Statin Adjunctive Therapy for TB

Phase 2

Completed

Conditions: Tuberculosis

Interventions: Drug: Pravastatin

Registration Number: NCT03456102

Lead Sponsor: Johns Hopkins University

Brief Summary: There is an urgent need for novel therapies to shorten TB treatment and improve long-term lung function outcomes. Host-directed therapies (HDT) have received significant attention recently given the ability of M. tuberculosis to subvert host immune responses and cause destructive lung pathology. Statins are among the most promising HDT agents for TB. In addition to having a highly favorable safety profile, statins have been shown to have anti-TB activity in macrophages, to synergize with anti-TB drugs, and to shorten the duration of TB treatment in the standard mouse model.

The StAT-TB trial will comprise two different stages. In the 14-day Stage 1 study, investigators will test the safety and tolerability, as well as Pharmacokinetics (PK), of two different doses of pravastatin co-administered with standard anti-TB treatment. In Stage 2, investigators will test the ability of pravastatin adjunctive therapy (dose to be determined in Stage 1) to shorten the mean time to sputum culture conversion (primary endpoint) and improve lung function outcomes (secondary endpoints) relative to the standard regimen. In addition, investigators will continue to investigate the anti-TB mechanism of action of pravastatin in order to further improve HDT options for TB in the future.

Detailed Description: Not available

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 Mycobacterium tuberculosis (MTB)/resistance to rifampicin (RIF) with a cycle threshold (Ct) <28.
Documentation of HIV status
Weight ≥45 kg
Karnofsky score of at least 60
Ability to provide informed consent
Ability to adhere to study follow-up visits
Ability to adhere to contraceptive requirements and willing to use two forms of contraception.
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 cluster of differentiation 4 (CD4+) T-cell count <100/mm3
Use of antiretroviral drugs
Hemoglobin concentration less than 7 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 three times the upper limit of normal, 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 < 100,000/mm3, White Blood Cell (WBC) < 2500 (mcL))
Pregnant or breastfeeding;
Silico-tuberculosis.
Currently receiving TB treatment
Concomitant disorders or conditions for which isoniazid, rifampin, pyrazinamide, or ethambutol is contraindicated. These include sever hepatic damage, 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 known to be resistant to a first -line TB drug; for example rifampin.
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
Pravastatin 40 mg	Pravastatin	Pravastatin 40 mg, isoniazid 300 mg, rifampin 450 mg (weight \<50 kg) or 600 mg (weight \>50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days
Pravastatin 80 mg	Pravastatin	Pravastatin 80 mg, isoniazid 300 mg, rifampin 450 mg (weight \<50 kg) or 600 mg (weight \>50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days Arm 2 will only be recruited if pravastatin 40 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.
Pravastatin 120 mg	Pravastatin	Pravastatin 120 mg, isoniazid 300 mg, rifampin 450 mg (weight \<50 kg) or 600 mg (weight \>50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days 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.
Pravastatin 160 mg	Pravastatin	Pravastatin 160 mg, isoniazid 300 mg, rifampin 450 mg (weight \<50 kg) or 600 mg (weight \>50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days 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
Safety of Escalating Doses of Pravastatin as Assessed by Number of Adverse Events	Up to 30 days	Safety of escalating doses of pravastatin (40 mg - 160 mg) when co-administered with rifampin, as evidenced by number of Grade 3 or higher adverse events.

Secondary Outcome Measures