Evaluation of Pharmacokinetics and Safety Tolerability of Higher Doses of Rifampic (HighRif C)

Evaluation of Pharmacokinetics and Safety Tolerability of Higher Doses of Rifampicin in Children With Newly Diagnosed Uncomplicated Tuberculosis

Tuberculosis in children is a major public health problem and it contributes 10% of the total TB cases worldwide. TB treatment outcomes in children are challenged by insufficient consideration of the relationships between doses administered, concentrations achieved and eventual desirable and undesirable effects (pharmacodynamics) of TB drugs. Rifampicin is a pivotal TB drug and data from adults suggest that a much higher dose of rifampicin (35 mg/kg instead of 10 mg/kg), resulting in much higher rifampicin exposures in plasma, is safe and tolerable and may provide a higher efficacy. The dose needed in children to achieve the same exposure in plasma is unknown.

Study Overview

• Status: Completed
• Conditions: Clinical Trial
• Intervention / Treatment: Drug: Evaluation of high dose rifampicin in children

Detailed Description

Tuberculosis (TB) in children is a major public health problem . It has a global estimate of >100,000 deaths per year and is included in the top ten causes of mortality in children worldwide. Children contribute 10% of the total TB cases worldwide. More than 75% of the worldwide estimated cases of TB in children occur in the 30 high burden countries, Tanzania being one of them. The enormous burden of pediatric TB in these countries is due to the TB epidemic amongst adults and the simultaneous HIV pandemic and a child less than 14 years of age whether HIV infected or not is at a high risk of developing the disease. Subsequent dissemination of the mycobacterium and progression of the disease is also fast in children.

Knowledge on the efficacy and safety of medicines for children is still very limited and sometimes children are still being treated as small adults. However, adult dosing cannot be logically extrapolated to children according to weight or age because of different pharmacokinetics, i.e. the relationship between doses administered and exposures (drug concentrations) achieved, in children as compared with adults . More specifically, these pharmacokinetic differences occur in the subsequent processes of absorption, distribution, metabolism and elimination of drugs, which are subject to physiological changes due to growth and development in children. Especially in young children, maturation of liver metabolism pathways and renal function are not completed.

In contrast, the pharmacodynamics of a drug, i.e. the relationship between concentrations achieved and eventual response is generally considered similar between adults and children, although differences in drug metabolism between children and adults may lead to differences in susceptibility to some adverse drug reactions. Thus, because of the differences in pharmacokinetics in children with different ages, they should not receive the same drug doses on mg/kg base as adults, and drug dosage selection in children should rather be based upon stages of growth and development. These drug doses should target the exposures that are efficacious in adults.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Hadija H Semvua, PhD; Phone Number: +255754377777; Email: h.semvua@kcri.ac.tz
• Study Contact Backup: Name: Tupokigwe S Jana, Diploma; Phone Number: +255784734602; Email: t.jana@kcri.ac.tz

Study Locations

• Tanzania
  • Arusha, Tanzania
    • Mt. Meru Hospital
  • Moshi, Tanzania
    • Huruma Hospital
  • Kilimanjaro
    • Moshi, Kilimanjaro, Tanzania, +255
      • Kilimanjaro Clinical Research Institute
  • Manyara
    • Babati, Manyara, Tanzania
      • Hydom Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 14 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Children aged 1 to 14 years with newly diagnosed Tuberculosis

Exclusion Criteria:

• Children with elevated liver function
• Children allergic to first line anti-TB drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Control arm; Participants will receive standard treatment of rifampicin	Drug: Evaluation of high dose rifampicin in children; Evaluation of severity of adverse event from grade 1 to 5; Other Names: Safety monitoring
Experimental: First High dose; Participants will receive 30mg per kg body weight of rifampicin	Drug: Evaluation of high dose rifampicin in children; Evaluation of severity of adverse event from grade 1 to 5; Other Names: Safety monitoring
Experimental: Second high dose; Particpants will receive 40mg per kg body weight of rifampicin	Drug: Evaluation of high dose rifampicin in children; Evaluation of severity of adverse event from grade 1 to 5; Other Names: Safety monitoring

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of high dose rifampicin	To know the maximum tolerable dose of rifampicin in children aged 1-14 years	54 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration	Maximum observed concentration	54 months
Time	To measure time to reach maximum concentration	54 months

Collaborators and Investigators

• Sponsor: Kilimanjaro Clinical Research Institute
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP)

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: May 28, 2020
• First Submitted That Met QC Criteria: June 18, 2020
• First Posted (Actual): June 18, 2020

Study Record Updates

• Last Update Posted (Actual): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Tuberculosis, Pharmacokinetics, safety/torelability
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin
• Other Study ID Numbers: TMA2017CDF-1876-HighRif C

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No