Clinical Trial Results:
Long Term Extension Trial of setmelanotide (RM-493) for patients who have completed a trial of Setmelanotide for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway.
This extension trial was conducted to characterise the safety and tolerability of setmelanotide for up to 7 additional years in patients who had completed treatment in a previous setmelanotide study. Participants had obesity associated with genetic defects upstream of the melanocortin-4 (MC4) receptor in the leptin-melanocortin pathway or with obesity related to other abnormalities in the melanocortin-4 receptor (MC4R) pathway. Patients continued taking the same dose of setmelanotide that was being administered at completion of the index study or for patients receiving blinded study drug in the index study, the starting dose and titration schedule from the index study were used in this study. Dose level changes were allowed at any time based on safety or efficacy findings. Safety was the primary endpoint. There were no secondary endpoints.
Patients aged 2 or older as per local regulations could be enrolled in the study if they had completed participation in a previous setmelanotide clinical study.
Overall, 205 patients aged 6-68 years (median 17.0) entered the trial; 61% of patients were female.
The median duration of exposure, including time in the index trial, was 3.19 years (range: 0.3-7.6) and >50% of patients were treated for >3 years (including 10.7% treated for >=5years).
|
Summary
|
|
EudraCT number |
2017-005006-35 |
Trial protocol |
DE FR NL GB BE ES GR |
Global end of trial date |
09 Jan 2025
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
18 Jul 2025
|
First version publication date |
18 Jul 2025
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
RM-493-022
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT03651765 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Rhythm Pharmaceuticals, Inc.
|
||
Sponsor organisation address |
222 Berkeley Street, 12th Floor, Boston, United States, MA 02116
|
||
Public contact |
Rhythm Clinical Trials, Rhythm Pharmaceuticals, Inc., +1 8572644280, clinicaltrials@rhythmtx.com
|
||
Scientific contact |
Physician Inquiry Clinical Trials, Rhythm Pharmaceuticals, Inc., +1 8572644280, clinicaltrials@rhythmtx.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
|
||
EMA paediatric investigation plan number(s) |
EMEA-002209-PIP01-17 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
09 Jan 2025
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
09 Jan 2025
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
09 Jan 2025
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary objective was to characterize safety and tolerability of setmelanotide in patients who had completed treatment in a previous trial with setmelanotide for obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway and obesity related to other abnormalities in MC4R pathway.
|
||
Protection of trial subjects |
The study was conducted in accordance with the International Council for Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirements.
After the study had been fully explained, written informed consent was obtained from either the patient or his/her guardian or legal representative prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent was in compliance with ICH-GCP and all applicable regulatory requirements.
Monitoring and auditing procedures developed or reviewed and approved by Rhythm were followed, in compliance with GCP guidelines.
To be eligible for continued treatment after 1 year on setmelanotide (including time on setmelanotide during the index study) patients had to display evidence of meaningful clinical benefit via weight-related treatment effect or other assessments. Thereafter, continued eligibility was assessed every 3 months.
|
||
Background therapy |
Female patients were allowed to use hormonal contraception as well as hormone replacement therapy. Unless concomitant medications were likely to present strong potential safety concerns, the goal of this protocol was to allow as many potential patients with these ultra-rare conditions as possible to participate in the study. Patients who entered this study could continue all current medications as prescribed. All concomitant medications were to be kept at a stable dose throughout the course of the study, unless a dose change was necessary to treat an AE. If any new medication for weight loss or a glucagon-like peptide-1 (GLP-1) agonist was started prior to or during the extension study, the Sponsor was to be informed. | ||
Evidence for comparator |
Not applicable; there was no comparator drug in this open-label extension trial. | ||
Actual start date of recruitment |
03 Jul 2018
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Netherlands: 14
|
||
Country: Number of subjects enrolled |
Spain: 10
|
||
Country: Number of subjects enrolled |
United Kingdom: 18
|
||
Country: Number of subjects enrolled |
Belgium: 2
|
||
Country: Number of subjects enrolled |
France: 13
|
||
Country: Number of subjects enrolled |
Germany: 32
|
||
Country: Number of subjects enrolled |
Greece: 3
|
||
Country: Number of subjects enrolled |
Canada: 6
|
||
Country: Number of subjects enrolled |
Israel: 1
|
||
Country: Number of subjects enrolled |
Réunion: 4
|
||
Country: Number of subjects enrolled |
United States: 102
|
||
Worldwide total number of subjects |
205
|
||
EEA total number of subjects |
74
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
38
|
||
Adolescents (12-17 years) |
68
|
||
Adults (18-64 years) |
97
|
||
From 65 to 84 years |
2
|
||
85 years and over |
0
|
||
|
|||||||||||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||||||||||
Recruitment details |
Patients aged 2 or older as per local regulations could be enrolled in the study if they had completed participation in a previous setmelanotide clinical study. | ||||||||||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||||||||||
Screening details |
All patients had completed participation in a previous setmelanotide clinical study. | ||||||||||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||||||||||
Period 1 title |
Treatment period (overall period)
|
||||||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||
Allocation method |
Not applicable
|
||||||||||||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||||||||||||
Blinding implementation details |
Not applicable; this was an open-label extension trial.
|
||||||||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||||||||
|
Arm title
|
Setmelanotide | ||||||||||||||||||||||||||||
Arm description |
This trial included patients from 7 index (parent) trials: RM-493-011: N = 9 RM-493-012: N = 13 RM-493-014: N = 119 RM-493-015: N = 12 RM-493-023: N = 37 RM-493-030: N = 14 RM-493-034: N = 1 | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Setmelanotide
|
||||||||||||||||||||||||||||
Investigational medicinal product code |
RM-493-mPEG-DSPE formulation
|
||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection
|
||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
||||||||||||||||||||||||||||
Dosage and administration details |
Patients received open label setmelanotide by subcutaneous (SC) injection QD each morning. Patients and/or their caretakers were responsible for all procedures associated with study drug administration throughout the study (i.e., drawing up, and administering study drug QD). Patients were instructed to rotate injection sites and to avoid tight fitting clothing near the injection site.
Patients began treatment at the same dose that was administered at the end of the index study, unless safety reasons justified a decrease, or if a potential effect on hunger or weight loss justified an increase. Setmelanotide doses >3 mg (or >5 mg in Germany, Canada, and the UK) were not permitted.
Patients previously on placebo began treatment using the local prescribing information up to a maximum dose based on the patient’s age and weight or the scheme used in the index study.
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Setmelanotide
|
|||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
This trial included patients from 7 index (parent) trials: RM-493-011: N = 9 RM-493-012: N = 13 RM-493-014: N = 119 RM-493-015: N = 12 RM-493-023: N = 37 RM-493-030: N = 14 RM-493-034: N = 1 | |||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Setmelanotide
|
||
Reporting group description |
This trial included patients from 7 index (parent) trials: RM-493-011: N = 9 RM-493-012: N = 13 RM-493-014: N = 119 RM-493-015: N = 12 RM-493-023: N = 37 RM-493-030: N = 14 RM-493-034: N = 1 | ||
|
|||||||||
End point title |
Treatment-emergent adverse events [1] | ||||||||
End point description |
The primary endpoint was the safety and tolerability of setmelanotide as assessed by the frequency of treatment-emergent adverse events (TEAEs).
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Throughout the study from Visit 1 through the patient’s last visit.
|
||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This was long-term extension trial to characterise safety and tolerability. Only a descriptive analysis of adverse events was planned. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All AEs reported from a patient's first visit to their last visit in the trial were documented.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Treatment-emergent AEs are displayed.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
27.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Setmelanotide
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
This trial included patients from 7 index (parent) trials: RM-493-011: N = 9 RM-493-012: N = 13 RM-493-014: N = 119 RM-493-015: N = 12 RM-493-023: N = 37 RM-493-030: N = 14 RM-493-034: N = 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
12 Apr 2018 |
Clarified that there was to be no gaps of setmelanotide treatment during the transition from the index study to the extension study.
Clarified that the participants must have demonstrated adequate efficacy as well as adequate safety in a previous setmelanotide study.
Added language to indicate different maximum allowable doses across various countries depending on requirements of competent authorities.
Decreased the maximum duration of patient participation from up to 5 years to up to 2 years.
|
||
15 Oct 2018 |
Entry criteria were updated to remove the requirement that a patient had to have shown efficacy in an index study to be eligible; patients had only to have completed participation in an index study and demonstrate safety in order to be eligible to enrol. |
||
16 Oct 2019 |
Extended the study duration from 2 to 5 years
Increased the expected number of patients from 100 to 150
Entry criterion was updated to include the requirement that a patient had to have shown clinical benefit (efficacy) in the index study in the opinion of primary investigator.
Specified that the primary investigator could assess depression and suicidality in patients who were unable to complete PHQ-9 or C-SSRS questionnaires due to significant neurocognitive defect for the purpose of determining study exclusion criteria.
Directions on dose adjustments were revised based on currently approved maximum daily setmelanotide dose in participating countries as well as current study drug administration guidance.
|
||
05 Aug 2021 |
Patients currently enrolled in this current study could exit the study at any time to participate in other setmelanotide clinical studies with the patients’ written informed consent, at the discretion of the Investigator and Sponsor.
The minimum age of enrollment was lowered from 6 to 2 years.
Patients were required to have experienced meaningful clinical benefit during prior setmelanotide treatment, with meaningful benefits described.
|
||
09 Nov 2022 |
Clarified the patient population applied to patients with rare genetic, syndromic, or acquired diseases of obesity and obesity potentially related to other abnormalities in the MC4R pathway; included newly revised label indications for setmelanotide.
Revised expected patient enrollment to 300 patients. Patients experiencing improvements in weight-related parameters or other meaningful clinical benefit would be further considered for study enrollment.
Allowed for inclusion of patients who may clinically benefit from study participation at the discretion of the Investigator.
Clarified that extension study re-entry would not be permitted if setmelanotide became commercially available for a given patient’s condition.
Added new information on dose adjustments based on BMI/BMI Z parameters and dosing considerations from other studies and provided further instruction for study drug administration.
|
||
12 May 2023 |
Permitted dose escalation up to 5 mg for adult patients who might benefit and had tolerated lower doses; provided rationale for dosing up to 5 mg and included reference to the IB for specific nonclinical and clinical experience.
The total study duration was extended from 5 to 7 years; expanded potential number of patients up to 500.
Provided clarity on initial starting dose and titration steps for patients who enter from a double-blind index study.
|
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| This was a long-term extension trial with a heterogenous population of patients, all treated with open-label setmelanotide. Safety was the primary endpoint. There were no secondary endpoints. | |||
