Phase I Interaction Study of Istaroxime and Digoxin in Subjects With Stable Heart Failure

October 21, 2014 updated by: Debiopharm International SA

A Randomized, Double-blind, Placebo-controlled Escalating Dose Phase I Interaction Study to Evaluate the Pharmacokinetics, Tolerability and Pharmacodynamics of Three Dose Levels of Debio 0614 (Istaroxime) as a 24-hour Constant Rate IV Infusion in Combination With Chronic Oral Digoxin Treatment in Patients With Controlled Cardiac Failure and Decreased Left Ventricular Systolic Function

This study explores a potential drug-drug interaction between istaroxime and digoxin in patients with stable CHF on chronic oral digoxin treatment.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

This is a single center, randomized, double blind, placebo controlled, escalating dose phase I interaction study. The three dose levels of istaroxime or placebo will be randomized sequentially to three cohorts (I to III) of 16 patients each (12 patients on istaroxime and 4 patients on placebo). Digoxin will be administered non blinded in all patients, once daily in the morning after a standardized breakfast, continuing with previously personalized dosage schedule during the screening period, treatment period, post treatment period and follow up period. Prior to accrual of cohorts II and III, a Data Monitoring Committee (DMC) will advise on the continuation to the next istaroxime dose, based on a predetermined safety review.

This 37 day study includes a screening period (Days -21 to -1), a treatment period (Day 1), a post treatment period (Days 2-4), and a follow up period (which includes one patient visit on Day 14). Patients will be confined in the phase I research center from Day -2 to Day 4.

Study Type

Interventional

Phase

  • Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Main screening inclusion criteria :

  • Signed informed consent;
  • Male or female patients ≥18 years;
  • Female patients of childbearing potential must not be pregnant;
  • Chronic stable cardiac function impairment (no change in heart failure medication over the last 3 months and without any dosage adjustment in the last 4 weeks);
  • Systolic blood pressure (SBP) of ≥ 90 mmHg and ≤ 140 mmHg;
  • LVEF ≤ 35% by any method (to be performed at screening if not measured within the last 12 months);
  • Chronic treatment (i.e. once daily dosing without interruption) with oral digoxin started at least 3 months prior to study entry and without any concomitant administration of other positive inotropic drugs;

Exclusion Criteria:

Main screening exclusion criteria :

  • Need for current or intermittent intravenous positive inotrope administration within the preceding 6 months, or hemodynamic support devices;
  • Acute coronary syndrome within the past 3 months;
  • Coronary artery bypass graft or percutaneous coronary intervention within the past 3 months;
  • Stroke within the past 6 months;
  • Atrial fibrillation or uncontrolled heart rate (HR) (> 100 beats per minute [bpm]);
  • Significant arrhythmia or second or third degree atrio-ventricular block;
  • Valvular disease as the primary cause of HF;
  • Significant ECG abnormalities as assessed by appropriately qualified physician or investigator including QTcF >450;
  • Positive testing for Human Immunodeficiency Virus (HIV), Hepatitis B and/or Hepatitis C;

Main randomization exclusion criteria:

  • HR > 100 bpm or < 50 bpm;
  • Serum potassium > 5.3 mmol/L or < 3.8 mmol/L and magnesium > 1.1 mmol/L or < 0.6 mmol/L,
  • TN I > ULN.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1
TREATMENT 0.5 μg/kg/min
Drug: Istaroxime
Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Placebo continuous i.v. infusion for 24 hours
Experimental: 2
TREATMENT 1.0 μg/kg/min
Drug: Istaroxime
Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Placebo continuous i.v. infusion for 24 hours
Experimental: 3
TREATMENT 1.5 μg/kg/min
Drug: Istaroxime
Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Placebo continuous i.v. infusion for 24 hours
Placebo Comparator: 4
PLACEBO
Drug: Istaroxime
Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours
Drug: Istaroxime
Placebo continuous i.v. infusion for 24 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Pharmacokinetic endpoints : Istaroxime PK parameters: - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) plasma concentrations - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) urine concentrations
Pharmacokinetic endpoints : Digoxin PK parameters: - Digoxin plasma concentrations
Safety endpoints: - Incidence of adverse events; - Change in vital signs; - Change in 12-lead ECG parameters; - Incidence of clinically or hemodynamically significant episodes of supraventricular or ventricular arrhythmias detected by continuous EC
Pharmacodynamic endpoints: - Change in echocardiographic parameters; - Change in SBP; - Change in non invasive cardiac output (Impedance cardiography) parameters.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Debiopharm International SA

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2009

Study Registration Dates

First Submitted

March 24, 2009

First Submitted That Met QC Criteria

March 24, 2009

First Posted (Estimate)

March 25, 2009

Study Record Updates

Last Update Posted (Estimate)

October 23, 2014

Last Update Submitted That Met QC Criteria

October 21, 2014

Last Verified

October 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Debio 0614-106
  • PAREXEL Study Number : 98378

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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