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

Otsuka

Status and phase: Completed; Phase 2

Conditions: Multidrug Resistant Tuberculosis

Treatments: Drug: Optimized Background Regimen (OBR); Drug: Delamanid; Drug: Delamanid Pediatric Formulation (DPF)

Study type: Interventional

Funder types: Industry

Identifiers

NCT01859923

2012-004620-38 (EudraCT Number)

242-12-233

Details and patient eligibility

About

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).

Full 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.

Enrollment: 37 patients

Sex: All

Ages: Under 17 years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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37 participants in 4 patient groups

Group 1: 12 to 17 Years of Age

Experimental group

Description:

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.

Treatment:

Drug: Optimized Background Regimen (OBR)

Drug: Delamanid

Group 2: 6 to 11 Years of Age

Experimental group

Description:

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.

Treatment:

Drug: Optimized Background Regimen (OBR)

Drug: Delamanid

Group 3: 3 to 5 Years of Age

Experimental group

Description:

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.

Treatment:

Drug: Optimized Background Regimen (OBR)

Drug: Delamanid Pediatric Formulation (DPF)

Group 4: Birth to 2 Years of Age

Experimental group

Description:

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 \[Visits 5 (Day 28), 7 (Day 56), 9 (Day 84), 11 (Day 126) and 12 (Day 154)\].

Treatment:

Drug: Optimized Background Regimen (OBR)

Drug: Delamanid Pediatric Formulation (DPF)