Pharmacokinetic Study With a Loading Dose of Clofazimine in Adult Patients With Nontuberculous Mycobacterial Disease

NCT05294146 | Completed Phase 2

• 1 other identifier: C-LOAD
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Clofazimine (CFZ) is a promising drug for the treatment of NTM diseases. CFZ is highly active in vitro against M. abscessus and M. avium, the most common NTM pathogens, and shows synergy with macrolides and amikacin. The results from limited clinical studies with CFZ-based treatment regimens are promising. CFZ is currently considered an alternative drug for patients with M. avium complex infections, who are intolerant of first-line drugs. CFZ is a first-line oral drug for treatment of M. abscessus infections. CFZ might prove to be a cornerstone in NTM treatment, but its optimal dosage is not known. The current dose for adults is 100 mg oncedaily. However, due to the complex pharmacokinetics (PK) of CFZ - it is highly protein bound, extremely lipophilic and accumulates in fatty tissues resulting in a long elimination half-life of \~30 days - it takes several months before steady state, and presumably effective, concentrations are achieved. With the use of a loading dose regimen concentrations similar to those at steady state could be reached faster, possibly leading to improved early treatment efficacy. The overarching aim of this study is to contribute to dose optimization of CFZ in the treatment of NTM diseases. It will be an explorative, single-center, one-arm, open label, pharmacokinetic study. A number of 10 patients with pulmonary or extrapulmonary NTM disease will be included. Patients will receive a loading dose regimen of 300 mg once daily for 4 weeks and will then continue with a standard dose of 100 mg once daily until a total 4 months of treatment with CFZ. The primary objective of this study is to describe the PK of CFZ, after 4 weeks of treatment with a loading dose regimen of 300 mg once daily, in adult patients with pulmonary or extrapulmonary NTM disease

Conditions

Nontuberculous Mycobacterial Diseases

Keywords

Pulmonary and extrapulmonary NTM diseases

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetic parameters of clofazimine after a loading dose regimen (1)

  The area under the curve (AUC0-24), after a loading dose regimen of 300 mg once daily for 4 weeks in adult patients with pulmonary or extrapulmonary NTM disease.

  24 hours sampling at Day 28 (+/- 2 days)

• Pharmacokinetic parameters of clofazimine after a loading dose regimen (2)

  The peak plasma concentration (Cmax), after a loading dose regimen of 300 mg once daily for 4 weeks in adult patients with pulmonary or extrapulmonary NTM disease.

  24 hours sampling at Day 28 (+/- 2 days)

• Pharmacokinetic parameters of clofazimine after a loading dose regimen (3)

  The plasma trough concentration (Cmin), after a loading dose regimen of 300 mg once daily for 4 weeks in adult patients with pulmonary or extrapulmonary NTM disease.

  24 hours sampling at Day 28 (+/- 2 days)

Secondary Outcomes (6)

• Difference between the highest measured concentrations of CFZ in this study and a reference study

  After approximately 1 and 4 months of treatment

• The predicted time (e.g. weeks) needed to reach steady state concentrations with and without a loading dose

  Expected: 1 to 4 months

• Predicted PK parameters (1)

  After approximately 1 and 4 months of treatment

• Predicted PK parameters (2)

  After approximately 1 and 4 months of treatment

• Predicted PK parameters (3)

  After approximately 1 and 4 months of treatment

Study Arms (1)

Loading dose Clofazimine

EXPERIMENTAL

All participants will receive an (experimental) oral loading dose regimen of 300 mg clofazimine (CFZ) once daily (= 3 capsules of 100 mg) for 4 weeks. Afterwards, all participants will continue with a standard oral dose of 100 mg clofazimine once daily (= 1 capsule of 100 mg) until a total 4 months of treatment with CFZ.

Drug: Clofazimine

Interventions

Clofazimine DRUG

All participants will receive an (experimental) oral loading dose regimen of 300 mg clofazimine once daily (= 3 capsules of 100 mg) for 4 weeks. Afterwards, all participants will continue with a standard oral dose of 100 mg clofazimine once daily (= 1 capsule of 100 mg) until a total 4 months of treatment with CFZ. Blood samples will be taken at Day 28 (+/- 2 days), Day 29 (Day 28 +1) and after 4 months of treatment to assess the pharmacokinetics of CFZ, both with the loading dose and the standard dose. In addition, the safety/tolerability of CFZ will monitored.

Also known as: Lamprene

Loading dose Clofazimine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The participant is diagnosed with pulmonary or extrapulmonary NTM disease and is eligible for treatment with CFZ
• The participant is at least 18 years of age
• The participant has a body weight (in light clothing and with no shoes) of at least 45 kg
• The participant is able and willing to provide written, informed consent

You may not qualify if:

• The participant is in poor general condition where participation in the study cannot be accepted per discretion of the Investigator
• There is evidence showing the participant has clinically significant metabolic, gastrointestinal, or other abnormalities that could possibly alter the PK of CFZ
• The participant is diagnosed with cystic fibrosis
• The participant has a prolongation of the QTc interval, \> 450 milliseconds for males and \> 460 milliseconds for females, on the screening ECG
• The participant has abnormal alanine aminotransferase (ALT) and/or aspartate transferase (AST) levels of \> 3 times the upper limit of the laboratory reference range at screening
• The participant is pregnant or is using inadequate contraceptive measures (if applicable)
• The participant is breastfeeding (if applicable)
• The participant has a known or suspected, current drug or alcohol abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the patient
• The participant has as history of allergy/hypersensitivity to CFZ

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud university medical center

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

Related Publications (1)

• Stemkens R, Lemson A, Koele SE, Svensson EM, Te Brake LHM, van Crevel R, Boeree MJ, Hoefsloot W, van Ingen J, Aarnoutse RE. A loading dose of clofazimine to rapidly achieve steady-state-like concentrations in patients with nontuberculous mycobacterial disease. J Antimicrob Chemother. 2024 Dec 2;79(12):3100-3108. doi: 10.1093/jac/dkae309.

  PMID: 39378281 DERIVED

MeSH Terms

Interventions

Clofazimine

Intervention Hierarchy (Ancestors)

Phenazines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Prof. dr. R.E. Aarnoutse, PharmD, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All participants will receive a loading dose regimen of 300 mg clofazimine (CFZ) once daily for 4 weeks and will then continue with a standard dose of 100 mg CFZ once daily until a total 4 months of treatment with CFZ.

Study Record Dates

• First Submitted: March 1, 2022
• First Posted: March 24, 2022
• Study Start: February 14, 2022
• Primary Completion: May 1, 2023
• Study Completion: August 8, 2023
• Last Updated: August 16, 2023

Record last verified: 2022-09

Locations

NL (1)