A Double-Blind Pharmacokinetic Interaction Study Evaluating the Effect of a Single IV Infusion of GGF2 or Placebo on Midazolam Pharmacokinetics in Patients With Heart Failure

Study Overview
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Brief Summary
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The study will examine midazolam pharmacokinetics following single dose administration of 3 planned dose levels of GGF2 .

Detailed Description
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This drug-drug interaction (DDI) study evaluates the potential effect of intravenously administered GGF2 on the elimination kinetics of midazolam.

Official Title
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Phase 1b Study of Pharmacokinetic Interaction, Evaluating the Effect of a Single IV Infusion of GGF2 or Placebo on Midazolam Pharmacokinetics in Patients With Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Other: Placebo
* Drug: GGF2
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: If female, must be at least 2 years post-menopausal or have bilateral oophorectomy, hysterectomy or documented sterility If male, must have documented sterility (by verbal report or previous vasectomy), or if non-sterile, must agree to use barrier contraception for the entire duration of the trial and until 3 months after the last dose of investigational product. Must also agree not to donate sperm during the study and up to 3 months after the last dose of investigational product Stable coronary disease without unstable angina or acute coronary syndrome in the last 6 months All cardiac medications, specifically beta-blockers, renin-angiotensin system inhibitors, aldosterone antagonists, hydralazine and nitrates are at a stable dose (at least 4 weeks) prior to Day 1 Exclusion Criteria: Any previous exposure to GGF2 or other neuregulins Initiation or change of a prescription medication within the 2 weeks prior to Day 1, and/or concomitant medication regimen is expected to change during the course of the study Known allergic reaction to midazolam, or any of the components of midazolam syrup (including cherry flavoring), or components of GGF2 diluent Known specific hepatic disease; total bilirubin >2 mg/dL, AST > 100 IU History of hepatic impairment (hepatitis B and C) Type I Diabetes Documented stroke or transient ischemic attack (TIA) within 2 months of study enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GGF2<br>Patients will be randomized to receive GGF2 or Placebo and on study day 3 administered a single IV infusion. Each patient will receive 5 oral doses of Midazolam syrup on study day 1 and days 4 through 7 respectively. | Drug: GGF2<br> <br> Drug: Midazolam<br> <br> |
| Placebo Comparator: Placebo<br>Patients will be randomized to receive GGF2 or Placebo and on study day 3 administered a single IV infusion. Each patient will receive 5 oral doses of Midazolam syrup on study day 1 and days 4 through 7 respectively. | Other: Placebo<br> <br> Drug: Midazolam<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of GGF2 IV infusion in patients with heart failure assessed by review of Treatment Emergent Adverse Events (TEAE) |  | 90 days (± 3 days) | 
| Pharmacokinetic (PK) parameter Area Under the Curve (AUC) of a single dose of midazolam when administered prior to and following a single IV infusion of GGF2 or Placebo |  | Day 1 to Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of 2D-Echocardiogram (2D-ECHO) or ECHO with contrast |  | Visit 1 (day-14 to day-1) and visits 2-5 (day 8 through day 90 ± 3 days) | 
| Change from baseline of the Six-Minute Walk Test (6MWT) |  | Visit 1 (day-14 to day-1) and visits 3-5 (day 14 through day 90 ± 3 days) | 
| Change from baseline of metabolic testing measuring maximum capacity of body to transport and use oxygen during incremental exercise (VCO2 and VO2 max) |  | Visit 1 (day-14 to day-1) and visits 3-5 (day 14 through day 90 ± 3 days) | 
| Change from baseline of the M.D. Anderson Symptom Inventory (MDASI) score | MDASI is a questionnaire asking patients about the severity of their heart disease symptoms and impact of the symptoms on daily functioning during the past 24 hours. Scale ranges from 0 (sympton has not been present) to 10 (the symptom was as bad as you can imagine it could be). | Visit 1 (day-14 to day-1) and visits 3-5 (day 14 through day 90 ± 3 days) |