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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT03882177

Collaborator

(none)

Enrollment

Location

Arms

34.3

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis Pulmonary Tuberculosis	Drug: Pravastatin Drug: Rifafour Dietary Supplement: Vitamin B6	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

35 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 21, 2020

Actual Primary Completion Date :

May 12, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: Pravastatin (40 mg) and 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.	Drug: Pravastatin Tablets, administered orally Drug: Rifafour Fixed-dose combination (isoniazid, rifampin, pyrazinamide, and ethambutol) tablets, administered orally Dietary Supplement: Vitamin B6 Administered orally.
Experimental: Arm 2: Pravastatin (80 mg) and 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.	Drug: Pravastatin Tablets, administered orally Drug: Rifafour Fixed-dose combination (isoniazid, rifampin, pyrazinamide, and ethambutol) tablets, administered orally Dietary Supplement: Vitamin B6 Administered orally.
Experimental: Arm 3: Pravastatin (120 mg) and 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.)	Drug: Pravastatin Tablets, administered orally Drug: Rifafour Fixed-dose combination (isoniazid, rifampin, pyrazinamide, and ethambutol) tablets, administered orally Dietary Supplement: Vitamin B6 Administered orally.
Experimental: Arm 4: Pravastatin (160 mg) and 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.)	Drug: Pravastatin Tablets, administered orally Drug: Rifafour Fixed-dose combination (isoniazid, rifampin, pyrazinamide, and ethambutol) tablets, administered orally Dietary Supplement: Vitamin B6 Administered orally.

Outcome Measures

Primary Outcome Measures

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

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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PHRU Non-Network CRS	Johannesburg	Gauteng	South Africa	1864

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Principal Investigator: Petros C. Karakousis, MD, Johns Hopkins University
Principal Investigator: Richard E. Chaisson, MD, Johns Hopkins University
Principal Investigator: Neil Martinson, MD, MPH, University of Witwatersrand, South Africa