A 6-Month Safety, Efficacy, and Pharmacokinetic (PK) Trial of Delamanid in Pediatric Participants With Multidrug Resistant Tuberculosis (MDR-TB)

• ClinicalTrials.gov Identifier: NCT01859923
• Recruitment Status: Completed
• First Posted: May 22, 2013
• Results First Posted: November 23, 2020
• Last Update Posted: November 23, 2020
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Multidrug Resistant Tuberculosis	Drug: Delamanid; Drug: Delamanid Pediatric Formulation (DPF); Drug: Optimized Background Regimen (OBR)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 37 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: July 20, 2013
• Actual Primary Completion Date: January 13, 2020
• Actual Study Completion Date: January 13, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Delamanid; 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.; Other Name: OPC-67683; Drug: Optimized Background Regimen (OBR); 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.
Experimental: 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.	Drug: Delamanid; 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.; Other Name: OPC-67683; Drug: Optimized Background Regimen (OBR); 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.
Experimental: 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.	Drug: Delamanid 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.; Drug: Optimized Background Regimen (OBR); 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.
Experimental: 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)].	Drug: Delamanid 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.; Drug: Optimized Background Regimen (OBR); 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.

Outcome Measures

Primary Outcome Measures :

1. 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).
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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 Outcome Measures :

1. Baseline QT Interval (QTcB) Effect [ Time Frame: Baseline (Day -1) ]
   The 12-lead ECG was performed to obtain recordings of heart rate (QT interval) to analyze QTcB effect.
2. PK/PD Relationship: POPPK Model Point Estimate for Slope of Linear Mixed Effects Model for Change in QTcB Interval Versus Delamanid Plasma Concentrations [ 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 ]
   The linear mixed effects model was applied to characterize the concentration-QTcB relationship of delamanid/DM-6705 to obtain population slope estimate.
3. Number of Participants With Treatment Outcome as Assessed by Principal Investigator [ Time Frame: Month 24 ]
   Treatment outcome was defined as favorable (cured and completed treatment) and unfavorable (lost to follow-up or died).
4. Number of Participants With Abnormal Chest X-ray [ 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 data for the chest X-ray with abnormality, as assessed by investigator is reported.
5. Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis [ 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 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.
6. Sputum Culture Conversion (SCC) [ Time Frame: 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.
7. Number of Participants With Palatability Score as Assessed by the Investigator [ Time Frame: 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.
8. Number of Participants With Palatability Score as Assessed by the Parent or Participant [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 0 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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
• 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)

Contacts and Locations

Locations

Philippines

De La Salle Health Sciences Institute

Dasmariñas, Cavite, Philippines

Lung Center of the Philippines

Quezon City, Metro Manila, Philippines

South Africa

Brooklyn Chest Hospital

Ysterplaat, Cape Town, South Africa

Sponsors and Collaborators

Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Principal Investigator: Melchor VG Frias, IV, MD; De La Salle Health Sciences Institute
• Principal Investigator: Anjanette Reyes-De Leon, MD; Lung Center of the Philippines
• Principal Investigator: Louvina van der Laan, MD; Brooklyn Chest Hospital

  Study Documents (Full-Text)

Documents provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Study Protocol  [PDF] February 28, 2019

Statistical Analysis Plan  [PDF] July 3, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Garcia-Prats AJ, Frias M, van der Laan L, De Leon A, Gler MT, Schaaf HS, Hesseling AC, Malikaarjun S, Hafkin J. Delamanid Added to an Optimized Background Regimen in Children with Multidrug-Resistant Tuberculosis: Results of a Phase I/II Clinical Trial. Antimicrob Agents Chemother. 2022 May 17;66(5):e0214421. doi: 10.1128/aac.02144-21. Epub 2022 Apr 11.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01859923
• Other Study ID Numbers: 242-12-233; 2012-004620-38 ( EudraCT Number )
• First Posted: May 22, 2013
• Results First Posted: November 23, 2020
• Last Update Posted: November 23, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• Access Criteria: Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com
• URL: https://clinical-trials.otsuka.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Tuberculosis; Tuberculosis, Multidrug-Resistant; Mycobacterium Infections; Actinomycetes Infections; Gram-Positive Infections; Bacterial Infections; Pediatric

Additional relevant MeSH terms:

Tuberculosis; Tuberculosis, Multidrug-Resistant; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections