Back to resultsSafety and Efficacy Trial of Delamanid for 6 Months in Participants With Multidrug-resistant Tuberculosis
Primary Purpose
Multidrug-resistant Tuberculosis
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Delamanid + OBR
Placebo + OBR
Sponsored by
About this trial
This is an interventional treatment trial for Multidrug-resistant Tuberculosis focused on measuring Multidrug-resistant tuberculosis
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).
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Delamanid + OBR
Placebo + OBR
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Time To Sputum Culture Conversion (SCC) During 6-Month Intensive Period Using The Mycobacteria Growth Indicator Tube (MGIT) System
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.
Secondary Outcome Measures
Proportion of Participants With SCC At 2 And 6 Months Using MGIT
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
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
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
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
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
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
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.
Full Information
NCT ID
NCT01424670
First Posted
August 25, 2011
Last Updated
May 13, 2019
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT01424670
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
September 2, 2011 (Actual)
Primary Completion Date
July 4, 2016 (Actual)
Study Completion Date
July 4, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multidrug-resistant Tuberculosis
Keywords
Multidrug-resistant tuberculosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
511 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Delamanid + OBR
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo + OBR
Arm Type
Placebo Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
Delamanid + OBR
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo + OBR
Intervention Description
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.
Primary Outcome Measure Information:
Title
Time To Sputum Culture Conversion (SCC) During 6-Month Intensive Period Using The Mycobacteria Growth Indicator Tube (MGIT) System
Description
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.
Time Frame
Month 6
Secondary Outcome Measure Information:
Title
Proportion of Participants With SCC At 2 And 6 Months Using MGIT
Description
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.
Time Frame
Month 2 and Month 6
Title
Proportion of Participants With Sustained SCC At Month 18, Month 24, And Month 30 Using MGIT
Description
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.
Time Frame
Month 18, Month 24, and Month 30
Title
Treatment Outcomes Assessed By Principal Investigators (PI)At The End Of Treatment With OBR
Description
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.
Time Frame
Month 24
Title
Number of Participants Who Developed Resistance To Delamanid
Description
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.
Time Frame
Up to Month 30
Title
Mean (Time Averaged) Area Under The Curve (AUC) Of Change From Baseline In Time To Detection (TTD) To Month 6 Using MGIT
Description
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.
Time Frame
Baseline, up to Month 6
Title
Mean Change From Baseline In TTD Using The MGIT System
Description
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).
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)
Title
Proportion of Participants With Final Outcome At Month 30 As A Treatment Success Or Failure (Including Relapse) Using MGIT
Description
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.
Time Frame
Month 30
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
69 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Global Clinical Development
Organizational Affiliation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Official's Role
Study Director
Facility Information:
City
Tartu
ZIP/Postal Code
51014
Country
Estonia
City
Riga
ZIP/Postal Code
LV-2118
Country
Latvia
City
Siauliai
ZIP/Postal Code
LT-76231
Country
Lithuania
City
Vilnius
ZIP/Postal Code
LT-10214
Country
Lithuania
City
Chisinau
ZIP/Postal Code
MD2025
Country
Moldova, Republic of
City
Vorniceni
ZIP/Postal Code
MD3737
Country
Moldova, Republic of
City
Alfonso Ugarte
ZIP/Postal Code
Lima 1
Country
Peru
City
Comas
ZIP/Postal Code
Lima 7
Country
Peru
City
El Agustino
ZIP/Postal Code
Lima 10
Country
Peru
City
Lima Cercado
ZIP/Postal Code
Lima 1
Country
Peru
City
Dasmariñas
State/Province
Cavite
ZIP/Postal Code
4114
Country
Philippines
City
Quezon City
State/Province
Metro Manila
ZIP/Postal Code
1104
Country
Philippines
City
Makati City
ZIP/Postal Code
1230
Country
Philippines
City
Quezon City
ZIP/Postal Code
1101
Country
Philippines
City
Cape Town
ZIP/Postal Code
7405
Country
South Africa
City
Durban
ZIP/Postal Code
4001
Country
South Africa
City
Klerksdorp
ZIP/Postal Code
2571
Country
South Africa
12. IPD Sharing Statement
Citations:
PubMed Identifier
30630778
Citation
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.
Results Reference
derived
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Safety and Efficacy Trial of Delamanid for 6 Months in Participants With Multidrug-resistant Tuberculosis
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