| CTRI Number |
CTRI/2025/03/082318 [Registered on: 13/03/2025] Trial Registered Prospectively |
| Last Modified On: |
28/01/2026 |
| Post Graduate Thesis |
No |
| Type of Trial |
BA/BE |
|
Type of Study
|
Comparative pharmacokinetic |
| Study Design |
Non-randomized, Multiple Arm Trial |
|
Public Title of Study
|
A clinical study to assess the drug exposure and evaluation of pretomanid, following oral administration in participants with liver disease compared with healthy subjects. |
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Scientific Title of Study
|
A Phase I, Non-Randomized, Open-Label, Single-Dose Study Comparing the Pharmacokinetics, Safety, and Tolerability of Pretomanid Tablets 200 mg in Subjects with Moderate and Severe Hepatic Impairment Relative to Matched Control Subjects with Normal Hepatic Function. |
| Trial Acronym |
Nil |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| PRET-TBZ-1001 Ver. 1.0; Date; SEP-26, 2024 |
Protocol Number |
|
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Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Dr Pradeep Kundapur |
| Designation |
Deputy General Manager |
| Affiliation |
Ecron Acunova Limited |
| Address |
No 52 2, Near Kasturba Hospital OPD Manipal
Udupi
KARNATAKA
576104
India |
| Phone |
9769666155 |
| Fax |
- |
| Email |
pradeep.kundapur@navitaslifesciences.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Pradeep Kundapur |
| Designation |
Deputy General Manager |
| Affiliation |
Ecron Acunova Limited |
| Address |
No 52 2, Near Kasturba Hospital OPD Manipal
Udupi
KARNATAKA
576104
India |
| Phone |
9769666155 |
| Fax |
- |
| Email |
pradeep.kundapur@navitaslifesciences.com |
|
Details of Contact Person
Public Query
|
| Name |
Dr Vasudev Shenoy |
| Designation |
Assistant Vice President |
| Affiliation |
Ecron Acunova Limited |
| Address |
No 52 2, Near Kasturba Hospital OPD Manipal
Udupi
KARNATAKA
576104
India |
| Phone |
9880599233 |
| Fax |
- |
| Email |
vasudev.shenoy@navitaslifesciences.com |
|
|
Source of Monetary or Material Support
|
| Mylan Laboratories limited, Plot No 564A22, Road No 92, JUbilee Hills, Hyderabad - 500096, Telangana |
|
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Primary Sponsor
|
| Name |
Mylan Laboratories Limited |
| Address |
Plot No 564A22, Road No 92, Jubilee Hills, Hyderabad - 500096, Telangana |
| Type of Sponsor |
Pharmaceutical industry-Global |
|
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Details of Secondary Sponsor
|
| Name |
Address |
| Mylan Laboratories Limited |
Plot NO 564A22, Road No 92, JUbilee Hills, Hyderabad - 500096, Telangana |
|
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Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 3 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Pradeep Kundapur |
Ecron Acunova Limited |
No 52-2, Near Kasturba Hospital, OPD, Manipal - 576104
Udupi
KARNATAKA |
08202206403
pradeep.kundapur@navitaslifesciences.com |
| Dr Vasudev Shenoy |
Ecron Acunova Limited |
V floor, MCODS Building, KMC Hospital, Attavar, Mangalore- 575 001
Dakshina Kannada
KARNATAKA |
08202206404
-
vasudev.shenoy@navitaslifesciences.com |
| Dr Vasudev Shenoy |
Kasturba Hospital |
Department of Gasteroenterology and Hepatology, 4 th Floor, Udupi - Hebri Rd, Madhav Nagar, Manipal, Karnataka
Udupi
KARNATAKA |
08202206404
vasudev.shenoy@navitaslifesciences.com |
|
Details of Ethics Committee
Modification(s)
|
| No of Ethics Committees= 4 |
| Name of Committee |
Approval Status |
| Central Ethics Committee |
Approved |
| Manipal Academy of Higher Education Ethics Commitee |
Approved |
| Manipal Academy of Higher Education Ethics Commitee |
Not Applicable |
| Manipal Academy of Higher Education Ethics Committee |
Approved |
|
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Regulatory Clearance Status from DCGI
|
|
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Health Condition / Problems Studied
|
| Health Type |
Condition |
| Healthy Human Volunteers |
Hepatic Impairment Patients and Health Volunteers |
| Patients |
(1) ICD-10 Condition: K729||Hepatic failure, unspecified, |
|
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Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Comparator Agent |
Pretomanid tablet 200 mg in nonhepatic impaired healthy subjects |
Pretomanid 200 mg tablets Manufactured by Mylan Laboratories Limited, a viatris Company, India
Dose: 200 mg ; Frequency: 1; Route of administration: Oral; Total duration of intervention: 13 days |
| Intervention |
Pretomanid tablet 200 mg in patient with moderate hepatic impairment |
Pretomanid 200 mg tablets Manufactured by Mylan Laboratories Limited, a viatris Company, India
Dose: 200 mg ; Frequency: 1; Route of administration: Oral; Total duration of intervention: 13 days |
| Intervention |
Pretomanid tablet 200 mg in patient with severe hepatic impairment |
Pretomanid 200 mg tablets Manufactured by Mylan Laboratories Limited, a viatris Company, India
Dose: 200 mg ; Frequency: 1; Route of administration: Oral; Total duration of intervention: 13 days |
|
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Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
70.00 Year(s) |
| Gender |
Both |
| Details |
Inclusion Criteria for Subjects with Moderate or Severe Hepatic Impairment Group 1 or 2
1 Males andor nonpregnant nonlactating females aged 18 to 70 years old inclusive
2 Each subject is required to weigh at least 50 kg and have a Body Mass Index BMI value less than or equal to 40 kg per m2 but greater than or equal to 18 kg per m2
3 Hepatically impaired subjects will be classified using Child Pugh System Subjects must have child Pugh B with the score of 7 to 9 moderate hepatic impairment or Child Pugh C with the score of 10 to 15 severe hepatic impairment with known medical history of liver disease with or without a known history of alcohol abuse and previous confirmation of liver cirrhosis by liver biopsy or other medical imaging technique including laparoscopy computed tomography scan magnetic resonance imaging or ultrasonography associated with unambiguous medical history
4 Acceptable laboratory values obtained at screening within 21 days prior to admission to the clinical facility or study center and either at or within 72 hours of admission to the clinical facility or study center
5 A normal or non clinically significant physical examination skin head eyes ears nose and throat thyroid neurological chest and lungs cardiovascular abdomen liver and spleen lymph nodes musculoskeletal and extremities including vital signs sitting blood pressure mm Hg sitting heart rate beats per min and oral body temperature and 12lead ECG as determined by the clinical facility or study center Investigator
6 Adequate venous access in both arms for the collection of a number of blood samples during the study
Inclusion Criteria for Non Hepatically Impaired Controls Group 3
1 Healthy Males and or nonpregnant nonlactating females aged 18 to 70 years old inclusive
2 Each subject is required to weigh at least 50 kg and have a Body Mass Index value less than or equal to 40 kg per m2 but greater than or equal to 18 kg per m2 Age 18 to 70 years old inclusive
3 The subjects will be matched to hepatic impaired subjects by age at screening The subject must meet age requirements at the time of signing the initial informed consent and the initial study medication administration
4 Subject is healthy as determined by no clinically significant findings from medical history physical examination skin head eyes ears nose and throat thyroid neurological chest and lungs cardiovascular abdomen liver and spleen lymph nodes musculoskeletal and extremities including vital signs sitting blood pressure mm Hg sitting heart rate beats min and oral body temperature and 12 lead ECG as determined by the clinical facility or study center Investigator
5 Acceptable laboratory values obtained at screening within 21 days prior to admission to the clinical facility or study center and either at or within 72 hours of admission to the clinical facility or study center
6 Adequate venous access in both arms for the collection of a number of blood samples during the study
|
|
| ExclusionCriteria |
| Details |
Subject must not be enrolled in the study if they meet any of the following criteria
Exclusion Criteria for Subjects with Moderate or Severe Hepatic Impairment Group 1 or 2
1 Institutionalized subjects
2 Subject with hypokalemia lesser than 3.5mEq per L severe hypomagnesemia lesser than 1.1 mg per dL or severe hypocalcemia lesser than 7.5 mg per dL
3 Aspartate aminotransferase AST or alanine transaminase ALT greater than 10 times the upper limit of normal
4 Creatinine clearance lesser than 60 ml per min per 1.73m2
5 Inability to swallow tablets
6 Any condition possibly affecting study drug absorption eg prior bariatric surgery gastrectomy ileal resection NOTE Participants who have undergone cholecystectomy and or appendectomy are eligible for this study as long as the surgery occurred more than 6 months prior to screening
7 Fluctuating or rapidly deteriorating hepatic function as indicated by widely varying or worsening of clinical and or laboratory signs of hepatic impairment 3 months prior to screening or within the screening period or the presence of any condition or finding which would jeopardize subject safety impact study result validity or diminish the subject ability to undergo all study procedures and assessment
8 History of fever or documented fever in the 48 hours prior to admission to the clinical facility or study center
9 History of clinically significant allergy or severe side effects with nitroimidazoles eg metronidazole and related substances and azole antifungals or aromatase inhibitors
10 Receipt of of a study drug vaccine or biologic in a clinical trial within 30 days prior to screening
History of seizures other than febrile seizures during childhood or known or suspected CNS disorders that may predispose to seizures
11 Use of any over the counter OTCmedication within 7 days prior to admission to the clinical facility or study center unless the substance would not likely impact the validity of the study results
12 Treatment with CYP3A4 enzyme altering drugs within 7 days prior to admission to the clinical facility or study center unless the substance would not likely impact the validity of the study results
13 QTcF interval greater than 440 msec males or greater than 450 msec females at screening or admission to the clinical facility or study center or a history of prolonged QTc interval
14 History of seizures other than febrile seizures during childhood or known or suspected CNS disorders that may predispose to seizures
15 Family history of Long QT Syndrome premature cardiac death or sudden death without a preceding diagnosis of a condition that could be causative of sudden death
16 Any other clinically significant ECG abnormality in the opinion of the site investigator at screening and admission to the clinical facility or study center
17 Donated blood greater than 500 mL or significant blood loss within the 30 days prior to admission to the clinical facility or study center
18 Planning to donate blood during the study or up to 14 days after dosing
19 Persons with a transjugular intrahepatic portosystemic shunt
20 History of liver transplantation or subjects in the severe hepatic impairment group that are expecting a liver transplant during the study participation period
21 Medical history suggestive of hepatocellular carcinoma HCC with an alpha-fetoprotein AFP level is greater than 50 ng per mL
For Non-Hepatically Impaired Controls Group 3
1 Institutionalized subjects
2 Inability to swallow tablets
3 Presence of any condition or finding which would jeopardize subject safety impact study result validity or diminish the subject ability to undergo all study procedures and assessments
4 History of fever or documented fever oral temperature greater than or equal to 100.4 F or greater than or equal to 38 degree celsius in the 48 hours prior to admission to the clinical facility or study center
5 History of clinically significant allergy or severe side effects with nitroimidazoles eg metronidazole and related substances and azole antifungals or aromatase inhibitors
6 Receipt of a study drug vaccine or biologic in a clinical trial within 30 days prior to screening
7 Use of any OTC medication within 7 days prior to admission to the clinical facility study center unless the substance would not likely impact the validity of the study results
8 Treatment with CYP3A4 enzyme altering drugs within 7 days prior to admission to the clinical facility or study center unless the substance would not likely impact the validity of the study results
9 QTcF interval greater than 450 msec males or greater than 450 msec females at screening or admission to the clinical facility or study center or a history of prolonged QTc interval
10 Family history of Long QT Syndrome premature cardiac death or sudden death without a preceding diagnosis of a condition that could be causative of sudden death
11 Any clinically significant ECG abnormality in the opinion of the site investigator at screening and admission to the clinical facility or study center
12 Donated blood greater than 500 mL or had significant blood loss within the 30 days prior to admission to the clinical facility or study center
13 Planning to donate blood during the study or up to 14 days after dosing
14 Pre-existing condition that interferes with normal GI anatomy or motility that could impair the absorption metabolism and or excretion of the IPs inflammatory bowel disease peptic ulcer or pancreatitis
15 Any food allergy intolerance restriction or special diet that in the opinion of the Principal Investigator or Medical Sub Investigator could contraindicate the subject participation in this study
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Method of Generating Random Sequence
|
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Method of Concealment
|
|
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Blinding/Masking
|
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Primary Outcome
|
| Outcome |
TimePoints |
| To evaluate the pharmacokinetics (PK) of pretomanid single dose in subjects with moderate and severe hepatic impairment (Child Pugh B and C, respectively) relative to matched control subjects with normal hepatic function |
Blood samples (1 x 6 mL) will be collected in blood collection tubes containing K2EDTA before dosing (pre dose) and at the following times thereafter 1, 2, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose. |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| To evaluate the safety and tolerability of pretomanid in subjects with moderate and severe hepatic impairment relative to matched control subjects with normal hepatic function. |
Vital Signs and Safety will be obtained at screening, and on Day -1 to Day 12. |
|
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Target Sample Size
|
Total Sample Size="24"
Sample Size from India="24"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
N/A |
|
Date of First Enrollment (India)
|
18/04/2025 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="0"
Months="6"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Not Yet Recruiting |
| Recruitment Status of Trial (India) |
Open to Recruitment |
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Publication Details
|
N/A |
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Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
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Brief Summary
|
Pretomanid is a nitroimidazole and is metabolized extensively in the liver (CYP3A4) and it has a low extraction ratio. Hepatic blood flow as well as hepatic functions are compromised in advanced liver disease conditions. Therefore, in comparison to healthy subjects, the pharmacokinetics of pretomanid is likely to be altered in subjects with hepatic impairment. We hypothesize that presence of advanced liver disease will have an impact on the metabolism of pretomanid. The purpose of this study is to evaluate the safety and pharmacokinetics of pretomanid in subjects with underlying liver disease defined as a Child-Pugh class of B (moderate hepatic impairment) or C (severe hepatic impairment). The severity of liver disease is based on five clinical features: 1) total bilirubin level, 2) serum albumin, 3) prothrombin time (measured as the international normalized ratio, INR), 4) the degree of ascites, and 5) the grade of hepatic encephalopathy. The total point score is then used to determine the subject’s Child-Pugh class. Pretomanid will be administered orally, and 200 mg will be the dose.
A single oral dose of pretomanid 200 mg will be taken once. The PK profile studies on oral dosing of pretomanid have been consistent for healthy subjects and subjects with pulmonary TB. Pretomanid is readily absorbed after oral administration and slowly eliminated in plasma. Pretomanid plasma concentrations increased in a dose-related manner after single-dose administration of up to 1000 mg in healthy subjects and subjects with TB. However, at doses above 200 mg/day, the increase was less than dose proportional. With increasing dosages, there is a trend toward increased side effects. Furthermore, efficacy studies have shown equivalent early bacterial activity at dosages ranging from 200 mg to 1200 mg. The primary purpose of this study is to delineate the effect of hepatic impairment on the plasma PK of pretomanid so as to guide the dosing recommendations for patients with hepatic impairment. The results from this study will enable the development of appropriate dosing recommendations in patients with impaired hepatic function. Therefore, this study will evaluate the PK of pretomanid, following oral administration in subjects with moderate or severe hepatic impairment using Child-Pugh class, (FDA 2003) compared to matched-healthy subjects with normal hepatic function.
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