Statin Adjunctive Therapy for TB
Condition: Tuberculosis
MeSH terms: Tuberculosis
Intervention: Pravastatin
Intervention description: Phase IIB clinical trial: A two-week safety/PK study to determine pravastatin exposures over 24 hours when given together with first-line treatment (HRZE) and ensure the combination is safe and well-tolerated.
A two-week safety/PK study to determine pravastatin exposures over 24 hours when given together with first-line treatment (HRZE) and ensure the combination is safe and well-tolerated.
Intervention MeSH terms: Pravastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

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.
    

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 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