A Phase I Study Comparing the Safety, Pharmacokinetics and Renal Effects of VRP-034 and Marketed Polymyxin B in Healthy Volunteers

Phase 1Not Yet RecruitingNCT07502144

Venus Remedies Limited48 enrolled

Overview

This is a Phase 1, single-center, randomized, double-blind, active-controlled clinical study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and nephrotoxicity attenuation potential of VRP-034 compared with commercially available polymyxin B in healthy adult male volunteers. VRP-034 is a supramolecular cationic formulation of polymyxin B developed with the objective of mitigating polymyxin B-associated nephrotoxicity while preserving its established antibacterial activity against MDR Gram-negative pathogens. Although polymyxin B remains an important last-line therapy for serious infections caused by carbapenem-resistant organisms, its clinical use is limited by dose-dependent renal toxicity. VRP-034 has been developed with a strategy aimed at reducing kidney injury without compromising antimicrobial exposure, and preclinical studies have demonstrated an improved renal safety profile compared with conventional formulations. This study consists of three single ascending dose (SAD) cohorts followed by one multiple-dose cohort. In the SAD phase, subjects will receive weight-based intravenous doses of polymyxin B (0.4 mg/kg, 0.75 mg/kg, and 1.5 mg/kg) administered over specified infusion durations. The multiple-dose cohort will receive 1.5 mg/kg every 12 hours for up to 2 days. An independent Data Safety Monitoring Board (DSMB) will review safety and pharmacokinetic data after each SAD cohort prior to dose escalation and before initiation of the multiple-dose cohort. The primary objective is to assess the effect of VRP-034 on polymyxin B-associated nephrotoxicity using a composite measure of novel urinary kidney injury biomarkers (qualified by US FDA). Secondary objectives include assessment of safety, tolerability, and pharmacokinetic parameters.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Eligibility

Sex: MALEMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy adult male human subjects aged between 18 and 45 years, both inclusive. * Subjects weight within normal range according to normal values for Body Mass Index 18.50 to 28.00 kg/m2, both inclusive with minimum of 50 kg weight. * Subjects with normal health as determined by personal medical history, clinical examination and laboratory examinations within the clinically acceptable range. * Subject with creatinine Clearance greater than and equal to 90 ml per min. * Subjects with haemoglobin greater than and equal to 11.5 gm percentage at the time of screening. * Subject should be non smoker, non alcoholic. Further details as mentioned in the approved protocol Exclusion Criteria: * Have significant diseases or clinically significant abnormal findings during screening like medical history, physical examination, laboratory evaluations, ECG, and chest X ray. * History or presence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological, urogenital or psychiatric disease or disorder. * Use of any hormone replacement therapy within three months prior to admission. * A depot injection or implant of any drug within three months prior to admission * Subjects with G6PD deficiency. * Abnormal USG KUB or clinically significant findings in volunteers * Difficulty with donating blood. * Positive screening test for any one or more i.e HIV, Hepatitis B and Hepatitis C or syphilis RPR. * Any other issue which, in the judgment of the Investigator, will make the subject ineligible for study participation Further details as mentioned in the approved protocol

Outcomes

Primary Outcomes

Geometric Mean of Fold Changes From Baseline in Six Urinary Kidney Injury Biomarkers (CLU, CysC, KIM-1, NAG, NGAL, OPN), Each Normalized to Urine Creatinine (Composite Measure)

The composite measure (CM) is calculated for each subject as the geometric mean of fold changes from baseline in six urinary biomarkers: Clusterin (CLU), Cystatin-C (CysC), Kidney Injury Molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), Neutrophil Gelatinase-Associated Lipocalin (NGAL), and Osteopontin (OPN). Each biomarker is normalized to urine creatinine prior to analysis. Fold change is defined as the ratio of post-dose to pre-dose normalized values. The CM is calculated as the exponential of the arithmetic mean of natural log-transformed fold changes. A CM value of 1.0 indicates no change from baseline, while higher values indicate increased nephrotoxicity and lower values indicate reduced nephrotoxicity. The natural log-transformed CM (ln\[CM\]) will be compared between treatment groups using an analysis of variance (ANOVA) model.

Time frame: 48 hours after first dose (multiple-dose cohort); 24 hours after dosing (SAD cohorts 2 and 3)

Secondary Outcomes

Geometric Mean of Fold Changes From Baseline in Six Urinary Kidney Injury Biomarkers (CLU, CysC, KIM-1, NAG, NGAL, OPN), Each Normalized to Urine Creatinine (Composite Measure)

Time frame: 24 hours after first dose (multiple-dose cohort); 48 hours after dosing (SAD cohorts 2 and 3)

Maximum plasma concentration (Cmax) of polymyxin B

Cmax will be derived from plasma concentration-time data using non-compartmental analysis and summarized by treatment group.

Time frame: SAD cohorts: up to 48 hours post-dose; multiple-dose cohort: up to 12 hrs after first dose and up to 48 hrs after fourth dose.

Area under the plasma concentration-time curve (AUC0-t) of polymyxin B

AUC0-t will be calculated using non-compartmental methods, and summarized by treatment group.

Time frame: SAD cohorts: up to 48 hours post-dose; multiple-dose cohort: up to 12 hours post first dose and up 48 hrs post fourth dose

Number of participants with acute kidney injury (AKI) based on RIFLE criteria

AKI will be assessed using serum creatinine changes from baseline and classified according to RIFLE criteria (Risk, Injury, Failure). Incidence will be summarized by treatment group.