Single-Dose Study to Evaluate the PKs of Pretomanid in Participants With Renal Impairment Compared to Participants With Normal Renal Function

NCT03896750 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 15-0037
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 3

Brief Summary

This is a Phase 1, open-label, single-dose, sequential group study to compare the safety and pharmacokinetics (PK) of pretomanid in the following groups of participants: 1) participants with severe renal impairment including those with end stage renal disease (ESRD) not on dialysis, and participants with mild or moderate renal impairment, designated as Groups 2, 3, and 4, respectively; and 2) participants with normal renal function matched to the above renal impairment groups, designated as Groups 1A, 1B, and 1C, respectively. The study will be conducted following a reduced PK study design in Part A. Part A will enroll participants from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 6 participants with severe renal impairment and ESRD, not on dialysis). A decision to proceed to Part B will be made after the PK of pretomanid, and safety in participants enrolled in Part A have been reviewed. If Part A demonstrates at least a 50% increase in pretomanid area under the plasma concentration-time curve (AUC) in Group 2 (severe renal impairments and ESRD, not on dialysis) relative to the exposures in Group 1A (matched participants with normal renal function), then the reduced PK study will extend to the full PK study to enroll participants into Part B (i.e., to investigate mild and moderate renal impairment). All Part B groups (1B, 1C, 3, and 4) will be enrolled concurrently. If the reduced PK study shows at least a 50% increase in AUC in patients with severe renal impairment and patients with ESRD not yet on dialysis relative to the matched healthy controls, a "full PK" renal impairment study in patients with all intermediate levels of renal function impairment should be conducted. Otherwise, no further study is recommended. The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK profiles of pretomanid in plasma and urine after a single oral dose of 200 mg in participants with renal impairment compared to matched healthy controls.

Conditions

Renal Impairment; Tuberculosis

Keywords

Open-Label; Pretomanid; Renal Pharmacokinetic; Single-Dose

Outcome Measures

Primary Outcomes (2)

• Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls

  The mean fold change of AUC(0-last) Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points was calculated by noncompartmental analysis using the linear up log down method. The mean fold change of each enrolled renal impairment arm as compared to the Healthy Matched Control arm was calculated by a linear regression model controlling for site.

  Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.

• Fold Change in Pretomanid AUC(0-infinity) in Participants With Renal Impairment as Compared to Matched Healthy Controls

  The mean fold change of AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda\_z where Clast was the last observed concentration and Lambda\_z is the elimination rate constant. The mean fold change of each enrolled renal impairment arm as compared to the Healthy Matched Control arm was calculated by a linear regression model controlling for site.

  Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.

Secondary Outcomes (24)

• Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points

  Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.

• Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points

  Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.

• Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points

  Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.

• Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points

  Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.

• Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points

  Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.

Study Arms (6)

Part A Group 1A

ACTIVE COMPARATOR

6 healthy participants with normal renal function: Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR \> / = 90 mL/min) matched to Group 2 by race, gender, age (+/- 10 years, but between 18 to 85 years of age) and body mass index (BMI) (18 to 40 kg/m\^2) will receive a single oral dose of 200 mg pretomanid

Drug: PA-824

Part A Group 2

EXPERIMENTAL

6 participants with severe renal impairment: Stage 4, Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR 15-29 mL/min), and End Stage Renal Disease (ESRD) not on dialysis: Stage 5, Modification of Diet in Renal Disease (MDRD) with estimated Glomerular Filtration Rate (eGFR \< 15 mL/min) matched to Group 1A will receive a single oral dose of 200 mg pretomanid

Drug: PA-824

Part B Group 1B

ACTIVE COMPARATOR

6 healthy participants with Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR of \> / = 90 mL/min) matched to Group 3 by race, gender, age (+/- 10 years, but between 18 to 85 years of age) and body mass index (BMI) (18 to 40 kg/m\^2) will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed

Drug: PA-824

Part B Group 1C

ACTIVE COMPARATOR

6 healthy participants: with Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR \> / = 90 mL/min) matched to Group 4 by race, gender, age (+/- 10 years, but between 18 to 85 years of age) and body mass index (BMI) (18 to 40 kg/m\^2) will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed

Drug: PA-824

Part B Group 3

EXPERIMENTAL

6 participants with mild renal impairment: Stage 2, Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR 60-89 mL/min) matched to Group 1B will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed

Drug: PA-824

Part B Group 4

EXPERIMENTAL

6 participants with moderate renal impairment: Stage 3, Modification of Diet in Renal Disease (MDRD) estimated Glomerular Filtration Rate (eGFR = 30-59 mL/min) matched to Group 1C will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed

Drug: PA-824

Interventions

PA-824 DRUG

PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.

Part A Group 1A; Part A Group 2; Part B Group 1B; Part B Group 1C; Part B Group 3; Part B Group 4

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have the ability to understand the requirements of the study and have provided written informed consent\* before any study-related procedure is performed.
• \*As evidence by signature on an informed consent document approved by the Institutional Review Board
• Agree to abide by the study restrictions.
• Are between the ages of 18 and 85 years, inclusive, at the time of enrollment.
• Must have mild, moderate, or severe renal impairment or end stage renal disease (ESRD), but are not on dialysis.
• Have no history of chronic tobacco/nicotine usage (i.e., \>10 cigarettes per day for 3 months minimum prior to admission).
• Have corrected QT interval by Fridericia (QTcF) \<460 msec on Electrocardiogram (ECG).
• Have a Body Mass Index (BMI) of 18 to 40 kg/m\^2 at enrollment.
• Women of childbearing potential\*\* must use an acceptable contraception method\*\*\* for the duration of the study.
• \*\*Not sterilized via tubal ligation, bilateral oophorectomy, bilateral salpingectomy, hysterectomy, implanted contraceptive device placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or \<1 year has passed since the last menses if menopausal.
• \*\*\*Includes, non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the participant receiving study product, barrier methods such as condoms with spermicide or diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill").
• If participant is male and capable of reproduction, agrees to avoid fathering a child for the duration of the study by using an acceptable method of birth control\*\*\*\*.
• Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product.
• Have the ability to understand the requirements of the study and have provided written informed consent\* before any study-related procedure is performed.
• \*As evidence by signature on an informed consent document approved by the Institutional Review Board (IRB).

You may not qualify if:

• History of known active TB.
• History of peptic ulcer disease.
• Known hypersensitivity to pretomanid or any of the excipients.
• History of any clinically significant uncontrolled cardiac abnormality (as deemed by the Principal Investigator (PI)).
• Any clinically significant electrocardiogram (ECG) abnormality at screening\*.
• \*Note: the following can be considered not clinically significant:
• \- Heart rate \</= 50 beats per minute (bpm) (sinus bradycardia with heart rate between 45 and 49, inclusive, is acceptable only in younger athletic participants, as determined by the Principal Investigator ))
• Mild first-degree atrioventricular (A-V) block (P-R interval \>0.23 seconds)
• Right or left axis deviation
• Incomplete right bundle branch block
• Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic participants
• History of, or screening results show a corrected QT interval by Fridericia (QTcF) \>/= 460 msec.
• Family history of Long-QT Syndrome or sudden death when a cause of death is unknown.
• Inability to swallow tablets.
• History of fever or documented fever (oral temperature \>/= 100.4 degrees F) in the 48 hours prior to admission to the hospital.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (3)

Advanced Pharma - Miami

Miami, Florida, 33147, United States

Location

Saint Louis University Center for Vaccine Development

St Louis, Missouri, 63104-1015, United States

Location

Alliance for Multispecialty Research, LLC - Knoxville

Knoxville, Tennessee, 37920, United States

Location

MeSH Terms

Conditions

Renal Insufficiency; Tuberculosis

Interventions

pretomanid

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: William Smith, MD
• Organization: Alliance for Multispecialty Research

william.smith@amrllc.com

(865) 305-9100

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 28, 2019
• First Posted: April 1, 2019
• Study Start: April 17, 2024
• Primary Completion: August 10, 2024
• Study Completion: October 28, 2024
• Last Updated: November 25, 2025
• Results First Posted: October 15, 2025

Record last verified: 2024-07-08

Locations

US (3)