Main objective:To explore the impact of setmelanotide on obesity in patients with various specific rare genetic mutations.Secondary objective:To assess the effects of setmelanotide on:* Safety and tolerability-Hunger* Waist circumferenceOptional sub…
ID
Source
Brief title
Condition
- Appetite and general nutritional disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The proportion of patients in each subgroup of RGDO who achieve at least 5%
body weight reduction from baseline, at ~3 months treatment with setmelanotide.
Measured At the end of ~3 months of treatment.
Secondary outcome
Secondary endpoints:
* Safety and tolerability of setmelanotide injection, assessed by the frequency
and severity of AEs, vital signs, and laboratory evaluations
* Change and percentage change from baseline in body weight
* Change from baseline in Daily and Global Hunger scores
* Change from baseline in waist circumference
Exploratory Endpoints
* Change from baseline in total body mass, including body fat and non-bone lean
mass, as measure by either dual-energy x-ray
absorptiometry (DXA) or bioelectrical impedance (BIA)
* Change from baseline in fasting lipids (total cholesterol, high density
lipoprotein cholesterol, low density lipoprotein cholesterol, and
triglycerides)
* Change from baseline in metabolic and hormonal assays and other exploratory
biomarkers
* Change from baseline in glycated hemoglobin (HbA1c)
* Evaluation of plasma pharmacokinetic (PK) parameters
* Change from baseline in quality of life as measured by the following
assessments:
* Impact of Weight on Quality of Life-Lite (IWQOL-Lite)
* EuroQoL-Five Dimension-5L (EQ-5D-5L) or EuroQoL-Five Dimension-Y
(EQ-5D-Y)
* The 12-Item Short Form Health Survey (SF-12) or 10-Item Short Form
Health Survey for Children (SF-10)
* Patient-Reported Behavioral Disturbance Questionnaire
* Change from baseline in mental health status as measured by the
Patient Health Questionnaire-9 (PHQ-9) and Columbia-Suicide Severity
Rating Scale (C-SSRS)
* Tanner Staging for patients who have yet to reach Tanner Stage V
Background summary
Rhythm Pharmaceuticals, Inc. has developed the trial drug setmelanotide, a MSH
messenger substance, to replace the messenger substances that are missing in
someone with certain gene variations.
The objective of this study is to demonstrate clinically meaningful weight loss
in patients with various rare genetic forms of obesity after a stable
therapeutic dose period, which is expected to be ~3 months of treatment in most
subjects. The primary endpoint is defined as the proportion of patients in each
subgroup of rare genetic disorders of obesity (RGDO) who achieve at least 5%
body weight reduction from baseline, at ~3 months of treatment with
setmelanotide.
The study is exploratory in nature and the sample size of the study for each
cohort is driven by clinical considerations. The total number of patients
enrolled per subtype with specific genetic obesity mutations may be increased
or decreased, depending upon the total number of affected patients identified.
These many rare genetic disorders are grouped together into one protocol for
administrative reasons, and otherwise would have been studied in separate
protocols. Hence, each rare genetic disorder will be treated as a separate
population for any statistical analysis, and therefore no multiplicity
adjustments will be planned in this early, proof-of-concept study.
The drug is administered once a day by subcutaneous injection (under the
skin).
The dosage is an once daily dosing; for patients 6 up to 16 years of age, 1.0,
2.0, or 3.0 mg, and for patients *16 years of age, 2.0 or 3.0 mg
All patients receive study treatment for 16 weeks. Patients may elect to
continue setmelanotide treatment by enrolling in an extension study
(RM-493-022) immediately following the last dose in this study; if the
extension study is not yet open at the current clinic site, patients may
continue treatment in the current study for up to one year, resulting in
treatment duration of up to 16 months.
Criteria for evaluation:
Efficacy:
The primary efficacy endpoint is the percent of patients in each subgroup
showing at least a 5% loss of body weight over ~3 months. Therefore, monthly
weight measurements will be obtained throughout the course of the trial.
Supporting efficacy endpoints will include change from baseline in Daily and
Global Hunger scores, body composition assessments (including total body
weight, fat mass, and non-bone lean mass) and waist circumference.
Safety:
The safety and tolerability of setmelanotide once daily (QD) subcutaneous (SC)
injection will be assessed by the frequency and severity of adverse events
(AEs) as well as changes in vital signs and laboratory evaluations.
Potential improvements in lipids (fasting cholesterol and triglycerides) as
well as glucose parameters as measured by fasting glucose and glycated
hemoglobin (HbA1c) will be assessed over time.
As required by Food and Drug Administration (FDA) for central nervous system
(CNS)-active obesity medications, changes in depression/suicidality as assessed
by the Columbia Suicide Severity Rating Scale (C-SSRS) and Patient Health
Questionnaire 9 (PHQ-9) will be monitored over the course of the trial.
Study objective
Main objective:
To explore the impact of setmelanotide on obesity in patients with various
specific rare genetic mutations.
Secondary objective:
To assess the effects of setmelanotide on:
* Safety and tolerability
-Hunger
* Waist circumference
Optional sub-study to further evaluate the PK profile.
participating in the 24-hour sub-study, 4 additional blood samples will
be collected after the same dose:
* 9, 10, and 12 hours (± 10 min) after dosing, and
*At approximately 24 hours after dosing; specifically, within 10 minutes
BEFORE the next dose of study drug.
Study design
This is a Phase 2 open-label, uncontrolled, proof-of-concept study assessing
the effect of setmelanotide on patients with rare genetic disorders of obesity
for which evidence supports a role of the leptin-melanocortin hypothalamic
pathway (the *MC4 pathway*). This study is designed as a *basket study*, using
similar procedures to assess treatment effects on different genetic populations
that share similar phenotypes of early onset, severe obesity and hyperphagia.
The differing rare genetic causes of obesity that will be enrolled in this
study are collectively referred to as different subgroups.
Intervention
Patient questionnaires
Blood sampling (safety, biomarkers, fasting Lipid panel, PK, Anti-RM-493
antibody)
Body composition (BIA, DXA)
Measurement Blood pressure, HR and ECG
Sub-study * if consented * PK sampling
Study burden and risks
Overall, setmelanotide has been generally well-tolerated in previous studies.
Drug *Related Treatment Emerengy AE*s (for which the adverse event was assessed
as possible or probably related to the study drug by the investigator) were
reported.
RM-493 has been given to 334 patients in studies ranging from a single dose to
a couple of years of treatment. It has been given to both healthy volunteers
and people suffering for a variety of diseases. The studies were conducted to
test the safety of RM-493 and, in some cases, to measure weight loss.
Pharmacodynamic data from a variety of animal models have shown improvements in
weight regulation, appetite suppression and energy expenditure. Setmelanotide
has also demonstrated meaningful weight reductions in early healthy obese
volunteer clinical studies. In a Phase 2 proof-of concept study, three LEPR
deficient patients were treated with setmelanotide and each demonstrated
compelling improvements on weight loss and hunger, with no signs of increased
blood pressure or heart rate.
The PI and staff (and other covering clinicians) will be available at all times
to study participants in the event of a clinical emergency: both this
availability and how to reach the investigator in an emergency will be clearly
communicated orally and in writing to the study participants. All study
interventions will be provided free of cost.
The current Investigator Brochure describes a comprehensive summary of AEs
reported to date
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Age
Inclusion criteria
1. Patients with the following genotypes and/or clinical assessment:
a. POMC/PCSK1/LEPR heterozygous
b. POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or
homozygous deficiency obesity
c. POMC/PCSK1/LEPR composite heterozygous (two or more mutations in two or more
genes) deficiency obesity
d. Smith-Magenis Syndrome (SMS)
e. SH2B1 deficiency obesity
f. Chromosomal rearrangement of the 16p11.2 locus causing obesity
g. CPE compound heterozygous or homozygous deficiency obesity
h. Leptin deficiency obesity with loss of response to metreleptin
i. SRC1 deficiency obesity
j. MC4R deficiency obesity
Note: The specific genotype for all patients must be reviewed by the Sponsor
prior to study enrollment to confirm that the patient meets Inclusion Criterion
#1. In addition, enrollment of patients in some subgroups may be prioritized by
the Sponsor in order to ensure enrollment of patients with (1) well described,
loss-of-function genetic mutations, (2) a variety of genetic variants, or (3)
genetic variants likely to respond to setmelanotide.
2. Age 6 years and above.
3. Obese, defined as Body Mass Index (BMI) * 30 kg/m2 for patients *16 years of
age or BMI * 95th percentile for age and gender for patients 6 up to 16 years
of age.
4. Study participant and/or parent or guardian is able to communicate well with
the Investigator, to understand and comply with the requirements of the study,
and is able to understand and sign the written informed consent/assent.
5. Female participants of child-bearing potential must be confirmed
non-pregnant, and agree to use contraception as outlined in the protocol.
Female participants of non-childbearing potential, defined as surgically
sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal
ligation), post-menopausal for at least 12 months (and confirmed with a
screening Follicle-Stimulating Hormone [FSH] level in the post-menopausal lab
range), and failure to have achieved menarche, do not require contraception
during the study.
6. Male participants with female partners of childbearing potential must agree
to a double-barrier method if they become sexually active during the study.
Male patients must not donate sperm during and for 90 days following their
participation in the study.
Exclusion criteria
1. Recent intensive (within 2 months) diet and/or exercise regimen with or
without the use of weight loss agents including herbal medications that has
resulted in > 2% weight loss.
2. Use of any medication that is approved to treat obesity within three months
of first dose of study drug (e.g., orlistat, lorcaserin,
phentermine-topiramate, naltrexone-bupropion). Note: Glucagon-like peptide-1
(GLP-1) receptor agonists may be used up to the dose approved for the treatment
of diabetes mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) as long
as (1) is it not being prescribed for the treatment of obesity, (2) the dose
has been stable for at least three months prior to enrollment, (3) the patient
has not experienced weight loss during the previous three months, AND (4) the
patient intends to keep the dose stable throughout the course of the study.
3. Gastric bypass surgery within the previous six months or any prior gastric
bypass surgery resulting in >10% weight loss durably maintained from the
baseline pre-operative weight with no evidence of weight regain. Specifically,
patients may be considered if surgery was not successful, or resulted in
<10% weight loss compared to pre-operative baseline weight or clear evidence
of weight regain after an initial response to bariatric surgery. All patients
with a history of bariatric surgery must be discussed with and receive approval
from the Sponsor prior to enrollment.
4. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other
psychiatric disorder(s) that the Investigator believes will interfere
significantly with study compliance. Neurocognitive disorders affecting ability
to consent will not be disqualifying as long as an appropriate guardian able to
give consent has been appointed.
5. A PHQ-9 score of * 15 or any suicidal ideation of type 4 or 5 on the C-SSRS
during Screening, any lifetime history of a suicide attempt, or any suicidal
behavior in the last month. Note: Patients who are unable to complete the PHQ-9
or C-SSRS due to significant neurocognitive defects may be allowed to enroll in
the study, as long as in the opinion of the Primary Investigator there are no
clinical signs or symptoms of suicidal behavior.
6. Current, clinically significant pulmonary, cardiac, or oncologic disease
considered severe enough to interfere with the study and/or confound the
results. Any patient with a potentially clinically significant disease should
be reviewed with the Sponsor to determine eligibility.
7. HbA1c >9.0% at Screening
8. History of significant liver disease or abnormal liver tests on Screening
(i.e. > 1.5 x upper limit of normal [ULN] for alanine transaminase [ALT],
aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin ). Note:
Patients entering the study with SRC1 haploinsufficiency obesity must be
evaluated during the Screening Period for hepatic fibrosis by appropriate
imaging techniques (e.g., transient elastography or magnetic resonance
elastography). Any patient with moderate or greater fibrosis (e.g., the
equivalent of a METAVIR score * 2) will be excluded from the study. Note: A
patient with a diagnosis of non-alcoholic fatty liver disease (NAFLD) or
non-alcoholic steatohepatitis (NASH) may be allowed to enroll in the study,
after consultation with the Sponsor. Other significant liver disease, such as
cirrhosis, are exclusionary.
9. Glomerular filtration rate (GFR) < 30 mL/min at Screening.
10. History or close family history (parents or siblings) of skin cancer or
melanoma (not including non-invasive/infiltrative basal or squamous cell
lesion), or patient history of ocular-cutaneous albinism.
11. 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 a qualified dermatologist
during Screening. Any concerning lesions identified during the Screening Period
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 study.
12. Patient is, in the opinion of the Study Investigator, not suitable to
participate in the study.
13. Participation in any clinical study with an investigational drug/device
within 3 months prior to the first day of dosing.
14. Patients previously enrolled in a clinical study involving setmelanotide or
any previous exposure to setmelanotide.
15. Significant hypersensitivity to any excipient in the study drug.
16. Inability to comply with QD injection regimen.
17. Females who are breastfeeding or nursing.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-000387-14-NL |
| ClinicalTrials.gov | NCT03013543 |
| CCMO | NL70159.078.19 |