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Antibiotic

Pretomanid for Kidney Failure

Phase 1

Recruiting

Research Sponsored by National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Subject Inclusion Criteria for Healthy Subjects (Groups 1A-1C): Have the ability to understand the requirements of the study and have provided written informed consent before any study related procedure is performed. Agree to abide by the study restrictions. Are healthy male or non-pregnant female, between the ages of 18 and 70, inclusive, with normal GFR > / = 90 at screening. Are free from tobacco/nicotine usage (30-day minimum from screening visit). Have a normal QTc interval < 500 msecs on electrocardiogram (ECG). Have a body mass index of 18 to 35 kg/m^2. Women of childbearing potential must use an acceptable contraception method for the duration of the study. If subject 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

Be older than 18 years old

Must not have

Subject Exclusion Criteria for Healthy Subjects (Groups 1A-1C): History of known active TB. History of peptic ulcer disease. Have known hypersensitivity to pretomanid or any of the excipients. History of any clinically significant uncontrolled cardiac abnormality. Any clinically significant ECG abnormality at screening. Family history of Long-QT Syndrome or sudden death without a preceding diagnosis of a condition that could be causative of sudden death. Inability to swallow tablets. History of fever or documented fever (oral temperature > / = 100.4 degrees Fahrenheit) in the 48 hours prior to admission to the hospital. Resting pulse rate < 50 or > 100 bpm at Screening. At Screening blood pressure > 140/90 mm Hg or < 90/65 mm Hg (sitting). History of or screening results show a QTc interval > / = 500 msecs. History of hypokalemia or hypomagnesemia. Positive result of urine drug screen or blood alcohol screen prior to hospital admission. Significant history of drug and/or food allergies. For women, subject is pregnant, breastfeeding or planning to conceive for the duration of the study. Any contraindication to the use of nitromidazoles, or prior treatment with pretomanid or delamanid. Treatment with strong CYP450 enzyme inducers or inhibitors within 7 days prior to admission or during the study, unless the substance would not likely impact the validity of the study results. Use of St. John's Wort within 7 days prior to admission and during the entire study. Consumption of products containing grapefruit within 5 days prior to dosing until discharged from the hospital. Donation of whole blood or blood products > 500 mL within 30 days and/or plans to donate during the study or up to 14 days after dosing. Participation in another interventional clinical trial within 30 days prior to dosing until after the last study visit. Hemoglobin < 10.0 g/dL in both men and women at the screening visit. Positive Screening test for HCV, HBV, or HIV. Renal transplant. Presence of any condition or finding which would jeopardize subject safety, impact study result validity, or diminish the subject's ability to undergo all study procedures and assessments. Semen donation for the duration of the study. AST and ALT > 2.0 x ULN. Hyperbilirubinemia > 1.5 x ULN.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 96 hours

Awards & highlights

No Placebo-Only Group

Summary

This trial is a Phase I, open-label, single dose, sequential group study to compare the safety and pharmacokinetics of pretomanid in subjects with severe renal impairment including those with End Stage Renal Disease (ESRD) not needing dialysis, subjects with mild or moderate renal impairment, and subjects with normal renal function. The primary objective is to evaluate the PK profiles of pretomanid in plasma and urine after a single oral dose of 200 mg in subjects with renal impairment compared to matched healthy controls.

Who is the study for?

This trial is for adults aged 18-70 with varying degrees of kidney function, from normal to severe impairment, but not on dialysis. Participants must be non-smokers, have a healthy weight range (BMI 18-35), and a normal heart rhythm. Women should not be pregnant and must use birth control; men agree to prevent pregnancy during the study.

What is being tested?

The study tests how a single dose of Pretomanid (PA-824) behaves in the body (its pharmacokinetics) in people with different levels of kidney health compared to those with normal kidneys. It involves taking one oral dose and monitoring its presence in blood and urine over three months.

What are the potential side effects?

While specific side effects are not listed here, participants will be monitored for any adverse reactions due to Pretomanid intake. This includes checking organ functions, vital signs, and overall health status throughout the trial.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

The exclusion criteria for healthy subjects are: - History of active tuberculosis - History of peptic ulcer disease - Allergy to pretomanid or any of its components - Uncontrolled heart problems - Abnormal heart rhythm - Family history of Long-QT Syndrome or sudden death - Difficulty swallowing tablets - Recent fever - Resting pulse rate too low or too high - High or low blood pressure - Abnormal heart rhythm history - Low potassium or magnesium levels - Positive urine drug screen or blood alcohol screen - Significant history of drug and/or food allergies - Pregnancy, breastfeeding, or planning to conceive during the study - Inability to use nitromidazoles or previously treated with pretomanid or delamanid - Use of certain medications within 7 days prior to admission - Use of St. John's Wort or grapefruit products within specific timeframes - Recent blood donation - Recent participation in another clinical trial - Low hemoglobin levels - Positive screening test for HCV, HBV, or HIV - Renal transplant - Any condition that could affect safety or study results - Semen donation during the study - Abnormal liver function tests

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 96 hours

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 96 hours

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 96 hours for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Secondary study objectives

Concentrations of pretomanid metabolites (M19 and M50) in plasma

Excretion of representative metabolites M19 and M50 in urine

Side effects data

From 2020 Phase 3 trial • 109 Patients • NCT02333799

52%

Peripheral sensory neuropathy

43%

Anaemia

41%

Nausea

36%

Dermatitis acneiform

36%

Vomiting

34%

Headache

20%

Neuropathy peripheral

20%

Transaminases increased

18%

Haemoptysis

18%

Decreased appetite

16%

Rash

14%

Abdominal pain

14%

Diarrhoea

14%

Back pain

14%

Gamma-glutamyltran sferase increased

14%

Dyspepsia

14%

Pruritus

11%

Amylase increased

11%

Abdominal pain upper

Blood urea increased

Pleuritic pain

Upper respiratory tract infection

Gastritis

Thrombocytopenia

Costochondritis

Lipase increased

Hypoglycaemia

Insomnia

Dry skin

Urinary tract infection

Conjunctivitis allergic

Abnormal loss of weight

Acne

Hypertension

Hyperamylasaemia

Pulmonary Tuberculosis

Alanine aminotransferase increased

Cough

Lower respiratory tract infection

Constipation

Abdominal Pain Upper

Dyspnoea

Myalgia

Pancreatitis Haemorrhagic

Aspartate aminotransferase increased

Pancreatitis

Dizziness

Depression Suicidal

Neutropenia

Disseminated Tuberculosis

Upper Gastrointestinal Haemorrhage

Abnormal Loss of Weight

Tuberculoma of Central Nervous System

Seizure

Generalized Anxiety Disorder

Generalized Tonic-Clonic Seizure

Influenza

Pain in extremity

Pneumothorax Spontaneous

Chronic obstructive pulmonary disease

Haematemesis

Syncope

Asthma

Multiple Organ Dysfunction Syndrome

100%

80%

60%

40%

20%

Study treatment Arm

Bedaquiline + PA-824 + 600mg BID Linezolid

Bedaquiline + PA-824 + 1200mg QD Linezolid

Total

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

6Treatment groups

Experimental Treatment

Active Control

Group I: Part B Group 4Experimental Treatment1 Intervention

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

Group II: Part B Group 3Experimental Treatment1 Intervention

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

Group III: Part A Group 2Experimental Treatment1 Intervention

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

Group IV: Part A Group 1AActive Control1 Intervention

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

Group V: Part B Group 1BActive Control1 Intervention

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

Group VI: Part B Group 1CActive Control1 Intervention

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

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

PA-824

2010

Completed Phase 3

~1160

0 / 2Eligibility criteria met