Safety, Tolerability, and Effect of TMC207 and Efavirenz in Healthy Volunteers
A Phase I, Safety, Tolerability, and Pharmacokinetic Interaction Study of Single-Dose TMC207 and Efavirenz in Healthy Volunteers
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
Tuberculosis (TB) is the second most deadly infectious disease after HIV. Multidrug-resistant TB (MDR-TB) has emerged as a worldwide epidemic, limiting treatment options. HIV infected people with suppressed immune systems are particularly susceptible to TB, and TB is the leading cause of death among people with HIV. Treating people infected with both HIV and TB is particularly problematic because rifamycins, the drug class usually used to treat TB, lower the effectiveness of certain anti-HIV medications. Studies of pharmacokinetics (PK), the interactions between drugs and body, are needed to determine which anti-TB and anti-HIV medications can be safely and effectively combined. This study will examine TMC207, a new anti-TB medication with the potential to shorten TB treatment time, combined with efavirenz (EFV), an antiretroviral (ARV) medication used in many first-line treatment regimens for HIV. The study will test PK and safety of this combination in healthy volunteers.
Participation in this study will last 49 days. At entry, participants will complete basic assessments, including taking a medical history and completing a physical exam, an eye exam, an electrocardiogram (ECG) to measure heartbeat, a pregnancy test, and a blood test. Certain behaviors and substances will be prohibited during the study, including consuming grapefruit, alcohol, or caffeine (on PK visit days); taking nutritional supplements, over-the-counter herbal medicines, and certain medicines and drugs from other studies; and excessive smoking. Participants will also be asked to keep a medication diary to record all medications they take during the study.
All participants will receive study medications on the same schedule: a single dose of TMC207 on Days 1 and 29, and daily dosing of EFV on Days 15 to 43.
Participants will complete two PK visits, one from Days 1 to 3, and one from Days 28 to 31. During PK visits, participants will have their vital signs checked and undergo an ECG, and they may also complete a limited physical exam, give a medication history, and report on symptoms. They will have multiple blood samples taken via a catheter left in place for the 3-day visit. Blood samples will be taken before receiving TMC207; 1, 2, 3, 4, 5, 6, 8, and 12 hours after receiving TMC207; and again on the mornings of Days 2 and 3.
Participants will complete six outpatient visits over the 11 days following each PK visit and one outpatient visit on Day 21, between PK visits. At outpatient visits participants will complete a blood draw and may complete a limited physical exam and medical history, record symptoms, and review their medication diaries.
On Day 49 participants will complete their last study visit, repeating many of the assessments from baseline testing. In the case of side effects or abnormal blood tests, participants may be monitored longer for safety reasons.
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 1
Contactos y Ubicaciones
Ubicaciones de estudio
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California
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San Francisco, California, Estados Unidos, 94110
- Ucsf Aids Crs
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Maryland
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Baltimore, Maryland, Estados Unidos, 21287
- Johns Hopkins Adult AIDS CRS
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North Carolina
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Chapel Hill, North Carolina, Estados Unidos, 27514
- Unc Aids Crs
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Ohio
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Columbus, Ohio, Estados Unidos, 43210
- The Ohio State Univ. AIDS CRS
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Tennessee
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Nashville, Tennessee, Estados Unidos, 37232-2582
- Vanderbilt Therapeutics CRS
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: N / A
- Modelo Intervencionista: Asignación cruzada
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
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Experimental: TMC207 alone and with EFV
Participants will receive single-dose TMC207 alone and then single-dose TMC207 with EFV.
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Oral dose of 600 mg daily, taken in the evening
Otros nombres:
Single oral dose of 400 mg in the morning
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Periodo de tiempo |
|---|---|
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Area under curve (AUC) over 336 hours of TMC207, measured when dosed alone and when dosed together with efavirenz (EFV) 600 mg daily
Periodo de tiempo: Measured at baseline and Days 1 to 15, 28, and 29 to 43
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Measured at baseline and Days 1 to 15, 28, and 29 to 43
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Signs or symptoms of toxicity ranked Grade 2 or higher, according to the DAIDS adverse event (AE) grading table
Periodo de tiempo: Throughout study
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Throughout study
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Medidas de resultado secundarias
Medida de resultado |
Periodo de tiempo |
|---|---|
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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
Periodo de tiempo: Measured at baseline and Days 1 to 15, 28, and 29 to 43
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Measured at baseline and Days 1 to 15, 28, and 29 to 43
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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
Periodo de tiempo: Measured at baseline and on Day 28
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Measured at baseline and on Day 28
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Correlation between AUC over 24 hours of EFV and AUC over 336 hours of TMC207
Periodo de tiempo: Measured at baseline and Days 1 to 15, 28, and 29 to 43
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Measured at baseline and Days 1 to 15, 28, and 29 to 43
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Colaboradores e Investigadores
Investigadores
- Silla de estudio: Kelly Dooley, MD, Johns Hopkins University
Publicaciones y enlaces útiles
Publicaciones Generales
- 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.
- 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.
- 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.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Finalización primaria (Actual)
Finalización del estudio (Actual)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Infecciones
- Infecciones bacterianas
- Infecciones bacterianas y micosis
- Infecciones por bacterias grampositivas
- Infecciones por Actinomycetales
- Infecciones por micobacterias
- Tuberculosis
- Mecanismos moleculares de acción farmacológica
- Agentes antiinfecciosos
- Agentes Antivirales
- Inhibidores de la transcriptasa inversa
- Inhibidores de la síntesis de ácidos nucleicos
- Inhibidores de enzimas
- Inhibidores de enzimas del citocromo P-450
- Inductores de enzimas de citocromo P-450
- Inductores de citocromo P-450 CYP3A
- Inductores de citocromo P-450 CYP2B6
- Inhibidores del citocromo P-450 CYP2C9
- Inhibidores del citocromo P-450 CYP2C19
- Efavirenz
Otros números de identificación del estudio
- A5267
- 10749 (Identificador de registro: DAIDS ES)
- ACTG A5267
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .
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