Clinical trial NCT00685360: A Trial to Evaluate OPC 67683 in Participants With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis, Pulmonary
Tuberculosis, Multidrug Resistant
Extensively Drug-Resistant Tuberculosis
Keywords: Tuberculosis
Pulmonary
Multidrug resistant
Antitubercular Agents
OPC 67683
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2008-05-28
Enrollment: 481
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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), participants will be randomized to receive:

* 100 mg OPC-67683 twice daily (BID)
* 200 mg OPC-67683 BID
* Placebo BID

After 56 days participants will complete their optimized background regimen (OBR).

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

* OBR plus 100 mg OPC-67683 BID
* OBR plus 200 mg OPC-67683 BID
* OBR plus placebo BID

The three treatment groups will comprise approximately 140 participants 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 participants (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 participants with and without cavities visible in the lung fields on baseline chest radiograph will be allocated to each treatment group. A total of approximately 430 male or female participants 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. Participants 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 criteria: Inclusion Criteria:

* Provide written, informed consent prior to all trial-related procedures
* Male and female participants aged between 18 and 64 years, inclusive.
* Either mycobacterial culture of sputum positive for growth of Mycobacterium tuberculosis or sputum smear positive for acid fast bacilli within 60 days prior to the expected date of enrollment.
* Participant with TB caused by isolates of Mycobacterium 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 participants 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 participants must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30 weeks 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 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 alanine transaminase (ALT) and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range.
* Current clinically relevant changes in the electrocardiogram (ECG) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (in both male and female participants), or of either the QT interval corrected by Fridericia's formula (QTcF) or QT interval corrected by Bazett's formula (QTcB) interval over 430 milliseconds in male participants and 450 milliseconds in female participants.
* Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
* For participants with human immunodeficiency virus (HIV) infection, cluster of differentiation 4 helper/inducer T cell\[s\] (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 participant in the opinion of the investigator.
* Administered an investigational medicinal product (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 participant not a good candidate for the trial or may prevent the participant from reliably participating in the entire course of the trial.

Primary outcomes:
measure: Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using the Mycobacteria Growth Indicator Tube (MGIT) System
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)
measure: Tmax 1 and 2: Time to Maximal Peak Concentration (Tmax) for Delamanid Following First and Second Daily Dose
timeFrame: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Cmax 1 and 2: Maximal Peak Concentration (Cmax) for Delamanid Following First and Second Daily Dose
timeFrame: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for Delamanid
timeFrame: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Accumulation Ratio for Cmax (Rac[Cmax]) for Delamanid
timeFrame: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Accumulation Ratio for AUC From Time 0 to 24 Hours (Rac[AUC0-24h]) for Delamanid
timeFrame: Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Time to Maximal Peak Concentration (Tmax) for Delamanid Metabolite (DM)-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
timeFrame: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Maximal Peak Concentration (Cmax) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
timeFrame: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
timeFrame: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Accumulation Ratio for Cmax (Rac[Cmax]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
timeFrame: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Accumulation Ratio for AUC (Rac[AUC]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
timeFrame: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
measure: Elimination Half-life (t1/2) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
timeFrame: 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose on Day 56
Secondary outcomes:
measure: Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using Solid Culture Media
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)
measure: Change From Baseline in Time to Culture Positivity Using the MGIT System
timeFrame: Baseline, Day 84
measure: Area Under the Curve (AUC) of Change From Baseline in Time to Culture Positivity in the MGIT System
timeFrame: Baseline to Day 57
measure: Percentage of Participants With Sputum Culture Negative at Day 57 Using the MGIT System Without Consideration of Subsequent Culture Results
timeFrame: Day 57
measure: Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using the MGIT System Without Respect to Interim Culture Results
timeFrame: Day 57 and Day 84
measure: Percentage of Participants With Sputum Culture Negative at Day 57 Using Solid Culture Media Without Respect to Subsequent Culture Results
timeFrame: Day 57
measure: Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using Solid Culture Media Without Respect to Interim Culture Results
timeFrame: Day 57 and Day 84
measure: Percentage of Participants Who Achieved SCC From the MGIT System Analyzed by Cochran-Armitage Linear Trend Test for Dose-response Relationship
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)
measure: Percentage of Participants Who Achieved Initial SCC Using the MGIT System
timeFrame: Day 57
measure: Percentage of Participants Who Achieved Initial SCC Using the Solid Culture Media
timeFrame: Day 57
measure: Percentage of Participants Who Achieved Final SCC Using MGIT
timeFrame: Day 57
measure: Percentage of Participants Who Achieved Final SCC Using Solid Culture Media
timeFrame: Day 57
measure: Percentage of Participants With Clinically Significant Physical Examination Findings, Including Vision and Neuropsychiatric Assessments
timeFrame: From first dose of study drug up to post treatment period (Day 84)
measure: Percentage of Participants With Clinically Significant Vital Sign Abnormalities
timeFrame: From first dose of study drug up to post treatment period (Day 84)
measure: Percentage of Participants With Categorical Changes in 12-lead Electrocardiogram Results at Day 56
timeFrame: Baseline up to Day 56
measure: Percentage of Participants With Clinically Significant Laboratory Test Abnormalities
timeFrame: From first dose of study drug up to post treatment period (Day 84)
measure: Percentage of Participants With Clinically Significant Audiometry Findings
timeFrame: From first dose of study drug up to post treatment period (Day 84)
measure: Percentage of Participants Using Concomitant Medications
timeFrame: From first dose of study drug up to post treatment period (Day 84)
measure: Percentage of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From first dose of study drug up to post treatment period (Day 84)
measure: Time-matched Change From Baseline (Day -1) in QTcF at Day 56
timeFrame: Baseline, and 2, 3, 4, 10, 12, and 24 hours post dose on Day 56
measure: Mean Change From Baseline in QTcF
timeFrame: Baseline, Days 1, 14, 28 and 56
measure: Mean Change From Baseline in QTcB
timeFrame: Baseline, Days 1, 14, 28 and 56
measure: Mean Change From Baseline in Ventricular Rate
timeFrame: Baseline, Days 1, 14, 28 and 56
measure: Mean Change From Baseline in PR Interval
timeFrame: Baseline, Days 1, 14, 28 and 56
measure: Mean Change From Baseline in QRS Interval
timeFrame: Baseline, Days 1, 14, 28 and 56
measure: Mean Change From Baseline in QT Interval
timeFrame: Baseline, Days 1, 14, 28 and 56
measure: Percentage of Participants With Change in ECG Morphological Patterns From Baseline
timeFrame: Baseline, Days 1, 14, 28 and 56
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: University of Texas Health Center at Tyler / Heartland National TB Center / Texas Center for Infectious Disease
state: Texas
city: Beijing
country: China
facility: Beijing Chest Hospital
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital
city: Cairo
country: Egypt
facility: Abbassia Chest Hospital
city: Tallinn
country: Estonia
facility: North Estonian Medical Centre Foundation
city: Tartu
country: Estonia
facility: Tartu University Lung Hospital
city: Osaka
country: Japan
facility: Kinki Chuo Chest Hospital
city: Tokyo
country: Japan
facility: Fukujuji Hospital
city: Changwon
country: Korea, Republic of
facility: Masan Medical Center
city: Masan
country: Korea, Republic of
facility: National Masan Hospital
city: Seoul
country: Korea, Republic of
facility: Younsei University Medical Center (YUMC), Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Riga
country: Latvia
facility: Clinic of Tuberculosis and Lung Diseases
city: Carrion
country: Peru
facility: Hospital Nacional Daniel Alcides Carrión
city: Lima
country: Peru
facility: Hospital Nacional Sergio E. Bernales
city: Unanue
country: Peru
facility: Hospital Nacional Hipolito Unanue
city: Manila
country: Philippines
facility: Tropical Disease Foundation
Study officials:
affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, Gao M, Awad M, Park SK, Shim TS, Suh GY, Danilovits M, Ogata H, Kurve A, Chang J, Suzuki K, Tupasi T, Koh WJ, Seaworth B, Geiter LJ, Wells CD. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012 Jun 7;366(23):2151-60. doi: 10.1056/NEJMoa1112433.