A Study to Evaluate the Efficacy and Safety of TMC207 in Patients With Pulmonary Infection With Multi-drug Resistant Mycobacterium Tuberculosis

This study has been withdrawn prior to enrollment.
(PhIII program revised; TMC207-C210 cancelled)
Sponsor:
Information provided by (Responsible Party):
Janssen Infectious Diseases BVBA
ClinicalTrials.gov Identifier:
NCT01600963
First received: April 24, 2012
Last updated: February 6, 2014
Last verified: February 2014
  Purpose

The purpose of this study is to provide safety and efficacy data for TMC207 and to demonstrate that TMC207 added to a background regimen (BR) is superior to treatment with the BR plus placebo.


Condition Intervention Phase
Multi-drug Resistant Tuberculosis
Drug: Arm A Double-blind Phase: TMC207
Drug: Arm B Double-blind Phase: Placebo
Drug: Treatment Failure During Double-blind Phase: TMC207
Drug: Treatment Failure During Follow-up Phase: TMC207
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III Placebo-controlled, Double-blind, Randomized Trial to Evaluate the Efficacy and Safety of TMC207 in Subjects With Sputum Smear-positive Pulmonary Infection With Multi-drug Resistant Mycobacterium Tuberculosis (MDR-TB)

Resource links provided by NLM:


Further study details as provided by Janssen Infectious Diseases BVBA:

Primary Outcome Measures:
  • Number of patients with favorable treatment outcome at Week 60 [ Time Frame: Week 60 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Number of patients with confirmed culture conversion at Week 84 [ Time Frame: Week 84 ] [ Designated as safety issue: No ]
  • Number of patients with confirmed culture conversion at Week 60 or at time of trial discontinuation [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • The number of patients with development of pre-extensively drug-resistant tuberculosis and extensively drug-resistant tuberculosis [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Time to sputum culture conversion [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients with negative culture and smear for tuberculosis [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Time to positive signal in Mycobacteria Growth Indicator Tube (MGIT960) [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients with confirmed culture conversion by lung cavity status [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients with confirmed culture conversion by geographic region [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients with confirmed culture conversion by human immunodeficiency virus status [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients with confirmed culture conversion by baseline resistance to anti-tuberculosis therapy [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients with Tuberculosis Symptom Profile symptoms at Week 36 and at the end of the treatment-free follow up [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of tuberculosis-related deaths per investigator assessment [ Time Frame: Up to Week 132 ] [ Designated as safety issue: Yes ]
  • Number of patients with weight gain (greater than 5 percent) at Week 36 and at the end of the treatment-free follow up [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients with improvements in laboratory assessments at Week 36 and at the end of the treatment-free follow up [ Time Frame: Up to Week 132 ] [ Designated as safety issue: Yes ]
  • Number of patients with improvements in chest radiograph assessments at Week 36 and at the end of the treatment-free follow up [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients that received salvage regimen with favorable treatment outcome 24 weeks after the end of the individualized salvage regimen [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Mean plasma concentrations of TMC207 [ Time Frame: Up to Week 36 ] [ Designated as safety issue: No ]
  • Mean plasma concentrations of N-monodesmethyl metabolite of TMC207 [ Time Frame: Up to Week 36 ] [ Designated as safety issue: No ]
  • Number of patients affected by an adverse event [ Time Frame: Up to Week 132 ] [ Designated as safety issue: Yes ]
  • Number of patients with confirmed culture conversion at Week 36 [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients who required lung surgeries (resection or pneumonectomy) during the study [ Time Frame: Week 84 ] [ Designated as safety issue: No ]
  • Number of patients with confirmed culture conversion by baseline albumin grade [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
  • Number of patients with confirmed culture conversion by baseline TMC207 minimal inhibitory concentration [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
    Minimal inhibitory concentration is defined as lowest concentration of an antimicrobial agent that will inhibit the visible growth of an organism.

  • Number of patients with confirmed culture conversion at Week 132 [ Time Frame: Week 132 ] [ Designated as safety issue: No ]
  • Number of patients who required lung surgeries (resection or pneumonectomy) during the study [ Time Frame: Week 132 ] [ Designated as safety issue: No ]
  • Number of patients who experienced death [ Time Frame: Up to Week 132 ] [ Designated as safety issue: Yes ]
  • Number of patients will be qualified as cure based on the WHO outcome definition and the number of treatment failures, deaths, transfer out/defaults, and treatment completed [ Time Frame: Up to Week 132 ] [ Designated as safety issue: No ]
    Cure is defined as an multidrug-resistant tuberculosis (MDR-TB) patient who has completed the study procedures according to the protocol and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of the study. If only one positive culture is reported during that time, a patient may still be considered cured, provided that this positive culture is followed by a minimum of 3 consecutive negative cultures taken at least 30 days apart. Treatment failure is defined as a patient who completed the study procedures and was not cured as per the "Cure" definition based on the WHO classification during the study procedures. Defaults is defined as patients who discontinued study procedures for any reason. Treatment completed is defined as an MDR-TB patient who has completed the study procedures but does not meet the definition for cure or treatment failure due to lack of bacteriologic results.


Enrollment: 0
Study Start Date: March 2014
Estimated Study Completion Date: November 2022
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A Drug: Arm A Double-blind Phase: TMC207
Type=exact number, unit=mg, number=400 mg for the first 2 weeks and 200 mg 3 times per week for the remainder of the treatment period, form=tablet, route=oral administration.
Drug: Treatment Failure During Double-blind Phase: TMC207
Type=exact number, unit=mg, number=200 mg 3 times per week, form=tablet, route=oral administration.
Drug: Treatment Failure During Follow-up Phase: TMC207
Type=exact number, unit=mg, number=400 mg once daily for 2 wks and 200mg three times per week for 22 weeks, form=tablet, route=oral administration.
Placebo Comparator: Arm B Drug: Arm B Double-blind Phase: Placebo
Form=tablet, route=oral administration, taken once daily for 2 weeks then 3 times per week for the remainder of the treatment period.
Drug: Treatment Failure During Double-blind Phase: TMC207
Type=exact number, unit=mg, number=200 mg 3 times per week, form=tablet, route=oral administration.
Drug: Treatment Failure During Follow-up Phase: TMC207
Type=exact number, unit=mg, number=400 mg once daily for 2 wks and 200mg three times per week for 22 weeks, form=tablet, route=oral administration.

Detailed Description:

This is a randomized (individuals will be assigned by chance to study treatments), double-blind (individual and investigator will not know the identity of study treatments), placebo (substance containing no active medication)-controlled, 2-arm study in patients with sputum smear-positive pulmonary infection with multi-drug resistant tuberculosis (MDR-TB) defined as tuberculosis (TB) due to infection with a strain of Mycobacterium tuberculosis (M. tuberculosis) that is resistant to both isoniazid and rifampin, or pre-extensively drug resistant (pre-XDR-TB) defined as TB due to infection with an MDR strain of M. tuberculosis that is resistant either to at least one of the injectable second-line drugs [amikacin, kanamycin, or capreomycin] or to any fluoroquinolone, but not both). Approximately 600 patients with sputum smear-positive pulmonary infection with MDR-TB or pre-XDR TB will receive a background regimen (BR) of MDR-TB therapy and will be randomly assigned in a 1:1 ratio to one of 2 treatment arms (Arms A [TMC207 + BR] and B [placebo + BR]). All patients will receive TMC207 or placebo in combination with a BR of MDR-TB therapy. TMC207 (or matching placebo) will be taken as oral tablets at a once daily dose of 400 mg for the first 2 weeks and 200 mg 3 times/week for the remaining period of TMC207 (or matching placebo) administration. The study will consist of a screening phase of a maximum of 3 weeks, a 36-week double-blind treatment phase, followed by a 48-week follow-up phase up to Week 84, also referred to as the treatment-free follow-up. After the treatment-free follow-up phase, there will be a safety follow-up phase of 48 weeks up to Week 132. Patients from Arms A or B who fail treatment according to prespecified criteria will be given the option to receive 24 weeks of TMC207 plus an individualized salvage regimen taken for a duration consistent with national TB guidelines. Efficacy and pharmacokinetic evaluations will be performed at time points as detailed in the protocol. Safety will be monitored throughout the study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- Diagnosed with sputum smear-positive pulmonary Mycobacterium multi-drug resistant tuberculosis; including pre-extensively drug resistant TB, and positive for acid fast bacilli on direct smear examination of expectorated or induced sputum specimen (>=1+ smear positive within the preceding 3 weeks) at screening and also on Day -1

Exclusion Criteria:

  • Has known infection with extensively drug resistant tuberculosis isolate
  • Has a clinically significant active medical condition such as, but not limited to, hepatic, pancreatic, renal, cardiovascular, gastrointestinal, hematologic, neurologic, locomotor, immunologic, ophthalmologic (e.g., corneal opacification or ulcers, uveitis, chorioretinitis), metabolic (except stable diabetes based on the investigator's judgement), endocrine, oncological disease, muscular disease (e.g., myositis, rhabdomyolysis), or psychiatric, dermatological illness, or any other illness that the investigator considers should exclude the patient or that could interfere with the interpretation of the study results. Eligibility of patients with poorly controlled diabetes as indicated by hemoglobin A1c higher than the normal range at screening should be based on the investigators judgment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01600963

  Show 44 Study Locations
Sponsors and Collaborators
Janssen Infectious Diseases BVBA
Investigators
Study Director: Janssen Infectious Diseases BVBA Clinical Trial Janssen Infectious Diseases BVBA
  More Information

No publications provided

Responsible Party: Janssen Infectious Diseases BVBA
ClinicalTrials.gov Identifier: NCT01600963     History of Changes
Other Study ID Numbers: CR100807, TMC207-TIDP13-C210, 2011-000653-23, U1111-1135-7013
Study First Received: April 24, 2012
Last Updated: February 6, 2014
Health Authority: United States: Food and Drug Administration
Estonia: The State Agency of Medicine
Ukraine: State Pharmacological Center - Ministry of Health
Brazil: National Health Surveillance Agency
Cambodia: Ministry of Health
China: Food and Drug Administration
Ethiopia: Drug Administration and Control Authority
Georgia: Ministry of Health
Korea: Food and Drug Administration
Latvia: State Agency of Medicines
Mexico: Federal Commission for Sanitary Risks Protection
Peru: Instituto Nacional de Salud
Philippines: Bureau of Food and Drugs
Russia: Ministry of Health of the Russian Federation
South Africa: Medicines Control Council
Taiwan: Department of Health
Turkey: Ministry of Health
Vietnam: Ministry of Health
Thailand: Food and Drug Administration

Keywords provided by Janssen Infectious Diseases BVBA:
Multi-drug resistant tuberculosis
Pre-extensively drug resistant tuberculosis
TMC207
Background regimen

Additional relevant MeSH terms:
Mycobacterium Infections
Tuberculosis
Tuberculosis, Multidrug-Resistant
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections

ClinicalTrials.gov processed this record on July 29, 2014