Clinical Trial Results:
An Open Label, 1-Year Trial, including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Early Onset POMC Deficiency Obesity due to Bi-Allelic Loss-of-Function POMC or PCSK1 Genetic Mutation
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Summary
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EudraCT number |
2016-002320-83 |
Trial protocol |
DE GB FR BE ES |
Global end of trial date |
16 Jul 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Jan 2022
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First version publication date |
11 Jan 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RM-493-012
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02896192 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Rhythm Pharmaceuticals, Inc.
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Sponsor organisation address |
222 Berkeley Street, Boston, United States, MA 02116
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Public contact |
Chief Medical Officer, Rhythm Pharmaceuticals, Inc., +1 857-264-4280, EU_medinfo@rhythmtx.com
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Scientific contact |
Chief Medical Officer, Rhythm Pharmaceuticals, Inc., +1 857-264-4280, EU_medinfo@rhythmtx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002209-PIP01-17 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 May 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 May 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Jul 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in patients with pro-opiomelanocortin (POMC) deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment.
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Protection of trial subjects |
The IRB/IEC reviewed all appropriate study documentation in order to safeguard the rights, safety, and well-being of the patients. The study was only conducted at sites where IRB/IEC approval had been obtained. The protocol, investigator brochure (IB), informed consent, advertisements (if applicable), written information given to the patients (including diary cards), safety updates, annual progress reports, and any revisions to these documents was provided to the IRB/IEC by the Investigator.
Although the study procedures and assessments required per protocol were classified as “No or Minimal Risk” (apart from DEXA which is classified as “Minor Increase over Minimal Risk”) per the 2008 Guidance Document “Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Pediatric Population”, considerations for reducing pain in distress in participants younger than 18 years of age were included in the protocol.
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Background therapy |
Unless concomitant medications were likely to present a strong potential safety concern, to allow as many as possible patients with this ultra-rare condition to participate in the study, patients were allowed chronic concomitant medications while participating in the study, including: 1) Growth hormone 2) Contraceptives 3) Hormone replacement therapy (female patients were permitted hormonal contraception as well as hormone replacement therapy) 4) Anti-hypertensives 5) Statins and other lipid-lowering therapies 6) Thyroxine or other thyroid supplements 7) Other medications commonly used in patients with obesity: endocrine therapies (e.g., estrogens, Fosamax, hydrocortisone, vitamin and calcium supplements, diabetic therapies including insulin); and other medications (e.g., carnitor, Coenzyme Q10, vitamins, anti-constipation medications, anti-allergic medications). 8) Except for low threshold drugs (i.e., anticonvulsants, digoxin, Coumadin, etc.), other medications were permitted if the patient was on a stable dose upon consultation with the Sponsor. Medications that could impact the efficacy assessments during the study were prohibited. Anorectic agents or drugs with anorexia as a non-rare side effect were prohibited for the duration of the study. | ||
Evidence for comparator |
No active comparator was used in the study, but the study was powered based upon natural history data. There was a double-blind randomized withdrawal period, which included 4 weeks placebo and 4 weeks active treatment. | ||
Actual start date of recruitment |
14 Feb 2017
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Scientific research | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Germany: 7
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Country: Number of subjects enrolled |
Canada: 1
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Country: Number of subjects enrolled |
United States: 1
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Worldwide total number of subjects |
15
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EEA total number of subjects |
13
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
5
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Adolescents (12-17 years) |
5
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Adults (18-64 years) |
5
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients aged >= 6 years, with bi-allelic, homozygous / compound heterozygous genetic status for POMC or PCSK1, with loss-of-function (LOF) variant for each allele conferring severe obesity phenotype were eligible. If age ≥18 years, body mass index (BMI) ≥30 kg/m2; if <18 years, BMI ≥95th percentile for age (by gender) on growth chart assessment. | ||||||||||||||
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Pre-assignment
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Screening details |
At screening, a blood sample was obtained for genotyping for mechanisms considered to be possibly related to the safety or efficacy response to the study medication (e.g., other obesity related genes). Complete physical, relevant bloodwork and other standard assessments were performed. All bloodwork was collected between Study Day -28 and -14. | ||||||||||||||
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Period 1
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Period 1 title |
Baseline (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
Blinding implementation details |
This was an open-label study with a dose titration period lasting 2 to 12 weeks (dependent upon number of dose escalations required to determine an individual’s therapeutic dose) followed by a further 10 weeks of open-label treatment at the therapeutic dose. This was followed by an 8-week withdrawal period (4 weeks placebo and 4 weeks on setmelanotide; timing of each was randomly assigned) then continued treatment with setmelanotide to the end of 1-year's treatment.
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Arms
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Arm title
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All treated patients | ||||||||||||||
Arm description |
All patients treated with setmelanotide, includes a combination of 10 patients enrolled in a 'pivotal cohort' and 5 patients in a 'supplemental' cohort. In total, 13 patients had POMC genetic mutations, and 2 patients had PCSK1 genetic mutations. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Setmelanotide
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Investigational medicinal product code |
RM-493-mPEG-DSPE
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Study patients were administered study drug by subcutaneous (SC) injection once daily (in the morning). The dose titration phase lasted up to 12 weeks with assessments every 2 weeks to determine if a dose should be increased. Once the patient’s therapeutic dose was reached, the same dose was administered for up to 1 year (except during a planned 4-week withdrawal period after a minimum of 12 weeks treatment at the therapeutic dose). Initial doses administered were 1.0 mg (adult patients) or 0.5 mg (paediatric and adolescent patients), and the maximum potential dose following the dose titration process was 3.0 mg or 2.5 mg daily depending on the maximum approved dose in the specific participating country as well as the age of the patient.
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Baseline characteristics reporting groups
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Reporting group title |
All treated patients
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Reporting group description |
All patients treated with setmelanotide, includes a combination of 10 patients enrolled in a 'pivotal cohort' and 5 patients in a 'supplemental' cohort. In total, 13 patients had POMC genetic mutations, and 2 patients had PCSK1 genetic mutations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
All treated patients
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Reporting group description |
All patients treated with setmelanotide, includes a combination of 10 patients enrolled in a 'pivotal cohort' and 5 patients in a 'supplemental' cohort. In total, 13 patients had POMC genetic mutations, and 2 patients had PCSK1 genetic mutations. | ||
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End point title |
Body weight change [1] | ||||||||
End point description |
The primary endpoint in this study was defined as the proportion of patients who met the ≥10% weight loss threshold (responders) after approximately 1 year of treatment with setmelanotide, compared to the proportion from historical data (at most, 5% responders in the null population). This endpoint analysis was performed solely on designated responders and therefore on the FAS population.
The proportion of patients who had at least 10% weight reduction at ~1 year vs baseline was analysed via the exact binomial test, at 1-sided 5% of significance level, against the null hypothesis that the proportion was less than or equal to 5% and the alternative hypothesis was that the proportion was greater than 5%. The 2-sided 90% CI of the proportion was calculated using the exact Clopper-Pearson method.
Results of the analysis: point estimate: 85.7% (90% CI 61.46, 97.40), p<0.0001, indicating the primary efficacy endpoint was met.
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End point type |
Primary
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End point timeframe |
Baseline to 1 year
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End point title |
Percentage change in body weight | ||||||||
End point description |
Mean percentage of body weight change (kg) from baseline after 1 year of treatment with setmelanotide within the DUS population (defined as all patients who received any study drug, demonstrated ≥5 kg weight loss or 5% of body weight over 12-week open-label treatment period, and proceeded into the double-blind, placebo-controlled withdrawal period).
A linear mixed model repeated measures analysis of variance with a fixed term for time and baseline and a random effect for patients was used. An unstructured covariance matrix was used to model the expected different variances among the participants. In the event the mixed model did not converge with an unstructured covariance matrix, a compound-symmetric then Toeplitz covariance matrix was employed instead.
Results of the analysis: LS mean change: -25.73% (90% CI -28.49, -22.98), p<0.0001, indicating this key secondary efficacy endpoint was met.
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End point type |
Secondary
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End point timeframe |
Change from baseline to Week 52
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in hunger score | ||||||||
End point description |
Evaluation of the mean percent change in hunger scores (weekly average hunger score of the daily worst [most] hunger score in 24 hours) in patients ≥12 years of age at the end of approximately 1 year of treatment within a single group of patients.
A linear mixed model repeated measures analysis of variance with a fixed term for time and baseline and a random effect for patients was used. An unstructured covariance matrix was used to model the expected different variances among the participants. In the event the mixed model did not converge with an unstructured covariance matrix, a compound-symmetric then Toeplitz covariance matrix was employed instead.
Results of analysis: LS mean change: -27.77% (90% CI -40.58, -14.96), p=0.0005, indicating this key secondary efficacy endpoint was met.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 52
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| No statistical analyses for this end point | |||||||||
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End point title |
Improvement in daily hunger score | ||||||||
End point description |
Evaluation of the proportion of patients ≥12 years of age achieving at least 25% improvement in worst (most) hunger score following 1 year of treatment with setmelanotide. This endpoint analysis was performed solely on designated responders and therefore based on the FAS population.
The proportion of patients who had at least 25% improvement in hunger score at ~1 year vs baseline was analysed via the exact binomial test, at 1-sided 5% of significance level, against the null hypothesis that the proportion was less than or equal to 5% and the alternative hypothesis was that the proportion was greater than 5%. The 2-sided 90% CI of the proportion was calculated using the exact Clopper-Pearson method.
Results of the analysis: point estimate: 50% (90% CI: 19.29, 80.71); p=0.0004, indicating this key secondary efficacy endpoint was met.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 52.
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Adverse events information
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Timeframe for reporting adverse events |
From baseline to end of treament
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Adverse event reporting additional description |
The relatedness assessment was as reported by the investigator.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
All treated patients
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Reporting group description |
All patients treated with setmelanotide, includes a combination of 10 patients enrolled in a 'pivotal cohort' and 5 patients in a 'supplemental' cohort. In total, 13 patients had POMC genetic mutations, and 2 patients had PCSK1 genetic mutations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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18 Aug 2016 |
Ths amendment included the following changes:
Revised definition of females of nonchildbearing potential in inclusion criterion 5, and revised inclusion criterion 6 related to male participants of childbearing potential requiring double barrier contraception. |
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01 Sep 2016 |
Ths amendment included the following changes for Germany:
Revised highest allowable dose titration to 2.5 mg rather than 3.0 mg, and clarified dose titration; updated inclusion 4; added exclusion 15 regarding institutionalized patients or dependents of the sponsor, Investigator or study site were ineligible for the study; and added Appendix to protocol documenting considerations specific to pediatric populations. |
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14 Sep 2016 |
Ths amendment included the following changes for France:
Added the same 2008 Guidance for Reducing Pain and Suffering in adolescent populations; clarified inclusion and exclusions, contraception requirements were brought into alignment with GCP/ICH Guidelines, and end of trial definition and clarification of Termination/Final Visit assessments. |
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23 Feb 2017 |
This amendment incorporated revisions from the previous two country amendments in a global update and additionally, two Global Hunger Questions were added to the study to help assess hunger and were to be administered at clinic visits as specified within the protocol.
Other substantial updates included: Modified the rationale for doses selected to have the protocol encompass all competent regional authorities’ requests.
Modified exclusion criterion 6 to have globally acceptable language with regard to restrictive or obstructive lung disease referencing NYHA Class 3 heart failure, etc.
Modified dose titration maximum allowable dose language (and duration of dose titration) to encompass all competent authorities’ request. 2008 Guidance for Reducing The Pain and Suffering in the adolescent population was incorporated.
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22 May 2017 |
This amendment allowed inclusion of pediatric patients as young as 6 years of age; included bone age assessments; included neurocognitive assessments in patients 6 to 16 years of age; included dose titration guidelines for patients between 6 to 11 years of age; and included age appropriate hunger questions, quality of life assessments, and pediatric age range versions of C-SRS and PHQ-9. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/3313729 |
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