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

Phase 4

Completed

Conditions: Healthy

Interventions: Drug: Moxifloxacin
Drug: Setmelanotide
Drug: Oral Placebo
Drug: SC Placebo

Registration Number: NCT05046132

Lead Sponsor: Rhythm Pharmaceuticals, Inc.

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 77

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1: Setmelanotide 2-7 mg + Placebo for Moxifloxacin	Oral Placebo	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.
Group 2: Placebo for Setmelanotide + Moxifloxacin 400 mg + Placebo for Moxifloxacin	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.
Group 2: Placebo for Setmelanotide + Moxifloxacin 400 mg + Placebo for Moxifloxacin	Oral Placebo	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.
Group 2: Placebo for Setmelanotide + Moxifloxacin 400 mg + Placebo for Moxifloxacin	SC Placebo	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.
Group 3: Placebo for Setmelanotide + Placebo for Moxifloxacin + Moxifloxacin 400 mg	Oral Placebo	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.
Group 3: Placebo for Setmelanotide + Placebo for Moxifloxacin + Moxifloxacin 400 mg	SC Placebo	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.
Group 1: Setmelanotide 2-7 mg + Placebo for Moxifloxacin	Setmelanotide	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.
Group 3: Placebo for Setmelanotide + Placebo for Moxifloxacin + Moxifloxacin 400 mg	Moxifloxacin	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.

Primary Outcome Measures

Name	Time	Method
Setmelanotide Concentration-related Placebo-corrected Change From Baseline (CHFB) in Fridericia's Correction (QTcF) at Day 10	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	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.
Setmelanotide Concentration-related Placebo-corrected CHFB in QTcF at Day 16	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	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.

Secondary Outcome Measures

Name	Time	Method
Placebo-corrected CHFB in HR After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 16	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	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.
Placebo-corrected CHFB in QTcF Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 10	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	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.
Placebo-corrected CHFB in PR Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 10	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	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.
Placebo-corrected CHFB in PR Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 16	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	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.
Placebo-corrected CHFB in QRS Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 10	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	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.
Placebo-corrected CHFB in QRS Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 16	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	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.
Placebo-corrected CHFB in Heart Rate (HR) After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 10	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	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.
Placebo-corrected CHFB in QTcF Intervals After Administration of SC Setmelanotide or Oral Moxifloxacin at Day 16	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	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.
Number of Participants With at Least One Treatment-Emergent Abnormal Value in PR Intervals After Administration of SC Setmelanotide	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)	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
Number of Participants With at Least One Treatment-Emergent Abnormal Value in QRS Intervals After Administration of SC Setmelanotide	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)	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
Number of Participants With at Least One Treatment-Emergent Abnormal Value in QTcF Intervals After Administration of SC Setmelanotide	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)	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)
Number of Participants With at Least One Treatment-Emergent Abnormal Finding in T-wave Morphology and U-wave Presence After Administration of SC Setmelanotide	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)	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
Moxifloxacin Concentration-related CHFB in QTcF at Day 10	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	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.
Moxifloxacin Concentration-related CHFB in QTcF at Day 16	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	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.
Number of Participants With at Least One Treatment-Emergent Abnormal Value in HR Intervals After Administration of SC Setmelanotide	Day 10 (for setmelanotide 3 mg) and Day 16 (for setmelanotide 7mg)	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