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Trial of High-Dose Rifampin in Patients With TB (HIRIF)

Primary Purpose

Tuberculosis

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Higher-Dose Rifampin

About this trial

This is an interventional treatment trial for Tuberculosis

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Florida
Socios En Salud Sucursal Perú
School of Clinical Sciences at University of Liverpool
St. George's University of London

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

No Intervention

Experimental

Arm Label

RIF 600

RIF 900

RIF 1200

Arm Description

Outcomes

Primary Outcome Measures

Steady State Pharmacokinetic Exposure of RIF

The endpoint is the (dimensionless) ratio of AUC0-6 mcg/ml*h to MIC99.9 mcg/ml

Secondary Outcome Measures

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

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.

Full Information

NCT ID

NCT01408914

First Posted

August 2, 2011

Last Updated

October 17, 2017

Sponsor

Harvard University Faculty of Medicine

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

1. Study Identification

Unique Protocol Identification Number

NCT01408914

Brief Title

Trial of High-Dose Rifampin in Patients With TB

Acronym

HIRIF

Official Title

Randomized Trial of High-Dose Rifampin in Patients With New, Smear-Positive TB

Study Type

Interventional

2. Study Status

Record Verification Date

October 2017

Overall Recruitment Status

Completed

Study Start Date

September 2013 (undefined)

Primary Completion Date

April 2016 (Actual)

Study Completion Date

April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Harvard University Faculty of Medicine

Collaborators

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderOutcomes Assessor

Allocation

Randomized

Enrollment

180 (Actual)

8. Arms, Groups, and Interventions

Arm Title

RIF 600

Arm Type

No Intervention

Arm Title

RIF 900

Arm Type

Experimental

Arm Title

RIF 1200

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Higher-Dose Rifampin

Other Intervention Name(s)

rifadin, rifampicin

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.

Primary Outcome Measure Information:

Title

Steady State Pharmacokinetic Exposure of RIF

Description

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)

Secondary Outcome Measure Information:

Title

Sputum Culture Sterilization During the Initial 8 Weeks of Treatment

Description

Number of participants that are sputum culture (in LJ) negative for TB at 8 weeks

Time Frame

Until 8 weeks of treatment are completed

Title

Incidence of Rifampin-related Grade 2 or Higher Adverse Events

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

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: 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Carole D Mitnick, Sc.D

Organizational Affiliation

Harvard Medical School (HMS and HSDM)

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Geraint Davies, B.M., Ph.D

Organizational Affiliation

University of Liverpool

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610-0486

Country

United States

Facility Name

Socios En Salud Sucursal Perú

City

Lima 6

Country

Peru

Facility Name

School of Clinical Sciences at University of Liverpool

City

Liverpool

Country

United Kingdom

Facility Name

St. George's University of London

City

London

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

27567500

Citation

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.

Results Reference

background

PubMed Identifier

28559269

Citation

Peloquin 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. Erratum In: Antimicrob Agents Chemother. 2017 Aug 24;61(9):

Results Reference

result

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Trial of High-Dose Rifampin in Patients With TB

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