Clinical trial NCT04855760
Conditions: Major Depressive Disorder
Keywords: REL-1017
Sponsor: Relmada Therapeutics, Inc.
Start date: 2021-04-01; Completion date: 2023-07-27
Enrollment: 627 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a 1-year, multicenter, open-label, long-term study to assess the safety of REL-1017 once daily (QD) as monotherapy or as adjunctive treatment of Major Depressive Disorder. Adjunctive study participants continued to take their current antidepressant therapy in addition to the study drug for the duration of the treatment period.

Detailed description:
This was a multicenter, open-label, long-term study of REL-1017 to evaluate the long-term safety and long-term durability of response in patients with MDD. Patients who completed previous randomized, double-blind Phase 3 trials (NCT04688164, NCT04855747, NCT05081167) of REL-1017 as adjunctive therapy or monotherapy for MDD were asked to continue treatment with REL-1017 25 mg daily for up to 1 year. De novo patients who satisfied inclusion/exclusion criteria also were enrolled and received a 75 mg loading dose of REL-1017 on Day 1 followed by a maintenance dose of 25 mg REL-1017 daily for the remainder of the study (Days 2-365). When REL-1017 was administered as adjunctive treatment, patients continued to use a stable dosage of their concomitant antidepressants.

Arms: arm 1: Roll-over participants received 25 mg REL-1017 (one 25 mg REL-1017 tablet), orally, per day, either as a monotherapy or in addition to their ongoing antidepressant (ADT), rolling over from the monotherapy study REL-1017-303 or the adjunctive therapy studies REL-1017-301 and REL-1017-302, respectively.

De Novo participants received a 75 mg REL-1017 loading dose (three 25 mg REL-1017 tablets) on Day-1 of the 365-day treatment period. From Day-2 to Day-365, participants received 25 mg REL-1017 either as monotherapy or as adjunctive therapy.
Interventions: intervention 1: REL-1017
Intervention descriptions: intervention 1: REL-1017 tablet

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Protocol Title: A Phase 3, Multicenter, Open-Label Study to Assess the Long-
Term Safety of REL-1017 as a Treatment of Major Depressive Disorder 
(RELIANCE-OLS) 
Protocol Number: REL-1017-310 
NCT Number 
NCT04855760 
Name of Investigational Product: 
REL-1017 
Phase of Development: 
3 
Indication: 
Major Depressive Disorder 
Sponsor: 
Relmada Therapeutics Inc. 
Protocol Date: 
March 04 2022 
 
 
Certain information within this protocol has been redacted to protect either personally 
identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 
• Names, addresses, and other personally identifiable information  
• Proprietary information, such as scales or coding systems, which are considered 
confidential 
• information. 
• Other information as needed to protect the trade secret and/or confidential information of 
Relmada Therapeutics 
 


CLINICAL STUDY PROTOCOL 
 
 
 
A Phase 3, Multicenter, Open-Label Study to Assess the Long-Term Safety of 
REL-1017 as a Treatment of Major Depressive Disorder (RELIANCE-OLS) 
 
Protocol Number: REL-1017-310 
 
 
Name of Investigational Product: 
REL-1017 
Phase of Development: 
3 
Indication: 
Major Depressive Disorder 
Sponsor: 
 
 
Relmada Therapeutics, Inc. 
 
2222 Ponce de Leon Blvd, Floor 3 
Coral Gables, FL 33134 
 
 
Protocol Version: 
Amendment Version:  
4.0 
3.0 
Protocol Date: 
04-Mar-2022 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Relmada Therapeutics, Inc. Any 
unauthorized copying or use of this document is prohibited. 
 
 


PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
A Phase 3, Multicenter, Open-Label Study to Assess the Long-Term 
Safety of REL-1017 as a Treatment of Major Depressive Disorder 
(RELIANCE-OLS) 
Protocol Number: 
REL-1017-310 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Council for Harmonisation (ICH) guidelines for current Good Clinical Practice 
(GCP), and applicable regulatory requirements. 
Sponsor Signatory 
 
 
Relmada Therapeutics, Inc.  
Signature 
Date (DD-Mmm-YYYY) 


INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 3, Multicenter, Open-Label Study to Assess the Long-Term 
Safety of REL-1017 as a Treatment of Major Depressive Disorder 
(RELIANCE-OLS) 
Protocol Number: 
REL-1017-310 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2): 
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)/Independent Ethics Committee (IEC), except where necessary to eliminate 
an immediate hazard to the study participants 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, 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. 
 
<Name> 
<Title> 
Investigator Signature 
Date (DD-Mmm-YYYY) 
Institution 
 




  
 
 
  
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
Pharmacokinetics (De novo participants only) 
To evaluate pharmacokinetics (PK) 
of REL-1017 and potential 
metabolites 
• 
REL-1017 concentration at 2.5 hours after first dose and at 
subsequent timepoints 
 
Study Design 
This is a 1-year open-label study (OLS) following the randomized 
double-blind placebo-controlled Phase 3 studies. De novo participants 
(adjunctive ADT or monotherapy) who have not been part of prior Phase 
3 studies with REL-1017 may also be enrolled. Participants in the OLS 
from REL-1017-301 or REL-1017-302 will continue to take their 
prescribed ADT plus REL-1017. Participants from REL-1017-303 will 
continue to refrain from use of concomitant ADT. 
All participants who complete the REL-1017 Phase 3 studies without any 
safety issues that would preclude participation in this OLS (according to 
the Investigator) are eligible. 
Investigational 
Product/Reference 
Product 
REL-1017 25 mg tablets 
Study Drug, Dose 
Schedule, and Mode of 
Administration 
REL-1017 25 mg tablets once daily (QD) for oral administration (PO) 
for up to 1 year.  
Participants enrolling from REL-1017-301 or REL-1017-302 will be 
asked to stay on a stable dosing regimen of their current ADT for the 
duration of their participation in the study while exposed to REL-1017. 
Participants enrolling from REL-1017-303 will be asked to continue 
refraining from use of concomitant ADT. Dosing of REL-1017 will take 
place once daily, preferably at the same time as the first-line ADT is 
taken for adjunct therapy participants. 
The following loading dose schedule will be used for de novo participants 
only:  


Day 1 – loading dose:  
• 
Three REL-1017 25 mg tablets (75 mg total) administered at the 
clinical study site  
Day 2 to Day 365 – maintenance dose:  
• 
One REL-1017 25 mg tablet QD  
 
Study Population and 
Duration of Participation 
All participants who complete the REL-1017 Phase 3 studies without any 
safety issues that would preclude participation in this OLS (according to 
the Investigator) are eligible. To achieve an adequate number of 
participants who will complete 6 months and 12 months of the study, 
respectively, REL-1017-310 may enroll de novo participants who have 
not been part of prior Phase 3 studies with REL-1017.  De novo 
participants will undergo Screening assessments for eligibility to 
participate in this study. All participants will be enrolled for up to 13 
months consisting of 12 months of treatment and a 1-month post-
treatment follow-up visit. 
Planned Sample Size 
To evaluate overall safety of REL-1017, the sample size for the OLS 
aims to achieve at least 300 participants completing 6 months and at least 
100 participants completing 12 months of the study.    
 
 
Inclusion Criteria 
(de novo participants 
only) 
REL-1017-310 de novo participants will undergo Screening assessments 
and must meet all the following inclusion criteria to participate in this 
study. 
1. Must be able to read, speak, and understand English or Spanish 
and must provide written informed consent prior to the initiation 
of any protocol-specific procedures. 
2. Male or female participant, age 18 to 65 years, inclusive. 
3. 
  
.  
4. Participant is willing and able to commit to meet all study 
requirements, adhere to both approved ADT (as applicable) and 
study drug regimen, and complete all assessments and all 
scheduled visits, per Investigator judgment. 
5. Women of childbearing potential (WOCBP) and men whose 
sexual partners are WOCBP must use at least 1 highly effective 
method of contraception from Screening and for at least 2 months 
after the last study drug administration. For men with female 
sexual partners of childbearing potential, examples of medically 
acceptable forms of contraception include vasectomy or male 
condom for participants, plus an additional method of 
contraception for their female partners. Highly effective methods 
of contraception are those which have a failure rate of <1% (when 
implemented consistently and correctly) and include: 
o Intrauterine device (IUD) 
o Bilateral tubal ligation, bilateral salpingectomy, or 
bilateral tubal occlusive procedure  
o Hormonal contraceptives (e.g., oral, patch, or injectable) 


o A double-barrier protection method (e.g., condom, 
sponge, or vaginal diaphragm with spermicide cream, 
foam, or gel) 
o Abstinence from heterosexual intercourse is accepted if 
this is the participant’s usual lifestyle and must be 
continued until at least 2 months after the last dose of 
study drug.  
Women who are not of childbearing potential must be 
congenitally or surgically sterile (hysterectomy and/or bilateral 
oophorectomy/salpingo-oophorectomy, as determined by the 
participant’s medical history) or must be post-menopausal. Post-
menopausal is defined as being amenorrheic for at least 1 year 
without another cause and a follicle-stimulating hormone (FSH) 
level ≥40 mIU/mL as confirmation. 
6. Diagnosed with MDD as defined by the Diagnostic and Statistical 
Manual, Fifth Edition (DSM-5), and confirmed by the Structured 
Clinical Interview for DSM-5 Disorders (SCID-5). 
7. Hamilton Depression Rating Scale-17 (HAMD17) 
 at 
Screening and independently confirmed by State versus trait; 
Assessability; Face validity; Ecological validity; and Rule of three 
Ps [pervasive, persistent, and pathological] (SAFER) assessment. 
8. At Baseline, before definitive admission and randomization of the 
participant, the MADRS10 scale will be administered and the 
participant must show a MADRS10 
 
9. Diagnosed with a current major depressive episode (MDE) lasting 
from 8 weeks to 36 months as defined by the DSM-5 and 
confirmed by the SCID-5 for MDD, as well as independent 
confirmation of the HAMD17 score, 
 
 
 
 
 
For de novo participants enrolling for REL-1017 adjunctive therapy: 
10. Treated for at least 6 weeks prior to Screening and stabilized for 
at least 6 weeks prior to Baseline on an approved dosing regimen 
of ADT medications (e.g., selective serotonin reuptake inhibitor 
[SSRI], serotonin and norepinephrine reuptake inhibitor [SNRI], 
bupropion (a norepinephrine–dopamine reuptake inhibitor 
[NDRI] and nicotinic receptor antagonist) during the current 
MDE, and committed to remaining on the same stable dosing 
regimen during the Screening period and for the entire study 
duration, 
 
 
 
 
 
Note: Discontinuation of any of the listed ADT must occur at 


least 6 weeks prior to Baseline.  
 
 
Note: An electronic dosing diary (eDiary) will be used beginning 
at Screening to document the stability of background 
antidepressant(s); only participants reporting a minimum of 80% 
adherence during Screening will be randomized.  
11. 
 
 
 
 
 
 
  
For de novo participants enrolling for REL-1017 monotherapy: 
12. 
 
 
 
 
 
 
Exclusion Criteria 
(de novo participants 
only)  
REL-1017-310 de novo participants will undergo Screening assessments. 
Individuals meeting any of the following criteria are ineligible to 
participate in this study. 
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, Medical Monitor, or Sponsor designee would 
jeopardize the safety of the participant or the validity of the study 
results, including established QT prolongation, long QT 
syndrome, torsades de pointes, bradyarrhythmia, ventricular 
tachycardia, uncompensated heart failure (greater than New York 
Heart Association [NYHA] Class 1 congestive heart failure 
[CHF]), uncontrolled hypokalemia, or uncontrolled 
hypomagnesemia. 
2. More than class 2 angina pectoris or a myocardial infarction (MI) or 
acute coronary syndrome within the past 3 months. 
3. Any medical, psychiatric condition, or social context that, in the 
opinion of the Investigator, Medical Monitor, or Sponsor designee 
is likely to unfavorably alter the risk-benefit of subject 
participation, to interfere with protocol compliance, or to 
confound safety or efficacy assessments. 
4. Have any significant illness, of any nature, including possible 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
related fever or other symptoms, requiring hospitalization, 


emergency treatment, or isolation (quarantine) within 4 weeks 
prior to Screening or during the Screening period, and as 
determined by the Investigator. 
5. History or first degree relative with history of unexplained sudden 
death or long QT syndrome. 
6. Triplicate 12-lead ECG with average QTcF ≥450 msec, and/or a 
QRS interval ≥120 msec at Screening. 
7. Current or recent uncontrolled orthostasis or orthostatic 
hypotension necessitating treatment. 
8. Poorly controlled diabetes as defined by a glycosylated 
hemoglobin (HbA1c) >7.5%, despite standard care.  
9. 
 
 
10. 
 
 
 
12. 
 
 
 
 
 
13. 
  
 
 
15. History of allergy or hypersensitivity to methadone or related 
drugs. 
16. 
 
 
 
 
 
 
 
17. Participants who, in the Investigator’s judgment, are at significant 
risk for suicide. A participant with a C-SSRS ideation score of 4 
or 5 within the last 6 months or any suicide attempt within the 
past year of either Screening or Baseline must be excluded. 
18. Any lifetime history of bipolar I or II disorder, psychosis and/or 
mania as defined by the DSM-5 and confirmed by psychiatric 
history and/or examination by the Investigator. 
19. Comorbid moderate to heavy alcohol or substance use disorder, as 
defined by DSM-5, at Screening or within the 12 months prior to 
Screening. Heavy drinking is defined as an average of 3 or more 
drinks per day, in the last month.  
20. A positive result on the urine drug/alcohol screen within 30 days 
prior to Baseline (Day 1). At Investigator discretion, in 
consultation with the Medical Monitor, a retest is permitted. 
21. 
 




Statistical Data Analysis 
Study analysis populations, defined as follows: 
Screened/Enrolled Set: The Screened/Enrolled Set will include all 
participants who signed an informed consent.  
Full Analysis Set (FAS): All participants who received at least 1 
dose of study drug in the OLS and had at least 1 post-Baseline 
efficacy assessment, irrespective of any deviation from the protocol 
or premature discontinuation. The FAS will be used for analysis of 
efficacy. 
Safety Set: All participants who received at least 1 dose of study 
drug in the OLS. This population will be used for the analysis of 
safety. 
Safety data analysis 
Descriptive statistics of the safety and efficacy of the participants in the 
OLS will be presented based on the prior double-blind treatment groups: 
Double-blind placebo, double-blind REL-1017, de novo.  In general, the 
Baseline for each assessment will be the last value collected prior to the 
first open-label dose. 
Summaries of efficacy results will be presented for the FAS, and 
summaries of safety results will be presented for the Safety Set; all will be 
summarized by the treatment groups “REL-1017 in double-blind study,” 
“placebo in double-blind study,” “de novo,” “pooled placebo and de 
novo,” and “overall”. 
Continuous safety and tolerability assessments (e.g., vital signs, weight, 
BMI, body temperature, ECG parameters, and laboratory parameters) will 
be summarized using descriptive statistics for values for each visit, and 
additionally for change from Baseline of OLS.  
The time course of absolute values and change from Baseline will be 
presented in descriptive statistics and figures.  
Categorical safety data (e.g., categorical laboratory parameters, ECG 
overall evaluation, QT/QTcF categories) and central tendency effects will 
be presented by number and percentage of participants in the respective 
category for each visit.  
The number and percentage of participants with TEAEs, serious adverse 
events (SAEs), AEs associated with discontinuation, and TEAEs by 
severity and relationship to study treatment will be summarized by system 


organ class and preferred term, using the Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0. 
All summaries of TEAEs will be provided for the TEAEs in OLS (i.e., 
AEs that started or worsened in severity after first dose in the OLS). 
Comorbidities and comedications will be summarized in count and 
frequency tables. 
Exploratory Efficacy variables 
Continuous efficacy variables will be reported using descriptive statistics 
for values for each visit, and additionally for change from Baseline of 
OLS. The time course of absolute values and change from Baseline will 
be presented in figures.  
Categorical efficacy data will be presented by number and percentage of 
participants in the respective category for each visit.