Trial of High-Dose Rifampin in Patients With TB
Condition: Tuberculosis
MeSH terms: Tuberculosis
Intervention: Higher-Dose Rifampin
Intervention description: The intervention phase of this trial will last 8 weeks. During that time, subjects will receive the following companion drugs: isoniazid (INH, 5 mg/kg/day), ethambutol (EMB, 20 mg/kg/day), and pyrazinamide (PZA, 25 mg/kg/day), pyridoxine (50 mg), the standard doses used in treatment. Subjects will also be randomized to receive one of the following weight-based doses of the study drug, rifampin (RIF): 10 mg/kg/day (standard dose, control), 15 mg/kg/day (intervention 1), 20 mg/kg/day (intervention 2). All patients will receive at least standard dose of RIF, the efficacy of which in multidrug-treatment for TB is well established. Placebo will be used to control only the additional RIF capsules provided in the intervention arms.
Intervention MeSH terms: Rifampin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Enrollment: 180.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the potential of high doses of rifampin (RIF) to
      shorten treatment for tuberculosis (TB) without causing more adverse events. The hypotheses
      are that higher doses of RIF will result in higher blood concentrations of RIF; higher blood
      concentrations will result in tuberculosis bugs being killed more quickly; and, both of these
      will happen without more adverse events. Patients with active, infectious, drug-susceptible
      TB who agree to participate will be randomly assigned to 1 of 3 doses of RIF. All patients
      will also receive standard doses of regular (3) companion drugs for 2 months of daily,
      supervised therapy. The study will assess the following among the 3 study arms (oral doses of
      RIF 10, 15 & 20 mg/kg/day) during the initial 8 weeks of treatment: 1) the amount of RIF in
      the blood after at least 14 days of treatment; 2) the difference in the number of
      tuberculosis bugs killed; 3) the frequency of adverse events.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Newly diagnosed pulmonary TB with acid-fast bacilli (>=2+) in a stained sputum smear,
             ultimately confirmed by culture.

          -  Susceptibility of isolate to INH and RIF by HAIN test.

          -  Willingness to undergo HIV testing according to the National Health Guidelines for TB
             control in Peru. The study will also consider patients who have had negative HIV
             serostatus documented within six months prior to enrollment or if verifiable positive
             serostatus was documented using a validated test any time previously.

          -  Age >/= 18 years and <61 years.

          -  Signed informed consent.

          -  Negative serum pregnancy test (women of childbearing potential).

          -  Women with child-bearing potential must agree to practice a double-barrier method of
             birth control during treatment. Adequate contraceptives (condoms and spermicide) will
             be provided by the study to avoid pregnancy among female subjects.

          -  Karnofsky score of at least 50 (requires considerable assistance and frequent medical
             care).

          -  Intends to remain in jurisdiction of health center during study and follow up.

        Exclusion Criteria:

          -  Body weight <30 kg.

          -  Prior treatment with multidrug anti-TB therapy for more than one month.

          -  Resistance on HAIN to INH and/or RIF. These patients will be treated according to
             local programmatic guidelines.

          -  Central nervous system or miliary TB.

          -  Clinical or radiological signs suggestive of pericardial or pleural involvement.

          -  Presence of significant hemoptysis. Patients who cough up frank blood (more than
             blood-streaked sputum) will not be eligible for enrollment.

          -  Known intolerance to any of the study drugs; use of concomitant drugs that interfere
             with the pharmacokinetics of anti-TB drugs; use of concomitant hepatotoxic drugs
             (other than companion study drugs) for which potential drug interactions or
             synergistic toxicity are known: boosted protease inhibitors, non-nucleoside reverse
             transcriptase inhibitors, azole antifungals and statins; use of antibiotics that are
             contraindicated during the study's TB therapy; current daily use of acetaminophen or
             paracetamol for two weeks or more.

          -  History of liver disease.

          -  Uncontrolled condition that might interfere with drug absorption, distribution,
             metabolism or excretion (i.e. chronic gastrointestinal disease, renal insufficiency
             defined by creatinine clearance <60mL/min).

          -  Uncontrolled diabetes mellitus (HbA1c>7.5%).

          -  Refusal to be tested for HIV infection; HIV infection with contraindication for
             treatment with efavirenz (including resistance).

          -  Pulmonary silicosis.

          -  Breastfeeding.

          -  Rifampin contraindications such as hypersensitivity or jaundice.

          -  Likely difficulty adhering to the protocol, as assessed by the investigator.

          -  Laboratory results in the 14 days preceding enrollment showing:

               1. Serum amino alanine transferase (ALT) >2 times upper limit of normal

               2. Serum total bilirubin concentration >2.5 times upper limit of normal

               3. Serum creatinine concentration > 2 times upper limit of normal and/or creatinine
                  clearance <60 mL/min

               4. Hemoglobin concentration < 7.0 g/dL

               5. Platelet count < 150,000/mm3

               6. White blood count <4500 cells/μL.

          -  Having a serological test positive for HBVsAg (hepatitis B virus surface antigen) or
             for HCVAb (hepatitis C virus antibody)test.