Multidrug Resistant TuberculosisPhase 2NCT01859923
A 6-Month Safety, Efficacy, and Pharmacokinetic (PK) Trial of Delamanid in Pediatric Participants With Multidrug Resistant Tuberculosis (MDR-TB)
A Phase 2 study testing Delamanid, Delamanid Pediatric Formulation (DPF) and Optimized Background Regimen (OBR) in people with Multidrug Resistant Tuberculosis, run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 3 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 0 to 17 years
- Conditions the study is for
- Multidrug Resistant Tuberculosis
- What is being tested?
- Delamanid, Delamanid Pediatric Formulation (DPF) and Optimized Background Regimen (OBR)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 20 Jul 2013to 13 Jan 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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)
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
Philippines2 sites
De La Salle Health Sciences Institute
Dasmariñas, Cavite
Lung Center of the Philippines
Quezon City, National Capital Region
About this study
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
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).
Read the 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.
- Conditions
- Multidrug Resistant Tuberculosis
- Being tested
- Delamanid, Delamanid Pediatric Formulation (DPF), Optimized Background Regimen (OBR)
- Keywords
- Tuberculosis, Tuberculosis, Multidrug-Resistant, Mycobacterium Infections, Actinomycetes Infections, Gram-Positive Infections, Bacterial Infections, Pediatric
- Medical subject headings
- Tuberculosis, Multidrug-Resistant, Tuberculosis, Mycobacterium Infections, Bacterial Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DelamanidDrug
Also called OPC-67683
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.
Delamanid Pediatric Formulation (DPF)Drug
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.
Optimized Background Regimen (OBR)Drug
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.
| Study group | Role | What they receive |
|---|---|---|
| Group 1: 12 to 17 Years of Age | Experimental | 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. Receives: Drug: Delamanid; Drug: Optimized Background Regimen (OBR) |
| Group 2: 6 to 11 Years of Age | Experimental | 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. Receives: Drug: Delamanid; Drug: Optimized Background Regimen (OBR) |
| Group 3: 3 to 5 Years of Age | Experimental | 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. Receives: Drug: Delamanid Pediatric Formulation (DPF); Drug: Optimized Background Regimen (OBR) |
| Group 4: Birth to 2 Years of Age | Experimental | 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)]. Receives: Drug: Delamanid Pediatric Formulation (DPF); Drug: Optimized Background Regimen (OBR) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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 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.
Measured: 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 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.
Measured: 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 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.
Measured: 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 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.
Measured: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
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.
Measured: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
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.
Measured: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
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.
Measured: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
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.
Measured: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
Secondary outcomes (8)
Baseline QT Interval (QTcB) Effect
The 12-lead ECG was performed to obtain recordings of heart rate (QT interval) to analyze QTcB effect.
Measured: 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
The linear mixed effects model was applied to characterize the concentration-QTcB relationship of delamanid/DM-6705 to obtain population slope estimate.
Measured: 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
Treatment outcome was defined as favorable (cured and completed treatment) and unfavorable (lost to follow-up or died).
Measured: Month 24
Number of Participants With Abnormal Chest X-ray
The data for the chest X-ray with abnormality, as assessed by investigator is reported.
Measured: 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 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.
Measured: 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)
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.
Measured: 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
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.
Measured: Days 1, 28, 56 and 182
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.
Measured: Days 1, 28, 56 and 182
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2013 (estimated)
- Study start20 Jul 2013
- Primary completion13 Jan 2020
- Study completion13 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Multidrug Resistant TuberculosisStudies of the same condition, open and under way.
- More trials run by Otsuka Pharmaceutical Development & Commercialization, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Melchor VG Frias, IV, MD, Principal investigator, De La Salle Health Sciences InstituteAnjanette Reyes-De Leon, MD, Principal investigator, Lung Center of the PhilippinesLouvina van der Laan, MD, Principal investigator, Brooklyn Chest Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01859923
- Sponsor's protocol ID
- 242-12-233
- Other IDs
- 2012-004620-38
- Status last verified
- Oct 2020
- First submitted
- 15 May 2013
- Last updated
- 23 Nov 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 35404075
Study at a glance
From the registry record, last updated by the sponsor on 23 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01859923
- Acronym / sponsor ID
- 242-12-233
- Conditions
- Multidrug Resistant Tuberculosis
- Keywords
- Tuberculosis, Tuberculosis, Multidrug-Resistant, Mycobacterium Infections, Actinomycetes Infections, Gram-Positive Infections, Bacterial Infections, Pediatric
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- Otsuka Pharmaceutical Development & Commercialization, Inc.Industry (pharma, biotech, devices)
- Study start
- 20 Jul 2013 (actual)
- Primary completion
- 13 Jan 2020 (actual)
- Study completion
- 13 Jan 2020 (actual)
- First posted
- 22 May 2013 (estimated)
- Results
- Posted 23 Nov 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Group 1: 12 to 17 Years of Age | Experimental | Drug: Delamanid, Drug: Optimized Background Regimen (OBR)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. |
| Group 2: 6 to 11 Years of Age | Experimental | Drug: Delamanid, Drug: Optimized Background Regimen (OBR)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. |
| Group 3: 3 to 5 Years of Age | Experimental | Drug: Delamanid Pediatric Formulation (DPF), Drug: Optimized Background Regimen (OBR)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. |
| Group 4: Birth to 2 Years of Age | Experimental | Drug: Delamanid Pediatric Formulation (DPF), Drug: Optimized Background Regimen (OBR)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)]. |
Who may qualify
- Ages
- 0 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (11 listed)
- 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:
- Negative urine pregnancy test for female participants who have reached menarche
- Written informed consent/assent
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DelamanidAlso: OPC-67683Participants 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. | Drug | Group 1: 12 to 17 Years of Age, Group 2: 6 to 11 Years of Age |
| 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 | Group 3: 3 to 5 Years of Age, Group 4: Birth to 2 Years of Age |
| 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. | Drug | 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 |
Primary outcome
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 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.
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.
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.
8 secondary outcomes
Baseline QT Interval (QTcB) Effect
Time frame: 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
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
Number of Participants With Treatment Outcome as Assessed by Principal Investigator
Time frame: Month 24
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)
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)
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)
Number of Participants With Palatability Score as Assessed by the Investigator
Time frame: Days 1, 28, 56 and 182
Number of Participants With Palatability Score as Assessed by the Parent or Participant
Time frame: Days 1, 28, 56 and 182
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Nov 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35404075Garcia-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.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Melchor VG Frias, IV, MD principal investigator
De La Salle Health Sciences Institute
Anjanette Reyes-De Leon, MD principal investigator
Lung Center of the Philippines
Louvina van der Laan, MD principal investigator
Brooklyn Chest Hospital
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Delamanid, Delamanid Pediatric Formulation (DPF) and Optimized Background Regimen (OBR) in people with Multidrug Resistant Tuberculosis, run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Philippines, South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01859923, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Nov 2020.