A Trial to Evaluate OPC 67683 in Participants With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)

NCT00685360 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 242-07-2042007-005229-31
• Study Type: interventional
• Target: 481
• Locations: 9 countries
• Sites: 17

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).

Conditions

Tuberculosis, Pulmonary; Tuberculosis, Multidrug Resistant; Extensively Drug-Resistant Tuberculosis

Keywords

Tuberculosis; Pulmonary; Multidrug resistant; Antitubercular Agents; OPC 67683

Outcome Measures

Primary Outcomes (12)

• Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using the Mycobacteria Growth Indicator Tube (MGIT) System

  Sputum culture conversion was defined to occur at the time of the collection of a sputum specimen with mycobacterial culture negative for growth of Mycobacterium tuberculosis (MTB) followed by at least one additional sputum specimen with mycobacterial culture negative for growth at least 27 days after the first negative specimen and not followed by any sputum specimens positive for growth in the MGIT system at any point during the remainder of the 84-day trial after the first negative culture.

  From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)

• Tmax 1 and 2: Time to Maximal Peak Concentration (Tmax) for Delamanid Following First and Second Daily Dose

  Time to maximum (peak) plasma concentration following the first daily dose (Cmax1) was reported as tmax1 and time to maximum (peak) plasma concentration following the second daily dose (Cmax2) was reported as tmax2. Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.

  Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• Cmax 1 and 2: Maximal Peak Concentration (Cmax) for Delamanid Following First and Second Daily Dose

  Maximum (peak) plasma concentration following the first daily dose was reported as Cmax1 and maximum (peak) plasma concentration following the second daily dose was reported as Cmax2. Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.

  Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for Delamanid

  Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.

  Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• Accumulation Ratio for Cmax (Rac[Cmax]) for Delamanid

  Data for Rac (Cmax) up to Day 56 was collected on Days 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was computed.

  Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• Accumulation Ratio for AUC From Time 0 to 24 Hours (Rac[AUC0-24h]) for Delamanid

  Data for Rac (AUC) up to Day 56 was collected on Days 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was computed.

  Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• 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

  Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.

  0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• Maximal Peak Concentration (Cmax) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722

  Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.

  0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• 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

  Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.

  0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• Accumulation Ratio for Cmax (Rac[Cmax]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722

  Data for Rac (Cmax) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, pharmacokinetic (PK) analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (Cmax) was not available.

  0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• Accumulation Ratio for AUC (Rac[AUC]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722

  Data for Rac (AUC) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, PK analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (AUC) was not available.

  0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

• Elimination Half-life (t1/2) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722

  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 (27)

• Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using Solid Culture Media

  From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)

• Change From Baseline in Time to Culture Positivity Using the MGIT System

  Baseline, Day 84

• Area Under the Curve (AUC) of Change From Baseline in Time to Culture Positivity in the MGIT System

  Baseline to Day 57

• Percentage of Participants With Sputum Culture Negative at Day 57 Using the MGIT System Without Consideration of Subsequent Culture Results

  Day 57

• Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using the MGIT System Without Respect to Interim Culture Results

  Day 57 and Day 84

Study Arms (3)

Delamanid 100 mg BID + OBR

EXPERIMENTAL

Participants received delamanid 100 milligrams (mg) (two 50 mg tablets), orally, BID with two matching placebo tablets plus optimized background regimen (OBR) for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on World Health Organization (WHO) guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.

Drug: Delamanid; Drug: Optimized Background Regimen (OBR); Drug: Placebo

Delamanid 200 mg BID + OBR

EXPERIMENTAL

Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.

Drug: Delamanid; Drug: Optimized Background Regimen (OBR)

Placebo + OBR

PLACEBO COMPARATOR

Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.

Drug: Optimized Background Regimen (OBR); Drug: Placebo

Interventions

Delamanid DRUG

Delamanid was administered orally twice daily as 50-mg tablets under fed conditions in the morning and evening.

Also known as: OPC-67683

Delamanid 100 mg BID + OBR; Delamanid 200 mg BID + OBR

Optimized Background Regimen (OBR) DRUG

Selection and administration of the treatment medications (i.e., OBRs) was based on World Health Organization (WHO's) Guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country. Study Investigator could change OBR for a participant based on participant's tolerability and drug susceptibility testing (DST) results.

Delamanid 100 mg BID + OBR; Delamanid 200 mg BID + OBR; Placebo + OBR

Placebo DRUG

Placebo tablets matching 50-mg tablets of delamanid

Delamanid 100 mg BID + OBR; Placebo + OBR

Eligibility Criteria

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

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (17)

University of Texas Health Center at Tyler / Heartland National TB Center / Texas Center for Infectious Disease

San Antonio, Texas, 78223, United States

Location

Beijing Chest Hospital

Beijing, 101149, China

Location

Shanghai Pulmonary Hospital

Shanghai, 200433, China

Location

Abbassia Chest Hospital

Cairo, Egypt

Location

North Estonian Medical Centre Foundation

Tallinn, 13419, Estonia

Location

Tartu University Lung Hospital

Tartu, 13419, Estonia

Location

Kinki Chuo Chest Hospital

Osaka, 591-8555, Japan

Location

Fukujuji Hospital

Tokyo, 204-8522, Japan

Location

Clinic of Tuberculosis and Lung Diseases

Riga, LV2118, Latvia

Location

Hospital Nacional Daniel Alcides Carrión

Carrion, Callao 2, Peru

Location

Hospital Nacional Sergio E. Bernales

Lima, Lima 41, Peru

Location

Hospital Nacional Hipolito Unanue

Unánue, Lima 10, Peru

Location

Tropical Disease Foundation

Manila, 1229, Philippines

Location

Masan Medical Center

Changwon, 138-736, South Korea

Location

National Masan Hospital

Masan, 631-710, South Korea

Location

Younsei University Medical Center (YUMC), Severance Hospital

Seoul, 120-752, South Korea

Location

Samsung Medical Center

Seoul, 135-710, South Korea

Location

Related Publications (1)

• 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.

  PMID: 22670901 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis; Tuberculosis

Interventions

OPC-67683

Condition Hierarchy (Ancestors)

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: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.

clinicaltransparency@otsuka-us.com

1-609-524-6788

Study Officials

• Study Director

  Otsuka Pharmaceutical Development & Commercialization, Inc.

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2008
• First Posted: May 28, 2008
• Study Start: May 8, 2008
• Primary Completion: June 11, 2010
• Study Completion: June 11, 2010
• Last Updated: December 1, 2021
• Results First Posted: December 1, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will share
• Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

Locations

ES (2); LA (1); PE (3); CN (2); KR (4); JP (2); PH (1); US (1); EG (1)