Study of Setmelanotide Effects on QTc (Corrected QT) Interval in Healthy Participants

A Randomized, Double-Blind, 3-arm, Parallel Group, Placebo- and Positive-controlled Study to Investigate the Effects of Setmelanotide on QTc Interval in Healthy Subjects

This was a double-blind, randomized, placebo- and positive-controlled, parallel group, 3-arm study that assessed the potential for therapeutic and supratherapeutic concentrations of setmelanotide to affect the QTc corrected by the Fredericia method (QTcF) interval.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Setmelanotide; Drug: Oral Placebo; Drug: Moxifloxacin; Drug: SC Placebo

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Parexel Early Phase Clinical Unit (Los Angeles)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participant has body mass index (BMI) between 18.0 and 30.0 kilogram per meter square (kg/m^2), inclusive.
• Participant is in good health, as confirmed by no clinically significant findings from medical history, physical examination, 12-lead Electrocardiogram (ECG), vital signs measurements, clinical laboratory evaluations, and liver function tests at Screening and Check-in.
• Female participants of childbearing potential must be confirmed non-pregnant and agree to use contraception.
• Male participants with female partners of childbearing potential must agree to use contraception. Male participants must also not donate sperm during and for 90 days following their participation in the study.
• Participant is a nonsmoker (for at least 3 months) with negative urinary cotinine test at Screening and agrees to abstain from alcohol, recreational drugs (including marijuana), and tobacco or nicotine-containing products for the duration of the study.
• Participant is able to comprehend and is willing to sign an informed consent form and abide by the study restrictions.

Exclusion Criteria:

• Participant has sustained systolic blood pressure (SBP) >150 millimeters of mercury (mmHg) or <90 mmHg or a diastolic blood pressure (DBP) >100 mmHg or <60 mmHg in the supine position at Screening or Day 1 of each study period, respectively.
• Participant has supine pulse rate of <45 beats per minute (bpm) or >100 bpm.
• Participant has abnormal screening ECG indicating a second- or third-degree atrioventricular block, or one or more of the following: QRS>110 millisecond (msec) , QTcF >450 msec for males and >470 msec for females, PR interval >200 msec.
• Participant has a history of risk factors for Torsades de Pointes (TdP), including unexplained syncope, diagnosis or family history of Brugada syndrome or long QT syndrome, heart failure, myocardial infarction, angina, or clinically significant abnormal laboratory assessments including hypokalemia, hypercalcemia, or hypomagnesaemia.
• Glomerular filtration rate (GFR) <60 milliliter per minute (mL/min) at Screening.
• Participant has significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion).
• Participant has history or close family history (parents or siblings) of melanoma or participant history of ocular-cutaneous albinism.
• Participant has significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder (as determined by the Investigator).
• Participant has suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening, a history of a suicide attempt in the last 20 years, or any suicidal behavior in the last month.
• Participant has participated in any clinical study with an investigational drug/device within 30 days (or 5 half-lives) prior to the first day of dosing.
• Participant was previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
• Participant has inability to comply with once daily dosing (QD) injection regimen.
• Female participants who are breastfeeding or nursing.
• Participant has cognitive impairment that, in the investigator's opinion, precludes participation to the study.
• Participant is, in investigator's opinion, otherwise not suitable to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: Setmelanotide 2-7 mg + Placebo for Moxifloxacin; Participants received titrated doses of 2-7 milligrams (mg) setmelanotide once daily by subcutaneous (SC) injection, starting with a dose of 2 mg from Days 1 to 7, 3 mg from Days 8 to 10, 5 mg from Days 11 to 13 and 7 mg from Days 14 to 16. Participants also received single oral dose of placebo matching moxifloxacin on Days 10 and 16.	Drug: Setmelanotide; Administered once daily via SC injection.; Drug: Oral Placebo; Placebo capsules via oral administration.
Active Comparator: Group 2: Placebo for Setmelanotide + Moxifloxacin 400 mg + Placebo for Moxifloxacin; Participants received placebo matching setmelanotide once daily by SC injection from Days 1 to 16. Participants also received a single oral dose of 400 mg moxifloxacin on Day 10 and a single oral dose of placebo matching moxifloxacin on Day 16.	Drug: Oral Placebo; Placebo capsules via oral administration.; Drug: Moxifloxacin; Moxifloxacin capsules via oral administration.; Drug: SC Placebo; Placebo via SC injection.
Active Comparator: Group 3: Placebo for Setmelanotide + Placebo for Moxifloxacin + Moxifloxacin 400 mg; Participants received placebo matching setmelanotide once daily by SC injection from Days 1 to 16. Participants also received a single oral dose of placebo matching moxifloxacin on Day 10 and a single oral dose of 400 mg moxifloxacin on Day 16.	Drug: Oral Placebo; Placebo capsules via oral administration.; Drug: Moxifloxacin; Moxifloxacin capsules via oral administration.; Drug: SC Placebo; Placebo via SC injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Setmelanotide Concentration-related Placebo-corrected Change From Baseline (CHFB) in Fridericia's Correction (QTcF) at Day 10	Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Baseline and Day 10. ECG analysts were blinded to the treatment, timepoint and participant. QT interval was corrected for heart rate using QTcF. CHFB in QTcF was calculated at each timepoint.	Baseline and Day 10: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hours (hrs) postdose
Setmelanotide Concentration-related Placebo-corrected CHFB in QTcF at Day 16	Continuous 12-lead digital ECG recording was performed on Baseline and Day 16. ECG analysts were blinded to the treatment, timepoint and participant. QT interval was corrected for heart rate using QTcF. CHFB in QTcF was calculated at each timepoint.	Baseline and Day 16: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Placebo-corrected CHFB in Heart Rate (HR) After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 10	The CHFB in HR was analyzed using an analysis of variance model (ANOVA) including treatment, time and their interaction as main factors and structuring the residual matrix in order to account for the repeated measurement pattern of the data. HR was considered as covariate. Placebo corrected values were reported in the inferential statistics.	Baseline and Day 10: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hours (hrs) postdose
Placebo-corrected CHFB in HR After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 16	The CHFB in HR was analysed using an ANOVA including treatment, time and their interaction as main factors and structuring the residual matrix in order to account for the repeated measurement pattern of the data. HR was considered as covariate.	Baseline and Day 16: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose
Placebo-corrected CHFB in QTcF Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 10	The CHFB in QTcF was analyzed using an ANOVA including treatment, time and their interaction as main factors and structuring the residual matrix in order to account for the repeated measurement pattern of the data. HR was considered as covariate.	Baseline and Day 10: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose
Placebo-corrected CHFB in QTcF Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 16	The CHFB in QTcF was analysed using an ANOVA including treatment, time and their interaction as main factors and structuring the residual matrix in order to account for the repeated measurement pattern of the data. HR was considered as covariate.	Baseline and Day 16: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose
Placebo-corrected CHFB in PR Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 10	The CHFB in PR was analyzed using an ANOVA including treatment, time and their interaction as main factors and structuring the residual matrix in order to account for the repeated measurement pattern of the data. HR was considered as covariate.	Baseline and Day 10: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose
Placebo-corrected CHFB in PR Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 16	The CHFB in PR was analysed using an ANOVA including treatment, time and their interaction as main factors and structuring the residual matrix in order to account for the repeated measurement pattern of the data. HR was considered as covariate.	Baseline and Day 16: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose
Placebo-corrected CHFB in QRS Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 10	The CHFB in QRS was analysed using an ANOVA including treatment, time and their interaction as main factors and structuring the residual matrix in order to account for the repeated measurement pattern of the data. HR was considered as covariate.	Baseline and Day 10: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose
Placebo-corrected CHFB in QRS Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 16	The CHFB in QRS was analyzed using an ANOVA including treatment, time and their interaction as main factors and structuring the residual matrix in order to account for the repeated measurement pattern of the data. HR was considered as covariate.	Baseline and Day 16: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose
Number of Participants With at Least One Treatment-Emergent Abnormal Value in HR Intervals After Administration of SC Setmelanotide	A treatment-emergent abnormality/finding was defined as any abnormality/finding not already reported on any of the ECGs collected before the administration. Abnormal findings included: HR (<40 beats/min, HR>120 beats/min and Relative CHFB >25%) Relative CHFB = 100*(Value-Baseline)/Baseline	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)
Number of Participants With at Least One Treatment-Emergent Abnormal Value in PR Intervals After Administration of SC Setmelanotide	A treatment-emergent abnormality/finding was defined as any abnormality/finding not already reported on any of the ECGs collected before the administration. Abnormal findings included: PR (>220 msec, Relative CHFB >25%); Relative CHFB = 100*(Value-Baseline)/Baseline	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)
Number of Participants With at Least One Treatment-Emergent Abnormal Value in QRS Intervals After Administration of SC Setmelanotide	A treatment-emergent abnormality/finding was defined as any abnormality/finding not already reported on any of the ECGs collected before the administration. Abnormal findings included: QRS ( >120 msec, Relative CHFB >25%); Relative CHFB = 100*(Value-Baseline)/Baseline	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)
Number of Participants With at Least One Treatment-Emergent Abnormal Value in QTcF Intervals After Administration of SC Setmelanotide	A treatment-emergent abnormality/finding was defined as any abnormality/finding not already reported on any of the ECGs collected before the administration. Abnormal findings included: QTcF (450<QTc<=480 msec, 480<QTc<=500 msec, QTc>500 msec, 30<CHFB in QTc<=60 msec, CHFB in >60 msec)	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)
Number of Participants With at Least One Treatment-Emergent Abnormal Finding in T-wave Morphology and U-wave Presence After Administration of SC Setmelanotide	A treatment-emergent abnormality/finding will be defined as any abnormality/finding not already reported on any of the ECGs collected before the administration. Abnormal findings included : QTcF Increase From Baseline, > 30 msec And < 60 msec	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)
Moxifloxacin Concentration-related CHFB in QTcF at Day 10	Continuous 12-lead digital ECG recording was performed on Baseline and Day 10. ECG analysts were blinded to the treatment, timepoint and participant. CHFB in QTcF was calculated at each timepoint.	Baseline and Day 10: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose
Moxifloxacin Concentration-related CHFB in QTcF at Day 16	Continuous 12-lead digital ECG recording was performed on Baseline and Day 16. ECG analysts were blinded to the treatment, timepoint and participant. CHFB in QTcF was calculated at each timepoint.	Baseline and Day 16: Pre dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 24 hrs postdose

Collaborators and Investigators

• Sponsor: Rhythm Pharmaceuticals, Inc.
• Investigators: Study Chair: David Meeker, MD, Rhythm Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2021
• Primary Completion (Actual): April 7, 2022
• Study Completion (Actual): April 7, 2022

Study Registration Dates

• First Submitted: July 30, 2021
• First Submitted That Met QC Criteria: September 7, 2021
• First Posted (Actual): September 16, 2021

Study Record Updates

• Last Update Posted (Actual): May 3, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Healthy Volunteers
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin
• Other Study ID Numbers: RM-493-032; 263791 (Other Identifier: Paraxel)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No