Effect of Repeated Dosing of Naproxcinod on Renal Hemodynamic and on Sodium Balance in Healthy Volunteers Before and After a Single Dose of Furosemide

A Phase 1, Single-Center, Randomized, Parallel-group, Placebo- and Naproxen- Controlled, Double-blind Study to Evaluate the Effect of Naproxcinod 750 mg Bid Administered for 8 Days on the Renal Hemodynamics, Natriuretic and Renin Responses to a Single Bolus IV Dose of Furosemide 40 mg in Male Healthy Normotensive Volunteers

This phase 1 study is an 8-day treatment period, randomized, controlled, double-blind, 3 parallel-groups, monocentric study. The primary objective is to evaluate the effect of naproxcinod on the renal function when co-administered with furosemide in comparison to naproxen and placebo.

Study Overview

• Status: Completed
• Conditions: Renal Hemodynamics
• Intervention / Treatment: Drug: placebo; Drug: furosemide; Drug: Naproxen; Drug: naproxcinod

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 33 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Healthy, non smoker male subjects aged 18 and 35 years (inclusive), at the Screening visit.
2. Body Mass Index (BMI) strictly between 18 and 30 kg/m² (inclusive) with body weight≥ 50 kg at the Screening visit.
3. Normal physical examination at the Screening visit.
4. Normal ECG (12-lead) at the Screening visit, as judged by the Investigator.
5. At Screening and run-in period visits , Systolic Blood Pressure (SBP) between 100 and 139 mmHg (inclusive) and Diastolic Blood Pressure (DBP) between 50 and 89 mmHg (inclusive).
6. At Screening and run-in period visits, HR between 45 and 90 bpm (inclusive).
7. Subjects must be able to understand the written information sheet and informed consent and comply with all study requirements.
8. Subjects must provide a written, dated and signed informed consent prior to any study procedure.

Exclusion Criteria:

1. A history of hypersensitivity reactions (such as asthma, rhinitis, or urticaria) to aspirin, naproxen or any other NSAIDs; or hypersensitivity or contraindications to organic nitrate drugs or hypersensitivity to furosemide or to sinistrine or PAH.
2. Family history of hypertension which may disqualify the subject, as judged by the investigator..
3. History of any clinically relevant gastrointestinal (such as gastritis or gastric ulcer), respiratory, psychiatric, neurologic, kidney, liver, cardiac disease, bleeding disorder, other disease/condition or abnormal physical finding which may interfere with the study objectives. The investigator may disqualify any subject for a sound medical or psychiatric reason.
4. History or presence of ASAT >40UI/L, ALAT >40UI/L, serum bilirubin 3 times above the Upper Limit of Normal range at the Screening visit.
5. Creatinine clearance inferior/equal to 80 ml/min as calculated with the Cockcroft-Gault formula (Appendix 5 of the protocol) at the Screening visit.
6. Plasmatic potassium <3.5 mmole/L at the Screening visit.
7. Seropositivity for HBs, HBc, HIV 1 or HIV 2 at the Screening visit.
8. Donations of blood, plasma or platelets within 3 months prior to the Screening visit or donation planned during the 3 months following Day 8.
9. Any clinically significant abnormal laboratory values at the Screening visit.
10. At the Screening visit, after 1 minute in a standing position, a drop of more than 20 mmHg in SBP or 10 mmHg in DBP or a clinical manifestation of postural hypotension.
11. Chronic use of any drugs (prescription or OTC) within 4 weeks prior to Visit 2 (single use of medication such as paracetamol for headache will be tolerated at the lowest possible dose).
12. Intake of any Nitric Oxide Synthase Inhibitor within 1 month before Screening visit.
13. History of drug addiction or alcohol abuse as defined by DSM IVR, diagnostic criteria for drug and alcohol abuse or drug addiction.
14. Positive drug screening (opiates, cannabinoids, cocaine, benzodiazepines, amphetamines, barbiturates) at the Screening visit.
15. Current participation or participation within 60 days prior to the Screening visit, in another investigational study, including the present study or any previous enrolment in a naproxcinod study.
16. In custody due to an administrative or a legal decision, or under tutelage, or being admitted to a sanitary or social institution.
17. Any direct or indirect involvement with the study conduct or staff at site or any family link with study site staff.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Drug: placebo; placebo
Active Comparator: naproxen	Drug: Naproxen; Naproxen 500 mg bid
Experimental: naproxcinod	Drug: furosemide; furosemide; Drug: naproxcinod; naproxcinod 750 mg bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To evaluate the effect of naproxcinod on the renal function when co-administered with furosemide in comparison to naproxen and placebo	Day 8, between H3 and H9

Secondary Outcome Measures

Outcome Measure	Time Frame
to assess the effect of naproxcinod on blood pressure (BP) in comparison with naproxen and placebo over 1 week and when co-administered with furosemide + to assess the general safety and tolerability	for over 1 week
To evaluate the effect of naproxcinod when administered alone on renal function, after a week of administration, in comparison with naproxen and placebo.	Day 8 at H4

Collaborators and Investigators

• Sponsor: NicOx

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: May 27, 2009
• First Submitted That Met QC Criteria: May 27, 2009
• First Posted (Estimate): May 28, 2009

Study Record Updates

• Last Update Posted (Estimate): June 17, 2011
• Last Update Submitted That Met QC Criteria: June 16, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Gout Suppressants; Sodium Potassium Chloride Symporter Inhibitors; Nitric Oxide Donors; Furosemide; Naproxen; Naproxen-n-butyl nitrate
• Other Study ID Numbers: HCT3012-X-113