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

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

Official Title
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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

Conditions
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Drug Toxicity

Intervention / Treatment
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* Drug: HPN-100
* Drug: HPN-100 or Placebo
* Drug: Placebo
* Drug: Moxifloxacin
* Drug: HPN-100
* Drug: HPN-100


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm 1<br>Cohort A: 9 mL HPN-100 or placebo Cohort B: 12 mL HPN-100 placebo | Drug: HPN-100<br>* single oral dose of 9 mL HPN-100 given via syringes 3 times daily for 3 days<br>Drug: HPN-100 or Placebo<br>* single oral dose of 12 mL HPN-100 given via syringes 3 times daily for 3 days<br>|
| Placebo Comparator: Arm 2<br>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: Placebo<br>* single oral (by mouth) dose of 9 mL placebo given via syringes 3 times daily for 3 days<br>Drug: Moxifloxacin<br>* single oral 400-mg dose on study Day 3<br>Drug: HPN-100<br>* single oral dose of 6 mL HPN-100 and 3 mL placebo given via syringes 3 times daily for 3 days<br>Drug: HPN-100<br>* single oral dose of 9 mL HPN-100 given via syringes 3 times daily for 3 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 |