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A Placebo-controlled, Phase 2 Trial to Evaluate OPC 67683 in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:
NCT00685360
First received: May 20, 2008
Last updated: August 31, 2011
Last verified: August 2011
  Purpose

This is a clinical trial to evaluate the safety and efficacy of OPC-67683 in the treatment of multidrug resistant tuberculosis (MDR TB) for 56 days. In addition to an optimized background regimen (OBR).patients will receive will be randomized to:

  • 100 mg OPC-67683 BID
  • 200 mg OPC-67683 BID
  • placebo BID After 56 days subjects will complete their OBR.

Condition Intervention Phase
Tuberculosis, Pulmonary
Tuberculosis, Multidrug Resistant
Extensively Drug-Resistant Tuberculosis
Drug: OPC-67683
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi Center, Randomized, Double-blind, Placebo-controlled Phase 2 Trial to Evaluate the Safety, Efficacy and Pharmacokinetics of Multiple Doses of OPC 67683 in Patients With Pulmonary Sputum Culture-Positive, Multidrug-resistant Tuberculosis

Resource links provided by NLM:


Further study details as provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Primary Outcome Measures:
  • The primary efficacy endpoint is the proportion of patients who achieve sputum mycobacterial culture conversion within 56 full days or less of treatment. [ Time Frame: 84 days ] [ Designated as safety issue: No ]
  • Reported adverse events, physical examination, vital signs (blood pressure, heart rate, body temperature and weight), standard 12-lead ECG, clinical laboratory assessment results (hematology, chemistry, urinalysis). [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • PK: For OPC-67683, tmax, Cmax, AUC0-24h , ratios of accumulation for Cmax and AUC0-24h, Day 14, 28 or 56/Day 1. For the metabolites, tmax, Cmax, AUC0-24h , ratios of accumulation for Cmax and AUC0-24h , Day 14, 28 or 56/Day 1] [ Time Frame: 84 days ] [ Designated as safety issue: No ]
  • Efficacy: Change from baseline in time to culture positivity using the MGIT® system. AUC of change from baseline in time to culture positivity in the MGIT® system [ Time Frame: 84 days ] [ Designated as safety issue: No ]
  • Efficacy: Proportion of patients with sputum mycobacterial culture negative for growth at Day 57 (1=negative, 0=positive) using the MGIT® culture system without regard to subsequent culture results. [ Time Frame: 84 days ] [ Designated as safety issue: No ]
  • Efficacy: Proportion of patients achieving sputum culture conversion from positive growth at baseline (pre-dose) to negative growth on solid mycobacterial culture media within 56 full days of treatment out of all evaluable patients. [ Time Frame: 84 days ] [ Designated as safety issue: No ]
  • Efficacy: Proportion of patients with sputum mycobacterial culture positive for growth at baseline who have negative growth at Day 57 (1=negative, 0=positive) using solid culture media without regard to subsequent culture results. [ Time Frame: 84 days ] [ Designated as safety issue: No ]
  • Efficacy: Dose-response in sputum culture conversion rates for results from the MGIT system. Dose-response in sputum culture conversion rates for results from solid culture media. [ Time Frame: 84 days ] [ Designated as safety issue: No ]

Enrollment: 481
Study Start Date: April 2008
Study Completion Date: October 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: OPC-67683
100 mg BID will be administered as two 50 mg tablets together with two matching placebo tablets for a total of four tablets administered twice a day (total daily dose of OPC-67683 is 200 mg) for 56 days. .
Experimental: 2 Drug: OPC-67683
200 mg BID will be administered as four 50 mg tablets administered twice a day for (total daily dose of OPC-67683 is 400 mg) 56 days.
Placebo Comparator: 3 Drug: Placebo
Placebo will be administered as four 50 mg tablets matching the OPC-67683 tablets administered twice a day for 56 days

Detailed Description:

This is a multi center, randomized, double-blinded, stratified, placebo-controlled clinical trial in three parallel groups. Patients will be randomized to one of the following three treatment groups:

  • Optimized Background Regimen (OBR) plus 100 mg OPC-67683 twice daily
  • OBR plus 200 mg OPC-67683 twice daily
  • OBR plus placebo twice daily

The three treatment groups will comprise approximately 140 patients each (male or female). The trial will consist of the following periods:

  • Pre-treatment Period (Visits 1 to 3 [Day -9 to Day -1])
  • Treatment Period (Visits 4 to 59 [Days 1 to 56])
  • Post-treatment Period (Visits 60 to 64 [Days 57 to 84]) Enrolled patients (those accepted into the screening period of the trial who signed an informed consent form) will be stratified at randomization by extent of pulmonary TB; an equal number of patients with and without cavities visible in the lung fields on baseline chest radiograph will be allocated to each treatment group. A total of 430 male or female patients aged 18 to 64 years, inclusive, with pulmonary, sputum culture-positive MDR TB (TB caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampicin) or with sputum smears positive for acid fast bacilli (AFB) and a positive rapid test for rifampicin resistance on direct sputum within 60 days prior to the expected date of enrollment. Patients with positive AFB smears and a positive rapid rifampicin resistance test will be enrolled as presumptively culture positive and withdrawn as ineligible if they are confirmed to not have sputum culture positive MDR TB.
  Eligibility

Ages Eligible for Study:   18 Years to 64 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provide written, informed consent prior to all trial-related procedures
  • Male and female patients aged between 18 and 64 years, inclusive.
  • Either mycobacterial culture of sputum positive for growth of M. tuberculosis or sputum smear positive for acid fast bacilli within 60 days prior to the expected date of enrollment.
  • Patient with TB caused by isolates of M. tuberculosis complex confirmed to be resistant to treatment with isoniazid and rifampicin, or with positive rapid test for rifampicin resistance on direct sputum positive for acid fast bacilli within 60 days prior to the expected date of enrollment.
  • Findings on chest radiograph consistent with TB.
  • Able to produce sputum for mycobacterial culture.
  • Female patients of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control (for example, two of the following precautions: tubal ligation, vaginal diaphragm, intrauterine device, oral contraceptives, contraceptive implant, combined hormonal patch, combined injectable contraceptive or depot-medroxyprogesterone acetate) throughout the participation in the trial and for 22 weeks after last dose (to cover duration of ovulation).
  • Male patients must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30weeks after last dose (to cover duration of spermatogenesis).

Exclusion Criteria:

  • A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time.
  • Use of the medications in Section 4.1 of the protocol including: use of amiodarone at any time during the previous 12 months, use of other anti-arrhythmics for the previous 30 days, and use of certain other medications, including certain anti-depressants, anti-histamines, and macrolides, for the previous 14 days.
  • Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels ≥265 micromol/L or hepatic impairment characterized by ALT and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range.
  • Current clinically relevant changes in the ECG such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (in both male and female patients), or of either the QTcF or QTcB interval over 430 milliseconds in male patients and 450 milliseconds in female patients.
  • Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
  • For patients with HIV infection, CD4 cell count < 350/mm3 or on treatment with anti-retroviral medication for HIV infection.
  • Karnofsky score < 60%.
  • Any diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.
  • Evidence of clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
  • Known or suspected alcohol abuse, that is, abuse sufficient enough to compromise the safety or cooperation of the patient in the opinion of the investigator.
  • Administered an IMP within 1 month prior to Visit 1 (Screening [Days -9 to -3]).
  • Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form.
  • Recent use of methadone, benzodiazepines, cocaine, amphetamine/metamphetamine, tetrahydrocannabinol, barbiturates, tricyclic antidepressants, and opiates as determined by a urine drug screen unless evidence is provided that the positive drug screen is the result of authorized medications products prescribed by a physician for a non abuse related indication.
  • Any disorder that in the judgment of the investigator makes the subject not a good candidate for the trial or may prevent the patient from reliably participating in the entire course of the trial.
  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: NCT00685360

Locations
China
Shanghai, China
Egypt
Cairo, Egypt
Estonia
Tartu, Estonia
Japan
Osaka, Japan
Tokyo, Japan
Korea, Republic of
Masan, Korea, Republic of
Seoul, Korea, Republic of
Latvia
Riga, Latvia
Philippines
Manila, Philippines
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigators
Study Director: Charles D. Wells, M.D. Otsuka Pharmaceutical Development & Commercialization, Inc.
  More Information

No publications provided by Otsuka Pharmaceutical Development & Commercialization, Inc.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT00685360     History of Changes
Other Study ID Numbers: 242-07-204
Study First Received: May 20, 2008
Last Updated: August 31, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Tuberculosis
Pulmonary
Multidrug resistant
Antitubercular Agents
OPC 67683

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Multidrug-Resistant
Tuberculosis, Pulmonary
Extensively Drug-Resistant Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections

ClinicalTrials.gov processed this record on September 22, 2014