Tuberculosis Treatment Shortening Trial

NCT00130247 | Completed Phase 3 Results FDA Drug

• 1 other identifier: 01-009
• Study Type: interventional
• Target: 394
• Locations: 3 countries
• Sites: 3

Brief Summary

Tuberculosis (TB) is a serious infection that can affect the lungs and other parts of the body. The usual way to treat TB is to take 4 medicines by mouth every day for 2 months, then take 2 of the same medicines for 4 more months, for a total of 6 months. The purpose of this study is to see if taking 4 months of TB medicines is as effective in curing some TB patients as taking 6 months of TB medicines. Study participants will include 758 human immunodeficiency virus (HIV)-non-infected individuals, ages 18-60. Participants will be treated with 4 standard drugs called isoniazid, rifampicin, pyrazinamide and ethambutol. All individuals will take TB medicines for at least 4 months. After 4 months of treatment, if no TB germs are growing in sputum samples, participants will be assigned to either stop taking TB medicine (4 months of treatment) or to continue taking TB drugs for 2 more months (6 months of treatment). Participants will be involved in study procedures for up to 30 months.

Conditions

Tuberculosis

Keywords

Brazil; Philippines; Tuberculosis; Uganda

Outcome Measures

Primary Outcomes (2)

• Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat

  Patients who presented with TB after completion of study phase treatment but before the end of follow-up were classified as relapses. A bacteriologic relapse was defined as a patient who became consistently culture-positive \[defined as at least 1 of the following\]: (a) at least 1 sputum mycobacterial culture growing at least 10 colonies of MTB on solid medium; (b) 2 or more respiratory secretion cultures that are positive for MTB in liquid media; or (c) any culture from an extrapulmonary site that is positive for MTB during follow-up after successful completion of initial anti-TB treatment.

  30 months

• Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol

  Patients who presented with TB after completion of study phase treatment but before the end of follow-up were classified as relapses. A bacteriologic relapse was defined as a patient who became consistently culture-positive \[defined as at least 1 of the following\]: (a) at least 1 sputum mycobacterial culture growing at least 10 colonies of MTB on solid medium; (b) 2 or more respiratory secretion cultures that are positive for MTB in liquid media; or (c) any culture from an extrapulmonary site that is positive for MTB during follow-up after successful completion of initial anti-TB treatment.

  30 months

Secondary Outcomes (9)

• Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat

  2 years

• Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol

  2 years

• Relapses at 1 and 2 Years

  1 and 2 years after successful completion of initial anti-TB treatment

• Acquired Drug Resistance in Patients Who Relapsed

  2 years

• Immunologic: Changes in Cytokine Levels in Mycobacterium Tubercolosis (MTB) Antigen-stimulated Whole Blood Culture Supernatants - Results Are Pending

  After 2 and 6 months of anti-TB treatment and upon relapse

Study Arms (2)

2EHRZ/2HR arm

EXPERIMENTAL

Daily treatment with isoniazid (INH), rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks.

Drug: Ethambutol; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Rifampin

2EHRZ/4HR arm

ACTIVE COMPARATOR

Daily treatment with Isoniazid (INH), rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks.

Drug: Ethambutol; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Rifampin

Interventions

Ethambutol DRUG

Mycobacteriostatic agent given to prevent emergence of drug resistance to other 1st line drugs; dosages are 15-25 milligram (mg)/ kilogram (kg)/day (d).

2EHRZ/2HR arm; 2EHRZ/4HR arm

Isoniazid DRUG

Hydrazide of isonicotininc acid; antimicrobial activity is limited to mycobacteria where it inhibits the synthesis of mycolic acids.

2EHRZ/2HR arm; 2EHRZ/4HR arm

Pyrazinamide DRUG

1st line bactericidal agent; dosages are 15-30 mg/kg/d, up to 2 grams (gm)/d.

2EHRZ/2HR arm; 2EHRZ/4HR arm

Rifampin DRUG

1st line bactericidal agent which inhibits deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase; dosages are 10 mg/kg/d (up to 600 mg/d).

2EHRZ/2HR arm; 2EHRZ/4HR arm

Eligibility Criteria

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

You may qualify if:

• Adults, male or female, aged 18-60. -Newly diagnosed initial episodes of pulmonary tuberculosis. Sputum smear-positive and -negative patients are eligible for enrollment. The diagnosis of tuberculosis must be confirmed by culture. Acid fast bacteria (AFB) smear positive patients found later not to have tuberculosis (TB) (i.e. those with non-tuberculous mycobacterial disease) and those without culture confirmation \[at least one culture on solid media growing \> 10 colonies of Mycobacterium tuberculosis (MTB) or a positive BACTEC or Mycobacteria growth indicator tube (MGIT) enriched liquid culture growing MTB\] will be removed from the study. -Chest X-ray and clinical findings consistent with tuberculosis. -Hemoglobin greater than or equal to 8 gm/dL (greater than or equal to 5.0 mmol/L). -Serum creatinine \< 2 mg/dL (\< 177 micro mol/L). -Serum aspartate aminotransferase (AST) \< 1.5 times the upper limit of normal for the testing laboratory, and serum total bilirubin \< 1.3 mg/dL (22.2 micro mol/L). -Random serum glucose less than or equal to 150 mg/dl (8.3 mmol/L). -Ambulatory. -Willing to provide informed consent for study participation, provide required specimens for examination, and to undergo and receive results of human immunodeficiency virus (HIV) testing. -Willing to receive supervised anti-TB treatment. -Completion of the required 112 doses of chemotherapy within 18 weeks of starting treatment.

You may not qualify if:

• Human immunodeficiency virus (HIV)-infected. -History of prior tuberculosis or history of previous tuberculosis treatment. -Pregnant or breastfeeding. -Cavitary tuberculosis on initial chest X-ray (taken within 14 days of study entry). -Exposure to person(s) with known drug resistant tuberculosis. -Patients receiving chronic steroids or other immunosuppressive medications. -Extra-pulmonary tuberculosis. -Patients with drug resistant tuberculosis (resistance to isoniazid (INH), rifampicin, pyrazinamide or ethambutol). -Professional sex worker, alcoholic and/or intravenous (IV) drug abuser. -Silicosis or other serious chronic medical problems including diabetes mellitus or chronic renal failure. Final determination of eligibility will be made after review of drug susceptibility testing results on an initial sputum isolate and results of all sputum cultures. Pregnant patients may not be enrolled in the study. Patients in the 4 month arm who become pregnant during months 5 and 6 of study participation will be dropped from the study and receive an additional 2 months of treatment with INH and rifampicin.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (3)

Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center

Vitória, Espírito Santo, 29040-091, Brazil

Location

Makati Medical Center

Makati City, National Capital Region, 1229, Philippines

Location

Mulago Hospital Complex

Kampala, 99999, Uganda

Location

Related Publications (7)

• Johnson JL, Thiel BA. Time until relapse in tuberculosis treatment trials: implication for phase 3 trial design. Am J Respir Crit Care Med. 2012 Sep 1;186(5):464. doi: 10.1164/ajrccm.186.5.464. No abstract available.

  PMID: 22942350 BACKGROUND

• Palaci M, Dietze R, Hadad DJ, Ribeiro FK, Peres RL, Vinhas SA, Maciel EL, do Valle Dettoni V, Horter L, Boom WH, Johnson JL, Eisenach KD. Cavitary disease and quantitative sputum bacillary load in cases of pulmonary tuberculosis. J Clin Microbiol. 2007 Dec;45(12):4064-6. doi: 10.1128/JCM.01780-07. Epub 2007 Oct 10.

  PMID: 17928422 RESULT

• Bark CM, Dietze R, Okwera A, Quelapio MI, Thiel BA, Johnson JL. Clinical symptoms and microbiological outcomes in tuberculosis treatment trials. Tuberculosis (Edinb). 2011 Nov;91(6):601-4. doi: 10.1016/j.tube.2011.05.007. Epub 2011 Aug 2.

  PMID: 21813327 RESULT

• Colangeli R, Jedrey H, Kim S, Connell R, Ma S, Chippada Venkata UD, Chakravorty S, Gupta A, Sizemore EE, Diem L, Sherman DR, Okwera A, Dietze R, Boom WH, Johnson JL, Mac Kenzie WR, Alland D; DMID 01-009/Tuberculosis Trials Consortium Study 22 Teams. Bacterial Factors That Predict Relapse after Tuberculosis Therapy. N Engl J Med. 2018 Aug 30;379(9):823-833. doi: 10.1056/NEJMoa1715849.

  PMID: 30157391 RESULT

• Bark CM, Thiel BA, Johnson JL. Pretreatment time to detection of Mycobacterium tuberculosis in liquid culture is associated with relapse after therapy. J Clin Microbiol. 2012 Feb;50(2):538. doi: 10.1128/JCM.06193-11. Epub 2011 Nov 23. No abstract available.

  PMID: 22116143 RESULT

• Johnson JL, Hadad DJ, Dietze R, Maciel EL, Sewali B, Gitta P, Okwera A, Mugerwa RD, Alcaneses MR, Quelapio MI, Tupasi TE, Horter L, Debanne SM, Eisenach KD, Boom WH. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med. 2009 Sep 15;180(6):558-63. doi: 10.1164/rccm.200904-0536OC. Epub 2009 Jun 19.

  PMID: 19542476 RESULT

• Maciel EL, Brioschi AP, Peres RL, Guidoni LM, Ribeiro FK, Hadad DJ, Vinhas SA, Zandonade E, Palaci M, Dietze R, Johnson JL. Smoking and 2-month culture conversion during anti-tuberculosis treatment. Int J Tuberc Lung Dis. 2013 Feb;17(2):225-8. doi: 10.5588/ijtld.12.0426.

  PMID: 23317958 RESULT

MeSH Terms

Conditions

Tuberculosis

Interventions

Ethambutol; Isoniazid; Pyrazinamide; Rifampin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Ethylenediamines; Diamines; Polyamines; Amines; Organic Chemicals; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrazines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Limitations and Caveats

Enrollment was stopped early and the number of patients enrolled was 1/2 of the original sample size. The study was completed.

Results Point of Contact

• Title: John L. Johnson, M.D., Principal Investigator
• Organization: Case Western Reserve University, Tuberculosis Research Unit

jlj@case.edu

(216) 368-1949

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 12, 2005
• First Posted: August 15, 2005
• Study Start: April 8, 2002
• Primary Completion: September 2, 2008
• Study Completion: November 28, 2008
• Last Updated: November 8, 2018
• Results First Posted: January 27, 2010

Record last verified: 2010-04-20

Locations

BR (1); PH (1); UG (1)