Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (TMC207-CL001)

NCT01215110 | Completed Phase 2 Results

• 1 other identifier: TMC207-CL001
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief Summary

The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of TMC207 at multiple doses as determined by the rate of change of log10 colony forming units (CFU) per ml sputum over the time period Day 7-14 in participants with smear positive pulmonary tuberculosis (TB). A control group will receive standard treatment.

Conditions

Pulmonary Tuberculosis

Keywords

Bedaquiline; Sirturo; Early Bactericidal Activity; EBA; Pulmonary Tuberculosis; TMC207

Outcome Measures

Primary Outcomes (1)

• Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-14).

  The rates of change were calculated from the two slopes of the bi-linear (piece-wise) regression, for each treatment group. The nodes (point of inflection, i.e. where slope changes) used in these bi-linear regressions, as determined by visual inspection, were Day 3.5. node. Throughout the analyses, the established node at Day 2.5 was used in the Rifafour e-275 arm. Note that to facilitate interpretation the sign of these slopes were reversed for log10CFU/ml.

  Fourteen consecutive days of treatment

Secondary Outcomes (10)

• Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 7-14).

  Days 7-14 of fourteen consecutive days of treatment

• Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 2-14).

  Days 2-14 of fourteen consecutive days of treatment

• Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-2).

  Two consecutive days of treatment

• Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14)

  Fourteen consecutive days of treatment

• Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2)

  Two consecutive days of treatment

Study Arms (5)

TMC207 700/500/400

EXPERIMENTAL

TMC207- 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14

Drug: TMC207

TMC207 500/400/300

EXPERIMENTAL

TMC207- 500 mg Day 1; 400 mg Day 2 and 300 mg Days 3-14.

Drug: TMC207

TMC207 400/300/200

EXPERIMENTAL

TMC207- 400 mg Day 1; 300 mg Day 2 and 200 mg Days 3-14

Drug: TMC207

TMC207 200/100

EXPERIMENTAL

TMC207- 200 mg Day 1 and 100 mg Days 2-14

Drug: TMC207

Rifafour e-275 mg

ACTIVE COMPARATOR

Rifafour e-275 mg

Drug: Rifafour e-275 mg

Interventions

TMC207 DRUG

TMC207 200/100; TMC207 400/300/200; TMC207 500/400/300; TMC207 700/500/400

Rifafour e-275 mg DRUG

Rifafour e-275 mg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide written, informed consent prior to all trial-related procedures including HIV testing.
• Male or female, aged between 18 and 65 years inclusive.
• Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
• Newly diagnosed, previously untreated, uncomplicated, sputum smear-positive, pulmonary TB.
• A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
• Sputum positive on direct microscopy for acid-fast bacilli …(at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD)/World Health Organization (WHO) scale).
• Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).
• Females may participate if they are of non-childbearing potential, if they are using effective birth control methods and are willing to continue practicing birth control methods throughout treatment or if they are non-heterosexually active or willing to practice sexual abstinence throughout the treatment period or have a vasectomized partner (confirmed sterile). Therefore to be eligible for this study women of childbearing potential should either:1) use a double barrier method to prevent pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal based contraceptives in combination with a barrier contraceptive, or 3) use an intrauterine device in combination with a barrier contraceptive. They must also be willing to continue these contraception until 6 months after last study drug or 6 months after discontinuation from study medication in case of premature discontinuation. (Note: Hormone-based contraception may not be reliable when taking TMC207; therefore, hormone-based contraceptives cannot be used by female patients to prevent pregnancy).
• Male patients must be willing to use a condom with spermicide when having heterosexual intercourse throughout treatment and until 1 month after last study drug administration or 1 month after discontinuation from study medication in case of premature discontinuation.

You may not qualify if:

• Evidence of clinically significant metabolic, gastrointestinal neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
• Known or suspected hypersensitivity to study medications (including any rifamycin antibiotics)
• Rifampicin-resistant and/or isoniazid-resistant bacteria detected with a sputum specimen collected within the pre-treatment period and tested at the study laboratory.
• Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the investigator.
• Current or past history of alcohol and/or drug use that, in the investigator's opinion, would compromise the participant's safety or compliance to the study protocol procedures.
• HIV infected patients:
• having a cluster of differentiation 4 (CD4)+ count \<300 cells/µL;
• or having received antiretroviral therapy medication within the last 90 days:
• or having received oral or intravenous antifungal medication within the last 90 days;
• or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).
• Significant cardiac arrhythmia requiring medication
• Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start.
• Patients with the following QT/corrected QT(QTc) interval characteristics at screening:
• Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QT corrected for heart rate using Fridericia's method (QTcF) interval \>450 ms at screening;
• History of additional risk factors for Torsade de Pointes, e.g., heart failure, hypokalemia, family history of Long QT Syndrome;

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (1)

Karl Bremer Hospital

Belville, Cape Town, 7531, South Africa

Location

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

bedaquiline

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Daniel E. Everitt, MD, Vice President and Senior Medical Officer
• Organization: Global Alliance for TB Drug Development

Dan.Everitt@tballiance.org

212-227-7540

Study Officials

• Andreas Diacon

  TASK APPLIED SCIENCE, Karl Bremer Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2010
• First Posted: October 6, 2010
• Study Start: April 1, 2010
• Primary Completion: August 1, 2010
• Study Completion: September 1, 2010
• Last Updated: April 26, 2017
• Results First Posted: April 26, 2017

Record last verified: 2017-01

Locations

ZA (1)