Within Subject Variability Study of ER Torsemide 20 mg Tablet in Healthy Subjects

Randomized,Open Label,Balanced,Two Treatment, Four Period, Two Sequence, Single Oral Dose, Crossover, Replicate Study Under Fasting Conditions to Test Within Subject Variability of 20mg ER Torsemide and Demadex Tablets in Healthy Adults

The study will evaluate the within-subject variability of 20mg ER torsemide as compared to 20mg IR torsemide (Demadex) in fully replicate double-crossover trial in healthy volunteers, who are consuming a high-salt diet (300 mmol/day). The study will also evaluate the effects of ER torsemide and IR torsemide on 24h sodium excretion and total urinary excretion.

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Diseases; Congestive Heart Failure
• Intervention / Treatment: Drug: Demadex 20mg Tablet; Drug: ER Torsemide 20mg Tablet

Detailed Description

Immediate Release (IR) Torsemide is a highly effective natriuretic drug but its short duration of action is a major drawback, which allows significant post-dose sodium retention, and as consequence, limits salt loss in patients with heart failure, unless dietary salt intake is severely restricted. Extended Release (ER) torsemide is being developed to address the drawback by prolonging the duration of action to increase sodium excretion even in patients who consume high salt diet (300 mmol/day).

In addition, IR torsemide induces large and abrupt urination that, in some patients, causes incontinence, and as a result, compliance becomes challenging. ER torsemide is formulated to cause robust but gradual urination over an extended period to reduce accidental wetting and improve compliance.

In this study, ER torsemide is tested for within-subject variability in fully replicate design double-crossover trial in healthy volunteers who are on a 300 mmol/day sodium diet (high salt diet). The primary endpoint of the study is full pharmacokinetics measurements after a single dose of either ER torsemide or IR torsemide (Demadex). The secondary endpoints are 24h sodium excretion and total urinary excretion.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• India
  • Bangalore, India
    • I.E.C. Consultants

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy male or female, non-smoker, weight 50 kg for male and 45 kg for female, clinically acceptable laboratory profiles with ECG and chest X-ray performed within 6 months

Exclusion Criteria:

• participation in bioavailability/bioequivalence studies,
• history of drug abuse or alcohol dependence,
• history of allergies including drug allergies,
• known hypersensitivity to Torsemide or related drugs,
• presence of clinically significant disorder,
• systolic blood pressure <90 mm Hg or > 140 mm Hg diastolic blood pressure,
• history of incontinence,
• positive urine drug screening etc.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Demadex 20mg Tablet; Demadex (IR Torsemide) 20mg tablet once daily is the reference listed drug (RLD) and is marketed for decades to treat edema in Chronic Congestive Heart Failure (CHF) and Chronic Kidney Disease (CKD) patients	Drug: Demadex 20mg Tablet; Immediate Release (IR) Torsemide; Other Names: Torsemide
Experimental: ER Torsemide 20mg Tablet; ER Torsemide 20mg tablet once daily is is the new formulation that will release the active ingredient over an extended period	Drug: ER Torsemide 20mg Tablet; Extended Release Torsemide 20 mg tablet given once daily; Other Names: ER Torsemide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak plasma concentration	Peak tosremide plasma concentration (Cmax) (ng/ml)	24 hour
Total plasma concentration	Area under the plasma concentration versus time curve (AUC) (hr/ng/ml)	24 hour
Urinary excretion	Torsemide excretion in urine (microgram/min) over 24h post dose	24 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary sodium excretion	24h sodium (mmol/min)	24 hour
Urine output	24h total urinary output (l/day)	24 hour

Collaborators and Investigators

• Sponsor: Sarfez Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Christopher Wilcox, MD, PhD, Georgetown University

Publications and helpful links

General Publications

• Murray MD, Deer MM, Ferguson JA, Dexter PR, Bennett SJ, Perkins SM, Smith FE, Lane KA, Adams LD, Tierney WM, Brater DC. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001 Nov;111(7):513-20. doi: 10.1016/s0002-9343(01)00903-2.

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2017
• Primary Completion (Actual): July 20, 2017
• Study Completion (Actual): July 20, 2017

Study Registration Dates

• First Submitted: July 8, 2017
• First Submitted That Met QC Criteria: July 11, 2017
• First Posted (Actual): July 12, 2017

Study Record Updates

• Last Update Posted (Actual): April 18, 2018
• Last Update Submitted That Met QC Criteria: April 17, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Urologic Diseases; Renal Insufficiency; Heart Failure; Kidney Diseases; Renal Insufficiency, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Torsemide
• Other Study ID Numbers: CLCD-058-15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No