Tuberculosis
Conditions
Brief 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.
Detailed description
This is a Phase II, multi-site, dose-ranging trial comparing 3 doses of RIF in a multidrug regimen for treatment of smear-positive, pulmonary TB. The intervention phase of this prospective, randomized, double-blinded trial will last 8 weeks, the duration of the standard intensive phase for short-course chemotherapy for TB. 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. Subjects, clinicians, and laboratory staff will be blinded to study arm. All patients in the same weight band will receive the same total number of tablets (fixed-dose combination plus RIF and/or placebo). Blinding is essential to reduce the probability of biased reporting of adverse events. After randomization, other covariates that may result in heterogeneity within strata (e.g., presence of cavitation, HIV serostatus), will be adjusted for in analyses. It is important to maintain the ability to measure the effect (if any) of these potential characteristics on treatment outcome. If we were to stratify on these characteristics, we could not estimate their confounding (or interaction) effect. All doses will be delivered orally and fully supervised. All patients will receive weight-based doses of fixed-dose combinations according to package inserts. This will be supplemented by active RIF capsules or placebos, or both, according to weight and treatment arm. They will also all receive 50 mg of pyridoxine to prevent peripheral neuropathy, a common side effect of INH.
Interventions
DRUGHigher-Dose Rifampin
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.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Sanofi
Harvard School of Public Health (HSPH)
Brigham and Women's Hospital
University of Liverpool
St George's, University of London
University of Florida
Socios en Salud
Harvard University Faculty of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steady State Pharmacokinetic Exposure of RIF | At any time during the intensive phase of treatment, after steady state has been reached (at a minimum, after 14 days of daily RIF delivery) | The endpoint is the (dimensionless) ratio of AUC0-6 mcg/ml\*h to MIC99.9 mcg/ml |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sputum Culture Sterilization During the Initial 8 Weeks of Treatment | Until 8 weeks of treatment are completed | Number of participants that are sputum culture (in LJ) negative for TB at 8 weeks |
| Incidence of Rifampin-related Grade 2 or Higher Adverse Events | Throughout the 12 weeks post treatment initiation | Number of participants experiencing at least one rifampin-related grade 2 or higher adverse events during the initial 8 weeks of treatment and up to four weeks after. |
Countries
Peru, United Kingdom, United States
Participant flow
Recruitment details
Recruitment was done through routine passive case detection in operation at ambulatory facilities in the Peruvian public health system (DISA IV-Lima Este and DISA V- Lima Ciudad).
Pre-assignment details
180 participants were randomized in a 1:1:1 allocation to the 10, 15, and 20 mg/kg treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| 10 mg/kg 10 mg/kg RIF | 60 |
| 15 mg/kg 15 mg/kg RIF | 60 |
| 20 mg/kg 20 mg/kg RIF | 60 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Change in local TB/HIV norms | 0 | 1 | 1 |
| Overall Study | Could not complete tx in protocol period | 5 | 5 | 6 |
| Overall Study | Late exclusion | 0 | 3 | 3 |
| Overall Study | Lost to Follow-up | 4 | 1 | 2 |
| Overall Study | Moved out of study jurisdiction | 1 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | 10 mg/kg | 15 mg/kg | 20 mg/kg | Total |
|---|---|---|---|---|
| Age, Continuous | 24 years | 25 years | 27 years | 25 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 60 Participants | 60 Participants | 59 Participants | 179 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 57 Participants | 51 Participants | 54 Participants | 162 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants | 12 Participants |
| Race (NIH/OMB) White | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 21 Participants | 19 Participants | 26 Participants | 66 Participants |
| Sex: Female, Male Male | 39 Participants | 41 Participants | 34 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 60 | 30 / 60 | 21 / 60 |
| serious Total, serious adverse events | 2 / 60 | 1 / 60 | 5 / 60 |
Outcome results
Primary
Steady State Pharmacokinetic Exposure of RIF
The endpoint is the (dimensionless) ratio of AUC0-6 mcg/ml\*h to MIC99.9 mcg/ml
Time frame: At any time during the intensive phase of treatment, after steady state has been reached (at a minimum, after 14 days of daily RIF delivery)
Population: Analysis was completed in 168 participants evaluable for pharmacokinetics, as samples were unable to be collected in 12 study participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 10 mg/kg | Steady State Pharmacokinetic Exposure of RIF | 115.6988 Ratio |
| 15 mg/kg | Steady State Pharmacokinetic Exposure of RIF | 201.9725 Ratio |
| 20 mg/kg | Steady State Pharmacokinetic Exposure of RIF | 284.4278 Ratio |
Secondary
Incidence of Rifampin-related Grade 2 or Higher Adverse Events
Number of participants experiencing at least one rifampin-related grade 2 or higher adverse events during the initial 8 weeks of treatment and up to four weeks after.
Time frame: Throughout the 12 weeks post treatment initiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg/kg | Incidence of Rifampin-related Grade 2 or Higher Adverse Events | 26 Participants |
| 15 mg/kg | Incidence of Rifampin-related Grade 2 or Higher Adverse Events | 31 Participants |
| 20 mg/kg | Incidence of Rifampin-related Grade 2 or Higher Adverse Events | 23 Participants |
Secondary
Sputum Culture Sterilization During the Initial 8 Weeks of Treatment
Number of participants that are sputum culture (in LJ) negative for TB at 8 weeks
Time frame: Until 8 weeks of treatment are completed
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg/kg | Sputum Culture Sterilization During the Initial 8 Weeks of Treatment | 46 Participants |
| 15 mg/kg | Sputum Culture Sterilization During the Initial 8 Weeks of Treatment | 44 Participants |
| 20 mg/kg | Sputum Culture Sterilization During the Initial 8 Weeks of Treatment | 45 Participants |