TuberculosisPhase 2HIRIFNCT01408914
Trial of High-Dose Rifampin in Patients With TB
A Phase 2 study testing Higher-Dose Rifampin in people with Tuberculosis, run by Harvard University Faculty of Medicine at 4 sites in 3 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Tuberculosis
- What is being tested?
- Higher-Dose Rifampin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 180 participants
- Where
- 4 sitesin 3 countries
- Study dates
- Sep 2013to Apr 2016
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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).
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- 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.
Who cannot join
- 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.
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- 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:
- Serum amino alanine transferase (ALT) >2 times upper limit of normal
- Serum total bilirubin concentration >2.5 times upper limit of normal
- Serum creatinine concentration > 2 times upper limit of normal and/or creatinine clearance <60 mL/min
- Hemoglobin concentration < 7.0 g/dL
- Platelet count < 150,000/mm3
- 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.
Trial locations and contacts
4 sites in 3 countries.
4 sites in 3 countries
United Kingdom2 sites
School of Clinical Sciences at University of Liverpool
Liverpool
St. George's University of London
London
United States1 site
University of Florida
Gainesville, Florida, 32610-0486
About this study
Official title: Randomized Trial of High-Dose Rifampin in Patients With New, Smear-Positive TB
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.
Read the 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.
- Conditions
- Tuberculosis
- Being tested
- Higher-Dose Rifampin
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Higher-Dose RifampinDrug
Also called rifadin, rifampicin
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.
| Study group | Role | What they receive |
|---|---|---|
| RIF 600 | No intervention | Not described |
| RIF 900 | Experimental | Not described Receives: Drug: Higher-Dose Rifampin |
| RIF 1200 | Experimental | Not described Receives: Drug: Higher-Dose Rifampin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Steady State Pharmacokinetic Exposure of RIF
The endpoint is the (dimensionless) ratio of AUC0-6 mcg/ml*h to MIC99.9 mcg/ml
Measured: 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)
Secondary outcomes (2)
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
Measured: Until 8 weeks of treatment are completed
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.
Measured: Throughout the 12 weeks post treatment initiation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Aug 2011 (estimated)
- Study startSep 2013
- Primary completionApr 2016
- Study completionApr 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 180 participants (actual)
Sponsor and investigators
- Lead sponsor
- Harvard University Faculty of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- 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
- Responsible party
- Principal investigator, Carole Mitnick, Harvard University Faculty of Medicine
- Investigators
- Carole D Mitnick, Sc.D, Principal investigator, Harvard Medical School (HMS and HSDM)Geraint Davies, B.M., Ph.D, Principal investigator, University of Liverpool
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01408914
- Sponsor's protocol ID
- 11-0050
- Other IDs
- 5U01AI091429-03
- Acronym
- HIRIF
- Status last verified
- Oct 2017
- First submitted
- 2 Aug 2011
- Last updated
- 20 Nov 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Milstein M, Lecca L, Peloquin C, Mitchison D, Seung K, Pagano M, Coleman D, Osso E, Coit J, Vargas Vasquez DE, Sanchez Garavito E, Calderon R, Contreras C, Davies G, Mitnick CD. Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial. BMC Infect Dis. 2016 Aug 27;16(1):453. doi: 10.1186/s12879-016-1790-x.
PubMed 27567500Peloquin CA, Velasquez GE, Lecca L, Calderon RI, Coit J, Milstein M, Osso E, Jimenez J, Tintaya K, Sanchez Garavito E, Vargas Vasquez D, Mitnick CD, Davies G. Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis. Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00038-17. doi: 10.1128/AAC.00038-17. Print 2017 Aug.
PubMed 28559269Mackay E, Platt G, Peloquin CA, Brooks MB, Coit JM, Velasquez GE, Pertinez H, Vargas D, Sanchez E, Calderon RI, Jimenez J, Tintaya K, Garcia D, Osso E, Lecca L, Mitnick C, Davies GR. Impact of Pharmacogenetics on Pharmacokinetics of First-Line Antituberculosis Drugs in the HIRIF Trial. J Infect Dis. 2025 Aug 14;232(2):e258-e265. doi: 10.1093/infdis/jiaf195.
PubMed 40239986
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Trial of High-Dose Rifampin in Patients With New, Smear-Positive TB
- ClinicalTrials.gov ID
- NCT01408914
- Acronym / sponsor ID
- HIRIF / 11-0050
- Conditions
- Tuberculosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 180 participants (actual)
- Lead sponsor
- Harvard University Faculty of MedicineUniversity, hospital or other
- Collaborators
- 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
- Study start
- Sep 2013
- Primary completion
- Apr 2016 (actual)
- Study completion
- Apr 2016 (actual)
- First posted
- 3 Aug 2011 (estimated)
- Results
- Posted 13 Jul 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| RIF 600 | No intervention | – |
| RIF 900 | Experimental | Drug: Higher-Dose Rifampin |
| RIF 1200 | Experimental | Drug: Higher-Dose Rifampin |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Higher-Dose RifampinAlso: rifadin, rifampicinThe 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. | Drug | RIF 1200, RIF 900 |
Primary outcome
Steady State Pharmacokinetic Exposure of RIF
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)
The endpoint is the (dimensionless) ratio of AUC0-6 mcg/ml*h to MIC99.9 mcg/ml
2 secondary outcomes
Sputum Culture Sterilization During the Initial 8 Weeks of Treatment
Time frame: Until 8 weeks of treatment are completed
Incidence of Rifampin-related Grade 2 or Higher Adverse Events
Time frame: Throughout the 12 weeks post treatment initiation
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Nov 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 27567500Milstein M, Lecca L, Peloquin C, Mitchison D, Seung K, Pagano M, Coleman D, Osso E, Coit J, Vargas Vasquez DE, Sanchez Garavito E, Calderon R, Contreras C, Davies G, Mitnick CD. Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial. BMC Infect Dis. 2016 Aug 27;16(1):453. doi: 10.1186/s12879-016-1790-x.
- Results publication: PubMed 28559269Peloquin CA, Velasquez GE, Lecca L, Calderon RI, Coit J, Milstein M, Osso E, Jimenez J, Tintaya K, Sanchez Garavito E, Vargas Vasquez D, Mitnick CD, Davies G. Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis. Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00038-17. doi: 10.1128/AAC.00038-17. Print 2017 Aug.
- Derived from this study: PubMed 40239986Mackay E, Platt G, Peloquin CA, Brooks MB, Coit JM, Velasquez GE, Pertinez H, Vargas D, Sanchez E, Calderon RI, Jimenez J, Tintaya K, Garcia D, Osso E, Lecca L, Mitnick C, Davies GR. Impact of Pharmacogenetics on Pharmacokinetics of First-Line Antituberculosis Drugs in the HIRIF Trial. J Infect Dis. 2025 Aug 14;232(2):e258-e265. doi: 10.1093/infdis/jiaf195.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Carole D Mitnick, Sc.D principal investigator
Harvard Medical School (HMS and HSDM)
Geraint Davies, B.M., Ph.D principal investigator
University of Liverpool
4 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Higher-Dose Rifampin in people with Tuberculosis, run by Harvard University Faculty of Medicine at 4 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United Kingdom, United States, Peru. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Steady State Pharmacokinetic Exposure of RIF (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)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01408914, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Nov 2017.