Safety and Efficacy Trial of Delamanid for 6 Months in Participants With Multidrug-resistant Tuberculosis

• ClinicalTrials.gov Identifier: NCT01424670
• Recruitment Status: Completed
• First Posted: August 29, 2011
• Results First Posted: May 15, 2019
• Last Update Posted: May 15, 2019
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Tracking Information

• First Submitted Date: August 25, 2011
• First Posted Date: August 29, 2011
• Results First Submitted Date: October 9, 2018
• Results First Posted Date: May 15, 2019
• Last Update Posted Date: May 15, 2019
• Actual Study Start Date: September 2, 2011
• Actual Primary Completion Date: July 4, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 13, 2019)

Time To Sputum Culture Conversion (SCC) During 6-Month Intensive Period Using The Mycobacteria Growth Indicator Tube (MGIT) System [ Time Frame: Month 6 ]

SCC at 6 months was determined by the observation of a sputum specimen negative for growth of mycobacterium tuberculosis (MTB) using the MGIT culture system, followed by at least 1 confirmatory negative sputum culture at least 25 days after the first negative and not followed by a confirmed positive (defined as at least 2 observed positive results, not taking into account indeterminate, missing, or contaminated results). 2 specimens were collected at each visit and an algorithm in the statistical analysis plan (SAP) was used to define a single representative result. Time to SCC was then defined as the interval between the date of first dose of IMP and the date of first of 2 consecutive negative single representative time points that were at least 25 days apart. The median time in days to SCC up to Month 6 is presented.

Original Primary Outcome Measures (submitted: August 26, 2011)

• Sputum Culture Conversion [ Time Frame: 2 months ]
  Proportion of patients achieving SCC at 2 months.
• Time to Sputum Culture Conversion [ Time Frame: 6 months ]
  Distribution of the time to SCC during the 6-months of IMP treatment.

Current Secondary Outcome Measures (submitted: May 13, 2019)

• Proportion of Participants With SCC At 2 And 6 Months Using MGIT [ Time Frame: Month 2 and Month 6 ]
  SCC was evaluated at 2 and 6 months (6-month Intensive Period) using MGIT. SCC at 2 months was defined to occur at the date of collection of the first sputum specimen with mycobacterial culture negative for growth of MTB using MGIT culture, followed by at least 1 confirmatory negative MGIT culture result at least 25 days after the first negative specimen and not followed by any sputum specimens positive for growth in the MGIT culture at any point up to 3 months (Week 12). SCC at 6 months was determined by the observation of a sputum specimen negative for growth of MTB using the MGIT culture system, followed by at least 1 confirmatory negative sputum culture at least 25 days after the first negative and not followed by a confirmed positive (defined as at least 2 observed positive results, not taking into account indeterminate, missing, or contaminated results). 2 specimens were collected at each visit and an algorithm in the SAP was used to define a single representative result.
• Proportion of Participants With Sustained SCC At Month 18, Month 24, And Month 30 Using MGIT [ Time Frame: Month 18, Month 24, and Month 30 ]
  Sustained SCC was defined as SCC achieved by Month 6 and not followed by a confirmed positive thereafter, where confirmed positive was defined as 2 or more observed positive single representative culture results, not taking into account indeterminate, missing, or contaminated results. Sustained SCC was analyzed at Month 18 to 30 using MGIT.
• Treatment Outcomes Assessed By Principal Investigators (PI)At The End Of Treatment With OBR [ Time Frame: Month 24 ]
  Final treatment outcomes were assessed by the Principal Investigator (PI) at the end of treatment with OBR (24 months post randomization) according to the 2008 World Health Organization (WHO) outcome definitions for treating participants with multidrug-resistant tuberculosis (MDR TB). Frequency counts and percentage of participants achieving favorable and unfavorable outcomes were provided by treatment group. Participants who had non-missing Principal Investigator assessed treatment outcomes at the end of treatment with OBR were included in the analysis.
• Number of Participants Who Developed Resistance To Delamanid [ Time Frame: Up to Month 30 ]
  Acquired resistance was defined as a post-baseline resistant result at any time point after a Baseline susceptible result. The overall resistance to delamanid during the trial was assessed.
• Mean (Time Averaged) Area Under The Curve (AUC) Of Change From Baseline In Time To Detection (TTD) To Month 6 Using MGIT [ Time Frame: Baseline, up to Month 6 ]
  The value for TTD was defined (in days) as the time interval from inoculation until a MGIT machine detects a positive signal for a sputum culture. The AUC of the change from Baseline for TTD in days (from Baseline to Month 6) summarizes the overall participant response for the treatment period. The change from Baseline in original time to detection of MGIT positive signal, in days, up to 6 months was performed using AUC in MGIT. The Baseline was defined as the average of Day -1 and Day 1 values if cultures on both days were positive; if only 1 culture was positive, the value for TTD for the positive culture was used as the Baseline. The TTD is Time to Detection measured by day, so the unit of AUC of change from baseline in TTD is day*day. Since "Mean AUC" is reported, which is actually "Time Averaged AUC," the AUC was divided by the duration of the observation, and thus the unit of the Mean AUC is day.
• Mean Change From Baseline In TTD Using The MGIT System [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 24, Week 26, and Last visit (Month 18 or last visit for participants treated beyond Month 18) ]
  The value for TTD was defined (in days) as the time interval from inoculation until a MGIT machine detects a positive signal for a sputum culture during the routine 42-day incubation period. TTD analysis was based only on the corresponding qualitative sputum results of pure positive and pure negative cultures in days and hours of the initial positive signal for a culture from the MGIT printout. Mean change is reported for Baseline, Week 1, Week 2, Week 3, Week 24, Week 26, and Last visit (Month 18 or last visit for participants treated beyond Month 18).
• Proportion of Participants With Final Outcome At Month 30 As A Treatment Success Or Failure (Including Relapse) Using MGIT [ Time Frame: Month 30 ]
  Treatment success was defined as achieving SCC by 6 months using MGIT, completing the trial out to 30 months with sustained SCC and alive at the last contact for follow-up. All other participants were treatment failures who failed to achieve SCC by Month 6, achieved SCC but have a confirmed positive, early terminate from the trial prior to the Month 30 visit but are alive at the last contact for follow-up, lost to follow-up and vital status unknown and death.

Original Secondary Outcome Measures (submitted: August 26, 2011)

• Sputum Culture Conversion [ Time Frame: 2 months ]
  Proportion of patients with SCC using solid culture media
• Sputum Culture Conversion [ Time Frame: 6 months ]
  Proportion of patients with SCC using the MGIT system
• Durability of Sputum Culture Conversion [ Time Frame: 18 months ]
  Durability of SCC with the MGIT system during the Continuation Treatment and Post-treatment Follow-up periods
• Time to Sputum Culture Conversion [ Time Frame: 6 months ]
  Distribution of the time to SCC using solid culture media during 6-months of IMP treatment.
• Sputum Culture Conversion [ Time Frame: 6 months ]
  Proportion of patients with SCC using solid culture media
• Durability of Sputum Culture Conversion [ Time Frame: 30 months ]
  Durability of SCC with the MGIT system during the Continuation Treatment and Post-treatment Follow-up periods

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy Trial of Delamanid for 6 Months in Participants With Multidrug-resistant Tuberculosis
• Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate the Safety and Efficacy of Delamanid (OPC-67683) Administered Orally as 200 mg Total Daily Dose for Six Months in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis
• Brief Summary: The purpose of this trial is to determine whether delamanid is effective in the treatment of multidrug-resistant tuberculosis (MDR TB) in combination with other MDR TB medications during 6 months of treatment.

Detailed Description

The primary objective of this trial is to evaluate the efficacy of delamanid administered orally as 100 milligrams (mg) twice daily (BID) for 2 months followed by 200 mg once daily (QD) for 4 months in combination with an optimized background treatment regimen (OBR) versus placebo with OBR during the 6-month Intensive Period of MDR TB treatment. Following the 6-month Intensive Period, OBR was administered alone during the Continuation Period for 12 to 18 months (from Month 7 up to Month 24). The trial also included a post-treatment follow-up period of 6 to 12 months (Month 19 to Month 24 to the end of Month 30). OBR given throughout the study was administered as per World Health Organization (WHO) guidelines and national treatment norms.

This trial is a multicenter, randomized, double-blind, stratified, placebo-controlled trial that was conducted globally in 2 parallel groups at 17 sites in 7 countries qualified to treat MDR TB.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Multidrug-resistant Tuberculosis

Intervention

• Drug: Delamanid + OBR
  The assigned doses of delamanid were administered with an OBR. The selection and administration of the OBR were based on WHO's guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country.
• Drug: Placebo + OBR
  Matching placebo was administered with an OBR. The selection and administration of the OBR were based on WHO's guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country.

Study Arms

• Experimental: Delamanid + OBR

  In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.

  Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

  OBR given throughout the study was administered as per WHO guidelines and national treatment norms.

  Intervention: Drug: Delamanid + OBR
• Placebo Comparator: Placebo + OBR

  In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

  Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

  OBR given throughout the study was administered as per WHO guidelines and national treatment norms.

  Intervention: Drug: Placebo + OBR

• Publications *: von Groote-Bidlingmaier F, Patientia R, Sanchez E, Balanag V Jr, Ticona E, Segura P, Cadena E, Yu C, Cirule A, Lizarbe V, Davidaviciene E, Domente L, Variava E, Caoili J, Danilovits M, Bielskiene V, Staples S, Hittel N, Petersen C, Wells C, Hafkin J, Geiter LJ, Gupta R. Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial. Lancet Respir Med. 2019 Mar;7(3):249-259. doi: 10.1016/S2213-2600(18)30426-0. Epub 2019 Jan 7.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 13, 2013): 511
• Original Estimated Enrollment (submitted: August 26, 2011): 390
• Actual Study Completion Date: July 4, 2016
• Actual Primary Completion Date: July 4, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Provide written, informed consent
• Current diagnosis of MDR TB
• Chest radiograph consistent with TB
• Able to produce sputum
• Negative urine pregnancy test and agree to use a highly effective method of birth control and/or adequate method of contraception

Exclusion Criteria:

• Allergy to any nitro-imidazoles or nitro-imidazole derivates
• Diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated
• Use of disallowed medications
• Renal impairment
• Abnormal electrocardiogram (ECG) results
• Cardiovascular disorders
• Body mass index (BMI) < 16 kg/m^2
• Karnofsky score < 50%
• Significant metabolic, gastrointestinal, neurological, psychiatric, or endocrine diseases, active malignancy
• Alcohol abuse
• Pregnant, breast-feeding, or planning to conceive or father a child
• Recent use of methadone, benzodiazepines, cocaine, amphetamine/methamphetamine, tetrahydrocannabinol, barbiturates, and opiates
• Previous exposure to delamanid
• Administered an investigational medicinal product (IMP) within 1 month prior to Screening (Days -21 to -2).
• Evidence of extensively drug-resistant TB based on the definition from WHO
• Human immunodeficiency virus (HIV) co-infection for participants screened at sites not participating in the HIV subtrial (data from the HIV subtrial will be reported separately from the Clinical Study Report for Study 242-09-213).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 69 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Estonia, Latvia, Lithuania, Moldova, Republic of, Peru, Philippines, South Africa
• Removed Location Countries: India

Administrative Information

• NCT Number: NCT01424670
• Other Study ID Numbers: 242-09-213
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Global Clinical Development; Otsuka Pharmaceutical Development & Commercialization, Inc.

• PRS Account: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Verification Date: May 2019