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A 6-Month Safety, Efficacy, and Pharmacokinetic Trial of Delamanid in Pediatric Patients with Multi-Drug Resistant Tuberculosis

PHRR160526-001029

Protocol Number: 242-12-233

2012-CT0079

Phase 2, Open-label, Multi-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

This is a Phase 2, open-label, multi-dose multicenter trial to assess the safety, tolerability, PK, and efficacy of delamanid plus OBR in pediatric patients with MDR-TB over a 6-month treatment period. This long-term trial, an extension of Trial 242-12-232 (Trial 232), will be conducted in patients who have completed Trial 232. The current Trial 242-12-233 (Trial 233) will initially be conducted sequentially in two groups of pediatric patients by age group: Group 1 (ages 12 to 17 years) and Group 2 (ages 6 to 11 years).

Younger age groups (Group 3, [3 to 5 years] and Group 4, [0 to 2 years]) will be enrolled when the pediatric formulation becomes available. Details describing Groups 3 and 4 will be included in an amendment to this protocol.

Group 1 includes pediatric patients with MDR-TB age 12 to 17 years receiving OBR. Group 2 includes pediatric patients with MDR-TB age 6 to 11 years receiving OBR. Patients will be assigned to one of two treatment groups based on age:
  • Group 1 will receive delamanid 100 mg (2 x 50 mgtablets) (twice daily) BID orally (PO) plus OBR for6 months (180 days).
  • Group 2 will receive delamanid 50 mg (1 x 50 mgtablet) BID PO plus OBR for 6 months (180 days).
  • Group 3 (ages 3 - 5 years, inclusive) will receive pediatric formulation delamanid 25 mg BID + OBR (n= 12)
  • Group 4 (ages birth - 2 years, inclusive) will receive pediatric formulation delamanid (dose to be determined) BID + OBR (n = 12)
Both groups will have assessments at screening, during the treatment period, the post-treatment period, and the follow-up period, as indicated in the Schedule of Assessments. All patients must have completed the pediatric PK Trial 232 prior to enrollment into Trial 233. Those patients who have completed Trial 232 and choose to enter Trial 233 must rollover from Trial 232 within 30 days of completing that Trial. If any patients terminate Trial 232 early or choose not to enter Trial 233, patients will be recruited to first enter and complete Trial 232, and then rollover into Trial 233. Patients who terminate Trial 233 early will not be replaced.
 
The trial will be comprised of the following periods:
 
Screening Period (Day -30 to -1): Study data will either be taken from screening or Day 10 of Trial 232 or will be performed during the 30-day period immediately after completion of Trial 232 as described in the Schedule of Assessments.
 
Baseline (Day 0): Inclusion/exclusion criteria, physical examination and safety assessments including lab tests, signs and symptoms of tuberculosis (TB), audiometry and visual assessments, vital signs, height, weight, percentiles for age, body mass index (BMI), and ECG as described in the Schedule of Assessments. OBR administration as prescribed by investigator, and recording of adverse events (AEs)/immediately reportable events (IREs), and concomitant medications.
 
Treatment Period (Days 1 to 182): Morning and evening dosing of delamanid with meal. OBR administration as prescribed by investigator. Sparse blood draws for PK as described in the Schedule of Assessments. Signs and symptoms of TB, physical examination and other safety assessments including safety lab tests. Audiometry and visual assessments, and ECG at weeks and times shown in the Schedule of Assessments. Height, weight, and BMI beginning at Week 2 and assessed monthly, and collection of AEs/IREs, and concomitant medications.
 
Post-Treatment Period (Days 183 to 238):
Physical examination, vital signs, ECGs, safety labs, sparse blood draws for PK at visits and times described in the Schedule of Assessments. OBR dosing and collection of AEs/IREs, and concomitant medications.
 
Follow-up Period (Days 239 to 365) Six Month Post Last Delamanid Dose:
Physical examination, height and weight, BMI, percentiles for age, vital signs, and symptoms of TB, chest radiograph, audiometry and visual assessments, safety labs, thyroid function tests (for patients taking ethionamide or PAS), OBR administration, and collection of AEs/IREs and concomitant medications.

Treatment Outcome Follow-up (Day 730 [Month 24] + 2months): Collection of treatment outcome information as routinely documented in the patient medical records or in a national TB program.

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2013-08-13 63 2018-11-13 2020-01-13

Completed

Institution Classification Region LTO #
Otsuka Pharmaceutical Development and Commercialization, Inc. Private Business NCR CDRR-NCR-S-7
Institution Region
Otsuka Pharmaceutical Development and Commercialization, Inc. NCR
Name E-Mail Institution and Institution Address
Jeffrey Hafkin Jeffrey.Hafkin@otsuka-us.com Otsuka Pharmaceutical Development & Commercialization
Name E-Mail Institution and Institution Address
Jeffrey Hafkin Jeffrey.Hafkin@otsuka-us.com Otsuka Pharmaceutical Development & Commercialization
Name Expertise Affiliation
Anjanette O. Reyes-De Leon, MD Pediatrics Lung Center of the Philippines
Melchor Victor Frias, IV MD Pediatrics De La Salle Health Sciences Institute
Project Location Institutional Ethics Review Board
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
De La Salle Health Sciences Institute De La Salle Health Sciences Institute Independent Ethics Committee

Multi-Drug Resistant Tuberculosis

  • Safety and Tolerability Summary [Time Frame: 365 Days]  Safety and tolerability will be assessed by the following variables: physical examination including visual testing and audiometry, vital signs, treatment-emergent adverse events (TEAEs), EGGs and clinical laboratory tests
  • Pharmacokinetics (PK) [Time Frame: Days 1, 4, 56, 98, 154, 182, 189, 196, 203, 210, 238
  • Delamanid and metabolite plasma concentrations reported by age and dose group on Days 1, 14, 56, 98, 154, 182, 189, 196, 203, 210, 238.

Pharmacokinetics/Pharmacodynamics (PK/PD) Relationship Analysis of Delamanid and DM-6705 and Change in Corrected QT Interval [Time Frame: Days 1, 56, 154, 182, and 210]  ECG and blood samples for PK/PD analysis for changes in QTc as a function of delamanid and DM-6705 plasma concentrations on Days 1, 56, 154, 182, and 210.

Efficacy of Delamanid [Time Frame: 365 Days]

The efficacy of delamanid in treating pediatric MDR-TB patients will be evaluated by chest radiography (patients with pulmonary disease), change in body weight height, and evaluation of TB symptoms. Sputum culture conversion (for culture-positive patients) will be assessed in patients who are able to produce sputum (or provide other biological specimens) for microbiological evaluation.

Palatability of the Pediatric Formulation (Groups 3 and 4 only) [Time Frame: Days 1, 28, 56, 182]  Palatability of the delamanid pediatric formulation will be assessed using an age-appropriate visualhedonic scale and clinical assessment for Groups 3 and 4 only on Days 1, 28, 56, 182.

Completed

  • Philippines
  • South Africa

Clinical Trial

Protocol Number: 242-12-233

2012-CT0079

2013-02-27

0000-00-00

25

25

Unspecified

2013-08-13

Key Inclusion Criteria:

  • Successfully completed Trial 242-12-232
  • Male and female children
  • Age birth to 17 years
  • Confirmed diagnosis of MDR-TB OR
  • Presumptive diagnosis of MDR-TB including one of the following:
  1. Clinical specimen suggestive of TB
  2. Persistent cough lasting > 2 weeks
  3. Fever, weight loss, and failure to thrive
  4. Chest radiograph consistent with TB
  5. Sputum smear positive for acid-fast bacilli AND
  6. Household contact of a person with known MDR-TB or 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 patients who have reached menarche
  • Written informed consent/assent

Exclusion Criteria:

  • Patients who have not completed Trial 242-12-232
  • Positive test for HIV, previously identified as having HIV, or laboratory evidence of active hepatitis B or
  • 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
  • Preexisting cardiac conditions
  • Abnormalities in Screening ECG (including AV block, BBB or hemi-block, QRS prolongation > 120 msec, or QTcF > 450 msec in both males and females)
  • Concomitant condition such as renal impairment characterized by serum creatinine levels >1.5 mg/d L, hepatic impairment (ALT or AST > 3 x 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
  • Lansky Play Performance Score < 50 or Karnofsky Score < 50
  • Administered an IMP within 1 month prior to Visit 1
  • Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the information consent form (Groups 1 and 2 only)

Interventional

Delamanid

  • Group 1: 100 mg (2 x 50 mg tablets) delamanid BID plus OBR for 6 months
  • Group 2: 50 mg (1 x 50 mg tablet) delamanid BID plus OBR for 6 months
  • Group 3 includes pediatric MDR-TB patients age 3 to 5 years receiving OBR. Group 3 will be dosed as follows:
  • Group 4 includes pediatric MDR-TB patients age 0 to 2 years receiving OBR. Dosage will be determined after 6 patients completed the study 232.

Date Amendment Classification Reason
2019-04-29 Amendments related to the protocol Addition of interim analysis

Unspecified

Open Label

Unspecified

Parallel

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 of other anti-tuberculosis drugs in pediatric patients who completed Trial 242-12-232.

Phase II

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