Double-Blind Randomized Crossover Trial to Access Electrocardiogram Effects of HPN-100

Double-Blind Randomized Placebo-Control Trial to Evaluate Electrocardiogram Effects of HPN-100 as Defined by Clinical and Supratherapeutic Dose in Healthy Men and Women

Arm 1:

Primary Objective:

• To determine the safety and tolerability of multiple ascending, supratherapeutic doses of HPN-100.

Arm 2:

Primary Objective:

• To assess the effects of steady-state levels of HPN-100 metabolites (4 phenylbutyric acid [PBA], phenylacetic acid [PAA], and phenylacetylglutamine [PAGN]) on 12-lead electrocardiogram (ECG) parameters in healthy male and female subjects with the primary endpoint being the time-matched change from baseline in the QT interval corrected for heart rate (HR) based on an individual correction method (QTcI).

Study Overview

• Status: Completed
• Conditions: Drug Toxicity
• Intervention / Treatment: Drug: HPN-100; Drug: HPN-100 or Placebo; Drug: HPN-100; Drug: Placebo; Drug: Moxifloxacin

Detailed Description

Assess the effects of steady-state levels of HPN-100 metabolites (4-phenylbutryic acid (PBA), phenylacetic acid (PAA), and phenylacetylglutamine (PAGN) on 12-lead electrocardiogram (ECG) parameters in health male and female subjects with the primary endpoint being the time-matched change from baseline in the QT interval corrected for heart rate(HR) based on an individual correction method (QTcl).

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53704
      • Covance Clinical Pharmacology, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must be in good health
• Negative hepatitis panel and negative HIV antibody screens
• Females must be non-pregnant, non-lactating, and either postmenopausal or agree to to use adequate contraceptive methods throughout the study
• Males must either be sterile or willing to use adequate contraceptive methods throughout the study
• Willing and able to comply with all trial requirements
• Able to comprehend and willing to sign an Informed Consent Form (ICF)

Exclusion Criteria:

• History or clinical manifestations of significant allergic, metabolic, hepatic, renal, endocrine, hematological, pulmonary, cardiovascular, gastrointestinal, urological, neurological, or psychiatric disorders
• History of hypersensitivity or allergies to any drug compound
• History of stomach or intestinal surgery or resection
• History or presence of an abnormal ECG
• History of alcoholism or drug addiction within 1 year
• Use of any tobacco-containing or nicotine-containing products within 3 months
• Participated in any other clinical trial of an investigational drug (or a medical device) within 30 days
• Use of any prescription medications/products other than contraceptives within 14 days
• Use of any over-the-counter, non-prescription preparations (including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations) within 7 days
• Test positive for drug(s) of abuse, ethanol, or cotinine
• Have donated blood or blood components within 30 days
• Have received blood products within 2 months
• Have a history of unexplained syncope
• Have a family history of unexplained sudden death

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Arm 1; Cohort A: 9 mL HPN-100 or placebo Cohort B: 12 mL HPN-100 placebo	Drug: HPN-100; single oral dose of 9 mL HPN-100 given via syringes 3 times daily for 3 days; Drug: HPN-100 or Placebo; single oral dose of 12 mL HPN-100 given via syringes 3 times daily for 3 days; Drug: HPN-100; single oral dose of 6 mL HPN-100 and 3 mL placebo given via syringes 3 times daily for 3 days
Placebo Comparator: Arm 2; This study requires 4 periods. In each of the periods you will receive one of the dose groups listed below. At the completion of the study you will have participated in all 4 dose groups. The order in which you participate in each dose group will be randomly assigned. Dose Group A: 9 mL placebo via oral syringe 3 times daily for 3 days Dose Group B: single oral dose of 400 mg moxifloxacin on study Day 3 Dose Group C: 6 mL HPN-100 and 3 mL placebo via oral syringe 3 times daily for 3 days Dose Group D: 9 mL HPN-100 via oral syringe 3 times daily for 3 days	Drug: HPN-100; single oral dose of 9 mL HPN-100 given via syringes 3 times daily for 3 days; Drug: HPN-100; single oral dose of 6 mL HPN-100 and 3 mL placebo given via syringes 3 times daily for 3 days; Drug: Placebo; single oral (by mouth) dose of 9 mL placebo given via syringes 3 times daily for 3 days; Drug: Moxifloxacin; single oral 400-mg dose on study Day 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability as measured by the rate and severity of adverse events in each treatment group.	3-day treatment period
Changes from baseline QTcI as a measure of effects of study-state HPN-100 metabolites: PBA, PAA, and PAGN	4 treatment regimens for 3 days with a 4 day minimum washout period between treatments

Secondary Outcome Measures

Outcome Measure	Time Frame
Correlate time-matched ECG waveform changes to steady-state levels of HPN-100 by using QTcB and QTcF formulas to assess ECG morphologic changes.	4 treatment regimens for 3 days with a 4 day minimum washout period between treatments
Correlate time-matched QTcI change from baseline and serum levels of PBA, PAA, and PAGN drawn on Day 1, Day 2, Day 3, and Day 4	4 treatment regimens for 3 days with a 4 day minimum washout period between treatments
Gender differences in metabolism of HPN-100 as measured by time-matched serum levels of HTN-100, PBA, PAA, and PAGN via samples drawn on Day 1, Day 2, Day 3, and Day 4.	4 treatment regimens for 3 days with a 4 day minimum washout period between treatments
Number and severity of adverse events in each treatment group.	4 treatment regimens for 3 days with a 4 day minimum washout period between treatments

Collaborators and Investigators

• Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: May 31, 2010
• First Submitted That Met QC Criteria: May 31, 2010
• First Posted (Estimate): June 3, 2010

Study Record Updates

• Last Update Posted (Estimate): January 16, 2017
• Last Update Submitted That Met QC Criteria: January 13, 2017
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Drug-Related Side Effects and Adverse Reactions; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cryoprotective Agents; Moxifloxacin; Glycerol
• Other Study ID Numbers: HPN-100-010