Healthy Volunteers
Conditions
Keywords
VRP-034, Polymyxin B, PMB, supramolecular cationic formulation, nephrotoxicity, kidney injury biomarkers, novel urinary kidney injury biomarkers, polymyxin b-associated kidney injury, Acute kidney injury, Renal Guard Programme, NAG, NGAL, KIM-1, Cystatin C, Osteopontin, Clusterin, ELISA
Brief summary
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
DRUGVRP-034 (Polymyxin B 500,000 IU)
VRP-034 (Novel formulation of polymyxin B 500,000 IU) of Venus Remedies Limited
DRUGCommercially available Polymyxin B 500,000 IU (Poly-MxB)
Commercially available Polymyxin B 500,000 IU (Poly-MxB)
Sponsors
Venus Remedies Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 48 hours after first dose (multiple-dose cohort); 24 hours after dosing (SAD cohorts 2 and 3) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 24 hours after first dose (multiple-dose cohort); 48 hours after dosing (SAD cohorts 2 and 3) | 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. |
| Maximum plasma concentration (Cmax) of polymyxin B | 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. | Cmax will be derived from plasma concentration-time data using non-compartmental analysis and summarized by treatment group. |
| Area under the plasma concentration-time curve (AUC0-t) of polymyxin B | 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 | AUC0-t will be calculated using non-compartmental methods, and summarized by treatment group. |
| Number of participants with acute kidney injury (AKI) based on RIFLE criteria | Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14 | 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. |
| Change from baseline in serum creatinine | Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14 | Serum creatinine values will be measured and summarized as change from baseline by treatment group and time point. |
| Change from baseline in blood urea nitrogen (BUN) | Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14 | BUN values will be measured and summarized as change from baseline by treatment group and time point. |
| Change from baseline in urinary creatinine | Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14 | Urinary creatinine levels will be measured and summarized as change from baseline by treatment group and time point. |
| Change from baseline in urinary albumin | Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14 | Urinary albumin levels will be measured and summarized as change from baseline by treatment group and time point. |
| Change from baseline in urine total protein | Baseline (pre-dose), Day 1, Day 2, Day 7, Day 14 | Urine total protein will be measured and summarized as change from baseline by treatment group and time point. |
| Number of participants with treatment-emergent adverse events (TEAEs) | From first dose up to Day 14 | Treatment-emergent adverse events (TEAEs) are defined as any adverse event occurring or worsening after administration of study drug. TEAEs will be summarized by treatment group, severity (CTCAE v5.0), and relationship to study drug. |
Countries
India
Contacts
CONTACTSumit Saxena
CONTACTAnmol Aggarwal
PRINCIPAL_INVESTIGATORHiren Prajapati, MD Pharmacology
Veeda Clinical Research
Outcome results
None listed