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

Official title

A Single Center, Prospective, Double-blind, Balanced, Randomized, Two-treatment, Single-period, Single Ascending Dose (SAD) and Multiple-dose, Parallel, Phase I, Study to Compare the Safety, Tolerability and Pharmacokinetics of Test Formulation VRP-034 (Novel Formulation of Polymyxin B 500,000 IU) of Venus Remedies Limited vs Commercially Available Polymyxin B for Injection USP (Poly-MxB) 500,000 IU in Normal Healthy Adult Male Human Subjects

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.

Interventions

• Drug VRP-034 (Polymyxin B 500,000 IU)
  VRP-034 (Novel formulation of polymyxin B 500,000 IU) of Venus Remedies Limited
• Drug Commercially available Polymyxin B 500,000 IU (Poly-MxB)
  Commercially available Polymyxin B 500,000 IU (Poly-MxB)

Primary outcome measures

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

Secondary outcome measures (10)

• 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 [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 [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 [Time frame: Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14]
• Change from baseline in serum creatinine [Time frame: Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14]
• Change from baseline in blood urea nitrogen (BUN) [Time frame: Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14]
• Change from baseline in urinary creatinine [Time frame: Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14]
• Change from baseline in urinary albumin [Time frame: Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14]
• Change from baseline in urine total protein [Time frame: Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14]
• Number of participants with treatment-emergent adverse events (TEAEs) [Time frame: From first dose up to Day 14]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

India · 1 center

• Veeda Clinical Research Ltd — Ahmedabad

Publications

• Vishwakarma K, Bisht A, Kumar P, Kumar S, Akhter J, Payasi A, Chaudhary S, Aggarwal A. Toxicokinetic profiling of VRP-034: Evaluating its potential in mitigating polymyxin-B-associated nephrotoxicity. Int J Antimicrob Agents. 2025 Feb;65(2):107393. doi: 10.1016/j.ijantimicag.2024.107393. Epub 2024 Nov 28. PMID 39612992
• Payasi A, Yadav MK, Chaudhary S, Aggarwal A. Evaluating nephrotoxicity reduction in a novel polymyxin B formulation: insights from a 3D kidney-on-a-chip model. Antimicrob Agents Chemother. 2024 Oct 8;68(10):e0021924. doi: 10.1128/aac.00219-24. Epub 2024 Sep 3. PMID 39225483
• Pye K, Tasinato E, Shuttleworth S, Devlin C, Brown C. Comparison of the Impact of VRP-034 and Polymyxin B upon Markers of Kidney Injury in Human Proximal Tubule Monolayers In Vitro. Antibiotics (Basel). 2024 Jun 6;13(6):530. doi: 10.3390/antibiotics13060530. PMID 38927196

Identifiers

NCT: NCT07502144 · 23-VIN-0367 · CTRI/2026/02/104919

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗