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

Phase 2

Completed

Conditions: Tuberculosis
Pulmonary Tuberculosis

Interventions: Drug: Pravastatin
Drug: Rifafour
Dietary Supplement: Vitamin B6

Registration Number: NCT03882177

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

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm 1: Pravastatin (40 mg) and Rifafour	Vitamin B6	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.
Arm 2: Pravastatin (80 mg) and Rifafour	Rifafour	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.
Arm 4: Pravastatin (160 mg) and Rifafour	Rifafour	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.)
Arm 3: Pravastatin (120 mg) and Rifafour	Rifafour	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.)
Arm 3: Pravastatin (120 mg) and Rifafour	Vitamin B6	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.)
Arm 1: Pravastatin (40 mg) and Rifafour	Rifafour	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.
Arm 2: Pravastatin (80 mg) and Rifafour	Vitamin B6	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.
Arm 4: Pravastatin (160 mg) and Rifafour	Vitamin B6	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.)
Arm 3: Pravastatin (120 mg) and Rifafour	Pravastatin	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.)
Arm 1: Pravastatin (40 mg) and Rifafour	Pravastatin	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.
Arm 2: Pravastatin (80 mg) and Rifafour	Pravastatin	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.
Arm 4: Pravastatin (160 mg) and Rifafour	Pravastatin	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.)

Primary Outcome Measures

Name	Time	Method
Frequency of Grade 3 or Higher Adverse Events	Measured through Day 30	Graded using the DAIDS table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Permanently Discontinue Assigned Study Regimen for Any Reason	Measured through Day 14	(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)