
be powered for signal detection; however, summary statistics will be calculated, and effect size 
calculations will be performed for efficacy measures. 


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The sample size of 20 patients in each of the two active treatment groups (REL-1017 25 mg and 
50 mg) and 20 patients in the Placebo group was chosen to obtain reasonable evidence of safety 
and efficacy without exposing undue numbers of patients to the investigative product at this 
phase of clinical development. 


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9 STUDY ADMINISTRATION 
9.1 
Data Collection and Electronic Data Capture 
The Investigator or designee will record all required patient data using the specified data 
collection method agreed upon by Syneos Health, Inc., and Relmada (i.e., paper source and/or 
the electronic data capture [EDC] system). 
The study site will use a validated EDC system to enter patient data onto eCRFs. Data will be 
collected using the EDC system and entered into a quality controlled clinical database. Prior to 
the commencement of the study, items to be included in the clinical database will be determined, 
and suitable paper source documents will be created to ensure the appropriate collection of all 
required data. The clinical staff conducting the study will enter the required data onto source 
documents; and generally, different staff members (who have been trained to do so) will enter 
the data from source documents into the clinical database, although there may be some staff 
overlap. All entries, corrections, and alterations will be made by the Investigator or other 
authorized study personnel; and all data entries will be verified for accuracy and correctness. 
The EDC system is optimized for manual keying and review (including review by independent 
monitors) and maintains a full audit trail. For patients who do not qualify for the treatment phase 
of the study, data collected during the Screening Visit will not be entered into the clinical 
database. 
Clinical laboratory and PK data will be received from the laboratory as ASCII files and merged 
with the data from the clinical database. Scheduled Measurement System (SMS) data will be 
captured electronically and imported into the clinical database. 
The study file and all source data will be retained at the clinical site until notification is given by 
the Sponsor for destruction. 
9.2 
Regulatory and Ethical Considerations 
9.2.1 Ethical Conduct of the Study 
The Investigator will conduct the study in accordance with Good Clinical Practice (GCP) and all 
applicable regulations, including, where applicable, the principles that have their origin in the 
Declaration of Helsinki. The study will also be carried out in keeping with applicable national 
and local laws and regulations. This may include an inspection by the Sponsor’s representatives 
and/or regulatory authority’s representatives at any time. 
9.2.2 Regulatory Authority Approval 
In accordance with applicable local regulations, the Sponsor or designee will obtain approval 
from the appropriate regulatory agency prior to a site initiating the study in that country or 
jurisdiction. 
9.2.3 Ethics Approval 
The Investigator will ensure that this protocol is reviewed and approved by the appropriate IRB. 
The IRB will also review and approve the site’s ICF and any other written information provided 
to the patient, including any advertisements used for patient recruitment. Prior to the enrollment 


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of patients, the Investigator or designee will forward copies of the IRB approval and approved 
study documentation to the Sponsor. 
If, during the study, it is necessary to amend study documentation (e.g., protocol, ICF), the 
Investigator or designee will be responsible for ensuring that the IRB reviews and approves these 
amended documents. IRB approval of an amended ICF must be obtained before new patients 
consent to take part in the study using the amended form. Copies of the IRB approval of the 
amended study documentation and the approved materials will be forwarded to the Sponsor as 
soon as available. 
9.2.4 Patient Informed Consent 
At Screening, the Investigator or designee will inform the patient or, where applicable, the 
patient’s legally authorized representative (e.g., parent, guardian, next of kin, or other individual 
or body with appropriate jurisdiction) of all aspects pertaining to the patient’s participation in the 
study. 
The process for obtaining the patient’s informed consent will be in accordance with all 
applicable regulatory requirements. The Investigator or designee and the patient or the patient’s 
legally acceptable representative will both sign and date the ICF before the patient can 
participate in the study. The patient or patient’s legally acceptable representative will receive a 
copy of the consent form, and the original form will be retained in the site study records. The 
patient’s decision regarding participation in the study will be entirely voluntary. The Investigator 
or designee will emphasize to the patient or the patient’s legally acceptable representative that 
consent regarding study participation may be withdrawn at any time without penalty or loss of 
benefits to which the patient is otherwise entitled. 
If the ICF is amended during the study, the Investigator will follow all applicable regulatory 
requirements pertaining to the implementation and use of the amended ICF, including use for 
previously consented patients. 
9.2.5 Principal Investigator Reporting Requirements 
In accordance with applicable local regulatory requirements, the Investigator may be obligated to 
provide periodic safety updates on the conduct of the study at his or her research site and 
notification of study closure to the IRB. Such periodic safety updates and notifications are the 
responsibility of the Investigator and not of the Sponsor. The Sponsor will be provided with 
copies of all notifications sent to the IRB. 
9.3 
Privacy 
The research site’s Privacy Officer will provide guidance on privacy issues to the Investigator. 
The Investigator or designee is responsible for complying with applicable privacy regulations per 
his or her jurisdiction. Only information identified in this protocol will be collected. The 
information collected will only be used for the purposes identified in this protocol. 
9.3.1 Patient Identifiers 
To ensure patient anonymity and to limit disclosure, patients will be assigned a unique patient 
Screening number after signing the ICF at their first assessment. Patients will be assigned unique 


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randomization numbers at the time of randomization. These patient identifiers will be cross-
referenced in the patient’s chart. The patient identifiers will not contain any potentially 
identifiable information. 
A patient identifier log will be maintained, linking each patient’s name to the corresponding 
patient identifiers. This log will be stored at the research site in a secure location. 
9.3.2 Purpose of Collecting Personal Information and Use 
The purpose of collecting personal information from patients (including health and medical 
information) during this study is for scientific research and/or as supportive evidence for 
drug-related submissions to regulatory authorities, in compliance with legal or regulatory 
requirements. 
9.3.3 Access and Disclosure of Personal Information 
The knowledge gained through this study is the property of Relmada Therapeutics, Inc. The 
Sponsor, representatives, and affiliated companies of the Sponsor; the IRB; the FDA, and other 
regulatory agencies may inspect patient medical records related to the study to check the validity 
and accuracy of the data gathered in this study. Patient medical records (with patient initials 
and/or date of birth only) may be copied. The confidentiality of patient records will be 
maintained except where the release of information is required by law. 
With the agreement of the patient, the Investigator may inform the patient’s primary care 
physician about his or her participation in the study and will forward any clinically significant 
findings from clinical tests such as the ECG and laboratory tests. The primary care physician 
may contact the Investigator for any further information regarding the patient’s participation in 
the study. The patient has the right to request access to and request corrections of his or her 
medical record. 
Syneos Health ensures that any authorized third party that performs services on behalf of Syneos 
Health acts in a manner consistent with the Syneos Health Privacy Policy. While every effort 
will be made to protect the privacy of patient information, absolute confidentiality cannot be 
guaranteed. This does not limit the duty of the researchers and others to protect patient privacy. 
9.3.4 Release of Patient Information 
The results of this study will be reported in such a manner that patients will not be identifiable in 
any way. Published reports or presentations will refer to grouped data or coded individual data 
and not to any identifiable individuals. Study reports sent to the Sponsor or drug regulatory 
agencies (e.g., the FDA) will not include patient names. 
9.3.5 Consent for Collection, Access, Use and Disclosure of Patient Information 
By signing the ICF, the patient consents to the collection, access, use, and disclosure of his or her 
information as described in the ICF document. If a patient withdraws consent, some of the 
patient’s information may still be collected, used, and disclosed by those involved in this study 
per applicable laws. 


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9.4 
Study Monitoring 
9.4.1 Quality Control by Syneos Health 
Syneos Health performs quality control at intervals to ensure that the clinical study is conducted 
and data are generated, documented (recorded), and reported in compliance with this study 
protocol; Syneos Health’s SOPs; the FDA; the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP E6 consolidated 
guidelines; and other applicable regulations. The extent, nature, and frequency of quality control 
reviews will be based on Syneos Health’s SOPs and such considerations as the study objectives 
and/or endpoints, purpose of the study, study design complexity, and enrollment rate. 
9.4.2 Study Monitoring by Sponsor and/or Third Party 
If applicable and in accordance with the applicable regulations, GCP, and the Sponsor’s 
procedures, Sponsor and/or third-party monitors will periodically contact or visit the research 
site, as required. The extent, nature, and frequency of on-site visits will be based on such 
considerations as the study objectives and/or endpoints, the purpose of the study, study design 
complexity, and enrollment rate. 
During these contacts, the monitor may: 
• Check and assess the progress of the study. 
• Review study data that have been collected. 
• Conduct source document verification (for those measures that have separate source 
documents and assuming the source documents are compared to the eCRF). 
• Identify any issues and address their resolution. 
• Prepare a monitoring report. 
This will be done to verify that: 
• The data are authentic, accurate, and complete; 
• The safety and rights of patients are being protected; and, 
• The study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate the Investigator’s time and/or the time of research site staff to the monitor to discuss 
findings and any relevant issues. 
At a minimum, source documentation will be available to substantiate the Patient ID, eligibility, 
and participation; proper informed consent procedures; dates of visits; adherence to protocol 
procedures; records of safety and efficacy parameters; adequate reporting and follow-up of AEs; 
administration of concomitant medication; and dates of patient completion, discontinuation from 
treatment, or withdrawal from the study, including the reason if appropriate. 


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An unblinded monitor independent of the study team will visit the sites to review the pharmacy 
records to ensure proper drug management during the study. The unblinded monitor will review 
drug receipt/dispensing/return records and study drug administration information to ensure all 
records are in order. 
In addition to contact during the study, the monitor will also contact the site prior to the start of 
the study to discuss the protocol and data collection procedures with research site personnel. 
At study closure, monitors will also conduct all activities as indicated in Section 9.7, Study and 
Site Closure. 
9.4.3 Principal Investigator’s Data Responsibility 
The completed eCRFs will be reviewed against source documents by the monitor at each 
monitoring visit. If any data, signatures, or forms are missing or incorrect, the Investigator or 
designee will be informed and corrections will be made. Electronic Case Report Forms will be 
collected from the study site at the termination of the study after all monitoring visits and data 
queries are completed. 
9.5 
Data Quality Assurance 
Actions to ensure the accuracy and reliability of data include the selection of qualified Investigators 
and appropriate study centers; the review of protocol procedures with the Investigator and associated 
study personnel prior to study start; the design of suitable source documents with appropriate 
instructions for use; the internal audit of source data according to GCP and internal procedures to 
ensure their accuracy, completeness, and verifiability; as well as the periodic site monitoring by the 
Sponsor. Written instructions will be provided for the collection, preparation, and shipment of blood, 
plasma, and urine samples. The Sponsor or designee will review source documents for accuracy and 
completeness during on-site monitoring visits and after their return to the Sponsor; any discrepancies 
will be resolved with the Investigator or designee, as appropriate. The data will be entered into the 
clinical study database and verified for accuracy using the study-specific data verification plan. 
9.6 
Study and Site Closure 
Upon completion of the study, the following activities, when applicable, will be conducted by 
the monitor in conjunction with the Investigator or designee, as appropriate: 
• Return of all study data to the Sponsor 
• Data clarifications or resolutions 
• Accounting, reconciliation, and final disposition of used and unused study drugs 
• Review of site study records for completeness 
• Return of treatment codes to the Sponsor 
In addition, the Sponsor reserves the right to suspend or prematurely discontinue this study at 
any time and for any reason. If such action is taken, the Sponsor will discuss this with the 
Investigator (including the reasons for taking such action) at that time. The Sponsor will 
promptly inform any other Investigators and/or institutions conducting the study if the study is 


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suspended or terminated for safety reasons and will inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the Investigator will inform the IRB promptly and provide the study patients with 
the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data will be returned to the Sponsor. In 
addition, the site will conduct final disposition of all unused study drugs in accordance with the 
Sponsor’s procedures for the study. 
Financial compensation to the Investigators and/or institutions will be in accordance with the 
agreement established between the Investigator and the Sponsor. 
9.7 
Records Retention 
Following closure of the study, the Investigator will maintain a copy of all site study records in 
their original format in a safe and secure location in accordance with the applicable FDA 
regulatory requirements. Records shall be maintained for a period of 2 years following the date a 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and the FDA is notified. 
Essential documents include: 
• Signed informed consent documents for all patients 
• Patient ID code list, Screening log (if applicable), and enrollment log 
• Record of all communications between the Investigator and the IRB 
• Copies of eCRFs and of documentation of corrections for all patients 
• Investigational product accountability records 
• All other source documents (e.g., patient medical records, hospital records, laboratory 
records) 
• All other documents as listed in Section 8 of the ICH E6 guideline for GCP (essential 
documents for the conduct of a clinical study) 
Normally, these records will be held in the Investigator’s archives. If the Investigator is unable to 
meet this obligation, he or she will ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements will be documented. 
 


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Vos T, Barber RM, Bell B, et al. Global Burden of Disease Study 2013 Collaborators. 
Global, regional, and national incidence, prevalence, and years lived with disability for 
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Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for 
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Hardeveld F, Spijker J, De Graaf R, et al. Prevalence and predictors of recurrence of major 
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Dupuy JM, Ostacher MJ, Huffman J, et al. A critical review of pharmacotherapy for major 
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Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are 
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Shimoyama N, Shimoyama M, Elliott KJ, Inturrisi CE. d-Methadone is antinociceptive in 
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Relmada Therapeutics, Inc. Study REL-1017-111, “A Phase 1 Study to Investigate the 
Safety, Tolerability, and Pharmacokinetic Profile of Single Ascending Doses of 
d-Methadone in Healthy Subjects.” 
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PsychoGenics, Inc. RMA003 FS Preliminary Report. “Evaluation of the Antidepressant 
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Ebert B, Thorkildsen C, Andersen S, et al. Opioid analgesics as noncompetitive 
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Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the 
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Callahan RJ, Au JD, Paul M, et al. Functional inhibition by methadone of N methyl 
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15. 
Lin C, Somberg T, Molnar J, Somberg J. The effects of chiral isolates of methadone on the 
cardiac potassium channel IKr. Cardiology 2009;113(1):59-65. 
16. 
Eap CB, Crettol S, Rougier JS, et al. Stereoselective block of hERG channel by 
(S) methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin 
Pharmacol Ther 2007;81(5):719-728. 
17. 
Silverman DA, Nettleton RT, Spencer KB, et al. S-Methadone Augments R methadone 
induced respiratory depression in the neonatal guinea pig. Respir Physiol Neurobiol 
2009;169(3):252-261. 
18. 
Schmidt N, Brune K, Williams KM, Geisslinger G. Stereoselective pharmacokinetics of 
methadone in beagle dogs. Chirality 1994;6(6):492-495. 
19. 
Scott C, Robbins EB, Chen KK. Pharmacologic comparison of the optical isomers of 
methadon. J Pharm Exp Ther 1948;93(3):282-286. 
20. 
Allen JW, Horais KA, Tozier NA, Yaksh TL. Opiate pharmacology of intrathecal 
granulomas. Anesthesiology 2006;105(3):590-598. 
21. 
Yaksh TL, Tozier N, Horais K, et al. Toxicology profile of N-methyl-D-aspartate 
antagonists delivered by intrathecal infusion in the canine model. Anesthesiology 
2008;108(5):938-949. 
22. 
FDA Guidance. Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics in adult healthy volunteers. Jul 2005 
(https://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf%23search=%27guidekin
es+for+industry+sfe+starting%27). 
23. 
Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid 
antidepressant effects of NMDA antagonists. Science 2010;329(5994):959-964. 
24. 
Dwyer JM, Lepack AE, Duman RS. mTOR activation is required for the antidepressant 
effects of mGluR2/3 blockade. Int J Neuropsychopharmacol 2012;15(4):429 434. 
25. 
Voleti B, Navarria A, Liu RJ, et al. Scopolamine rapidly increases mammalian target of 
rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. 
Biol Psychiatry 2013;74(10):742-749. 
26. 
Liu, RJ, Duman C, Kato T, et al. GLYX 13 produces rapid antidepressant responses with key 
synaptic and behavioral effects distinct from ketamine. Neuropsychopharm 
2013(Apr);38(5):729-742. 
27. 
Duman RS, Aghajanian GK. Synaptic dysfunction in depression: novel therapeutic targets. 
Science 2012;338(6103):68-72. 
28. 
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: 
new insights from stress and rapid-acting antidepressants. Nat Med 2016;22(3):238-249. 
29. 
Relmada Therapeutics, Inc. Study: “Evaluation of the Antidepressant Effects of 
d-Methadone in the Forced Swim Test in Rats.” 


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30. 
Desseilles M, Witte J, Chang TE, et al. Massachusetts General Hospital SAFER criteria for 
clinical trials and research. Harv Rev Psychiatry 2013;21(5):269-274. 
31. 
Olsen GD, Wendel HA, Livermore JD, et al. Clinical effects and pharmacokinetics of 
racemic methadone and its optical isomers. Clin Pharmacol Ther 1977;21(2):147-157. 
32. 
Fraser HF, Isbell H. Human pharmacology and addictiveness of certain dextroisomers of 
synthetic analgesics. Bull Narc 1962;14:25-35. 
33. 
Isbell H, Eisenman AJ. The addiction liability of some drugs of the methadon series. J 
Pharmacol Exp Ther 1948;93(3):305-313. 
34. 
Boulton DW, Arnaud P, DeVane CL. A single dose of methadone inhibits cytochrome 
P-4503A activity in healthy volunteers as assessed by the urinary cortisol ratio. Br J Clin 
Pharmacol 2001;51(4):350-354. 
35. 
Pedrelli P, Blais M, Alpert J, et al. Reliability and validity of the Symptoms of Depression 
Questionnaire (SDQ). CNS Spectr 2014;19(6):535-546.  
36. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric 
interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(S20):22-33. 
37. 
Chandler GM, Iosifescu DV, Pollack MH, et al. RESEARCH: validation of the 
Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). 
CNS Neurosci Ther 2010;16(5):322-325. 
38. 
Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch 
Gen Psychiatry 1988;45(8):742-747. 
39. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for 
the Montgomery-Åsberg Depression Rating Scale (SIGMA). Br J Psychiatry 
2008;192(1):52-58. 
40. 
Structured Interview Guide for the MADRS. Royal College of Psychiatrists, 2011. 
Developed from Williams JBW, Kobak KA.  Development and reliability of a structured 
interview guide for the Montgomery-Asberg Depression Rating Scale (SIGMA). Br J 
Psychiatry 2008;192:52-58. 
41. 
Montgomery SA, Asberg M. A new depressions scale designed to be sensitive to change. 
Br J Psychiatry 1979;134:382-389. 
42. 
Busner J, Targum SD. The Clinical Global Impressions Scale: applying a research tool in 
clinical practice. Psychiatry (Edgmont) 2007;4(7):28-37. 
43. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry 2011;168(12):1266-1277. 


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44. 
Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the 
Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress 
1998;11(1):125-136.  
45. 
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs 2003;35(2):253-259. 
46. 
Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS): recent developments 
in ascertainment and scaling. Psychopharmacol Bull 1988;24:97-99.  
47. 
The 4-Item Positive Symptom Rating Scale was adapted from the Expanded Version of the 
BPRS developed by: Ventura J, Lukoff D, Nuechterlein KH, Liberman RP, Green MF, and 
Shaner, A Manual for the expanded Brief Psychiatric Rating Scale. International Journal of 
Methods Psychiatry Research 1993;3:227-244.  


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11 APPENDICES 
11.1 Amount of Blood Drawn per Study Period 
 
PK 
Sample 
DNA 
Sample 
Safety 
Total 
Clinical 
Chemistry 
Hematology 
Serology 
Blood Volume (mL) [Number of Samples] 
Approximate 
volume per 
sample (mL) 
4 mL 
4 mL 
5 mL 
4 mL 
5 mL 
– 
Screening 
0 
0 
5 [1] 
4 [1] 
5 [2] 
14 [4] 
Check-in 
5 [1] 
4 [1] 
5 [1] 
14 [3] 
Treatment 
Period 
4 [7] 
4 [1] 
5 [1] 
4 [1] 
5 [1] 
46 [11] 
Follow-up 
4 [2] 
0 
5 [1] 
4 [1] 
0 
17 [4] 
Total 
91 mL [21] 
DNA = Deoxyribonucleic Acid; PK = Pharmacokinetic(s). 
Note: Blood volumes shown in the table are approximate. Additional blood samples may be taken if 
needed to follow up on individual patient safety. 
 
 
 
 
 


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11.2 SAFER Interview 
 
 
 
 


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11.3 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
 
 


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11.4 Clinician Administered Dissociative States Scale (CADSS) 
 


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11.5 Clinical Opiate Withdrawal Scale (COWS) 
 
 
 
 


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11.6 4-Item Positive Symptom Rating Scale (4-Item PSRS) 
 
 
11.7 Antidepressant Treatment Response Questionnaire (ATRQ) 
 
MGH ANTIDEPRESSANT TREATMENT RESPONSE QUESTIONNAIRE (ATRQ) 
 
Copyright by Massachusetts General Hospital 
 
(Non-Geriatric Population: 18 to 64 years of age)(Global) 
 
Note: The minimum therapeutic dose for each antidepressant treatment  in Section I is based on prescribing information, 
relevant literature, and consultation with expert clinicians. 


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Section I. Antidepressant Medications 
 
Instructions: 
 
1. Please check (√) the names of any medications that the patient has taken since the beginning of THIS CURRENT 
EPISODE of depression. 
2. Please check (√) if the daily dosage of the medication was equal to or greater than the minimum therapeutic dose 
for at least 6 weeks.  
3. Only for those taken at the minimum therapeutic dose for at least 6 weeks, indicate the amount (%) of improvement 
in depression that the patient reported when they felt it was working at its best. 
4. If the subject initially experienced an improvement of ≥50% and then lost that response (tolerance/bradyphylaxis), 
that medication will not be counted towards a failed antidepressant trial. 
 
Tricyclic Antidepressants 
 
Generic Name 
Taken during 
THIS current 
episode of 
depression(√) 
Took at least this dose* 
for at least 6 weeks?  
(√) 
Only for those taken at minimum 
therapeutic dose for at least 6 weeks: 
 
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best. 
 
A. 75% to 100% 
B. 50% to <75% 
C. 26% to  <50% 
D. ≤25% 
doxepin 
 
150mg/d            
 
 
clomipramine 
 
150mg/d          
 
 
amoxapine 
 
150mg/d           
 
 
amitriptyline    
 
150mg/d         
 
 
maprotiline   
 
150mg/d           
 
 
desipramine  
 
150mg/d           
 
 
nortriptyline      
 
75 mg/d             
 
 
doxepin     
 
150mg/d           
 
 
trimipramine     
 
150mg/d           
 
 
imipramine 
 
150mg/d                
 
 
protriptyline       
 
30mg/d                      
 
pipofezine   
 
150mg/d             
 
 
noxiptiline   
 
100mg/d                   
 
 
* If the dose is below the minimum dose required, a blood level that is within the therapeutic (antidepressant) range is 
also acceptable. 
 
 
Monoamine Oxidase Inhibitors (MAOIs) 
 
Generic Name 
Taken during 
THIS current 
episode? (√) 
Took at least this dose for at least 
6 weeks? (√) 
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks: 
 
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best. 


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A. 75% to 100% 
B. 50% to <75% 
C. 26% to  <50% 
D. ≤25% 
isocarboxazid 
 
30mg/d                
 
 
phenelzine       
 
45mg/d                
 
 
tranylcypromine  
 
30mg/d                     
 
 selegiline patch  
 
6 mg/24 hrs 
 
 
 moclobemide 
 
300 mg/d 
 
 
 pirlindole 
 
200 mg/d 
 
 
 
 
Selective Serotonin Reuptake Inhibitors (SSRIs) 
 
Generic Name 
Taken during 
THIS current 
episode? (√)  
Took at least this dose 
 at least 6 weeks? (√) 
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks: 
 
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best. 
 
A. 75% to 100% 
B. 50% to <75% 
C. 26% to  <50% 
D. ≤25% 
 fluvoxamine        
 
50mg/d            
 
 
 paroxetine       
 
20/25mg/d         
 
 
 fluoxetine     
 
20 mg/d            
 
 
 sertraline       
 
50 mg/d            
 
 
 citalopram           
 
20mg/d            
 
 
escitalopram           
 
10 mg/d            
 
 
vilazodone   
 
40 mg/d         
 
 
 vortioxetine   
 
10 mg/d         
 
 
 
 
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) 
 
Generic Name 
Taken during 
THIS current 
episode? (√) 
Took at least this dose for at least 6 
weeks? (√) 
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks: 
 
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best. 
 
A. 75% to 100% 
B. 50% to <75% 
C. 26% to  <50% 
D. ≤25% 
venlafaxine / 
venlafaxine XR          
 
150 mg/d          
 
 


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duloxetine            
 
60mg/d          
 
 
 desvenlafaxine         
 
50mg/d          
 
 
 milnacipran           
 
100mg/d          
 
 
 levomilnacipran         
40mg/d          
 
 
 
 
Other Antidepressants 
 
Generic Name 
Taken during 
THIS current 
episode? (√) 
Took at least this dose for at 
least 6 weeks? (√) 
Only for those taken at minimum 
therapeutic dose for at least 6 
weeks: 
 
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression he/she 
reported when they feel it was 
working at its best. 
 
A. 75% to 100% 
B. 50% to <75% 
C. 26% to  <50% 
D. ≤25% 
 trazodone       
 
300mg/d          
 
 
 bupropion     
 
300mg/d          
 
 
mirtazapine        
 
15 mg/d         
 
 
 mianserin           
 
30 mg/d         
 
 
opipramol 
 
150 mg/d 
 
 
nefazodone 
 
300 mg/d 
 
 
agomelatine 
 
25 mg/d 
 
 
tianeptine 
 
37.5 mg/d 
 
 
reboxetine 
 
4 mg/d 
 
 
 
 
 


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Section II. FDA-Approved Medications added to Augment /Boost Antidepressant Effect 
 
Instructions: 
 
1. Please check (√) the names of any medication you have taken to augment or boost the antidepressant effect during  
THIS CURRENT EPISODE of depression. 
2. Please check (√) if the subject took at least this dose for at least 6 weeks in combination with an antidepressant treatment from Sect
I. 
3. Please indicate the name of antidepressant treatment from Section I this drug was taken with to augment /boost its antidepressant 
effect. 
4. Please indicate the amount (%) of improvement in depression that the patient reported when they felt this 
combination was working at its best. 
 
Generic Name 
Taken during 
THIS current 
episode? (√) 
Took at least this 
dose for at least 6 
weeks in 
combination with an 
antidepressant 
treatment from 
Section I**? 
 (√) 
 Name of 
Antidepressant 
Treatment from 
Section I (see above) 
this drug was taken 
with 
Only for those taken at 
minimum therapeutic dose for 
at least 6 weeks: 
 
Based on subject’s feedback, 
indicate the amount (%) of 
improvement in depression 
he/she reported when they 
feel the combination was 
working at its best. 
 
A. 75% to 100% 
B. 50% to <75% 
C. 26% to  <50% 
D. ≤25% 
Aripiprazole 
 
5 mg/d 
 
 
 
Quetiapine 
 
200 
mg/d 
 
 
 
Brexpiprazole 
 
1 mg/d 
 
 
 
 
**The antidepressant treatment from Section I must also have been taken at the minimum therapeutic dose during the 6 
weeks that the medication was taken to augment/boost antidepressant effect. 
 
11.8 Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale 
(SIGMA) 
 
STRUCTURED INTERVIEW GUIDE FOR THE 
MONTGOMERY AND ASBERG DEPRESSION RATING SCALE (SIGMA) 
 
Janet B.W. Williams, Ph.D. and Kenneth A. Kobak, Ph.D. 
 
INTERVIEWING GUIDELINES: The questions in bold for each item should be asked exactly as 
written unless the information has been previously obtained, in which case it is appropriate to restate 
the information for confirmation.  Follow-up questions are provided for use when further exploration 
or additional clarification of symptoms is necessary.  The specified questions should be asked until 
you have enough information to rate the item confidently.  In some cases, you may also have to add 
your own follow-up questions to obtain necessary information.  Note that questions in parentheses 
are optional, for use, for example, if information is unknown.  Statements in ALL CAPITALS are 
interviewer instructions and should not be read to the subject. 
 
RATING GUIDELINES: Ratings should be based on the subject's condition as observed in the past 


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week (past 7 days).  As specified in the item descriptions, three of the items, Reduced Sleep, 
Reduced Appetite, and Inability to Feel, are rated as present only when they reflect a change from 
before the depression began (EUTHYMIC BASELINE).  The interviewer should attempt to identify 
the most recent 2-month period of non-depressed functioning and use this as a reference point. In 
some cases, such as when the subject has dysthymia, the referent should be to the last time the 
subject felt alright (i.e., not depressed or high) for at least a few weeks.  When a clear euthymic 
baseline cannot be established because of chronic depressive symptoms, these three items should be 
rated as observed over the past 7 days instead of comparing to a previous time point. 
 
This interview guide is based on the Montgomery-Asberg Depression Rating Scale (MADRS) 
(Montgomery SA, Asberg M: A new depression scale designed to be sensitive to change. Br J 
Psychiatry; 1979 134:  382-9).  The scale itself has been retained in its original form, except for 
reversing the order of the first two items.  This guide adds interview questions to aid in the 
assessment and application of the MADRS.  Previous versions of this guide appeared in 1988, 1992, 
1996, 2005 and 2008. 
  
©2008, 2011 The Royal College of Psychiatrists.  The SIGMA may be copied by individual 
researchers or clinicians for their own use without seeking permission from the publishers.  The 
scale must be copied in full and all copies must acknowledge the following source: Williams JBW, 
Kobak KA.  Development and reliability of a structured interview guide for the Montgomery-Asberg 
Depression Rating Scale (SIGMA).  Br J Psychiatry 2008;192:52-58.  Brianne Brown, PsyD, 
contributed to this revision.  Written permission must be obtained from the Royal College of 
Psychiatrists for copying, distribution to others, for replication (in print, online or by any other 
medium), and translations.  Scientific correspondence should be addressed to Dr. Janet Williams at 
jbwwny@gmail.com.  To inform an ongoing survey, researchers and clinicians are asked to notify 
Dr. Williams of their intention to use the SIGMA. 
 
 


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STRUCTURED INTERVIEW GUIDE FOR THE 
MONTGOMERY AND ASBERG DEPRESSION RATING SCALE (SIGMA) 
 
PT’S INITIALS: ________  PT’S ID: ________ 
 
INTERVIEWER: 
_________________ 
 
 TIME BEGAN SIGMA: _____ AM / PM 
 
DATE: __ __ __ __ __ __ 
 
OVERVIEW: 
I’d like to ask you some questions about the past week.  How have you been feeling since last (DAY 
OF WEEK)? 
IF OUTPATIENT:  Have you been working?  (What kind of work do you do?  Have you been able to 
work your normal hours?) 
IF NOT WORKING OR WORKING LESS, CLARIFY WHY. 
 
 


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In the past week, have you been feeling sad or 
unhappy?  (Depressed at all?)  IF YES: Can 
you describe what this has been like for you?  
(IF UNKNOWN: How bad has that been?) 
 
 
IF DEPRESSED:  Does the feeling lift at all if 
something good happens? How much does your 
mood lift? Does the feeling ever go away 
completely?  (How often have you had lifts in 
your mood this week?  What things have made 
you feel better?)   
 
 
How often did you feel (depressed/OWN 
EQUIVALENT) this past week?  (IF 
UNKNOWN: How many days this week did 
you feel that way?  How much of each day?)  
 
 
In the past week, how have you been feeling 
about the future?  (Have you been discouraged 
or pessimistic?)  What have your thoughts been?  
How (discouraged or pessimistic) have you 
been?  How often have you felt that way?  Do 
you think things will ever get better for you?   
 
 
ESTABLISH EUTHYMIC BASELINE: 
When was the last time you were well, not 
depressed at all, for at least 2 months? 
 
 
1.  REPORTED SADNESS.  Representing reports 
of depressed mood, regardless of whether it is 
reflected in appearance or not.  Includes low spirits, 
despondency or the feeling of being beyond help 
and without hope.  Rate according to intensity, 
duration, and the extent to which the mood is 
reported to be influenced by events. 
 
0 - Occasional sadness in keeping with the 
circumstances. 
1 –  
2 - Sad or low but brightens up without difficulty. 
3 –  
4 - Pervasive feelings of sadness or gloominess.  
The mood is still influenced by external 
circumstances. 
5 –  
6 – Continuous or unvarying sadness, misery, or 
despondency. 
 


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RATING BASED ON OBSERVATION 
DURING INTERVIEW AND THE 
FOLLOWING QUESTIONS. 
 
In the past week, do you think you have 
looked sad or depressed to other people?  Did 
anyone say you looked sad or down?   
 
How about when you’ve looked in the mirror; 
did you look gloomy or depressed?   
 
IF YES: How sad or depressed do you think you 
have looked?  How much of the time over the 
past week do you think you have looked 
depressed or down? 
 
Has it been hard for you to laugh or smile in 
the past week?   
 
2.  APPARENT SADNESS.  Representing 
despondency, gloom and despair.  (More than just 
ordinary transient low spirits) reflected in speech, 
facial expressions, and posture.  Rate by depth and 
inability to brighten up. 
 
0 – No sadness 
1 –  
2 - Looks dispirited but does brighten up without 
difficulty. 
3 -   
4 - Appears sad and unhappy most of the time. 
5 –  
6 – Looks miserable all the time.  Extremely 
despondent. 
 
 
 
 
 
 
Have you felt tense or edgy in the last week? 
Have you felt anxious or nervous? 
 
IF YES:  Can you describe what that has been 
like for you?  How bad has it been?   
 
What about feeling fearful that something 
bad is about to happen?   
 
How much of the time have you felt 
(anxious/tense/OWN EQUIVALENT) over the 
past week?   
 
Have you felt panicky in the past week?  IF 
YES:  Can you describe this feeling?  How often 
have you felt this way?   
 
IF YES TO ANY TENSION SYMPTOM:  How 
hard has it been to control these feelings?  (What 
has it taken to help you feel calmer?  Has 
anything worked to calm you down?)   
 
 
3.  INNER TENSION.  Representing feelings of 
ill-defined discomfort, edginess, inner turmoil, 
mental tension mounting to either panic, dread, or 
anguish.  Rate according to intensity, frequency, 
duration and the extent of reassurance called for. 
 
0 - Placid.  Only fleeting inner tension. 
1 -   
2 - Occasional feelings of edginess and ill-defined 
discomfort. 
3 –  
4 – Continuous feelings of inner tension or 
intermittent panic which the patient can only master 
with some difficulty. 
5 –  
6 – Unrelenting dread or anguish.  Overwhelming 
panic. 
  
 
 
 
 
How has your sleeping been in the last week?  
(How many hours have you been sleeping, 
compared to usual?)   
 
Have you had trouble falling asleep? (How 
long has it been taking you to fall asleep this 
past week?  How many nights?) 
 
Have you been able to stay asleep through the 
night?  (Have you been waking up at all in the 
middle of the night?  How long does it take you 
to fall back to sleep?  How many nights?)  
 
Have there been any mornings this past week 
when you have awakened earlier than 
 
4.  REDUCED SLEEP.  Representing the 
experience of reduced duration or depth of sleep 
compared to the subject’s own normal pattern when 
well. 
 
0 - Sleeps as usual. 
1 -   
2 - Slight difficulty dropping off to sleep or slightly 
reduced, light, or fitful sleep. 
3 –  
4 – Sleep reduced or broken by at least 2 hours. 
5 –  
6 – Less than 2 or 3 hours sleep. 


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(EUTHYMIC BASELINE)? 
 
IF UNKNOWN:  Has your sleeping been 
restless or disturbed?   
 
How has your appetite been this past week?  
(What about compared to your usual appetite?)   
 
IF NOT REDUCED:  Have you been less 
interested in food?  (How much less?) 
 
Does food taste as good as usual?  IF LESS: 
How much less?  Does it have any taste at all?   
 
(Have you had to push yourself to eat or have 
other people had to urge you to eat?)   
 
 
 
5.  REDUCED APPETITE.  Representing the 
feeling of a loss of appetite compared with when 
well.  Rate by loss of desire for food or the need to 
force oneself to eat. 
 
0 - Normal or increased appetite. 
1 –  
2 - Slightly reduced appetite. 
3 –  
4 – No appetite.  Food is tasteless. 
5 –  
6 – Needs persuasion to eat at all. 
 
 
 
 
 
Have you had trouble concentrating or 
collecting your thoughts in the past week?  
(How about at home or at work?)  IF YES:  Can 
you give me some examples? (Have you been 
able to concentrate on reading a book or on the 
computer?  Do you need to read things over and 
over again?  Are you able to follow movies or 
television?)     
 
 
How often has that happened in the past week?  
Has this caused any problems for you?     
 
Have you had any trouble following a 
conversation?  (IF YES: How bad has that 
been?  How often has that happened this past 
week?)  
 
 
NOTE:  ALSO CONSIDER BEHAVIOR 
DURING INTERVIEW.  
 
 
6.  CONCENTRATION DIFFICULTIES.  
Representing difficulties in collecting one’s 
thoughts mounting to incapacitating lack of 
concentration.  Rate according to intensity, 
frequency, and degree of incapacity produced. 
 
0 - No difficulties in concentration. 
1 -   
2 - Occasional difficulties in collecting one’s 
thoughts. 
3 –  
4 – Difficulties in concentrating and sustaining 
thought which reduces ability to read or hold a 
conversation. 
5 –  
6 – Unable to read or converse without great 
difficulty. 
 
 
 
 


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Have you had any trouble getting started at 
things in the past week?  IF YES: What things?  
How bad has that been? 
Have you had difficulty getting started at simple 
routine everyday things (like getting dressed, 
brushing your teeth, showering)?   
 
 
 
Are you OK once you get started at things or is 
it still more of an effort to get something done?   
  
 
Has there been anything that you needed to do 
that you were unable to do?  Have you needed 
help to do things?   
IF YES:  What things?  How often?       
 
 
Have you done everyday things more slowly 
than usual?  
IF YES: Like what, for example?  How bad has 
that been?   
 
7.  LASSITUDE.  Representing a difficulty getting 
started, or slowness initiating and performing 
everyday activities. 
 
0 - Hardly any difficulty in getting started.  No 
sluggishness. 
1 -   
2 - Difficulties in starting activities. 
3 –  
4 – Difficulties in simple routine activities, which 
are carried out with effort. 
5 –  
6 – Complete lassitude.  Unable to do anything 
without help. 
 
Have you been less interested in things 
around you, or in activities you used to 
enjoy?  IF YES: What things? How much less 
interested in (those things) are you now 
compared to (EUTHYMIC BASELINE)?  
 
What things have you enjoyed this week?  
How much did you enjoy them?   
 
Has there been any change in your ability to 
feel emotions in the past week?  (Do you feel 
things less intensely than you used to, things like 
anger, grief, pleasure?)  IF YES: Can you tell 
me more about that? (IF UNKNOWN: Are you 
able to feel any emotions at all?)    
 
Have your feelings towards family and 
friends changed at all since (EUTHYMIC 
BASELINE)?  IF YES:  Do you feel less 
towards them than you used to?   
 
 
8.  INABILITY TO FEEL.  Representing the 
subjective experience of reduced interest in the 
surroundings, or activities that normally give 
pleasure.  The ability to react with adequate 
emotion to circumstances or people is reduced. 
 
0 - Normal interest in the surroundings and in other 
people. 
1 -   
2 - Reduced ability to enjoy usual interests. 
3 –  
4 – Loss of interest in the surroundings.  Loss of 
feelings for friends and acquaintances. 
5 –  
6 – The experience of being emotionally paralyzed, 
inability to feel anger, grief or pleasure, and a 
complete or even painful failure to feel for close 
relatives and friends. 
 
 


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Have you been putting yourself down, or 
feeling that you’re a failure in some way, over 
the past week?  (Have you been blaming 
yourself for things that you’ve done, or not 
done?)  IF YES: What have your thoughts been?  
How often have you felt that way?   
 
In the past week have you been feeling guilty 
about anything?  What about feeling as if you 
have done something bad or sinful?  IF YES:  
What have your thoughts been?  How often have 
you felt that way?   
 
 
ALSO CONSIDER RESPONSES TO 
QUESTIONS ABOUT PESSIMISM FROM 
ITEM 1. 
 
9.  PESSIMISTIC THOUGHTS.  Representing 
thoughts of guilt, inferiority, self-reproach, sinfulness, 
remorse, and ruin. 
 
0 - No pessimistic thoughts. 
1 -   
2 - Fluctuating ideas of failure, self-reproach, or self-
depreciation. 
3 –  
4 – Persistent self-accusations, or definite but still 
rational ideas of guilt or sin.  Increasingly pessimistic 
about the future. 
5 –  
6 – Delusions of ruin, remorse, or unredeemable sin.  
Self-accusations which are absurd and unshakeable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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This past week, have you felt like life isn’t 
worth living?  (IF NO: What about feeling as if 
you're tired of living?)   
IF YES: Tell me about that.  How often have you 
felt that way?  
 
This week, have you thought that you would 
be better off dead?  IF YES: Tell me about that.  
How often have you felt that way?   
 
Have you had thoughts of hurting or even 
killing yourself this past week?  IF YES:  What 
have you thought about?  How often have you 
had these thoughts?  How long have they lasted?  
Have you actually made plans?  IF YES:  What 
are these plans?  Have you made any preparations 
to carry out these plans?  (Have you told anyone 
about it?) 
 
10.  SUICIDAL THOUGHTS.  Representing the 
feeling that life is not worth living, that a natural death 
would be welcome, suicidal thoughts, and preparation 
for suicide.  Suicidal attempts should not in themselves 
influence this rating. 
 
0 - Enjoys life or takes it as it comes. 
1 –  
2 - Weary of life.  Only fleeting suicidal thoughts. 
3 -   
4 - Probably better off dead.  Suicidal thoughts are 
common, and suicide is considered as a possible 
solution, but without specific plans or intention. 
5 –  
6 – Explicit plans for suicide when there is an 
opportunity.  Active preparations for suicide. 
 
 
 
TIME ENDED SIGMA:    
 
 
_______________   
AM / PM 
 
TOTAL MADRS SCALE SCORE:    
 
_______ _______ 
 
 
 


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11.9 Symptoms of Depression Questionnaire (SDQ)  
SYMPTOMS OF DEPRESSION QUESTIONNAIRE (SDQ) 
TO BE ADMINISTERED AT : BASELINE, DAY 7, DAY 14 
 
Please answer all questions by circling the correct answer or the answer which seems the most appropriate to you. 
 
 
Instructions: Please read each item and circle the number above the statement that you think applies to you. Some questions use the 
words “minimally,” “moderately,” “markedly,” and “extremely.” Minimally means that this item happens to you only rarely or that it is 
mild when it happens. Moderately means that this item bothers you some of the time but that it does not interfere with your life in any 
way. Markedly means that this item bothers you quite a bit and that it causes you some problems in your life. That is, it interferes with 
your ability to do certain things that are important to you such as working, taking care of your family, or enjoying time with friends. 
Extremely means that this problem troubles you a lot and that it interferes with your ability to do a lot of things. 
 
1) 
How has your mood been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
sad 
 
sad 
 
sad 
 
sad 
 
2) 
How responsive has your mood been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more 
 
normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
flat 
 
flat 
 
flat 
 
flat 
 
3) 
How has your affect (or how to display you mood to the external world) been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
sad 
 
sad 
 
sad 
 
sad 
 
4) 
How prone to tears have you been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
tearful  
tearful  
tearful  
tearful 
 
5) 
How reactive have your been to positive things/events over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more 
 
normal  
minimally 
moderately 
markedly 
not reactive 
than usual 
 
 
less reactive 
less reactive 
less reactive 
at all 
 
 
6) 
How reactive have your been to negative things/events over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
more reactive 
more reactive 
more reactive 
reactive 
 
7) 
How has your motivation/interest/enthusiasm been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
 
8) 
How sensitive (e.g., thin-skinned) have your been to rejection/criticism over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 


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less 
 
normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
more reactive 
more reactive 
more reactive 
reactive 
 
9) 
How optimistic have your been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
More optimistic normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
pessimistic 
pessimistic 
pessimistic 
pessimistic 
 
10) 
How has your outlook on life been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more positive 
normal; minimally 
moderately 
markedly 
extremely 
than usual 
happy 
wishing to 
wishing to 
wishing to 
wishing to 
 
 
to be alive be dead 
be dead  
be dead  
be dead 
 
11) 
How has your outlook on suicide been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more against 
normally  
minimally 
moderately 
markedly 
extremely 
it than usual 
not thinking 
wishing to 
wishing to 
wishing to 
wishing to 
 
 
about it  
kill yourself 
kill yourself 
kill yourself 
kill yourself 
 
12) 
How has your outlook on harming your body been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more against 
normally  
minimally 
moderately 
markedly 
extremely 
it than usual 
not thinking 
wishing to 
wishing to 
wishing to 
wishing to 
 
 
about it  
harm yourself 
harm yourself 
harm yourself 
harm yourself 
 
13) 
How has your ability to fall asleep been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
easier 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
14) 
How has your ability to stay asleep in the middle of the night been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
easier 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
15) 
How has your ability to stay asleep around the time before waking up been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
easier 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
16) 
How has your wakefulness/alertness been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
 
17) 
How sleepy during the day have you been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
sleepy  
sleepy  
sleepy  
sleepy 
 


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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
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18) 
How much have you been oversleeping at night over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
increased 
increased 
increased 
increased 
 
19) 
How much have you been oversleeping during the day over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
normal  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
increased 
increased 
increased 
increased 
 
20) 
How has your energy been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
21) 
How heavy (in arms or legs) have you felt over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
heavy 
 
heavy 
 
heavy 
 
heavy 
 
22) 
How slowed down have you felt over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
slowed down 
slowed down 
slowed down 
slowed down 
 
23) 
How agitated have you felt over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
agitated  
agitated  
agitated  
agitated 
 
24) 
How irritable have you been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
irritable  
irritable  
irritable  
irritable 
 
25) 
Have you had anger attacks (suddenly feeling very angry and like exploding with anger) over the past 
week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
never 
 
almost never 
rarely 
 
sometimes 
frequently 
all the time 
 
26) 
How anxious/worried have you felt over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
anxious  
anxious  
anxious  
anxious 
 
 
27) 
Have you had panic attacks over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
felt calmer 
not at all  
rarely 
 
sometimes 
frequently 
all the time 
than normal 
 
 
 
28) 
How has your appetite been over the past week? 


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1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
29) 
Have you lost weight over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
gained  
not at all  
minimally 
mildly 
 
moderately 
markedly 
some weight 
 
30) 
Has your appetite been excessive over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
rarely 
 
sometimes 
frequently 
all the time 
 
31) 
Have you gained weight over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
lost 
 
not at all  
minimally 
mildly 
 
moderately 
markedly 
some weight 
 
32) 
Have you had tachycardia/palpitations over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
my heart rate 
not at all  
rarely 
 
sometimes 
frequently 
all the time 
felt slower than 
usual 
 
33) 
Have you had pains or aches over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
fewer aches 
not at all  
rarely 
 
sometimes 
frequently 
all the time 
and pains 
than usual 
 
34) 
Have you had gastrointestinal (stomach or bowel) symptoms over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
fewer symptoms not at all  
rarely 
 
sometimes 
frequently 
all the time 
than usual 
 
35)  
How has your ability to focus/sustain attention been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
36) 
How has your ability to remember/recall information been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
37) 
How has your ability to find words been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
38) 
How has your sharpness/mental acuity been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 


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greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
39) 
How has your ability to make decisions been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
40) 
How has your sexual functioning been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
41) 
How has your social functioning been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
42) 
How has your ability to work/study/function at home been over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
43) 
How guilty have you felt over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
guilty 
 
guilty 
 
guilty 
 
guilty 
 
44) 
How worthless have you felt over the past week? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
worthless 
worthless 
worthless 
worthless 
 
Copyright: Massachusetts General Hospital and Dr. Richard Shelton 
 
 
SYMPTOMS OF DEPRESSION QUESTIONNAIRE (SDQ) 
TO BE ADMINISTERED AT : DAY 2, DAY 4 
 
Please answer all questions by circling the correct answer or the answer which seems the most appropriate to you. 
 
Instructions: Please read each item and circle the number above the statement that you think applies to you. Some questions use the 
words “minimally,” “moderately,” “markedly,” and “extremely.” Minimally means that this item happens to you only rarely or that it is 
mild when it happens. Moderately means that this item bothers you some of the time but that it does not interfere with your life in any 
way. Markedly means that this item bothers you quite a bit and that it causes you some problems in your life. That is, it interferes with 
your ability to do certain things that are important to you such as working, taking care of your family, or enjoying time with friends. 
Extremely means that this problem troubles you a lot and that it interferes with your ability to do a lot of things. 
 
2) 
How has your mood been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
sad 
 
sad 
 
sad 
 
sad 


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2) 
How responsive has your mood been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more 
 
normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
flat 
 
flat 
 
flat 
 
flat 
 
3) 
How has your affect (or how to display you mood to the external world) been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
sad 
 
sad 
 
sad 
 
sad 
 
4) 
How prone to tears have you been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
tearful  
tearful  
tearful  
tearful 
 
5) 
How reactive have your been to positive things/events since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more 
 
normal  
minimally 
moderately 
markedly 
not reactive 
than usual 
 
 
less reactive 
less reactive 
less reactive 
at all 
 
 
6) 
How reactive have your been to negative things/events since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
more reactive 
more reactive 
more reactive 
reactive 
 
7) 
How has your motivation/interest/enthusiasm been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
8) 
How sensitive (e.g., thin-skinned) have your been to rejection/criticism since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
more reactive 
more reactive 
more reactive 
reactive 
 
9) 
How optimistic have your been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
More optimistic normal  
minimally 
moderately 
markedly 
extremely 
than usual 
 
 
pessimistic 
pessimistic 
pessimistic 
pessimistic 
 
10) 
How has your outlook on life been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more positive 
normal;  
minimally 
moderately 
markedly 
extremely 
than usual 
happy 
 
wishing to 
wishing to 
wishing to 
wishing to 
 
 
to be alive  
be dead  
be dead  
be dead  
be dead 
 
11) 
How has your outlook on suicide been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more against 
normally  
minimally 
moderately 
markedly 
extremely 
it than usual 
not thinking 
wishing to 
wishing to 
wishing to 
wishing to 
 
 
about it  
kill yourself 
kill yourself 
kill yourself 
kill yourself 


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12) 
How has your outlook on harming your body been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more against 
normally  
minimally 
moderately 
markedly 
extremely 
it than usual 
not thinking 
wishing to 
wishing to 
wishing to 
wishing to 
 
 
about it  
harm yourself 
harm yourself 
harm yourself 
harm yourself 
 
13) 
How has your ability to fall asleep been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
easier 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
14) 
How has your ability to stay asleep in the middle of the night been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
easier 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
15) 
How has your ability to stay asleep around the time before waking up been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
easier 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
17) 
How has your wakefulness/alertness been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
more 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
17) 
How sleepy during the day have you been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
sleepy  
sleepy  
sleepy  
sleepy 
 
18) 
How much have you been oversleeping at night since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
increased 
increased 
increased 
increased 
 
19) 
How much have you been oversleeping during the day since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
normal  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
increased 
increased 
increased 
increased 
 
20) 
How has your energy been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
21) 
How heavy (in arms or legs) have you felt since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
heavy 
 
heavy 
 
heavy 
 
heavy 
 


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22) 
How slowed down have you felt since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
slowed down 
slowed down 
slowed down 
slowed down 
 
23) 
How agitated have you felt since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
agitated  
agitated  
agitated  
agitated 
 
24) 
How irritable have you been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
irritable  
irritable  
irritable  
irritable 
 
25) 
Have you had anger attacks (suddenly feeling very angry and like exploding with anger) since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
never 
 
almost never 
rarely 
 
sometimes 
frequently 
all the time 
 
26) 
How anxious/worried have you felt since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
anxious  
anxious  
anxious  
anxious 
 
27) 
Have you had panic attacks since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
felt calmer 
not at all  
rarely 
 
sometimes 
frequently 
all the time 
than normal 
 
 
 
 
 
28) 
How has your appetite been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
29) 
Have you lost weight since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
gained  
not at all  
minimally 
mildly 
 
moderately 
markedly 
some weight 
 
30) 
Has your appetite been excessive since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
rarely 
 
sometimes 
frequently 
all the time 
 
31) 
Have you gained weight since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
lost 
 
not at all  
minimally 
mildly 
 
moderately 
markedly 
some weight 
 
32) 
Have you had tachycardia/palpitations since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
my heart rate 
not at all  
rarely 
 
sometimes 
frequently 
all the time 


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felt slower than 
usual 
 
33) 
Have you had pains or aches since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
fewer aches 
not at all  
rarely 
 
sometimes 
frequently 
all the time 
and pains 
than usual 
 
34) 
Have you had gastrointestinal (stomach or bowel) symptoms since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
fewer symptoms not at all  
rarely 
 
sometimes 
frequently 
all the time 
than usual 
 
35)  
How has your ability to focus/sustain attention been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
36) 
How has your ability to remember/recall information been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
37) 
How has your ability to find words been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
38) 
How has your sharpness/mental acuity been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
39) 
How has your ability to make decisions been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
greater  
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
40) 
How has your sexual functioning been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
41) 
How has your social functioning been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
totally 
than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
42) 
How has your ability to work/study/function at home been since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
better 
 
normal  
minimally 
moderately 
markedly 
totally 


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than normal 
 
 
diminished 
diminished 
diminished 
absent 
 
43) 
How guilty have you felt since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
guilty 
 
guilty 
 
guilty 
 
guilty 
 
44) 
How worthless have you felt since Baseline? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
less 
 
not at all  
minimally 
moderately 
markedly 
extremely 
than normal 
 
 
worthless 
worthless 
worthless 
worthless 
 
 
Copyright: Massachusetts General Hospital and Dr. Richard Shelton 
 
 


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11.10 Clinical Global Impressions (CGI) Scale 
 


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11.11 Structured Interview Guide for the Hamilton Depression Rating Scale-17 Item (SIGH-D) 
 
 


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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
Page 134 of 165 
 
 
 


Clinical Study Protocol Amendment 5 
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Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
Page 135 of 165 
 
 
 


Clinical Study Protocol Amendment 5 
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Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
Page 136 of 165 
 
 
 
 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
Page 137 of 165 
 
 
 
 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
Page 138 of 165 
 
 
11.12 Amendment 2: Table of Changes 
 
Section/Change 
Original Text 
Revised Text 
Sponsor Contact 
Updated 
 
Richard M. Mangano, PhD  
Chief Scientific Officer  
Relmada Therapeutics, Inc. 
275 Madison Avenue, Suite 702 
New York, NY, USA 10016 
Work: (646) 677-3859 
Cell: (484) 947-1682 
rmangano@relmada.com 
Sergio Traversa   
Chief Executive Officer 
Relmada Therapeutics, Inc. 
275 Madison Avenue, Suite 702 
New York, NY, USA 10016   
Work: 646-677-3853 
st@relmada.com  
CRO name updated. 
INC Research, Inc. 
Syneos Health, Inc. 
Change of Scale: 
QIDS-SR was replaced 
with SDQ in all sections 
referencing scales. 
Section 6.4.2.1: 
New Section 
Quick Inventory of Depressive 
Symptomatology Self-Report 
(QIDS-SR) 
Symptoms of Depression 
Questionnaire (SDQ) 
Introduction 
Added data to support 
dosing justification. 
…evaluated in this study, 
REL-1017-202.  The intent of 
this study is…. 
…evaluated in this study, 
REL-1017-202.  Additionally, the 
preclinical data for forced swim 
test in rats were used to identify 
efficacious doses… The intent of 
this study is…. 
Sample Size: 
Sample size increased to 
120 patients screened to 
randomize 20 subjects per 
arm 
Synopsis: 
Study Population and 
Duration of Participation 
Section 3.1: Study Design 
Section 3.2: Study 
Procedures 
Section 4.1: Number of 
Patients 
Approximately 90 patients will 
be screened, and approximately 
45 qualified patients will be 
randomized to study drug in a 
1:1:1 ratio (approximately 15 
patients per arm). 
Approximately 90 120 patients will 
be screened, and approximately 
45-60 qualified patients will be 
randomized to study drug in a 1:1:1 
ratio (approximately 15 20 patients 
per arm). 


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Section/Change 
Original Text 
Revised Text 
MGH CTNI Added, 
Entry Review Process 
Updated 
Synopsis 
Study Procedures 
Section 3.2 
Study Procedures 
…detailed in the Clinical 
Surveillance Team manual. 
 
Decisions regarding the 
inclusion of patients and 
assessment of patient safety 
throughout the study primarily 
remain at the discretion of the 
Investigator; however, the 
Sponsor or external medical 
team may request exclusion or 
discontinuation of a patient 
based on the entry criteria or 
patient safety. 
…detailed in the Clinical 
Surveillance Team Massachusetts 
General Hospital Clinical Trials 
Network and Institute [MGH 
CTNI]manual. 
…Subjects who are deemed 
eligible by the Principal 
Investigator and confirmed by the 
Medical Monitor will undergo the 
SAFER Interview by clinicians at 
the Clinical Trials Network 
Institute. Only subjects whose 
eligibility will be confirmed by the 
SAFER Interview will be allowed 
to proceed in the study Decisions 
regarding the inclusion of patients 
and assessment of patient safety 
throughout the study primarily 
remain at the discretion of the 
Investigator; however, the Sponsor 
or external medical team may 
request exclusion or 
discontinuation of a patient based 
on the entry criteria or patient 
safety. 
Clarifying Definition of 
Current Episode 
Synopsis 
Study Population and 
Duration of Participation 
Section 1.3.4: 
Rationale for Protocol 
REL-1017-202 
Section 3.3: 
Discussion of Study 
Design 
Adult patients with MDD 
with a current MDE who 
have experienced an 
inadequate response to 1 to 3 
courses of treatment with an 
antidepressant medication 
have been chosen for this 
study.  
Adult patients with MDD who are 
diagnosed with a current major 
depressive episode (MDE) and 
who have experienced an 
inadequate response to 1 to 
3 courses of treatment with an 
adequate dose and duration (as 
defined by the ATRQ) of an 
antidepressant medication for the 
current episode will be 
randomized to study drug in a 
1:1:1 ratio. have been chosen for 
this study. 


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Section/Change 
Original Text 
Revised Text 
Loading Dose:  
Loading dose of 75 mg 
REL-1017 added for 
initial dosing of Arm 1 
REL-1017 25 mg.  A dose 
of 100 mg REL-1017 
added for initial dose of 
Arm 2, 50 mg REL-1017. 
Section 5.1 
Study Drug 
Administration 
Patients will receive one of the 
following: 
• 25 mg of REL-1017… 
• 50 mg of REL-1017… 
• 100 mL of Ocean Spray® 
Diet Cranberry juice 
(Placebo). 
Patients will receive one of the 
following: 
Day 1 
• Arm 1: 75 mg of REL-1017 
provided as a powder and 
prepared as a solution with 
Ocean Spray® Diet 
Cranberry Juice on site to 
obtain a final volume of 
100 mL for dosing; 
• Arm 2: 100 mg of REL-1017 
provided as a powder and 
prepared as a solution with 
Ocean Spray® Diet 
Cranberry Juice on site to 
obtain a final volume of 
100 mL for dosing; 
• Arm 3: 100 mL of Ocean 
Spray® Diet Cranberry juice 
(Placebo). 
Day 2-6 
• Arm 1: 25 mg of REL-1017… 
• Arm 2: 50 mg of REL-1017… 
• Arm 3: 100 mL of Ocean 
Spray® Diet Cranberry juice 
(Placebo). 
Loading Dose: 
75 mg REL-1017 added 
for initial dosing of Arm 1 
REL-1017 25 mg.  A dose 
of 100 mg REL-1017 
added for initial dose of 
Arm 2, 50 mg REL-1017. 
Synopsis 
Study Drug, Dose 
Schedule, and Mode of 
Administration 
The following doses will be 
used in the study: 
• 
REL-1017 25 mg  
• REL-1017 50 mg Placebo 
• Ocean Spray® Diet 
Cranberry Juice) 
 
The following doses will be used 
in the study: 
• 
REL-1017 75 mg QD Day 1, 
25 mg REL-1017 QD Day 2-7 
• REL-1017 100 mg QD Day 1, 
50 mg REL-1017 QD Day 2-7 
• Placebo (Ocean Spray® Diet 
Cranberry Juice) 
 


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Section/Change 
Original Text 
Revised Text 
Loading Dose: 
75 mg REL-1017 added 
for initial dosing of Arm 1 
REL-1017 25 mg.  A dose 
of 100 mg REL-1017 
added for initial dose of 
Arm 2, 50 mg REL-1017. 
Section 5.4: 
Selection of Doses 
Not Applicable 
To reach steady state more 
quickly for REL-1017 25 mg 
and REL-1017 75 mg dosing 
arms, a loading dose on Day 1 
was added to each dosing arm, 
REL-1017 75 mg on Day 1 
followed by REL-1017 25 mg 
on Day 2-7 and REL-1017 
100 mg on Day 1 followed by 
REL-1017 50 mg on Day 2-7. 
Inclusion Criterion #1: 
Modification to allow 
enrollment of females 
>1 year postmenopausal. 
Synopsis: 
Inclusion Criteria 
Section 4.2: 
Inclusion Criteria 
Males between 18 and 65 years 
of age, inclusive. 
Males between 18 and 65 years 
of age, inclusive; and females 
between 18 and 65 years of 
age, who are >1 year 
postmenopausal. 
Inclusion Criterion #3: 
Duration of diagnosis of 
MDE requirements at 
study entry changed from 
12 months to 36 months.  
Synopsis:  
Inclusion Criteria 
Section 4.2: 
Inclusion Criteria 
Diagnosed with a current MDE 
lasting 8 weeks to 12 months as 
defined by the DSM-5 and 
confirmed by the MINI. 
Diagnosed with a current MDE 
lasting 8 weeks to 12 36 months as 
defined by the DSM-5 and 
confirmed by the MINI. 
 


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Section/Change 
Original Text 
Revised Text 
Inclusion Criterion #4: 
Updated duration of 
current MDD drug 
treatment from 6 weeks to 
8 weeks. 
Synopsis: 
Inclusion Criteria 
Section 4.2: 
Inclusion Criteria 
Treated with an adequate dosage 
of a selective serotonin reuptake 
inhibitor (SSRI), serotonin and 
norepinephrine reuptake 
inhibitor (SNRI), or bupropion 
during the current MDE for at 
least 6 weeks prior to Screening 
with the same, adequate dosage 
for the last 4 weeks. Minimum 
adequate doses are defined in the 
Antidepressant Treatment 
Response Questionnaire 
(ATRQ). 
Treated with an adequate dosage of 
a selective serotonin reuptake 
inhibitor (SSRI), serotonin and 
norepinephrine reuptake inhibitor 
(SNRI), or bupropion during the 
current MDE for at least 6 8 weeks 
prior to Screening with the same, 
adequate dosage for the last 
4 weeks. Minimum adequate doses 
are defined in the Antidepressant 
Treatment Response 
Questionnaire (ATRQ). 
Inclusion Criterion #5: 
Adjustment of inclusion 
criteria with the addition 
of SAFER 
Synopsis: 
Inclusion Criteria 
Section 4.2:  
Inclusion Criteria 
#5 Have experienced an 
inadequate response to 1 to 
3 courses of treatment with an 
antidepressant medication in 
the current episode, as defined 
as <50% improvement with an 
antidepressant medication at 
doses listed on the ATRQ. 
#5 Have experienced an 
inadequate response to 1 to 
3 courses of treatment with an 
antidepressant medication in the 
current episode, as defined as 
<50% improvement with an 
antidepressant medication at doses 
listed on the ATRQ SAFER 
Interview (Criteria: State versus 
trait; Assessability; Face validity; 
Ecological validity; and Rule of 
three Ps [pervasive, persistent, 
and pathological). 
Inclusion Criterion #6: 
Adjustment of inclusion 
criteria for Ham-D 
Synopsis: 
Inclusion Criteria 
Section 4.2:  
Inclusion Criteria 
#6 Hamilton Depression 
Rating Scale-17 
(HAM-D-17) ≥22 at 
Screening and Check-in 
(Day -1) with a score of ≥2 
on Questionnaire Item 1. 
#6 Hamilton Depression Rating 
Scale-17 (HAM-D-17) ≥2219 at 
Screening and Check-in 
(Day -1) with a score of ≥2 on 
Questionnaire Item 1. 
 
 
Inclusion Criterion 
#10: 
Modification to require 
ability to read and 
understand English 
Synopsis: 
Inclusion Criteria 
Section 4.2: 
Inclusion Criteria 
Must be able to read, speak, 
and understand the local 
language and must provide 
written informed consent 
prior to the initiation of any 
protocol-specific procedures. 
Must be able to read, speak, and 
understand the local 
languageEnglish and must 
provide written informed 
consent prior to the initiation of 
any protocol-specific 
procedures. 
Exclusion Criteria 
NEW:  
Not Applicable 
Any 12-lead ECG with 
repeated demonstration of QTc 


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Section/Change 
Original Text 
Revised Text 
ECG exclusion added 
Synopsis: 
Exclusion Criteria 
Section 4.3: 
Exclusion Criteria 
≥450 msec or a QRS interval 
≥120 msec at Screening. 
Exclusion Criterion #13:  
Clarified depressive 
disorder  
Synopsis: 
Exclusion Criteria 
Section 4.3: 
Exclusion Criteria 
Any lifetime history of bipolar I 
or II disorder, persistent 
depressive disorder, any 
psychotic disorder… 
developmental disorder 
Any lifetime history of bipolar I or 
II disorder, persistent depressive 
disorder, any psychotic disorder… 
developmental disorder 
Objectives: 
Added measurements for 
evaluation of Safety 
Objectives 
Synopsis 
Objectives 
Section 2.2.1: 
Primary Objectives 
To will assess the safety and 
tolerability of 25 mg and 50 mg 
of REL-1017 (d-methadone) 
compared to Placebo as 
adjunctive treatment in patients 
with major depressive disorder 
(MDD). 
Safety objectives will assess the 
safety and tolerability of 25 mg and 
50 mg of REL-1017 (d-methadone) 
compared to Placebo as adjunctive 
treatment in patients with major 
depressive disorder (MDD). The 
following assessments will be 
conducted to measure safety and 
tolerability throughout the study: 
• AEs 
• Vital signs 
• Weight 
• Physical examination 
• Clinical laboratory parameters 
(chemistry, hematology, and 
urinalysis) 
• Electrocardiogram (ECG) 
parameters 
• Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
• Clinician Administered 
Dissociative States Scale 
(CADSS) 
• Clinical Opiate Withdrawal 
Scale (COWS) 
• Brief Psychiatric Rating Scale 
– Positive Symptoms Subscale 
(BPRS-Positive) 
Objectives: 
Added measurements for 
evaluation of PK 
Objectives 
Not Applicable 
 
The PK profile of REL-1017 
25 mg and 50 mg following a 
loading dose of 75 mg will be 
evaluated on Day 1 through 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
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Section/Change 
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Revised Text 
Synopsis 
Objectives 
Section 2.2: 
Secondary Objectives 
Day 7, Day 8, Day 9, and Day 14 
where the data allow: 
• Maximum observed plasma 
concentration (Cmax) 
• Time to maximum observed 
plasma concentration (Tmax) 
• Area under the plasma 
concentration-time curve 
from time zero until the 
dosing interval of 24 hours 
(AUCtau) 
• Area under the plasma 
concentration-time curve 
from time zero until the last 
quantifiable time point 
(AUC0-last) on Day 7 
• Area under the plasma 
concentration-time curve 
from time zero to infinity 
(AUC0-inf) 
• Apparent termination 
elimination rate constant 
(λz) 
• Apparent terminal 
elimination half-life (t½) 
• Attainment of steady state 
• Steady state clearance 
(CSS/F) 
• Volume of distribution at 
steady state (VSS/F) 
• Accumulation ratios based on 
minimum observed plasma 
concentration (Cmin), Cmax, and 
AUCtau 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
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Section/Change 
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Objectives: 
Added measurements for 
evaluation of Efficacy 
Objectives 
 
Synopsis 
Objectives 
Section 2.2.2: 
Secondary Objectives 
To explore the efficacy of 25 mg 
and 50 mg of REL-1017 
(d-methadone) as adjunctive 
treatment in patients with MDD 
 
The efficacy objective is to explore 
the efficacy of 25 mg and 50 mg of 
REL-1017 (d-methadone) as 
adjunctive treatment in patients 
with MDD.  The following 
assessments will be conducted to 
evaluate efficacy: 
• Change from Baseline (Day 
1) to the End of the Dosing 
Period (EDP, Day 7) on the 
Montgomery-Asberg 
Depression Rating Scale 
(MADRS) 
• Change from Baseline (Day 
1) to EDP (Day 7) on the 
Symptoms of Depression 
Questionnaire (SDQ) 
• Change from Baseline 
(Day 1) to EDP (Day 7) on 
the Clinical Global 
Impressions of Severity 
(CGI-S)  
• Change from Baseline (Day 
1) to all other relevant visits 
on the MADRS, SDQ, and 
CGI-S. 
Prohibited 
Medications: 
Allowance of chronic 
and use of hypnotics 
during the study 
Section 4.4.1: 
Prohibited Medications 
Non-benzodiazepine sleep aids 
may be continued in the study, 
but no more than 3 times per 
week, at the doses listed in 
Table 3; and…. 
Prohibited… 
Med               Washout Period 
MAOIs                    14 Days 
TCA/Atypical            7 Days 
Benzodiazepine         7 Days 
Psychotropic….         7 Days 
Herbal...                     8 Days 
Non-benzodiazepine sleep aids may 
be continued in the study, but no 
more than 3 times per week, at the 
doses listed in Table 3; and…. 
 
Prohibited… 
Med               Washout Period 
MAOIs                    3 Months 
TCA/Atypical          3 Months 
Benzodiazepine       1 Month 
Psychotropic….       3 Months 
Herbal...                   1 Month 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
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Rater Qualifications: 
Section 4.6 added  
Not Applicable 
4.6 
Rater Qualifications  
Raters must demonstrate sufficient 
assessment experience as well as 
appropriate educational 
background and indication 
experience.  
Raters performing the clinical 
assessments will require training 
and approval by the Sponsor 
designated vendor prior to rating 
in this study. 
The vendors designated by the 
Sponsor will conduct rater 
qualification and will provide 
written and signed documentation 
about each rater’s certification 
and/or training.  
If possible, each subject will be 
interviewed and assessed 
throughout the study by the same 
rater.  
Section 6: 
Study Procedures and 
Assessments 
The pre-dose period on Day 1 
will be considered time zero. 
Other logistical considerations 
(e.g., sequence of events, 
assessment windows) will be 
outlined in study-specific 
procedures. 
The pre-dose period on Day 1 will 
be considered time zero. Other 
logistical considerations (e.g., 
sequence of events, assessment 
windows) will be outlined in study-
specific procedures. Post-Screening 
psychiatric scales will be 
administered using the timeframe 
since the last administration of the 
scale. 
Follow-up Assessments 
Added C-SSRS 
Synopsis: 
Procedures 
Section 6.1.8:  
Follow-Up: Added 
C-SSRS 
In the Follow-Up interview 
(Day 21), only, AEs and 
medications will be recorded 
(Table 1).  
In the Follow-Up interview 
(Day 21), only C-SSRS, AEs 
and medications will be 
recorded (Table 1).  


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
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Central ECGs: 
Added central ECG 
readings to the protocol. 
Section 6.2.4: 
12-Lead 
Electrocardiograms 
 
Not Applicable 
ECGs will be submitted 
electronically to central ECG 
reading center for evaluation 
of subject for entry into the 
study. The Investigator will 
make a final judgment on 
whether to include the 
subject’s ECGs meets the entry 
criteria for the study. 
ECG Clarification: 
Clarification of ECG 
capture and reading. 
 
Not Applicable 
If more than one ECG is collected, 
the mean of the replicate 
measurements will be reported. If 
any of the three individual ECG 
tracings has a QTc value 
≥500 msec, but the mean of the 
triplicates is not ≥500 msec, the 
data from the subject’s individual 
tracing will be described in a safety 
section of the study report to place 
the ≥500 msec value in appropriate 
clinical context. However, values 
from individual tracings within 
triplicate measurements that are 
≥500 msec will not be included in 
the categorical analysis unless the 
average from those triplicate 
measurements are also ≥500 msec. 
Changes from Baseline will be 
defined as the change between 
QTc post-dose from the 
time-matched average Baseline 
triplicates on Baseline Day 1 (V2). 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
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Table 1 
Section 6.2.5.8: 
Pregnancy Testing 
N.A. 
A urine pregnancy test and a 
serum follicle stimulating hormone 
(FSH) test will be administered to 
all female patients at Screening 
(Day 30 to Day 2). Negative test 
results are required for enrollment 
in the study. Another negative 
urine pregnancy test will be 
required at Check in (Day 1) for 
confirmation. 
Section 7.1.4:  
Other Adverse Events of 
Interest 
Addition of text 
The study drug will be 
administered under the 
supervision of study personnel, 
which should eliminate the 
opportunity for abuse during 
the course of the study.  
However, Investigators should 
take note of AEs that might 
suggest that the study drug has 
the potential for abuse.  For 
example, the occurrence of a 
euphoria-like response is a key 
observation in the clinical 
assessment of whether a test 
drug has abuse potential. 
Examples of Medical 
Dictionary for Regulatory 
Activities (MedDRA) Preferred 
Terms that may provide abuse-
related information about a 
drug include: 
• Euphoria-related terms 
- euphoric mood, 
elevated mood, feeling 
abnormal, feeling 
drunk, feeling of 
relaxation, dizziness, 
thinking abnormal, 
hallucination, 
inappropriate affect 


Clinical Study Protocol Amendment 5 
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Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
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Section/Change 
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Revised Text 
• Terms indicative of 
impaired attention, 
cognition, and mood - 
somnolence, mood 
disorders, and 
disturbances 
• Dissociative/psychotic 
terms - psychosis, 
aggression, confusion, 
and disorientation 
Drug withdrawal syndrome 
Appendices:  
Rating scales added 
Not Applicable 
Appendices 11.2-11.9 
Additional changes were made that were administrative or grammatical in nature. 
 
11.13 Amendment 3: Table of Changes 
 
Section/Change 
Original Text 
Revised Text 
Exclusion Criterion 
#1: 
Addition of safety 
criteria 
Synopsis: 
Exclusion Criterion #1 
Section 4.3: 
Exclusion Criterion #1 
Exclusion Criterion #1: 
History or presence of clinically 
significant abnormality as 
assessed by physical 
examination, medical history, 
12-lead ECG, vital signs, or 
laboratory values, which in the 
opinion of the Investigator 
would jeopardize the safety of 
the patient or the validity of the 
study results. 
Exclusion Criterion #1: 
History or presence of clinically 
significant abnormality as 
assessed by physical examination, 
medical history, 12-lead ECG, 
vital signs, or laboratory values, 
which in the opinion of the 
Investigator would jeopardize the 
safety of the patient or the validity 
of the study results, including 
torsades de pointes, any 
bradyarrhythmias, or 
uncompensated heart failure. 
Exclusion Criterion 
#4: 
Made Synopsis and 
Sect. 4.2 consistent 
Exclusion Criterion #4: 
History or family history of 
sudden unexplained death or 
long QT syndrome (measure of 
the time between the start of the 
Q wave and the end of the T 
wave in the heart’s electrical 
cycle). 
Exclusion Criterion #4: 
Added text: History or family 
history of sudden unexplained 
death or long QT syndrome 
(measure of the time between the 
start of the Q wave and the end of 
the T wave in the heart’s electrical 
cycle). 
Inclusion Criterion #9: 
Synopsis: 
Inclusion Criterion #9: 
Synopsis: 
Inclusion Criterion #9: 
Synopsis: 


Clinical Study Protocol Amendment 5 
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Section/Change 
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Revised Text 
Removed reference to 
protocol section 
(Synopsis is a stand-
along document) 
Male patients of reproductive 
potential must be using and 
willing to continue using 
medically acceptable 
contraception, as specified in 
section 4.4.2, from Screening 
and for at least 2 months after 
the last study drug 
administration. 
Male patients of reproductive 
potential must be using and 
willing to continue using 
medically acceptable 
contraception, as specified in the 
protocol, from Screening and for 
at least 2 months after the last 
study drug administration. 
Exclusion Criteria #15 
Section 4.3: 
Made consistent with 
Synopsis Exclusion 
Criteria #15 
Exclusion Criteria #15 
Section 4.3: 
Current diagnosis of alcohol or 
substance use disorder, as 
defined by DSM-5, at Screening 
or within the 12 months prior to 
Screening.  
Exclusion Criteria #15 
Section 4.3: 
Added text: Current diagnosis of 
alcohol or substance use disorder, 
as defined by DSM-5, at 
Screening or within the 12 months 
prior to Screening. Patients with 
the following diagnoses within the 
past 12 months, however, may be 
included at the Investigator’s 
discretion: mild alcohol use 
disorder, mild cannabis use 
disorder, and any severity tobacco 
use disorder. 
Revision of “Washout 
Period” 
Exclusion Criterion 
#19:  
Synopsis 
Section 4.3: 
Section 4.4.1: 
Prohibited Medications 
Table 3: 
Title 
Column Header 
Section 7.1.1: 
Adverse Events 
 
Exclusion Criterion #19: 
Synopsis: 
Patients taking medications 
prohibited in Section 4.4.1 of 
the protocol who are unable to 
safely complete the specified 
Washout Period. 
Section 4.3: 
Patients taking medications 
prohibited in Section 4.4.1 of 
the protocol who are unable to 
safely complete the specified 
Washout Period. 
Section 4.4.1: 
All patients must agree to 
discontinue all prohibited 
medications during the 
Screening period to meet the 
protocol-specified Washout 
Periods. Table 3 provides the 
required duration of washout for 
selected prohibited medications. 
Exclusion Criterion #19: 
Synopsis: 
Patients who did not safely 
discontinue prohibited 
medications. 
Section 4.3: 
Patients who did not safely 
discontinue medications 
prohibited in Section 4.4.1. 
Section 4.4.1: 
All patients must have 
discontinued all prohibited 
medications prior to the Screening 
period to meet the protocol 
requirements. Table 3 provides 
the required duration of time to 
discontinuation period for 
selected prohibited medications. 
 
Addition of text: All medications 
taken within 6 months prior to 
Screening must be noted on the 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
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Section/Change 
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Revised Text 
Table 3 Title:  
Duration of Washout for 
Selected Medications, 
Supplements, and Other 
Substances 
Table 3 Column Header:  
Washout Period Prior to Check-
In 
Section 7.1.1: Adverse Events 
During the study, an AE can 
also occur outside the time that 
the investigational product(s) 
was given (e.g., during a 
Washout Period). 
eCRF. 
Table 3 Title: 
Time from Discontinuation of 
Selected Medications, 
Supplements, and Other 
Substances 
Table 3 Column Header:  
Time from Discontinuation to 
Check-In 
Section 7.1.1: Adverse Events 
During the study, an AE can also 
occur outside the time that the 
investigational product(s) was 
given (e.g., during the time from 
discontinuation of prohibited 
medications). 
Exclusion Criterion 
#23 and 24:  
Section 4.3: 
Reversed order to be 
consistent with 
Synopsis 
#23: Patients who have 
participated in a clinical study with 
an investigational medication in 
the past 6 months, or who have 
participated in more than 4 
clinical studies with 
investigational medications in 
the past 2 years.  
#24: Patients taking 
fluvoxamine or St. John’s Wort. 
#23: Patients taking fluvoxamine 
or St. John’s Wort. 
#24: Patients who have 
participated in a clinical study 
with an investigational medication 
in the past 6 months, or who have 
participated in more than 4 
clinical studies with 
investigational medications in the 
past 2 years. 
Section 4.4.1: 
Prohibited Medications: 
Revision of 
benzodiazepine 
guidance 
 
Section 4.4.1: 
Non-benzodiazepine sleep 
aids may be continued in the 
study at the doses listed in 
Table 3; and initiation of 
these medications during the 
study is not allowed except 
that a wash-in period of at 
least 21 days with a steady 
dose is allowed during 
Screening for people coming 
off benzodiazepines. 
Section 4.4.1: 
Benzodiazepines and non-
benzodiazepine sleep aids taken 
as scheduled medications and at 
stable doses not higher than the 
FDA-approved label for at least 
30 days prior to the Check-in are 
allowed in the study. Any 
questions regarding these 
medications should be directed to 
the Study Medical Monitor. 
Initiation of these medications 
during the study is not allowed. 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
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Section/Change 
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Revised Text 
Section 4.4.1: 
Prohibited Medications: 
Addition of safety 
guidance to investigator 
Section 4.4.1: 
Not Applicable 
Section 4.4.1: 
Addition of: Due to each subject’s 
clinical condition being unique, 
there is no specific rescue plan or 
rescue therapy recommended for 
subjects. If a subject experiences a 
clinical condition, the Investigator 
should use clinical judgment and 
knowledge of the subject’s specific 
condition to institute the best 
treatment for that subject. 
Section 4.4.1: 
Table 3 
Section 4.4.1, Table 3: 
Prohibited Medications, 
Supplements, and Other 
Substances 
MAOIs          3 Months 14 Days 
TCA/Atypical  3 Months 7 Days 
Benzodiazepine 1 Month 7 Days 
Psychotropic…3 Months 7 Days 
Herbal...            1 Month 8 Days 
 
Footnote: Not Applicable 
Section 4.4.1, Table 3: 
Time From Discontinuation to 
Check-in 
MAOIs                    90 days 
TCA/Atypical          90 days 
PRN Benzodiazepine       30 days 
Psychotropic….       90 days 
Herbal...                   30 days 
 
Added to the footnote: These 
include off-label use of 
medications for depression. 
Added to footnote: PRN = As 
needed. 
Section 4.5: 
Patient Discontinuation/ 
Withdrawal Criteria 
 
Section 4.5: 
Not Applicable 
Section 4.5: 
Added bullet: Subjects with a QTc 
≥500 msec or ≥60 msec above the 
patient’s Baseline value will 
discontinue study medication and 
be re-assessed. The ECG should 
be repeated until values return 
below 500 msec, or ≥60 msec 
above Baseline. These findings 
will be reviewed by a cardiologist. 
Any additional intervention for the 
safety of the subject should be 
discussed with the Study Medical 
Monitor and Sponsor.  


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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
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Section 4.6: 
Rater Qualifications 
 
Section 4.6: 
The vendors designated by the 
Sponsor will conduct rater 
qualification and will provide 
written and signed 
documentation about each 
rater’s certification and/or 
training.  
Section 4.6: 
The vendors designated by the 
Sponsor will conduct rater 
qualification and will provide 
documentation about each 
rater’s certification and/or 
training.  
Section 6.2.5.1: 
Clinical Chemistry: 
Addition of magnesium 
Section 6.2.5.1: 
Quantitative analysis will be 
performed for the following 
analytes: alkaline 
phosphatase, albumin, 
calcium, chloride, creatinine, 
random glucose, potassium, 
ALT, AST, gamma-glutamyl 
transferase (GGT), lactate 
dehydrogenase, sodium, total 
bilirubin, urea, and 
testosterone. 
Section 6.2.5.1: 
Quantitative analysis will be 
performed for the following 
analytes: alkaline phosphatase, 
albumin, calcium, chloride, 
creatinine, random glucose, 
potassium, magnesium, ALT, 
AST, gamma-glutamyl 
transferase (GGT), lactate 
dehydrogenase, sodium, total 
bilirubin, urea, and testosterone. 
Section 6.6.3.2: 
CADSS correction 
 
Section 6.6.3.2: 
The CADSS is a 27-item scale 
with 19 items that are rated by 
the subject, and 8 items that are 
scored by an observer. 
Section 6.6.3.2: 
The CADSS is a 23-item scale 
with all items administered to the 
subject. 
Change of Scale: 
References to the CGI, 
CGI-S and CGI-I were 
modified in all sections 
referencing the scales. 
Synopsis: 
Endpoints, Statistical 
Data Analysis, Table 1, 
footnote “k,” and 
Abbreviations 
Section 2.2.2 
Efficacy 
Section 6.4.2.2 
Clinical Global 
Impressions 
Section 6.6.2.2 
Synopsis: 
Efficacy Endpoint: Change from 
Baseline (Day 1) to EDP (Day 
7) on the Clinical Global 
Impressions of Severity (CGI-S)  
Statistical Data Analysis: Not 
Applicable 
Section 2.2.2 
Not Applicable 
Section 6.4.2.2 
Clinical Global Impressions of 
Severity 
Section 6.6.2.2 
Clinical Global Impressions of 
Severity (CGI-S) 
The score ranges from 1 to 7, 
Synopsis: 
Efficacy Endpoint: The Clinical 
Global Impressions of 
Improvement (CGI-I) scale will be 
measured at pre-dose on Day 2, 
post-dose on Day 4 and Day 7 
within 3 hours of dosing, and on 
Day 14. 
Added bullet: Change from 
Baseline (Day 1) to EDP (Day 7) 
on the Clinical Global 
Impressions of Severity (CGI-S) 
scale will be measured at pre-dose 
on Day 1 and Day 2; post-dose on 
Day 4 and Day 7 within 3 hours of 
dosing; and on Day 14. 
Table 1, footnote “k” and 


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Section/Change 
Original Text 
Revised Text 
Clinical Global 
Impressions of Severity 
(CGI-S) 
Section 8.1.1: 
Analysis Populations 
Section 8.1.3.3: 
Secondary Objectives: 
Efficacy of REL-1017 
Section 8.1.4.5: 
Analysis of Efficacy 
Assessments 
Section 8.1.7: 
Missing Data 
Acronyms and 
Abbreviations: 
Appendix 11.9: 
 
 
and a lower CGI-S score 
indicates an increased response 
to therapy in the treatment of 
depression.  
Section 8.1.1: 
Not Applicable 
Section 8.1.3.3: 
Not Applicable 
Section 8.1.4.5: 
Not Applicable 
Section 8.1.7: 
Not Applicable 
Acronyms and Abbreviations: 
Not Applicable 
Appendix 11.9 
Replaced CGI-S scale with CGI 
(Severity and Improvement) 
scale 
Abbreviations modified to reflect 
this change. 
Added to Statistical Data 
Analysis: The CGI-I will be 
measured at pre-dose on Day 2, 
post-dose on Day 4 and Day 7 
within 3 hours of dosing, and on 
Day 14. 
Section 2.2.2 Addition of bullet: 
Evaluation of Clinical Global 
Impressions of Improvement 
(CGI-I) total score on Day 7 
(post-dose), as well as CGI-I 
scores on Days 2 (pre-dose), 4 
(post-dose), and 14. 
Section 6.4.2.2 
Clinical Global Impressions 
(CGI) Scale 
Added text: The CGI-I will be 
measured at pre-dose on Day 2, 
post-dose on Day 4 and Day 7 
within 3 hours of dosing, and on 
Day 14. 
Section 6.6.2.2 
Clinical Global Impressions 
(CGI) Scale 
The score ranges from 1 to 7, and 
a lower CGI-S score indicates 
lower levels of depression.  
Addition of CGI-I text: 
The CGI-I is a standard method 
used in clinical studies to quantify 
and track patient change over 
time. The scale is composed of 7 
ratings: 1 = very much improved; 
2 = much improved; 
3 = minimally improved; 4 = no 
change; 5 = minimally worse; 
6 = much worse; and 7 = very 
much worse. The score ranges 
from 1 to 7, and a lower CGI-I 
score indicates greater 
improvement in symptoms.42 
Section 8.1.1: 
Addition of: or CGI-I 


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Section/Change 
Original Text 
Revised Text 
Section 8.1.3.3: 
Addition of: Evaluation of CGI-I 
total score on Day 7 (post-dose), 
as well as CGI-I scores on Days 2 
(pre-dose), 4 (post-dose), and 14. 
Section 8.1.4.5:  
Addition of: The CGI-I will be 
administered pre-dose on Day 
2; post-dose on Day 4 and Day 
7 within 3 hours of dosing; and 
at EOP (Day 14). 
Section 8.1.7: 
Addition of: and CGI-I. 
Acronyms and Abbreviations: 
Addition of:  
CGI: Clinical Global Impressions 
CGI-I: Clinical Global 
Impressions of Improvement 
Appendix 11.10 
CGI of Severity and Improvement 
scale 
Change of Scale: 
BPRS – Positive 
Symptoms Subscale 
(BPRS) was replaced 
with the 4-Item PSRS in 
all sections referencing 
scales. 
Synopsis: 
Endpoints, Table 1, 
footnotes “l” and 
Abbreviations 
Section 2.1, Primary 
Objectives: 
BPRS-Positive 
Symptoms Subscale 
Section 6.2.6.4: 
BPRS-Positive 
Symptoms Subscale 
Section 6.6.3.4: 
BPRS-Positive 
Symptoms Subscale 
Synopsis: 
Endpoints, Table 1, footnotes 
“l” and Abbreviations: Brief 
Psychiatric Rating Scale - 
Positive Symptoms Subscale 
(BPRS-Positive) 
Section 2.1, Primary 
Objectives: 
Brief Psychiatric Rating Scale - 
Positive Symptoms Subscale 
(BPRS-Positive) 
Section 6.2.6.4: 
Brief Psychiatric Rating Scale - 
Positive Symptoms Subscale 
(BPRS-Positive) 
Section 6.6.3.4: 
Brief Psychiatric Rating Scale - 
Positive Symptoms Subscale 
(BPRS-Positive) 
Text deleted: 
The BPRS-Positive can be used 
Synopsis: 
Endpoints, Table 1, footnotes “l” 
and Abbreviations: 4-Item 
Positive Symptoms Rating Scale 
(4-Item PSRS) 
Section 2.1,Primary Objectives: 
4-Item Positive Symptoms Rating 
Scale (4-Item PSRS)  
Section 6.2.6.4: 
4-Item Positive Symptoms Rating 
Scale (4-Item PSRS) 
Section 6.6.3.4: 
4-Item Positive Symptoms Rating 
Scale (4-Item PSRS) 
Text added: 
The 4-Item PSRS was adapted 
from the Brief Psychiatric Rating 
Scale developed by Ventura and 
colleagues. It is a clinician-
administered scale intended to 
assess the extent to which a 


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Revised Text 
Section 7.1.3: 
Clinical Lab 
Abnormalities and 
Other Abnormalities 
Assessments 
Section 8.1.3.1: 
Primary Endpoint: 
Safety and Tolerability 
of REL-1017: BPRS-
Positive Symptoms 
Subscale 
Section 8.1.5: 
Demographics and 
Other Baseline 
Characteristics 
Section 10: 
Reference #45 
Appendix 11.6: 
Acronyms and 
Abbreviations 
 
to evaluate persons having or 
suspected of having 
schizophrenia or other psychotic 
disorder.39 The BPRS-Positive 
assesses the level of 18 
symptom constructs such as 
hostility, suspiciousness, 
hallucination, and grandiosity. It 
is based on the clinician's 
interview with the patient and 
observations of the patient's 
behavior over the previous 2 to 
3 days. The rater enters a 
number for each symptom 
construct that ranges from 1 (not 
present) to 7 (extremely severe). 
The positive symptoms subscale 
includes 4 items. 
Section 7.1.3: 
Clinical Laboratory 
Abnormalities and Other 
Abnormal Assessments: BPRS-
Positive  
Section 8.1.3.1: 
Primary Endpoint: Safety and 
Tolerability of REL-1017: 
BPRS-Positive  
Section 8.1.5: 
Demographics and Other 
Baseline Characteristics: BPRS-
Positive  
Section 10: 
Reference #45: 
Ventura J, Lukoff D, 
Nuechterlein KH, Liberman RP, 
Green MF, and Shaner, A 
Manual for the expanded Brief 
Psychiatric Rating Scale. 
International Journal of 
Methods Psychiatry Research 
1993; 3:227-244.  
Appendix 11.6: 
BPRS-Positive Symptoms 
Subscale 
Acronyms and Abbreviations: 
subject is currently experiencing 
positive psychotic symptoms. The 
scale assesses paranoia and 
hallucinations as well as some 
specific issues related to difficulty 
thinking and having unusual 
thoughts. When administering the 
scale, the rater enters a number 
for each of 4 symptom constructs 
with scores that range from 1 (not 
present) to 7 (extremely severe). 
Total score on the PSRS can 
range from 4 to 28. 
Section 7.1.3: 
Clinical Laboratory Abnormalities 
and Other Abnormal Assessments: 
4-Item PSRS 
Section 8.1.3.1: 
Primary Endpoint: Safety and 
Tolerability of REL-1017: 4-Item 
Positive Symptoms Rating Scale 
(4-Item PSRS) 
Section 8.1.5: 
Demographics and Other Baseline 
Characteristics: 4-Item PSRS 
Section 10: 
Reference #46: Added text: 
The 4-Item Positive Symptom 
Rating Scale was adapted from 
the Expanded Version of the 
BPRS developed by: Ventura J, 
Lukoff D, Nuechterlein KH, 
Liberman RP, Green MF, and 
Shaner, A Manual for the 
expanded Brief Psychiatric 
Rating Scale. International 
Journal of Methods Psychiatry 
Research 1993; 3:227-244.  
Appendix 11.6:  
4-Item Positive Symptom Rating 
Scale (4-Item PSRS)  
Acronyms and Abbreviations: 
4-Item PSRS: 4-Item Positive 


Clinical Study Protocol Amendment 5 
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Version: 6.0, 07-Mar-2019 
Confidential 
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Section/Change 
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Revised Text 
BPRS-Positive: Brief 
Psychiatric Rating Scale - 
Positive Symptoms Subscale 
Symptoms Rating Scale 
Appendix 11.7  
Added scale: 
Antidepressant 
Treatment Response 
Questionnaire (ATRQ) 
Appendix 11.7  
Not Applicable 
Appendix 11.7  
Added: Appendix 11.7 
Antidepressant Treatment 
Response Questionnaire 
(ATRQ) 
All Appendix numbering 
adjusted with inclusion of new 
Appendix. 
Appendix 11.8: 
Symptoms of 
Depression 
Questionnaire (SDQ): 
All questions (1-44): 
scale timeframe 
changed 
Appendix 11.8: 
“… over the past week?” 
Appendix 11.9: 
“… since Baseline?” 
SAFER Interview 
administration schedule 
modified 
Synopsis: 
Procedures 
Table 1 
Section 3.2: 
Study Procedures 
Synopsis and Section 3.2: 
Procedures: The interview will 
be performed remotely by the 
MGH CTNI rater, and the 
subject will be contacted at his 
or her home or other off-site 
location between the Screening 
and Baseline visits, during 
which call the above 
assessments will be performed. 
Table 1: SAFER Interview at 
Screening and Check-In 
 
Synopsis and Section 3.2 
Procedures: The interview will 
be performed remotely by the 
MGH CTNI rater, and the 
subject will be contacted at his 
or her home or other off-site 
location after the Screening 
Visit, during which call the 
above assessments will be 
performed. 
Table 1: SAFER Interview at 
Screening (deleted “at Check-in”). 
Section 10: 
References: 
SIGMA (2011) scale 
added 
Not Applicable 
Addition of reference to SIGMA 
scale version 2011: 
Structured Interview Guide for the 
MADRS. Royal College of 
Psychiatrists, 2011. Developed 
from Williams JBW, Kobak KA. 
Development and reliability of a 
structured interview guide for the  
Montgomery-Asberg Depression 
Rating Scale (SIGMA). Br J 
Psychiatry 2008;192:52-58. 
All reference numbering adjusted 


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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
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Section/Change 
Original Text 
Revised Text 
with inclusion of new reference. 
 
Additional changes were made that were administrative or grammatical in nature. 


Clinical Study Protocol Amendment 5 
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Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
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11.14 Amendment 4: Table of Changes 
Section/Change 
Original Text 
Revised Text 
Inclusion Criterion #1 
(Synopsis and 
Section 4.2): 
Addition of women of 
childbearing potential 
Inclusion Criterion #1: 
Males between 18 and 65 years 
of age, inclusive; and females 
between 18 and 65 years of age, 
inclusive, who are >1 year 
postmenopausal. 
Inclusion Criterion #1: 
Males and females between 
18 and 65 years of age, inclusive; 
and females between 18 and 65 
years of age, inclusive, who are 
>1 year postmenopausal. 
Inclusion Criterion #9 
(Synopsis and 
Section 4.2: 
Addition of women of 
child-bearing potential 
 
Inclusion Criterion #9: 
Male patients of reproductive 
potential must be using and 
willing to continue using 
medically acceptable 
contraception, as specified in 
Section 4.4.2, from Screening 
and for at least 2 months after 
the last study drug 
administration. 
Inclusion Criterion #9: 
Male and female patients of 
reproductive potential must be 
using and willing to continue 
using medically acceptable 
contraception, as specified in 
Section 4.4.2, from Screening and 
for at least 2 months after the last 
study drug administration. Female 
patients must have a negative 
pregnancy test, and must not be 
breastfeeding. 
Exclusion Criterion #5 
(Synopsis and 
Section 4.2): 
Revision of ECG 
criterion: QTc changed 
to QTcF 
Synopsis: 
Statistical Data 
Analysis: Safety 
Section 1.1.1 
Section 1.2.1 
Section 4.5 
Section 7.1.4 
Section 8.1.4.3 
 
 
Exclusion Criterion #5 
(Synopsis and Section 4.2): 
Any 12-lead ECG with repeated 
demonstration of corrected QT 
≥450 msec or a QRS interval 
≥120 msec at Screening. 
Synopsis: 
Statistical Data Analysis: 
Safety: 
Absolute values, change from 
Check-in (Day -1) in 12-lead 
ECG results and QT/QTc 
categories … 
Section 1.1.1 
Not Applicable 
Section 1.2.1: 
The single doses of REL-1017 
administered in this study 
appeared to be safe with no 
indication of respiratory 
depression or clinically 
significant QTc prolongation. 
Section 4.5: 
Subjects with a QTc ≥500 msec 
or ≥60 msec above the patient’s 
Exclusion Criterion #5 
(Synopsis and Section 4.2: 
Any 12-lead ECG with repeated 
demonstration of corrected QT 
≥450 msec or a QRS interval ≥120 
msec at Screening. An average 
QTcF ≥450 msec or an average 
QRS interval ≥120 msec from the 
12-lead ECGs performed at 
Screening. 
Synopsis: 
Statistical Data Analysis: Safety: 
Absolute values, change from 
Check-in (Day -1) in 12-lead ECG 
results and QT/QTcF categories 
Section 1.1.1: 
Added: The Fridericia formula 
will be used for QTc. 
Section 1.2.1: 
The single doses of REL-1017 
administered in this study 
appeared to be safe with no 
indication of respiratory 
depression or clinically significant 
QTcF prolongation. 


Clinical Study Protocol Amendment 5 
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Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
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Section/Change 
Original Text 
Revised Text 
Baseline value … 
Section 7.1.4: 
If any of the 3 individual ECG 
tracings has a QTc value ≥500 
msec, … 
Changes from Baseline will be 
defined as the change between 
QTc post-dose … 
Section 8.1.4.3: 
Absolute values, change from 
Check-in (Day -1) in 12-lead 
ECG results (average of 
triplicate assessments, where 
applicable), and QT/QTc 
categories … 
Overall interpretation and 
machine read intervals (HR, PR, 
QRS, QT and QTc) … 
Section 4.5: 
Subjects with a QTcF ≥500 msec 
or ≥60 msec above the patient’s 
Baseline value … 
Section 7.1.4: 
If any of the 3 individual ECG 
tracings has a QTcF value ≥500 
msec, … 
Changes from Baseline will be 
defined as the change between 
QTcF post-dose … 
Section 8.1.4.3: 
Absolute values, change from 
Check-in (Day -1) in 12-lead ECG 
results (average of triplicate 
assessments, where applicable), 
and QT/QTcF categories … 
Overall interpretation and 
machine read intervals (HR, PR, 
QRS, QT and QTcF) … 
Synopsis Table 1: 
Time and Events 
Schedule 
Added urine pregnancy 
test at EOP and FU 
Visits 
Synopsis Table 1: 
Added urine pregnancy test at 
EOP and FU Visits 
Synopsis Table 1: 
Added: “X” in the row “Urine 
Pregnancy Test for Females” in 
columns “EOP” and “FU” Visits. 
1.1.2: In Vivo: 
Addition of pre-clinical 
toxicology data 
1.1.2: In Vivo: 
Not Applicable 
1.1.2: In Vivo: 
Added: In a developmental 
toxicity study, pregnant CDÒ 
rats (Charles River 
Laboratories) were given daily 
oral gavage administration of 0 
(vehicle), 10, 20, and 40 mg/kg 
d-methadone hydrochloride on 
GD 6 through GD 17. No test 
article-related effects were 
observed on maternal survival, 
clinical findings, ovarian and 
uterine parameters (mean 
number of corpora lutea, 
implantation sites, viable 
fetuses/litter size, resorptions, 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
Confidential 
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Section/Change 
Original Text 
Revised Text 
and pre- and postimplantation 
loss), or macroscopic findings 
at any dose level evaluated. 
Test article-related, but non-
adverse, effects on maternal 
body weight and/or body 
weight change were observed 
at 10, 20, and 40 mg/kg/day 
and on food consumption at 
40 mg/kg/day. No test article-
related effects were observed 
on fetal sex ratios; body 
weights; or external, visceral, 
or skeletal examinations.  
No developmental toxicity was 
observed at any dose level 
tested. The no-observed-
adverse-effect level (NOAEL) 
for both maternal and 
developmental toxicity was set 
to be 40 mg/kg/day. Based on a 
60-kg human body weight and 
conversion of rat to human 
dose based on body surface 
area, the human equivalent 
dose (HED) was determined to 
be 387 mg. The dose provides 
approximately 15.48-fold and 
7.74-fold safety margins when 
compared to the 25 mg and 50 
mg doses of REL-1017-202). 
The safety margins 
calculations were based on the 
on the FDA Guidance 
“Estimating the Maximum 
Safe Starting Dose in Initial 
Clinical Trials for 
Therapeutics in Adult Healthy 
Volunteers” (Error! Reference s
ource not found.). 


Clinical Study Protocol Amendment 5 
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Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
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Section/Change 
Original Text 
Revised Text 
4.4.2: Contraceptive 
Precautions: 
Revision to precautions 
for male patients, and 
addition of 
contraceptive 
precautions for female 
patients 
4.4.2 Contraceptive 
Precautions: 
For men with female sexual 
partners of childbearing 
potential, examples of medically 
acceptable forms of 
contraception include true 
abstinence, vasectomy, or male 
condom for patients plus an 
additional method of 
contraception for their female 
partners.  
4.4.2 Contraceptive Precautions: 
For men with female sexual 
partners of childbearing 
potential, examples of 
medically acceptable forms of 
contraception include true 
abstinence, vasectomy, or male 
condom for patients plus an 
additional method of 
contraception for their female 
partners. Abstinence from 
heterosexual intercourse is 
accepted if this is your usual 
lifestyle and must be continued 
until at least 2 months after the 
last dose of study drug. 
Added: Females of child-
bearing potential (not 
surgically sterilized and 
between menarche and 1 year 
post menopause) must agree to 
use contraception through the 
end of the study and until at 
least 2 months after the last 
study drug administration. 
Surgical sterilization is defined 
as removal of the uterus and/or 
both ovaries. Acceptable forms 
of contraception for female 
patients include: 
• Intrauterine device (IUD) 
• Bilateral tubal ligation, 
bilateral salpingectomy or 
bilateral tubal occlusive 
procedure  
• Hormonal contraceptives 
(e.g., oral, patch, or 
injectable) 
• A double-barrier protection 
method (e.g., condom, 
sponge, or vaginal 
diaphragm with spermicide 


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Section/Change 
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Revised Text 
cream, foam, or gel)  
• Abstinence from 
heterosexual intercourse is 
accepted if this is your 
usual lifestyle and must be 
continued until at least 2 
months after the last dose 
of study drug. 
Women must also abstain from 
egg donation from Screening 
until at least 2 months after the 
last study drug administration. 
6.1.7 Outpatient 
Observation Period 
(Day 10 to Day 14): 
Pregnancy test added. 
6.1.7 Outpatient Observation 
Period (Day 10 to Day 14): 
Not Applicable 
6.1.7 Outpatient Observation 
Period (Day 10 to Day 14): 
Added: A confirmatory 
pregnancy test will be 
administered. 
6.1.8 Follow-Up 
Period (Day 15 to Day 
21): 
Pregnancy test added 
6.1.8 Follow-Up Period (Day 
15 to Day 21): 
Not Applicable 
6.1.8 Follow-Up Period (Day 15 
to Day 21): 
Added: A confirmatory 
pregnancy test will be 
administered if the visit is 
conducted at the site. 
 
Section 6.2.5.8: 
Pregnancy Testing: 
Pregnancy tests added. 
Section 6.2.5.8: Pregnancy 
Testing: 
Not Applicable 
Section 6.2.5.8: Pregnancy 
Testing: 
Added: 
Additional confirmatory 
pregnancy tests will be 
administered at the End of the 
Observation Period Visit (Day 14 
± 3 days and Follow-Up Visit 
(Day 21 ± 3 days). 


Clinical Study Protocol Amendment 5 
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Relmada Therapeutics, Inc. 
Safety, Tolerability, PK, and Symptom Response of REL-1017 
 
Version: 6.0, 07-Mar-2019 
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Section/Change 
Original Text 
Revised Text 
Section 7.3.3: 
Pregnancy 
Revised due to the 
inclusion of women of 
childbearing potential 
Section 7.3.3: 
Given that the effects of the 
study drug on sperm have not 
been fully elucidated, any 
pregnancy in the partner of a 
patient participating in the study 
will be reported to Relmada 
within 24 hours of learning of 
the event. Follow-up 
information will be obtained 
where possible (i.e., with the 
consent of the patient’s partner) 
regarding the course and 
outcome of the pregnancy, 
including any post-natal 
sequelae in the infant. 
 
Section 7.3.3: 
Given that the effects of the study 
drug on egg and sperm have not 
been fully elucidated, any 
pregnancy in the patient or 
partner of a patient participating in 
the study will be reported to 
Relmada within 24 hours of 
learning of the event. 
Follow-up information will be 
obtained where possible (i.e., with 
the consent of the patient or 
patient’s partner) regarding the 
course and outcome of the 
pregnancy, including any post-
natal sequelae in the infant. 
Section 10: 
References: 
Addition of FDA 
guidance reference 
Section 10: References: 
Not Applicable 
Section 10: References: 
Added: FDA Guidance, 
“Estimating the maximum safe 
starting dose in initial clinical 
trials for therapeutics in adult 
healthy volunteers”; Jul 2005. 
 
Additional changes were made that were administrative or grammatical in nature. 
11.15 Amendment 5: Table of Changes 
Section/Change 
Original Text 
Revised Text 
Page 2, Sponsor 
address: 
Updated sponsor 
address 
Page 2, Sponsor address: 
750 Third Avenue, 9th Floor 
New York, NY, USA 10017  
Work: 212-572-9606 
Page 2, Sponsor address: 
880 Third Avenue, 12th Floor 
New York, NY  10022 
Work: 212-547-9591 
Synopsis and Section 
4.2: Inclusion 
Criteria #9: 
Revised 
“breastfeeding” to 
“lactating” for clarity. 
Inclusion Criteria #9: 
… Female patients must have a 
negative pregnancy test, and must 
not be breastfeeding. 
Inclusion Criteria #9: 
… Female patients must have a 
negative pregnancy test, and must 
not be lactating. 
Section 4.4.2: 
Contraceptive 
Precautions 
• Two methods of 
contraception 
added 
• Abstinence 
removed from 1st 
Section 4.4.2:  
Females of child-bearing potential 
(not surgically sterilized and 
between menarche and 1 year post 
menopause) must agree to use 
contraception through the end of the 
study …  
Section 4.4.2:  
Females of child-bearing potential 
(not surgically sterilized and 
between menarche and 1 year post 
menopause) must agree to use 2 
methods of contraception through 
the end of the study … 
 


Clinical Study Protocol Amendment 5 
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and 4th paragraphs. 
 
 
Abstinence from heterosexual 
intercourse is accepted if this is 
your usual lifestyle and must be 
continued until at least 2 months 
after the last dose of study drug. 
Abstinence from heterosexual 
intercourse is accepted if this is 
your usual lifestyle and must be 
continued until at least 2 months 
after the last dose of study drug. 
Section 7.1.8:  
Serious Adverse 
Events and Serious 
Unexpected Adverse 
Events  
Safety reporting email 
address updated 
Section 7.1.8:  
INCDrugSafety@incresearch.com  
Section 7.1.8:  
safetyreporting@syneoshealth.com 
 
Additional changes were made that were administrative or grammatical in nature.