Clinical trial NCT03896750: Single-Dose Study to Evaluate the PKs of Pretomanid in Participants With Renal Impairment Compared to Participants With Normal Renal Function
Official title: A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics and Safety of Pretomanid in Participants With Renal Impairment Compared to Participants With Normal Renal Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Tuberculosis
Keywords: Open-Label
Pretomanid
Renal Pharmacokinetic
Single-Dose
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2019-04-01
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Detailed description: 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. The secondary objectives are 1) to assess the safety profile of a single oral dose of 200 mg pretomanid in renally impaired participants to matched healthy controls; and 2) to evaluate the PK profiles or representative pretomanid metabolites (M19 and M50) in plasma and urine.

Eligibility criteria: Inclusion Criteria:

Participant Inclusion Criteria for Patients with Renal Impairment (Groups 2-4)

1. 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
2. Agree to abide by the study restrictions.
3. Are between the ages of 18 and 85 years, inclusive, at the time of enrollment.
4. Must have mild, moderate, or severe renal impairment or end stage renal disease (ESRD), but are not on dialysis.
5. Have no history of chronic tobacco/nicotine usage (i.e., \>10 cigarettes per day for 3 months minimum prior to admission).
6. Have corrected QT interval by Fridericia (QTcF) \<460 msec on Electrocardiogram (ECG).
7. Have a Body Mass Index (BMI) of 18 to 40 kg/m\^2 at enrollment.
8. 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").
9. 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\*\*\*\*.

   \*\*\*\*In addition to the use of a barrier method (condom) unless vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #8, and/or abstinence from sexual intercourse with women.
10. Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product.

Participant Inclusion Criteria for Healthy Participants (Groups 1A-1C)

1. 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).
2. Agree to abide by the study restrictions.
3. Are healthy male or non-pregnant female, between the ages of 18 and 85 years, inclusive, with normal GFR \>90 at screening.
4. Have no history of chronic tobacco/nicotine usage (i.e., \>10 cigarettes per day for 3 months minimum prior to admission).
5. Have a normal corrected QT interval by Fridericia (QTcF) \<460 msec on ECG.
6. Have a Body Mass Index of 18 to 40 kg/m\^2 at enrollment.
7. 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").
8. 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\*\*\*\*.

   \*\*\*\*In addition to the use of a barrier method (condom) unless vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #7, and/or abstinence from sexual intercourse with women.
9. Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product.

Exclusion Criteria:

Participant Exclusion Criteria for Patients with Renal Impairment (Groups 2-4)

1. History of known active TB.
2. History of peptic ulcer disease.
3. Known hypersensitivity to pretomanid or any of the excipients.
4. History of any clinically significant uncontrolled cardiac abnormality (as deemed by the Principal Investigator (PI)).
5. 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
6. History of, or screening results show a corrected QT interval by Fridericia (QTcF) \>/= 460 msec.
7. Family history of Long-QT Syndrome or sudden death when a cause of death is unknown.
8. Inability to swallow tablets.
9. History of fever or documented fever (oral temperature \>/= 100.4 degrees F) in the 48 hours prior to admission to the hospital.
10. Resting pulse rate \<50 or \>110 bpm at Screening.
11. At Screening, blood pressure \>/= 20 mm Hg systolic or \>10 mm Hg diastolic above baseline\*\* (sitting).

    \*\*Baseline is most recent blood pressure in the last 3 months.
12. Current hyperkalemia or hypomagnesemia.
13. Positive result of urine drug screen or blood alcohol screen prior to hospital admission except for approved prescriptions that are not opiates and benzodiazepines.
14. Significant history of drug and/or food allergies (as deemed by the Principal Investigator (PI)).
15. For women, participant is pregnant (positive test for urine Human Chorionic Gonadotropin \[HCG\]) at screening or Admission, breastfeeding, or planning to conceive for the duration of the study.
16. Any contraindication to the use of nitroimidazoles, or prior treatment with pretomanid or delamanid.
17. Treatment with strong or moderate CYP3A4 inducers or inhibitors\*\*\* within 14 days before admission and during the study\*\*\*\*.

    \*\*\*Except hormonal contraceptives

    \*\*\*\*In the opinion of the site investigator
18. Use of St. John's Wort within 7 days prior to admission and during the entire study.
19. Consumption of products containing grapefruit within 5 days prior to dosing until Visit 01N.
20. Donation of whole blood or blood products \>500 mL within 30 days from screening and/or plans to donate during the study or up to 14 days after dosing.
21. Participation in another interventional clinical trial within 30 days prior to dosing until after the last study visit.
22. Hemoglobin (Hgb) \<8.0 g/dL in both men and women at the screening visit.
23. Positive Screening test for Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), or Human Immunodeficiency Virus (HIV).
24. Renal transplant.
25. Scheduled for hemodialysis or peritoneal dialysis.
26. Presence of any condition or finding\*\*\*\*\* which would jeopardize participant safety, impact study result validity, or diminish the participant's ability to undergo all study procedures and assessments.

    \*\*\*\*\*In the opinion of the investigator
27. For men, semen donation for the duration of the study.
28. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) \> 2.5 x Upper Limit of Normal (ULN).
29. Hyperbilirubinemia \>1.5 x Upper Limits of Normal (ULN).

Participant Exclusion Criteria for Healthy Participants (Groups 1A-1C)

1. History of known active TB.
2. History of peptic ulcer disease.
3. Known hypersensitivity to pretomanid or any of the excipients.
4. History of any clinically significant uncontrolled cardiac abnormality (as deemed by the Principal Investigator (PI)).
5. Any clinically significant ECG abnormality at screening.\*

   \*Note: the following can be considered not clinically significant:
   * Heart rate \</= 50 bpm (sinus bradycardia with heart rate between 45 and 49, inclusive, is acceptable only in younger athletic participants)
   * Mild first-degree 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
6. Family history of Long-QT Syndrome or sudden death when a cause of death is unknown.
7. Inability to swallow tablets.
8. History of fever or documented fever (oral temperature \>/= 100.4 degrees F) in the 48 hours prior to admission to the hospital.
9. At Screening blood pressure \>140/90 mm Hg or \<90/65 mm Hg (sitting).
10. History of, or screening results show a corrected QT interval by Fridericia (QTcF) \>460 msec.
11. Positive result of urine drug screen or blood alcohol screen prior to hospital admission except for approved prescriptions that are not opiates and benzodiazepines.
12. Significant history of drug and/or food allergies (as deemed by the Principal Investigator (PI)).
13. Women of childbearing potential with a positive urine pregnancy test within 24 hours prior to receipt of study product.
14. Any contraindication to the use of nitroimidazoles, or prior treatment with pretomanid or delamanid.
15. Treatment with strong or moderate CYP3A4 inducers or inhibitors\*\* within 14 days before admission and during the study\*\*\*.

    \*\*Except hormonal contraceptives

    \*\*\*In the opinion of the site Principal Investigator (PI)
16. Use of St. John's Wort within 7 days prior to admission and during the entire study.
17. Consumption of products containing grapefruit within 5 days prior to dosing until Visit 01N.
18. Donation of whole blood or blood products \>500 mL within 30 days from screening and/or plans to donate during the study or up to 14 days after dosing.
19. Participation in another interventional clinical trial within 30 days prior to dosing until after the last study visit.
20. Hgb \<10.0 g/dL in both men and women at the screening visit.
21. Positive Screening test for Hepatitis C virus (HCV), Hepatitis B virus (HBV), or Human Immunodeficiency Virus (HIV).
22. Renal transplant.
23. Presence of any condition or finding\*\*\*\* which would jeopardize participant safety, impact study result validity, or diminish the participant's ability to undergo all study procedures and assessments.

    \*\*\*\*In the opinion of the investigator
24. For men, semen donation for the duration of the study.
25. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) \> Upper Limits of Normal (ULN).
26. Bilirubin \> Upper Limits of Normal (ULN)

Primary outcomes:
measure: Apparent clearance of drug from plasma after drug administration (CL/F)
timeFrame: Up to 96 hours
measure: Apparent first-order terminal elimination rate constant (Lambda z) of pretomanid
timeFrame: Up to 96 hours
measure: Apparent volume of distribution (Vd/F)
timeFrame: Up to 96 hours
measure: Area under the plasma concentration-time curve from time zero to infinity (AUC-infinity)
timeFrame: Up to 96 hours
measure: Area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast)
timeFrame: Up to 96 hours
measure: Cumulative amount of pretomanid excreted into the urine from time 0 to the time t (Ae(0-t))
timeFrame: Up to 96 hours
measure: Fraction of pretomanid dose excreted into the urine (Ae%Dose)
timeFrame: Up to 96 hours
measure: Maximum plasma concentration of pretomanid (Cmax)
timeFrame: Up to 96 hours
measure: Percentage of Area under the plasma concentration-time curve from time 0 to infinity (AUC-infinity) obtained by extrapolation (%AUCex)
timeFrame: Up to 96 hours
measure: Renal clearance (CLR) of pretomanid
timeFrame: Up to 96 hours
measure: Terminal-phase elimination half-life (t1/2)
timeFrame: Up to 96 hours
measure: Time to peak (maximum) plasma concentration (Tmax)
timeFrame: Up to 96 hours
Secondary outcomes:
measure: Concentrations of pretomanid metabolites (M19 and M50) in plasma
timeFrame: Up to 96 hours
measure: Excretion of representative metabolites M19 and M50 in urine
timeFrame: Up to 96 hours
measure: Mean change from baseline in alanine aminotransferase (ALT)
timeFrame: Through Day 12
measure: Mean change from baseline in aspartate aminotransferase (AST)
timeFrame: Through Day 12
measure: Mean change from baseline in blood urea nitrogen (BUN)
timeFrame: Through Day 12
measure: Mean change from baseline in creatinine
timeFrame: Through Day 12
measure: Mean change from baseline in estimated glomerular filtration rate (eGFR)
timeFrame: Through Day 12
measure: Mean change from baseline in hemoglobin (Hgb)
timeFrame: Through Day 12
measure: Mean change from baseline in magnesium
timeFrame: Through Day 12
measure: Mean change from baseline in serum potassium
timeFrame: Through Day 12
measure: Mean change from baseline in total bilirubin
timeFrame: Through Day 12
measure: Mean change in oral temperature from baseline
timeFrame: Through Day 12
measure: Mean change in pulse from baseline
timeFrame: Through Day 12
measure: Mean change in sitting blood pressure from baseline
timeFrame: Through Day 12
measure: Mean change in the electrocardiogram (ECG) corrected QT interval by Fridericia (QTcF) interval from baseline
timeFrame: Through Day 5
measure: Number of participants reporting adverse events (AEs)
timeFrame: Day 1 to Day 12
measure: Plasma levels of representative metabolites M19 and M50
timeFrame: Up to 96 hours
Other outcomes:
Locations:
city: Miami
country: United States
facility: Advanced Pharma - Miami
state: Florida
city: Saint Louis
country: United States
facility: Saint Louis University Center for Vaccine Development
state: Missouri
city: Knoxville
country: United States
facility: Alliance for Multispecialty Research, LLC - Knoxville
state: Tennessee
Study officials:
References: