Safety, Tolerability, and Effect of TMC207 and Efavirenz in Healthy Volunteers

NCT00992069 | Completed Phase 1 DMC

• 3 other identifiers: A526710749ACTG A5267
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 5

Brief Summary

Common treatments for tuberculosis (TB) can interfere with certain antiretroviral (ARV) medications used to treat HIV. People whose immune systems are weakened by HIV infection are susceptible to TB, so it is important to find treatments for both that can be given in combination. This study will test the safety of combining a new medication for TB with an already approved HIV medication in healthy adults.

Conditions

Tuberculosis; HIV

Keywords

ARV; Pharmacokinetics; TMC207; Efavirenz

Outcome Measures

Primary Outcomes (2)

• Area under curve (AUC) over 336 hours of TMC207, measured when dosed alone and when dosed together with efavirenz (EFV) 600 mg daily

  Measured at baseline and Days 1 to 15, 28, and 29 to 43

• Signs or symptoms of toxicity ranked Grade 2 or higher, according to the DAIDS adverse event (AE) grading table

  Throughout study

Secondary Outcomes (3)

• Maximum observed plasma or serum concentration (Cmax) and oral clearance (CL/F) of TMC207 and AUC, Cmax, and CL/F of the M2 metabolite of TMC207 when dosed alone and when dosed together with EFV 600 mg daily

  Measured at baseline and Days 1 to 15, 28, and 29 to 43

• AUC over 24 hours, Cmax, Cmin, CL/F, and elimination half-life (T1/2) of EFV and host EFV metabolism genotype status (CYP2B6) obtained from whole blood samples taken at screening

  Measured at baseline and on Day 28

• Correlation between AUC over 24 hours of EFV and AUC over 336 hours of TMC207

  Measured at baseline and Days 1 to 15, 28, and 29 to 43

Study Arms (1)

TMC207 alone and with EFV

EXPERIMENTAL

Participants will receive single-dose TMC207 alone and then single-dose TMC207 with EFV.

Drug: Efavirenz (EFV); Drug: TMC207

Interventions

Efavirenz (EFV) DRUG

Oral dose of 600 mg daily, taken in the evening

Also known as: Sustiva

TMC207 alone and with EFV

TMC207 DRUG

Single oral dose of 400 mg in the morning

TMC207 alone and with EFV

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Females not of reproductive potential, defined as women who have been postmenopausal for at least 24 consecutive months or women who have undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation
• Females who have been surgically sterilized and all males must agree to use contraceptives if participating in sexual activity that could lead to pregnancy while receiving the protocol-specified medications and for 4 weeks after stopping the medication
• Absence of HIV-1 infection, as documented by any licensed enzyme-linked immunosorbent assay (ELISA) test kit, within 21 days prior to study entry
• Estimated creatinine clearance of more than 50 ml/min, within 21 days prior to study entry, calculated by the Cockcroft-Gault method
• Laboratory test results obtained within 21 days prior to entry, including negative pregnancy test, negative hepatitis B and C tests, and certain blood values

You may not qualify if:

• Use of any prescription medication known to inhibit or induce CYP3A metabolizing enzymes within 30 days prior to entry
• Planned use during the study, from day 0 through the last PK blood draw, of any of the following: prescription medication(s), herbal supplement(s), nutritional supplement(s), or over-the-counter medication(s). Multivitamins and acetaminophen, up to 650 mg every 6 hours as an analgesic, are permitted.
• Hospitalization for any reason, pharmacotherapy for serious illness, or use of any prescription medication(s) within 14 days prior to study entry
• Receipt of any investigational study drug within 21 days prior to study entry
• Known allergy, sensitivity, or hypersensitivity to EFV or TMC207 or components of their formulations, including cyclodextrin allergy
• Significant previous or active history of cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, or immunologic disease(s), as determined by the site investigator. This is inclusive of chronic illnesses or gastrointestinal conditions that may affect drug absorption, etc. Additionally, any medical condition that, in the opinion of the site investigator, would interfere with the volunteer's ability to participate in the protocol will exclude participation.
• Active illicit drug use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
• Suspicion of active tuberculosis (TB) by the site investigator
• Inability to abstain from alcoholic beverages, grapefruit, and grapefruit juice for the duration of the study
• For smokers, inability to smoke 5 cigarettes per day or less for the duration of the study
• Breastfeeding
• Electrocardiogram (ECG) showing first-degree or greater heart block or QT interval (QTc) greater than 440 ms within 21 days prior to study entry. First-degree heart block is defined as PR interval greater than 200 ms.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (5)

Ucsf Aids Crs

San Francisco, California, 94110, United States

Location

Johns Hopkins Adult AIDS CRS

Baltimore, Maryland, 21287, United States

Location

Unc Aids Crs

Chapel Hill, North Carolina, 27514, United States

Location

The Ohio State Univ. AIDS CRS

Columbus, Ohio, 43210, United States

Location

Vanderbilt Therapeutics CRS

Nashville, Tennessee, 37232-2582, United States

Location

Related Publications (3)

• Goldman RC, Plumley KV, Laughon BE. The evolution of extensively drug resistant tuberculosis (XDR-TB): history, status and issues for global control. Infect Disord Drug Targets. 2007 Jun;7(2):73-91. doi: 10.2174/187152607781001844.

  PMID: 17970220 BACKGROUND

• McIlleron H, Meintjes G, Burman WJ, Maartens G. Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution inflammatory syndrome. J Infect Dis. 2007 Aug 15;196 Suppl 1:S63-75. doi: 10.1086/518655.

  PMID: 17624828 BACKGROUND

• Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, Mc Neeley DF. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405. doi: 10.1056/NEJMoa0808427.

  PMID: 19494215 BACKGROUND

MeSH Terms

Conditions

Tuberculosis

Interventions

efavirenz; bedaquiline

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Kelly Dooley, MD

  Johns Hopkins University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2009
• First Posted: October 8, 2009
• Study Start: December 1, 2009
• Primary Completion: December 1, 2010
• Study Completion: December 1, 2010
• Last Updated: November 1, 2021

Record last verified: 2021-10

Locations

US (5)