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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Congestive Heart Failure, Chronic Kidney Diseases

Intervention / Treatment
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* Drug: Demadex 20mg Tablet
* Drug: ER Torsemide 20mg Tablet


Participation Criteria
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Eligibility Criteria
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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.

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

Sexes Eligible for Study
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Male

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Fully Replicate double-crossover
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Demadex 20mg Tablet<br>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<br>* Immediate Release (IR) Torsemide<br>* Other names: Torsemide;|
| Experimental: ER Torsemide 20mg Tablet<br>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<br>* Extended Release Torsemide 20 mg tablet given once daily<br>* Other names: ER Torsemide;|

What is the study measuring?
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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 |