Multidrug Resistant Tuberculosis
Conditions
Keywords
Tuberculosis, Tuberculosis, Multidrug-Resistant, Mycobacterium Infections, Actinomycetes Infections, Gram-Positive Infections, Bacterial Infections, Pediatric
Brief summary
The purpose of this trial is to assess the safety, tolerability, pharmacokinetics, and efficacy of long-term (6-month) treatment with delamanid plus an optimized background regimen (OBR) of other anti-tuberculosis drugs in pediatric participants who completed Study 242-12-232 (NCT01856634).
Detailed description
This study will assess the safety, tolerability, pharmacokinetics, and efficacy of delamanid plus an optimized background regimen in pediatric participants with MDR-TB over a 6-month treatment period. This long-term study, an extension of Study 242-12-232, will be conducted in participants who have completed Study 242-12-232.
Interventions
DRUGDelamanid
Participants received adult formulation delamanid as per regimen specified in the arm description. Morning dose of the delamanid BID regimen was given within 30 minutes after the start of a standard breakfast meal. The evening dose of the BID dose regimen was given 10 hours post morning dose and within 30 minutes after the start of a standard dinner meal.
DRUGDelamanid Pediatric Formulation (DPF)
Participants received delamanid as an extemporaneous suspension using the delamanid pediatric dispersible tablet formulation. Morning dose of the delamanid BID/once daily (QD) regimen was given within 30 minutes after the start of a standard breakfast meal. The evening dose of the BID dose regimen was given 10 hours post morning dose and within 30 minutes after the start of a standard meal.
Selection and administration of the treatment medications (i.e. OBRs) was based on Search Results Web result with site links World Health Organization (WHO's) Guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines. Study Investigator could change OBR for a participant based on his/her tolerability and drug susceptibility testing (DST) results.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Successfully completed Trial 242-12-232 * Confirmed diagnosis of MDR-TB OR * Presumptive diagnosis of pulmonary or extrapulmonary MDR-TB including one of the following: * Clinical specimen suggestive of tuberculosis disease * Persistent cough lasting \> 2 weeks * Fever, weight loss, and failure to thrive * Findings on recent chest radiograph (prior to Visit 1) consistent with TB AND * Household contact with a person with known MDR-TB or with a person who died while appropriately taking drugs for sensitive TB OR * On first-line TB treatment but with no clinical improvement * Negative urine pregnancy test for female participants who have reached menarche * Written informed consent/assent
Exclusion criteria
* Participants who have not completed Trial 242-12-232 * Laboratory evidence of active hepatitis B or C * Children with body weight \< 5.5 kg * For participants with human-immunodeficiency virus (HIV) co-infection, cluster difference-4 (CD4) cell count ≤ 1000/mm\^3 for children 1-5 years old, and ≤ 1500/mm\^3 for children less than 1 year old * History of allergy to metronidazole and any disease or condition in which metronidazole is required * Use of amiodarone within 12 months or use of other predefined antiarrhythmic medications within 30 days prior to first dose of delamanid * Serious concomitant conditions * Pre-existing cardiac conditions * Abnormalities in Screening electrocardiogram (ECG) \[including atrio-ventricular (AV) block, blood brain barrier (BBB) or hemi-block, QRS prolongation \> 120 milliseconds (ms), or QT interval corrected by Fridericia's formula (QTcF) \> 450 ms in both males and females\] * Concomitant condition such as renal impairment characterized by serum creatinine levels \> 1.5 mg/dL, hepatic impairment (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 3x upper limit of normal (ULN)), or hyperbilirubinemia characterized by total bilirubin \> 2x ULN * Current diagnosis of severe malnutrition or kwashiorkor * Positive urine drug screen (Groups 1 and 2 only) * Rifampicin and/or moxifloxacin within 1 week prior to the first dose of delamanid and/or any prior or concurrent use of bedaquiline * Lansky Play Performance Score \< 50 (not applicable for children \< 1 year old) or Karnofsky Score \< 50 * Administered an investigational medicinal product (IMP) within 1 month prior to Visit 1 other than delamanid given as IMP in Trial 242-12-232 * Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form (Groups 1 and 2 only)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE) | From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365) | An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant and that does not necessarily have a causal relationship with the treatment. A TEAE is defined as an AE that occurred after the administration of investigational medicinal product (IMP). |
| Number of Participants With Abnormal Physical Examination Values | From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365) | Physical examination included the examination of the abdomen; extremities; head, eyes, ears, nose (HEENT); neurological; skin and mucosae; thorax; urogenital; audiometry assessment and visual assessment. Participants with abnormal values, as assessed by the investigator were reported. |
| Number of Participants With Clinically Significant Abnormal Vital Sign Values | From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365) | Vital signs included weight (kg), height (cm), body temperature (degree Celsius), heart rate (beats/min), respiratory rate (breaths/minute), systolic and diastolic blood pressure (mm Hg), body mass index (BMI) (kg/m\^2). The criteria for clinically significant abnormal value for weight was decrease or increase of \>=5% in body weight relative to Baseline. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported. |
| Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365) | The criteria for clinically significant abnormal ECG values were ventricular rate outlier (\<50 bpm and decrease of \>=25%, \>100 bpm and increase of \>=25%), PR outlier (increase of \>=25% when PR \>200 milliseconds (ms)), QRS outlier (increase of \>=25% when QRS \>100 ms), QT (new onset (in treatment period but not at Baseline) \[\>500 ms\]), QT interval corrected by Bazett's formula (QTcB) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), QT interval corrected by Fridericia's formula (QTcF) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), new abnormal U waves, new ST segment changes, new T wave changes, new abnormal rhythm, new conduction abnormality were reported as categories. Only categories with data are reported. |
| Number of Participants With Clinically Significant Laboratory Test Abnormalities | From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365) | Laboratory assessments included parameters for serum chemistry, hematology and urinalysis along with adrenocorticotropic hormone, serum cortisol, free thyroxine, thyroid-stimulating hormone (TSH), and high sensitivity C-reactive protein cell count. The participants were categorized based on the clinically significant laboratory values as per protocol predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported. The normal ranges for those laboratory parameters were potassium 3.4 - 5.4 milliequivalents/liter (mEq/L), uric acid 3.9 - 8.2 mg/dL, partial thromboplastin time (PTT) 9.7 - 12.3 sec, platelet count 180 - 440 thousands platelets/μL. |
| Population Pharmacokinetic (POPPK) Model Point Estimate for Central Clearance (L) and Inter-compartmental Clearance (Q) of Delamanid | Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238 | Central clearance is defined as plasma volume in the vascular compartment that is cleared of drug per unit of time. Inter-compartmental clearance is defined as a ratio of the drug's distribution rate between the central compartment and the peripheral compartments over its circulating concentration (L/hr). Population point estimates were based on POPPK analysis to find one measure each for both L and Q. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid. |
| POPPK Model Point Estimate for Central Volume of Distribution (Vc) and Peripheral Volume of Distribution (Vp) of Delamanid | Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238 | Vc is defined as the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma. Vp is defined as the apparent volume needed to account for the total amount of drug in the body if the drug was evenly distributed throughout the body and in the same concentration as the site of sample collection such as peripheral venous plasma. Population point estimates were based on POPPK analysis to find one measure each for both Vc and Vp. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid. |
| POPPK Model Point Estimate for Absorption Rate Constant (Ka) of Delamanid | Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238 | Ka is defined as a measure of rate at which a drug enters into the circulatory system. Population point estimate for Ka was based on population PK analysis to find one measure. Population point estimates were based on POPPK analysis to find one measure for Ka. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid. |
| POPPK Model Point Estimate for Absorption Lag Time (ALAG1) of Delamanid | Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238 | ALAG1 is defined as the time delay prior to the commencement of drug absorption. Population point estimates were based on POPPK analysis to find one measure for ALAG1. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline QT Interval (QTcB) Effect | Baseline (Day -1) | The 12-lead ECG was performed to obtain recordings of heart rate (QT interval) to analyze QTcB effect. |
| PK/PD Relationship: POPPK Model Point Estimate for Slope of Linear Mixed Effects Model for Change in QTcB Interval Versus Delamanid Plasma Concentrations | Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238 | The linear mixed effects model was applied to characterize the concentration-QTcB relationship of delamanid/DM-6705 to obtain population slope estimate. |
| Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Month 24 | Treatment outcome was defined as favorable (cured and completed treatment) and unfavorable (lost to follow-up or died). |
| Number of Participants With Abnormal Chest X-ray | From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365) | The data for the chest X-ray with abnormality, as assessed by investigator is reported. |
| Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365) | The following signs and symptoms of tuberculosis were assessed by the investigator: cough, fever, weight loss, failure to thrive, hemoptysis, dyspnea, chest pain, night sweats and loss of appetite. |
| Sputum Culture Conversion (SCC) | From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365) | SCC was defined as a sputum specimen from a participant negative for growth of Mycobacterium tuberculosis (MTB), followed by at least one confirmatory negative sputum culture at least 27 days after the first negative sputum test and not followed by any sputum cultures positive for growth. |
| Number of Participants With Palatability Score as Assessed by the Investigator | Days 1, 28, 56 and 182 | The palatability of the pediatric formulation was assessed using an age-appropriate visual hedonic scale and clinical assessment (Groups 3 and 4 only). The palatability result was based on 1 of 5 responses: 1=Dislike very much, 2=Dislike a little, 3=Neither liked nor disliked, 4=Like a little, 5=Like very much. Participants were categorized based on different scores. The data per the investigator score are reported. |
| Number of Participants With Palatability Score as Assessed by the Parent or Participant | Days 1, 28, 56 and 182 | The palatability of the pediatric formulation was assessed using an age-appropriate visual hedonic scale and clinical assessment (Groups 3 and 4 only). The palatability result was based on 1 of 5 responses: 1=Dislike very much, 2=Dislike a little, 3=Neither liked nor disliked, 4=Like a little, 5=Like very much. The data per parent/patient score are reported. Participants were categorized based on different scores. |
Countries
Philippines, South Africa
Participant flow
Recruitment details
Participants took part in study at 3 investigative sites in Philippines and South Africa from July 20, 2013 to January 13, 2020. Participants received delamanid up to Day 182 in the treatment period and were followed up to Day 365 for safety and efficacy and up to Day 730 (Month 24) for treatment outcome.
Pre-assignment details
Pediatric participants with a diagnosis of multidrug-resistant tuberculosis (MDR-TB) who were on therapy with an optimized background regimen (OBR) of anti-tuberculosis drugs and completed study 242-12-232 (NCT01856634) were enrolled in this extension study 242-12-233 to receive delamanid based on the participant's age and weight.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: 12 to 17 Years of Age Participants 12 to 17 years old (inclusive) received adult formulation of delamanid 100 mg (2x50 mg tablets), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365. | 7 |
| Group 2: 6 to 11 Years of Age Participants 6 to 11 years old (inclusive) received adult formulation delamanid 50 mg (1x50 mg tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365. | 6 |
| Group 3: 3 to 5 Years of Age Participants 3 to 5 years old (inclusive) received 25 mg pediatric formulation of delamanid (DPF - suspension prepared using dispersible tablet), orally, BID plus OBR up to Day 182. Participants continued to receive OBR up to Day 365. | 12 |
| Group 4: Birth to 2 Years of Age Participants from birth to 2 years old (inclusive) received DPF (suspension prepared using dispersible tablet) for 182 days plus OBR. Participants continued to receive OBR up to Day 365. The DPF dose was based on the participant's body weight during the baseline visit:
* Participants \>10 kilograms (kg) received DPF 10 mg BID plus OBR
* Participants \>8 kg and ≤10 kg received DPF 5 mg BID plus OBR
* Participants ≥5.5 kg and ≤8 kg received DPF 5 mg once per day (QD) plus OBR
Delamanid dose was adjusted as needed for Group 4 participants based on the weight measurement at specified study visits \[Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)\]. | 12 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Group 1: 12 to 17 Years of Age | Group 2: 6 to 11 Years of Age | Group 3: 3 to 5 Years of Age | Group 4: Birth to 2 Years of Age | Total |
|---|---|---|---|---|---|
| Age, Continuous | 15.37 years STANDARD_DEVIATION 1.63 | 9.51 years STANDARD_DEVIATION 1.49 | 4.37 years STANDARD_DEVIATION 0.98 | 1.79 years STANDARD_DEVIATION 0.59 | 6.45 years STANDARD_DEVIATION 5.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 6 Participants | 12 Participants | 12 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 4 Participants | 8 Participants | 6 Participants | 25 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants | 6 Participants | 10 Participants |
| Region of Enrollment Philippines | 7 Participants | 4 Participants | 8 Participants | 6 Participants | 25 Participants |
| Region of Enrollment South Africa | 0 Participants | 2 Participants | 4 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 6 Participants | 6 Participants | 19 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants | 6 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 | 1 / 12 | 1 / 12 |
| other Total, other adverse events | 7 / 7 | 6 / 6 | 12 / 12 | 11 / 12 |
| serious Total, serious adverse events | 0 / 7 | 1 / 6 | 2 / 12 | 5 / 12 |
Outcome results
Primary
Number of Participants With Abnormal Physical Examination Values
Physical examination included the examination of the abdomen; extremities; head, eyes, ears, nose (HEENT); neurological; skin and mucosae; thorax; urogenital; audiometry assessment and visual assessment. Participants with abnormal values, as assessed by the investigator were reported.
Time frame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
Population: The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation. Overall number of participants analyzed are the participants with data available for analyses.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | Audiometry Assessment | 4 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | Abdomen | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | Skin and Mucosae | 2 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | Neurological | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | Extremities | 2 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | Visual Assessment | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | Urogenital | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | Thorax | 5 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Physical Examination Values | HEENT | 7 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | Skin and Mucosae | 6 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | Abdomen | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | Extremities | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | HEENT | 6 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | Neurological | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | Thorax | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | Urogenital | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | Audiometry Assessment | 3 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Physical Examination Values | Visual Assessment | 1 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | HEENT | 12 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | Skin and Mucosae | 6 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | Abdomen | 4 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | Thorax | 6 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | Extremities | 1 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | Urogenital | 1 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | Visual Assessment | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | Audiometry Assessment | 9 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Physical Examination Values | Neurological | 1 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | Neurological | 1 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | Urogenital | 3 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | Skin and Mucosae | 8 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | Extremities | 1 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | Abdomen | 2 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | Audiometry Assessment | 7 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | Thorax | 7 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | HEENT | 10 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Physical Examination Values | Visual Assessment | 1 Participants |
Primary
Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE)
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant and that does not necessarily have a causal relationship with the treatment. A TEAE is defined as an AE that occurred after the administration of investigational medicinal product (IMP).
Time frame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
Population: The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE) | 7 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE) | 6 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE) | 12 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE) | 12 Participants |
Primary
Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values
The criteria for clinically significant abnormal ECG values were ventricular rate outlier (\<50 bpm and decrease of \>=25%, \>100 bpm and increase of \>=25%), PR outlier (increase of \>=25% when PR \>200 milliseconds (ms)), QRS outlier (increase of \>=25% when QRS \>100 ms), QT (new onset (in treatment period but not at Baseline) \[\>500 ms\]), QT interval corrected by Bazett's formula (QTcB) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), QT interval corrected by Fridericia's formula (QTcF) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), new abnormal U waves, new ST segment changes, new T wave changes, new abnormal rhythm, new conduction abnormality were reported as categories. Only categories with data are reported.
Time frame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
Population: The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation. Overall number of participants analyzed are the participants with data available for analyses.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | New Conduction Abnormality | 6 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (Change > 60 ms) | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QRS Outliers | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (>450 ms) | 3 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (>480 ms) | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (>450 ms) | 7 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (Change > 60 ms) | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (Change >= 30 and <=60 ms) | 5 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | New Abnormal Rhythm | 5 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (Change >= 30 and <=60 ms) | 5 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | Ventricular Rate Outliers, Notable Increases | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (>450 ms) | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (>450 ms) | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (Change > 60 ms) | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (Change >= 30 and <=60 ms) | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | Ventricular Rate Outliers, Notable Increases | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | New Conduction Abnormality | 5 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (Change > 60 ms) | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QRS Outliers | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (>480 ms) | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | New Abnormal Rhythm | 4 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (Change >= 30 and <=60 ms) | 3 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (>450 ms) | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | New Conduction Abnormality | 5 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (>480 ms) | 1 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (Change > 60 ms) | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (Change >= 30 and <=60 ms) | 6 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | New Abnormal Rhythm | 6 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | Ventricular Rate Outliers, Notable Increases | 1 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QRS Outliers | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (>450 ms) | 8 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (Change >= 30 and <=60 ms) | 8 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (Change > 60 ms) | 0 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (Change >= 30 and <=60 ms) | 9 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (Change >= 30 and <=60 ms) | 9 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (>450 ms) | 0 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (>450 ms) | 5 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (Change > 60 ms) | 2 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcB, New Onset (>480 ms) | 0 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | New Abnormal Rhythm | 1 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | New Conduction Abnormality | 8 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QRS Outliers | 0 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | Ventricular Rate Outliers, Notable Increases | 4 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values | QTcF, New Onset (Change > 60 ms) | 1 Participants |
Primary
Number of Participants With Clinically Significant Abnormal Vital Sign Values
Vital signs included weight (kg), height (cm), body temperature (degree Celsius), heart rate (beats/min), respiratory rate (breaths/minute), systolic and diastolic blood pressure (mm Hg), body mass index (BMI) (kg/m\^2). The criteria for clinically significant abnormal value for weight was decrease or increase of \>=5% in body weight relative to Baseline. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported.
Time frame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
Population: The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation. Overall number of participants analyzed are the participants with data available for analyses.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormal Vital Sign Values | Increase of >=5% in Body Weight | 4 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Abnormal Vital Sign Values | Decrease of >=5% in Body Weight | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormal Vital Sign Values | Decrease of >=5% in Body Weight | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Abnormal Vital Sign Values | Increase of >=5% in Body Weight | 2 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormal Vital Sign Values | Decrease of >=5% in Body Weight | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Abnormal Vital Sign Values | Increase of >=5% in Body Weight | 10 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormal Vital Sign Values | Increase of >=5% in Body Weight | 10 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Abnormal Vital Sign Values | Decrease of >=5% in Body Weight | 1 Participants |
Primary
Number of Participants With Clinically Significant Laboratory Test Abnormalities
Laboratory assessments included parameters for serum chemistry, hematology and urinalysis along with adrenocorticotropic hormone, serum cortisol, free thyroxine, thyroid-stimulating hormone (TSH), and high sensitivity C-reactive protein cell count. The participants were categorized based on the clinically significant laboratory values as per protocol predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported. The normal ranges for those laboratory parameters were potassium 3.4 - 5.4 milliequivalents/liter (mEq/L), uric acid 3.9 - 8.2 mg/dL, partial thromboplastin time (PTT) 9.7 - 12.3 sec, platelet count 180 - 440 thousands platelets/μL.
Time frame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
Population: The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Low Platelet Count | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated PTT | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated Uric Acid | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated Potassium | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated Potassium | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Low Platelet Count | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated PTT | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated Uric Acid | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated Uric Acid | 1 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Low Platelet Count | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated Potassium | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated PTT | 2 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated Uric Acid | 0 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated PTT | 0 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Low Platelet Count | 1 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Clinically Significant Laboratory Test Abnormalities | Elevated Potassium | 1 Participants |
Primary
POPPK Model Point Estimate for Absorption Lag Time (ALAG1) of Delamanid
ALAG1 is defined as the time delay prior to the commencement of drug absorption. Population point estimates were based on POPPK analysis to find one measure for ALAG1. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid.
Time frame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
Population: Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: 12 to 17 Years of Age | POPPK Model Point Estimate for Absorption Lag Time (ALAG1) of Delamanid | 1.38 hour (hr) |
Primary
POPPK Model Point Estimate for Absorption Rate Constant (Ka) of Delamanid
Ka is defined as a measure of rate at which a drug enters into the circulatory system. Population point estimate for Ka was based on population PK analysis to find one measure. Population point estimates were based on POPPK analysis to find one measure for Ka. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid.
Time frame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
Population: Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: 12 to 17 Years of Age | POPPK Model Point Estimate for Absorption Rate Constant (Ka) of Delamanid | 0.254 per hour (1/hr) |
Primary
POPPK Model Point Estimate for Central Volume of Distribution (Vc) and Peripheral Volume of Distribution (Vp) of Delamanid
Vc is defined as the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma. Vp is defined as the apparent volume needed to account for the total amount of drug in the body if the drug was evenly distributed throughout the body and in the same concentration as the site of sample collection such as peripheral venous plasma. Population point estimates were based on POPPK analysis to find one measure each for both Vc and Vp. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid.
Time frame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
Population: Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | POPPK Model Point Estimate for Central Volume of Distribution (Vc) and Peripheral Volume of Distribution (Vp) of Delamanid | Central Volume of Distribution (Vc) | 254 liters (L) |
| Group 1: 12 to 17 Years of Age | POPPK Model Point Estimate for Central Volume of Distribution (Vc) and Peripheral Volume of Distribution (Vp) of Delamanid | Peripheral Volume of Distribution (Vp) | 347 liters (L) |
Primary
Population Pharmacokinetic (POPPK) Model Point Estimate for Central Clearance (L) and Inter-compartmental Clearance (Q) of Delamanid
Central clearance is defined as plasma volume in the vascular compartment that is cleared of drug per unit of time. Inter-compartmental clearance is defined as a ratio of the drug's distribution rate between the central compartment and the peripheral compartments over its circulating concentration (L/hr). Population point estimates were based on POPPK analysis to find one measure each for both L and Q. The exposure data were pooled across visits and participants to identify POPPK parameter estimates and were reported for delamanid.
Time frame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
Population: Population Pharmacokinetic (PK)/Pharmacodynamic (PD) analysis sample included all the participants with data available for PK/PD analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Population Pharmacokinetic (POPPK) Model Point Estimate for Central Clearance (L) and Inter-compartmental Clearance (Q) of Delamanid | Central Clearance (L) | 18.1 L/hr |
| Group 1: 12 to 17 Years of Age | Population Pharmacokinetic (POPPK) Model Point Estimate for Central Clearance (L) and Inter-compartmental Clearance (Q) of Delamanid | Inter-compartmental Clearance (Q) | 105 L/hr |
Secondary
Baseline QT Interval (QTcB) Effect
The 12-lead ECG was performed to obtain recordings of heart rate (QT interval) to analyze QTcB effect.
Time frame: Baseline (Day -1)
Population: Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Baseline QT Interval (QTcB) Effect | Delamanid | 0.0318 ms |
| Group 1: 12 to 17 Years of Age | Baseline QT Interval (QTcB) Effect | Metabolite DM-6705 | 0.0309 ms |
Secondary
Number of Participants With Abnormal Chest X-ray
The data for the chest X-ray with abnormality, as assessed by investigator is reported.
Time frame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
Population: The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Abnormal Chest X-ray | 7 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Abnormal Chest X-ray | 6 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Abnormal Chest X-ray | 12 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Abnormal Chest X-ray | 11 Participants |
Secondary
Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis
The following signs and symptoms of tuberculosis were assessed by the investigator: cough, fever, weight loss, failure to thrive, hemoptysis, dyspnea, chest pain, night sweats and loss of appetite.
Time frame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
Population: The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Dyspnea | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Chest Pain | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Cough | 6 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Failure to Thrive | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Loss of Appetite | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Weight Loss | 3 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Night Sweats | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Hemoptysis | 2 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Fever | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Hemoptysis | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Chest Pain | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Dyspnea | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Loss of Appetite | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Weight Loss | 5 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Cough | 4 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Night Sweats | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Failure to Thrive | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Fever | 2 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Hemoptysis | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Cough | 3 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Fever | 2 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Weight Loss | 7 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Failure to Thrive | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Dyspnea | 3 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Chest Pain | 0 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Night Sweats | 1 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Loss of Appetite | 2 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Chest Pain | 0 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Failure to Thrive | 3 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Weight Loss | 9 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Loss of Appetite | 6 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Night Sweats | 2 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Fever | 5 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Dyspnea | 2 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Hemoptysis | 0 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis | Cough | 7 Participants |
Secondary
Number of Participants With Palatability Score as Assessed by the Investigator
The palatability of the pediatric formulation was assessed using an age-appropriate visual hedonic scale and clinical assessment (Groups 3 and 4 only). The palatability result was based on 1 of 5 responses: 1=Dislike very much, 2=Dislike a little, 3=Neither liked nor disliked, 4=Like a little, 5=Like very much. Participants were categorized based on different scores. The data per the investigator score are reported.
Time frame: Days 1, 28, 56 and 182
Population: Participants from the safety sample aged below 5 years (Groups 3 and 4) and who received any amount of IMP in this study, regardless of any protocol deviation or violation were analyzed for this outcome measure. Number analyzed is the number of participants with data available for analyses at the given time point.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Like a Little | 2 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Like a Little | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Dislike Very Much | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Like Very Much | 9 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Like Very Much | 9 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Dislike Very Much | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Like Very Much | 11 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Dislike a Little | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Dislike Very Much | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Neither Liked Nor Disliked | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Dislike a Little | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Like a Little | 2 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Dislike a Little | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Like Very Much | 10 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Dislike Very Much | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Like a Little | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Dislike a Little | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Neither Liked Nor Disliked | 2 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Neither Liked Nor Disliked | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Neither Liked Nor Disliked | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Neither Liked Nor Disliked | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Neither Liked Nor Disliked | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Like Very Much | 11 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Like a Little | 5 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Like Very Much | 5 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Dislike Very Much | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Dislike a Little | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Like a Little | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 1 | Like Very Much | 8 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Dislike Very Much | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Dislike a Little | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Neither Liked Nor Disliked | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Like a Little | 2 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 28 | Like Very Much | 9 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Dislike Very Much | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Dislike a Little | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Neither Liked Nor Disliked | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 56 | Like a Little | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Dislike Very Much | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Investigator | Day 182 | Dislike a Little | 1 Participants |
Secondary
Number of Participants With Palatability Score as Assessed by the Parent or Participant
The palatability of the pediatric formulation was assessed using an age-appropriate visual hedonic scale and clinical assessment (Groups 3 and 4 only). The palatability result was based on 1 of 5 responses: 1=Dislike very much, 2=Dislike a little, 3=Neither liked nor disliked, 4=Like a little, 5=Like very much. The data per parent/patient score are reported. Participants were categorized based on different scores.
Time frame: Days 1, 28, 56 and 182
Population: Participants from the safety sample aged below 5 years (Groups 3 and 4) and who received any amount of IMP in this study, regardless of any protocol deviation or violation were analyzed for this outcome measure. Number analyzed is the number of participants with data available for analyses at the given time point.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Like Very Much | 11 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Like a Little | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Dislike Very Much | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Dislike a Little | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Neither Liked Nor Disliked | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Like a Little | 2 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Like Very Much | 9 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Dislike Very Much | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Dislike a Little | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Neither Liked Nor Disliked | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Like Very Much | 10 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Dislike Very Much | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Dislike a Little | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Neither Liked Nor Disliked | 1 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Like a Little | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Like Very Much | 11 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Dislike Very Much | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Dislike a Little | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Neither Liked Nor Disliked | 0 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Like a Little | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Like Very Much | 11 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Like Very Much | 8 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Dislike Very Much | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Like Very Much | 6 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Neither Liked Nor Disliked | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Dislike Very Much | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Dislike Very Much | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Dislike a Little | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Dislike a Little | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Neither Liked Nor Disliked | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Like Very Much | 7 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 1 | Like a Little | 3 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Neither Liked Nor Disliked | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Dislike a Little | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Dislike Very Much | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 56 | Like a Little | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Dislike a Little | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 182 | Like a Little | 4 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Neither Liked Nor Disliked | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Palatability Score as Assessed by the Parent or Participant | Day 28 | Like a Little | 3 Participants |
Secondary
Number of Participants With Treatment Outcome as Assessed by Principal Investigator
Treatment outcome was defined as favorable (cured and completed treatment) and unfavorable (lost to follow-up or died).
Time frame: Month 24
Population: The Safety Sample included participants who received any amount of IMP in this study, regardless of any protocol deviation or violation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Favorable (Cured + Treatment Completed) | 6 Participants |
| Group 1: 12 to 17 Years of Age | Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Unfavorable (Lost To Follow-up + Died) | 1 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Unfavorable (Lost To Follow-up + Died) | 0 Participants |
| Group 2: 6 to 11 Years of Age | Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Favorable (Cured + Treatment Completed) | 6 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Favorable (Cured + Treatment Completed) | 10 Participants |
| Group 3: 3 to 5 Years of Age | Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Unfavorable (Lost To Follow-up + Died) | 2 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Favorable (Cured + Treatment Completed) | 11 Participants |
| Group 4: Birth to 2 Years of Age | Number of Participants With Treatment Outcome as Assessed by Principal Investigator | Unfavorable (Lost To Follow-up + Died) | 1 Participants |
Secondary
PK/PD Relationship: POPPK Model Point Estimate for Slope of Linear Mixed Effects Model for Change in QTcB Interval Versus Delamanid Plasma Concentrations
The linear mixed effects model was applied to characterize the concentration-QTcB relationship of delamanid/DM-6705 to obtain population slope estimate.
Time frame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
Population: Population PK/PD analysis sample included all the participants with data available for PK/PD analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group 1: 12 to 17 Years of Age | PK/PD Relationship: POPPK Model Point Estimate for Slope of Linear Mixed Effects Model for Change in QTcB Interval Versus Delamanid Plasma Concentrations | Delamanid | 0.00792 ms/[ng/mL] |
| Group 1: 12 to 17 Years of Age | PK/PD Relationship: POPPK Model Point Estimate for Slope of Linear Mixed Effects Model for Change in QTcB Interval Versus Delamanid Plasma Concentrations | Metabolite DM-6705 | 0.0613 ms/[ng/mL] |
Secondary
Sputum Culture Conversion (SCC)
SCC was defined as a sputum specimen from a participant negative for growth of Mycobacterium tuberculosis (MTB), followed by at least one confirmatory negative sputum culture at least 27 days after the first negative sputum test and not followed by any sputum cultures positive for growth.
Time frame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
Population: Data for SCC could not be collected due to the paucity of sputum production in the participants.