Clinical Trials Register

Summary
EudraCT Number:	2021-002855-12
Sponsor's Protocol Code Number:	RM-493-034
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-11-03
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2021-002855-12

A.3

Full title of the trial

A 2-Stage (Open-Label Followed by Randomized Double-Blind, Placebo-Controlled Stage), Phase 2 Trial of Setmelanotide in Patients with Specific Gene Variants in the Melanocortin-4 Receptor Pathway

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study of setmelanotide in patients with obseity with specific genetic defects

A.3.2

Name or abbreviated title of the trial where available

Setmelanotide in patients with specific gene defects

A.4.1

Sponsor's protocol code number

RM-493-034

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04963231

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

P/215/2021

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Rhythm Pharmaceuticals Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Rhythm Pharmaceuticals Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Rhythm Pharmaceuticals Inc.
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	222 Berkeley Street, Suite 1200
B.5.3.2	Town/ city	Boston
B.5.3.3	Post code	MA02116
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 857 264 4280
B.5.5	Fax number	+1 857 264 4299
B.5.6	E-mail	oohayon@rhythmtx.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Imcivree
D.2.1.1.2	Name of the Marketing Authorisation holder	Rhythm Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/16/1703, EU/3/18/2101
D.3 Description of the IMP
D.3.1	Product name	Setmelanotide
D.3.2	Product code	RM-493
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Setmelanotide
D.3.9.1	CAS number	920014-72-8
D.3.9.2	Current sponsor code	RM-493
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Specific Gene Defects in the Melanocortin-4 Receptor Pathway, responsible for improper functions of certain
messenger materials in the body. E.g Melanocyte-Stimulating Hormone (MSH)

E.1.1.1

Medical condition in easily understood language

Improper function of certain messenger materials in the body that control body weight and hunger in people

E.1.1.2

Therapeutic area

Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the proportion of patients with obesity with genetic variants in a specific gene in the melanocortin-4 receptor (MC4R) pathway who achieve a clinically meaningful reduction in body weight in response to setmelanotide at the end of open-label treatment

E.2.2

Secondary objectives of the trial

To evaluate change in weight parameters and hunger in response to setmelanotide in patients with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients must have a pre-identified genetic variant in an established MC4R pathway gene that contributes to obesity.
2. Patients between the ages of 6 and 65, inclusive, at the time of signing Informed Consent or Assent.
3. Patients with obesity, defined as BMI ≥40 kg/m2 for patients ≥18 years of age or BMI ≥97th percentile for age and gender for
patients 6 to <18 years of age based on the United States (US) Centers for Disease Control and Prevention criteria.
4. Patient and/or parent or guardian is able to communicate well with the Investigator, to understand and
comply with the requirements of the trial (including the once daily [QD] injection regimen and all other trial procedures) and is able to understand and sign the written informed consent/assent. Patients who are unable to comply with all trial
procedures due to cognitive limitations or any other reason should not be enrolled.
5. Patient must meet one of the following requirements:
Female participants of childbearing potential, defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), must be confirmed non-pregnant and agree to use a highly effective form of contraception throughout the trial and for 90 days following the trial.
Highly effective forms of contraception are detailed below and in Section 8.9.7:
ovulation (i.e., oral, intravaginal, or transdermal)
- Progestin-only hormonal contraception associated with inhibition of ovulation (oral, implantable, or injectable)
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Vasectomy/vasectomized partner (provided that the vasectomized partner is the sole sexual partner of the female participant, and the vasectomized partner has received medical assessment of surgical success)
- Sexual abstinence, only if it is the preferred and usual lifestyle of the patient
Female participants of non-childbearing potential, defined as: permanently sterile (status post hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or post-menopausal for at least 12 months (and confirmed with a screening follicle-stimulating hormone level in the post-menopausal lab range) and do not require contraception during the trial.
Younger female patients who have not achieved sexual maturity at trial entry will be assessed for Tanner staging and required to comply with contraception requirements at first menarche.
Male participants with female partners of childbearing potential must agree to use a highly effective method contraception if they become sexually active during the trial or within 90 days following their participation in the trial. Male patients must also not donate sperm during and for 90 days following their participation in the trial.
6. Symptoms or behaviors of hyperphagia persistent during the patient’s life, including manifestations in childhood, as determined by the Investigator at screening.

E.4

Principal exclusion criteria

1. Patients with the following genetic variants: biallelic Bardet-Biedl Syndrome (BBS); biallelic Alström Syndrome 1 (ALMS1); homozygous, heterozygous, or compound heterozygous variants in MC4R, pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), leptin receptor (LEPR), nuclear receptor coactivator 1 (NCOA1; steroid receptor coactivator-1 [SRC1]) or SRC homology 2 B adapter protein 1 (SH2B1) genes as well as 16p11.2 chromosomal deletions that include the SH2B1 gene.
2. Weight loss >2% in the previous 3 months.
Patients will not be excluded for using regimens for weight maintenance or to prevent weight gain, such as dietary and/or exercise regimens, or medications, supplements or herbal treatments (e.g., orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion, glucagon-like peptide-1 [GLP-1] receptor agonists, etc.)
3. Bariatric surgery or procedure (e.g., gastric bypass/band/sleeve, duodenal switch, gastric balloon, intestinal barrier, etc.) within the last 6 months.
4. Documented diagnosis of current unstable major psychiatric disorder(s) (e.g., major depressive disorder, bipolar disorder, schizophrenia, etc.) or documented worsening psychiatric condition that required changes in treatment regimen within the previous 2 years, or other psychiatric related risks that the Investigator believes may interfere with trial compliance or patient safety.
5. Clinically significant depression or suicidality, as defined by: any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) during Screening, any suicide attempt during the patient’s lifetime, any suicidal behavior in the last month, or a Patient Health Questionnaire-9 (PHQ-9) score of ≥15 during Screening process.
6. Current, clinically significant pulmonary, cardiac, endocrine/metabolic, hepatic, or oncologic disease considered severe enough to interfere with the trial and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility.
7. Significant features of, or meeting the diagnostic criteria for, a genetic syndrome that is associated with obesity.
8. Glycated hemoglobin (HbA1C) >10.0% at Screening.
9. History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Patients with NAFLD or NASH will not be excluded based on this criterion
10. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at Screening. In patients ≥18 years of age the Modification of Diet in Renal Disease (MDRD) Equation should be used to calculate eGFR. In patients <18 years of age, the Bedside Schwartz Equation should be used for calculation of GFR.
11. History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
Note: If the type of skin cancer in patient’s or close family history is not known, then the patient should not be enrolled into the trial.
12. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by the Investigator during Screening. If any concerning lesions are identified during Screening, the patient should be referred to a dermatologist. Any concerning lesions identified during Screening will be biopsied and results known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient may need to be excluded from the trial.
13. Patient is, in the opinion of the Investigator, not suitable to participate in the trial.
14. Participation in any clinical trial with an investigational drug/device within 3 months or 5 half-lives, whichever is longer, prior to the first day of dosing.
15. Patients previously enrolled in a clinical trial involving setmelanotide or any previous exposure to setmelanotide.
16. Hypersensitivity to the active substance or to any of the excipients of the investigational medicinal products (active and placebo).
17. Females who are pregnant or breastfeeding, or planning or desiring to become pregnant during the duration of the trial.
18. Legally protected persons per local regulations (e.g., those that fall under the L1121-6 article of the Public Health code in France).
19. For France only: patient is <18 years of age.

E.5 End points

E.5.1

Primary end point(s)

The proportion of patients by genotype who demonstrate a significant clinically meaningful response (defined below) to setmelanotide at the end of Stage 1:
− For all patients: achieving a ≥5% reduction in BMI from Baseline

E.5.1.1

Timepoint(s) of evaluation of this end point

40 weeks

E.5.2

Secondary end point(s)

- Mean change and percent change in BMI from Baseline to end of Stage 1 in all patients and patients ≥18 years old, per gene
- Mean change and percent change in body weight from Baseline to end of Stage 1 in patients ≥18 years old, per gene
- Mean change in BMI Z-score from Baseline to end of Stage 1 in patients <18 years old, per gene
- Mean percent change in the weekly average of the daily maximal hunger score from Baseline to end of Stage 1 in patients ≥12 years old, per gene
- The proportion of patients ≥12 years old, per gene, who achieve a ≥2-point reduction (improvement) from Baseline to end of Stage 1 in the weekly average of the daily maximal hunger score.

E.5.2.1

Timepoint(s) of evaluation of this end point

40 weeks

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Israel

United Kingdom

United States

France

Germany

Greece

Netherlands

Spain

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1