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StAT-TB (Statin Adjunctive Therapy for TB): A Phase 2b Dose-finding Study of Pravastatin in Adults With Tuberculosis

Primary Purpose

Tuberculosis, Pulmonary Tuberculosis

Status

Completed

Phase

Phase 2

Locations

South Africa

Study Type

Interventional

Intervention

Pravastatin

Rifafour

Vitamin B6

About this trial

This is an interventional treatment trial for Tuberculosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

18 years of age or older
Clinical signs and symptoms of pulmonary tuberculosis
Abnormal chest radiograph consistent with pulmonary tuberculosis
At least one sputum positive for M. tuberculosis by Xpert MTB/RIF with a cycle threshold (Ct) less than 28.
Documentation of HIV status
Weight greater than or equal to 45 kg
Karnofsky score of at least 60
Ability to provide informed consent
Ability to adhere to study follow-up visits
Negative pregnancy test in women of child-bearing age
Ability to adhere to contraceptive requirements and willing to use two forms of contraception: 1) a double barrier method to prevent pregnancy (i.e. use of a condom with either diaphragm or cervical cap) or 2) use of an intrauterine device in combination with a barrier contraceptive. The participant must be willing to continue these contraceptive measures throughout the duration of the study and until one week after the last dose of study medication or one week after discontinuation from study medication in case of premature discontinuation.
Five days or fewer of anti-tuberculosis treatment within the previous 3 months

Exclusion Criteria:

A history of severe adverse reactions to any statin or any other study agent or contraindications to use of statins.
Current use of statins or other lipid-lower agents;
Clinical indication for statin therapy based on cardiovascular risk:
- Familial hypercholesterolemia
- Previous history of myocardial infarction or stroke
For HIV-positive individuals, a CD4+ T-cell count less than 350/mm^3
Use of antiretroviral drugs
Hemoglobin concentration less than 8 g/dL;
Baseline creatinine kinase elevation more than three times the upper limit of normal
Abnormal baseline laboratory values
- Baseline alanine aminotransferase (ALT) concentration more than 2.5 times the upper limit of normal (Grade 1)
- Serum creatinine concentration more than twice the upper limit of normal;
- Serum total bilirubin level greater than twice the upper limit of normal
- Platelet count less than 100,000/mm^3
- Absolute neutrophil count (ANC) less than 1,000/mm^3
Pregnant or breastfeeding;
Silico-tuberculosis.
Currently receiving TB treatment
Serologies or PCR positive for viral hepatitis (Hepatitis, B, C)
Concomitant disorders or conditions for which isoniazid, rifampin, pyrazinamide, or ethambutol is contraindicated. These include cirrhosis, acute liver disease of any cause, acute uncontrolled gouty arthritis and peripheral neuropathy.
Any medical or psychological condition which, in the view of the study investigator, makes study participation inadvisable.
Infection with an isolate determined to be resistant to rifampin by GeneXpert.
More than five days of anti-tuberculosis treatment within the previous 3 months
Planned or current use of cyclosporine, tacrolimus, erythromycin or colchicine
Central nervous system (CNS) TB
Extra-pulmonary TB only, not in combination with pulmonary TB
History of TB

Sites / Locations

PHRU Non-Network CRS

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Arm 1: Pravastatin (40 mg) and Rifafour

Arm 2: Pravastatin (80 mg) and Rifafour

Arm 3: Pravastatin (120 mg) and Rifafour

Arm 4: Pravastatin (160 mg) and Rifafour

Arm Description

Participants will receive pravastatin (40 mg) and Rifafour daily for 14 days. Pravastatin will be given alone on Day 1, and pravastatin + Rifafour will be given on Days 2-15. Vitamin B6 will be added to each of the regimens.

Participants will receive pravastatin (80 mg) and Rifafour daily for 14 days. Pravastatin will be given alone on Day 1, and pravastatin + Rifafour will be given on Days 2-15. Vitamin B6 will be added to each of the regimens.

Participants will receive pravastatin (120 mg) and Rifafour daily for 14 days. Pravastatin will be given alone on Day 1, and pravastatin + Rifafour will be given on Days 2-15. Vitamin B6 will be added to each of the regimens. (Arm 3 will only be recruited if pravastatin 80 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.)

Participants will receive pravastatin (160 mg) and Rifafour daily for 14 days. Pravastatin will be given alone on Day 1, and pravastatin + Rifafour will be given on Days 2-15. Vitamin B6 will be added to each of the regimens. (Arm 4 will only be recruited if pravastatin 120 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.)

Outcomes

Primary Outcome Measures

Frequency of Grade 3 or Higher Adverse Events

Graded using the DAIDS table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017

Secondary Outcome Measures

Number of Participants Who Permanently Discontinue Assigned Study Regimen for Any Reason

(Other than new recognition of participant ineligibility based on absence of M. tuberculosis growth in baseline sputum cultures, or growth of M. tuberculosis resistant to rifampin by GeneXpert)

Full Information

NCT ID

NCT03882177

First Posted

March 18, 2019

Last Updated

August 23, 2023

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

1. Study Identification

Unique Protocol Identification Number

NCT03882177

Brief Title

StAT-TB (Statin Adjunctive Therapy for TB): A Phase 2b Dose-finding Study of Pravastatin in Adults With Tuberculosis

Official Title

StAT-TB (Statin Adjunctive Therapy for TB): A Phase 2b Dose-finding Study of Pravastatin in Adults With Tuberculosis

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Completed

Study Start Date

February 21, 2020 (Actual)

Primary Completion Date

May 12, 2022 (Actual)

Study Completion Date

December 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to assess the safety, tolerability, and pharmacokinetics of pravastatin adjunctive therapy when combined with the standard tuberculosis (TB) treatment regimen in adults with TB.

Detailed Description

This study will assess the safety, tolerability, and pharmacokinetics of pravastatin adjunctive therapy when combined with the standard TB treatment regimen in adults with drug-sensitive TB. The pharmacokinetic data for pravastatin will be used to choose a dose to be studied as adjunctive TB treatment in subsequent trials. This study is a dose-escalation trial, and participants will be sequentially enrolled into four study arms. Participants will receive standard anti-TB therapy (Rifafour) and pravastatin daily for 14 days. Pravastatin will be given alone on Day 1, and pravastatin + Rifafour will be given on Days 2-15. Total study duration for participants will be 30 days, during which time participants will attend several study visits. Study visits may include sputum specimen collection, blood and urine collection, lung function testing, and pharmacokinetic assessments. All study participants will be referred appropriately to continue standard TB treatment at study completion.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis, Pulmonary Tuberculosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1: Pravastatin (40 mg) and Rifafour

Arm Type

Experimental

Arm Description

Arm Title

Arm 2: Pravastatin (80 mg) and Rifafour

Arm Type

Experimental

Arm Description

Arm Title

Arm 3: Pravastatin (120 mg) and Rifafour

Arm Type

Experimental

Arm Description

Arm Title

Arm 4: Pravastatin (160 mg) and Rifafour

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pravastatin

Intervention Description

Tablets, administered orally

Intervention Type

Drug

Intervention Name(s)

Rifafour

Intervention Description

Fixed-dose combination (isoniazid, rifampin, pyrazinamide, and ethambutol) tablets, administered orally

Intervention Type

Dietary Supplement

Intervention Name(s)

Vitamin B6

Intervention Description

Administered orally.

Primary Outcome Measure Information:

Title

Frequency of Grade 3 or Higher Adverse Events

Description

Graded using the DAIDS table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017

Time Frame

Measured through Day 30

Secondary Outcome Measure Information:

Title

Number of Participants Who Permanently Discontinue Assigned Study Regimen for Any Reason

Description

(Other than new recognition of participant ineligibility based on absence of M. tuberculosis growth in baseline sputum cultures, or growth of M. tuberculosis resistant to rifampin by GeneXpert)

Time Frame

Measured through Day 14

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 18 years of age or older Clinical signs and symptoms of pulmonary tuberculosis Abnormal chest radiograph consistent with pulmonary tuberculosis At least one sputum positive for M. tuberculosis by Xpert MTB/RIF with a cycle threshold (Ct) less than 28. Documentation of HIV status Weight greater than or equal to 45 kg Karnofsky score of at least 60 Ability to provide informed consent Ability to adhere to study follow-up visits Negative pregnancy test in women of child-bearing age Ability to adhere to contraceptive requirements and willing to use two forms of contraception: 1) a double barrier method to prevent pregnancy (i.e. use of a condom with either diaphragm or cervical cap) or 2) use of an intrauterine device in combination with a barrier contraceptive. The participant must be willing to continue these contraceptive measures throughout the duration of the study and until one week after the last dose of study medication or one week after discontinuation from study medication in case of premature discontinuation. Five days or fewer of anti-tuberculosis treatment within the previous 3 months Exclusion Criteria: A history of severe adverse reactions to any statin or any other study agent or contraindications to use of statins. Current use of statins or other lipid-lower agents; Clinical indication for statin therapy based on cardiovascular risk: Familial hypercholesterolemia Previous history of myocardial infarction or stroke For HIV-positive individuals, a CD4+ T-cell count less than 350/mm^3 Use of antiretroviral drugs Hemoglobin concentration less than 8 g/dL; Baseline creatinine kinase elevation more than three times the upper limit of normal Abnormal baseline laboratory values Baseline alanine aminotransferase (ALT) concentration more than 2.5 times the upper limit of normal (Grade 1) Serum creatinine concentration more than twice the upper limit of normal; Serum total bilirubin level greater than twice the upper limit of normal Platelet count less than 100,000/mm^3 Absolute neutrophil count (ANC) less than 1,000/mm^3 Pregnant or breastfeeding; Silico-tuberculosis. Currently receiving TB treatment Serologies or PCR positive for viral hepatitis (Hepatitis, B, C) Concomitant disorders or conditions for which isoniazid, rifampin, pyrazinamide, or ethambutol is contraindicated. These include cirrhosis, acute liver disease of any cause, acute uncontrolled gouty arthritis and peripheral neuropathy. Any medical or psychological condition which, in the view of the study investigator, makes study participation inadvisable. Infection with an isolate determined to be resistant to rifampin by GeneXpert. More than five days of anti-tuberculosis treatment within the previous 3 months Planned or current use of cyclosporine, tacrolimus, erythromycin or colchicine Central nervous system (CNS) TB Extra-pulmonary TB only, not in combination with pulmonary TB History of TB

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Petros C. Karakousis, MD

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Richard E. Chaisson, MD

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Neil Martinson, MD, MPH

Organizational Affiliation

University of Witwatersrand, South Africa

Official's Role

Principal Investigator

Facility Information:

Facility Name

PHRU Non-Network CRS

City

Johannesburg

State/Province

Gauteng

ZIP/Postal Code

1864

Country

South Africa

12. IPD Sharing Statement

Learn more about this trial

StAT-TB (Statin Adjunctive Therapy for TB): A Phase 2b Dose-finding Study of Pravastatin in Adults With Tuberculosis

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