Phase 2, Open-label, Multiple-dose Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of Delamanid (OPC-67683) in Pediatric Multidrug-resistant Tuberculosis Patients on Therapy With an Optimized Background Regimen of Anti-tuberculosis Drugs Over a 6-Month Treatment Period
Overview
- Phase
- Phase 2
- Intervention
- Delamanid
- Conditions
- Multidrug Resistant Tuberculosis
- Sponsor
- Otsuka Pharmaceutical Development & Commercialization, Inc.
- Enrollment
- 37
- Locations
- 3
- Primary Endpoint
- Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Group 1: 12 to 17 Years of Age
Participants 12 to 17 years old (inclusive) received adult formulation of delamanid 100 milligrams (mg) (2x50 mg tablets), orally, twice daily (BID) plus optimized background regimen (OBR) up to Day 182. Participants continued to receive OBR up to Day 365.
Intervention: Delamanid
Group 1: 12 to 17 Years of Age
Participants 12 to 17 years old (inclusive) received adult formulation of delamanid 100 milligrams (mg) (2x50 mg tablets), orally, twice daily (BID) plus optimized background regimen (OBR) up to Day 182. Participants continued to receive OBR up to Day 365.
Intervention: Optimized Background Regimen (OBR)
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.
Intervention: Delamanid
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.
Intervention: Optimized Background Regimen (OBR)
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.
Intervention: Delamanid Pediatric Formulation (DPF)
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.
Intervention: Optimized Background Regimen (OBR)
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 \[Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)\].
Intervention: Delamanid Pediatric Formulation (DPF)
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 \[Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)\].
Intervention: Optimized Background Regimen (OBR)
Outcomes
Primary Outcomes
Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE)
Time Frame: 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 Clinically Significant Abnormalities in Electrocardiogram (ECG) Values
Time Frame: 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
Time Frame: 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
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
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.
Number of Participants With Abnormal Physical Examination Values
Time Frame: 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
Time Frame: 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.
POPPK Model Point Estimate for Central Volume of Distribution (Vc) and Peripheral Volume of Distribution (Vp) of 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
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
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
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
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
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 Outcomes
- 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))
- 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))
- Number of Participants With Palatability Score as Assessed by the Investigator(Days 1, 28, 56 and 182)
- Baseline QT Interval (QTcB) Effect(Baseline (Day -1))
- 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)
- Number of Participants With Treatment Outcome as Assessed by Principal Investigator(Month 24)
- 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))
- Number of Participants With Palatability Score as Assessed by the Parent or Participant(Days 1, 28, 56 and 182)