Trial of High-Dose Rifampin in Patients With TB

NCT01408914 | Completed Phase 2 Results DMC

• 2 other identifiers: 11-00505U01AI091429-03
• Study Type: interventional
• Target: 180
• Locations: 3 countries
• Sites: 4

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.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Steady State Pharmacokinetic Exposure of RIF

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

  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

  Until 8 weeks of treatment are completed

• Incidence of Rifampin-related Grade 2 or Higher Adverse Events

  Throughout the 12 weeks post treatment initiation

Study Arms (3)

RIF 600

NO INTERVENTION

RIF 900

EXPERIMENTAL

Drug: Higher-Dose Rifampin

RIF 1200

EXPERIMENTAL

Drug: Higher-Dose Rifampin

Interventions

Higher-Dose Rifampin DRUG

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.

Also known as: rifadin, rifampicin

RIF 1200; RIF 900

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Harvard University Faculty of Medicine: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Sanofi: collaborator
• Harvard School of Public Health (HSPH): collaborator
• Brigham and Women's Hospital: collaborator
• University of Liverpool: collaborator
• St George's, University of London: collaborator
• University of Florida: collaborator
• Socios en Salud: collaborator

Study Sites (4)

University of Florida

Gainesville, Florida, 32610-0486, United States

Location

Socios En Salud Sucursal Perú

Lima, Peru

Location

School of Clinical Sciences at University of Liverpool

Liverpool, United Kingdom

Location

St. George's University of London

London, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 27567500 BACKGROUND

• 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.

  PMID: 28559269 RESULT

• Mackay 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.

  PMID: 40239986 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Rifampin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Carole Mitnick
• Organization: Harvard Medical School

Carole_Mitnick@hms.harvard.edu

617-432-6018

Study Officials

• Carole D Mitnick, Sc.D

  Harvard Medical School (HMS and HSDM)

  PRINCIPAL INVESTIGATOR

• Geraint Davies, B.M., Ph.D

  University of Liverpool

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 2, 2011
• First Posted: August 3, 2011
• Study Start: September 1, 2013
• Primary Completion: April 1, 2016
• Study Completion: April 1, 2016
• Last Updated: November 20, 2017
• Results First Posted: July 13, 2017

Record last verified: 2017-10

Locations

US (1); PE (1); GB (2)