Pretomanid for Kidney Failure

No longer recruiting at 4 trial locations

Overseen By William B Smith

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: CYP3A4 inducers, inhibitors

Disqualifiers: Active TB, Peptic ulcer, Cardiac abnormality, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to study the effects of pretomanid (PA-824) on individuals with varying levels of kidney function. Researchers seek to understand how the drug behaves in the body and assess its safety for those with kidney issues, including severe kidney failure, compared to individuals with normal kidney function. Participants will take a single dose of the drug, and researchers will monitor its presence in the blood and urine. The trial suits individuals with different kidney problems who are not on dialysis and do not smoke heavily. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new drug.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take strong or moderate CYP3A4 inducers or inhibitors within 14 days before admission and during the study, and you should avoid St. John's Wort and grapefruit products before and during the study.

Is there any evidence suggesting that pretomanid is likely to be safe for humans?

Research shows that the safety of pretomanid for people with kidney problems remains unknown. No studies have yet assessed its safety or effectiveness for those with kidney issues. As a result, there is no clear information on how the drug affects individuals with kidney failure or other kidney-related problems.

This is an early phase study, aimed at understanding pretomanid’s safety and its mechanism in the body. Early phase trials typically mark the first step in testing a new treatment in humans. They help researchers determine if the treatment is safe and identify any side effects.

Pretomanid is approved for other uses but not for kidney failure. It has been tested and found safe for other conditions, but its safety for kidney problems is still under investigation. Participants in the trial will be closely monitored to observe how their bodies respond to the treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for kidney failure?

Researchers are excited about pretomanid for kidney failure because it offers a potentially innovative approach compared to standard treatments like dialysis and kidney transplantation. Unlike these traditional methods, pretomanid is an oral medication, which could provide a less invasive and more convenient option for patients. Additionally, pretomanid might offer a new mechanism of action by targeting specific pathways involved in kidney function, potentially improving outcomes for those with renal impairment. This novel approach could lead to more effective management of kidney failure, providing hope for improved patient quality of life.

What evidence suggests that pretomanid might be an effective treatment for kidney failure?

Research shows that the effectiveness of pretomanid for people with kidney failure remains uncertain. Pretomanid treats certain types of tuberculosis, but its effects on individuals with varying kidney functions have not been extensively studied. This trial will explore its pharmacokinetics and safety across various treatment arms, including participants with mild, moderate, and severe renal impairment, as well as healthy participants for comparison. Clear information on its effectiveness or safety for those with kidney issues is lacking. As this is a new research area, the trials aim to understand how the drug moves and works in the bodies of people with kidney problems. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

Subject Inclusion Criteria for Patients with Renal Impairment (Groups 2-4): 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 between the ages of 18 and 70, inclusive, at the time of enrollment. Must have mild, moderate, severe or end stage renal disease but are not on dialysis. Are free from tobacco/nicotine usage (30-day minimum from screening visit). Have QTc interval on electrocardiogram (ECG) < 500 msec. 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

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

Exclusion Criteria

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

Criterion: You cannot participate if you have a history of active tuberculosis, peptic ulcer disease, allergy to the study drug, uncontrolled heart problems, abnormal heart readings, swallowing difficulties, recent fever, abnormal pulse rate, low potassium or magnesium levels, recent alcohol or drug use, strong drug interactions, use of certain herbal supplements or grapefruit products, recent blood donation, recent participation in another clinical trial, low hemoglobin levels, positive test for hepatitis or HIV, kidney transplant, or any condition that could affect your safety or the study results.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part A - Reduced PK Study

Participants receive a single oral dose of 200 mg pretomanid to evaluate pharmacokinetics and safety in severe renal impairment and matched healthy controls

Up to 96 hours

1 visit (in-person)

Part B - Full PK Study

Participants with mild and moderate renal impairment receive a single oral dose of 200 mg pretomanid after review of Part A results

Up to 96 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• PA-824

Trial Overview

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.

How Is the Trial Designed?

Group I: Part B Group 4 Experimental Treatment 1 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 3 Experimental Treatment 1 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 2 Experimental Treatment 1 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 1A Active Control 1 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 1B Active Control 1 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 1C Active Control 1 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

PA-824 is already approved in United States, European Union, India for the following indications:

Approved in United States as Pretomanid for:

• Multidrug-resistant tuberculosis
• Extensively drug-resistant tuberculosis

Approved in European Union as Pretomanid for:

• Multidrug-resistant tuberculosis
• Extensively drug-resistant tuberculosis

Approved in India as Pretomanid for:

• Multidrug-resistant tuberculosis
• Extensively drug-resistant tuberculosis

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

Doripenem, at a concentration of 5 mg/mL, demonstrated stability for up to 12 hours in 0.9% sodium chloride at room temperature, making it suitable for extended infusions.

The study confirmed that doripenem retains its potency and safety profile when prepared and stored properly, allowing for effective treatment of complicated infections within a practical time frame.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability of doripenem in vitro in representative infusion solutions and infusion bags. Psathas, PA., Kuzmission, A., Ikeda, K., et al.[2018]

Direct oral anticoagulants (DOACs) can be beneficial for patients with mild to moderate chronic kidney disease (CKD), especially those who cannot tolerate vitamin K antagonists, but their use in patients with severe renal impairment remains challenging due to limited data.

DOACs are not approved for patients with end-stage renal disease (ESRD) or those on dialysis, and careful monitoring of renal function is crucial for patients with CKD to avoid complications, particularly in high-risk groups like the elderly and diabetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DOAC use in patients with chronic kidney disease. Kcükköylü, S., Rump, LC.[2019]

Direct oral anticoagulants (DOACs) can be safely used in patients with chronic kidney disease (CKD) who have an estimated glomerular filtration rate (eGFR) above 60 mL/min, offering greater efficacy and safety compared to vitamin K antagonists (VKAs).

In patients with CKD stage 3, DOACs are as effective as VKAs but have a lower risk of bleeding; however, their use should be avoided in patients with an eGFR below 30 mL/min due to increased bleeding risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct oral anticoagulants in patients with chronic kidney disease: patient selection and special considerations. Lutz, J., Jurk, K., Schinzel, H.[2022]

In a study of eight patients with end-stage renal disease undergoing hemodialysis, the pharmacokinetics of panipenem/betamipron were evaluated, revealing that hemodialysis significantly increased the clearance of panipenem compared to patients not on dialysis.

The study recommends a dosing regimen of 500 mg/500 mg of panipenem/betamipron once daily for patients with end-stage renal disease, which is expected to provide similar clinical outcomes as in patients with normal kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of panipenem/betamipron in patients with end-stage renal disease. Ohashi, N., Uematsu, T., Nagashima, S., et al.[2019]

Direct oral anticoagulants (DOACs) are generally safer and more effective than vitamin K antagonists (VKAs) for most patients, but their safety and efficacy in patients with chronic kidney disease (CKD) remain uncertain due to the exclusion of these patients from major clinical trials.

Among DOACs, apixaban has the most research supporting its use in patients with end-stage renal disease (ESRD) and advanced CKD, but there is still a need for more studies to fully understand the risks and benefits of DOACs in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of direct oral anticoagulants in patients with chronic renal insufficiency: A review of the literature. Weber, J., Olyaei, A., Shatzel, J.[2019]

Subcutaneous semaglutide (Ozempic®), a GLP-1 receptor agonist, has shown significant efficacy in improving glycemic control and reducing HbA1c, albuminuria, and blood pressure in patients with advanced diabetic kidney disease (DKD) during a 6-month follow-up study involving patients on maintenance hemodialysis.

The treatment not only aids in weight loss and appetite suppression but also helps preserve residual kidney function, potentially improving patient outcomes and facilitating their inclusion on kidney transplant waiting lists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Semaglutide, a Glucagon-Like Peptide-1 Receptor Agonist in Real-Life: A Case Series of Patients in Maintenance Incremental Hemodialysis. De la Flor, JC., Lorenzo, JD., Marschall, A., et al.[2022]

In a trial involving 10 patients undergoing intermittent renal replacement therapy, administering 1 g of doripenem posthemodialysis was found to maintain effective plasma levels in anuric patients, suggesting a potential for improved treatment compliance and cost-effectiveness.

Doripenem was generally well-tolerated, with only one patient experiencing an allergic reaction, indicating a favorable safety profile for this antibiotic in patients with septic episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy. Vossen, MG., Ehmann, L., Pferschy, S., et al.[2019]

The use of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) has significantly increased from 9.2% to 89.3% between 2013 and 2018, while warfarin use has declined, particularly in patients with mild to moderate CKD.

Patients with severe CKD and end-stage CKD/dialysis showed poor time in therapeutic range (TTR) on warfarin, with median TTR dropping to 70.0% and 67.5%, respectively, indicating challenges in managing anticoagulation in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral anticoagulants, time in therapeutic range and renal function over time in real-life patients with atrial fibrillation and chronic kidney disease. Batra, G., Modica, A., Renlund, H., et al.[2022]

The lazaroid U83836E significantly protects against oxidative stress in kidney ischemia-reperfusion injury, as shown by reduced lipid peroxidation and improved glutathione levels in treated rats compared to controls.

Treatment with U83836E resulted in better renal function and less tissue damage after 24 hours of reperfusion, indicating its potential as a therapeutic intervention for oxidative stress-related kidney injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protection from renal ischemia-reperfusion injury by the 2-methylaminochroman U83836E. De Vecchi, E., Lubatti, L., Beretta, C., et al.[2022]

In a pilot trial involving 45 patients with chronic renal insufficiency undergoing contrast angiography, fenoldopam mesylate significantly improved renal plasma flow (RPF) by 15.8% compared to a 33.2% decrease in the control group, suggesting its potential to protect kidney function during contrast use.

The incidence of radiocontrast nephropathy (RCN) was lower in the fenoldopam group (21%) compared to the control group (41%), indicating that fenoldopam may reduce the risk of acute kidney injury associated with contrast agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenoldopam mesylate blocks reductions in renal plasma flow after radiocontrast dye infusion: a pilot trial in the prevention of contrast nephropathy. Tumlin, JA., Wang, A., Murray, PT., et al.[2019]

A comprehensive analysis of 921 plasma concentration data from 92 Japanese subjects revealed that doripenem pharmacokinetics can be effectively modeled using a two-compartment model, with creatinine clearance being the most significant factor affecting its clearance due to its renal excretion.

Simulations indicate that for patients with varying degrees of renal impairment, adjusted dosing regimens of doripenem can maintain effective drug exposure, ensuring sufficient therapeutic levels while minimizing the risk of toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of doripenem in Japanese subjects and Monte-Carlo simulation for patients with renal impairment. Matsuo, Y., Ishibashi, T., Kubota, R., et al.[2018]

Betamipron demonstrated a strong nephroprotective effect in rabbits, preventing extensive tubular necrosis caused by a high dose of DA-1131, as observed through kidney microscopy after 8 hours.

The treatment with betamipron significantly reduced the accumulation of DA-1131 in the kidneys, leading to faster renal clearance and a higher percentage of the drug being excreted unchanged in urine, indicating its effectiveness in protecting renal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nephroprotective effect of betamipron on a new carbapenem, DA-1131, in rabbits. Kim, SH., Kim, WB., Kwon, JW., et al.[2019]

Iomeprol was found to be safe and well tolerated in a study involving 30 subjects, including healthy volunteers and patients with varying degrees of renal impairment, with no clinically meaningful adverse events reported.

The pharmacokinetics of iomeprol showed that it is effectively eliminated in patients with renal impairment and those undergoing dialysis, suggesting that no dose adjustment is necessary for these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with renal impairment or end-stage renal disease requiring hemodialysis. Lorusso, V., Taroni, P., Alvino, S., et al.[2022]

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