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Ensayos clínicos

Ensayos clínicos

Efavirenz in HIV-infected and HIV/TB Co-infected Children

Patrocinador(es) del estudio: National Institute of Allergy and Infectious Diseases (NIAID)
Números de identificación: NCT00802802, IMPAACT P1070
  • Inscripciones abiertas

Propósito del estudio

Efavirenz (EFV) is an anti-HIV medicine that is commonly used to treat HIV infection in adults and children older than 3 years of age. This study is being conducted to look at the safety of EFV, blood levels of EFV, genetic factors that may affect blood levels of EFV, and how easy it is for infants and young children to take and tolerate EFV. This information will help recommend the best doses of EFV for children younger than 3 years of age.

Afección:Fase:
Infecciones por el VIH
Tuberculosis
Fase 1

Detalles del estudio

An increasing number of children in resource-limited countries require treatment for both

HIV and tuberculosis (TB); however, the options for antiretroviral therapy (ART) that is

compatible with concurrent rifampin-containing anti-TB therapy are limited. As a result,

treatment of HIV/TB coinfected patients remains difficult with multiple drug interactions,

very high pill burdens, overlapping toxicities, and possible immune reconstitution affecting

treatment outcomes.



The use of efavirenz (EFV) in adults and older children has allowed them to maintain their

non-nucleoside reverse transcriptase inhibitor (NNRTI) backbone while receiving TB therapy

including rifampin. In younger children with TB/HIV coinfection, the first-line treatment

recommendation has been the triple nucleoside reverse transcriptase inhibitor (NRTI)

regimen. However, this regimen has been shown to be less effective than an EFV plus

NNRTI-based regimen. In addition, triple NRTI regimens in resource-limited settings are

costly and have limited data in patients with TB, and monitoring for drug-related

hypersensitivity reactions is difficult. All of these factors make EFV an attractive agent

for use in HIV infected pediatric patients with and without TB coinfection. This study is

designed to provide necessary Phase I and II data on the safety, tolerance, and

pharmacokinetics of EFV when administered as opened capsules to pediatric patients younger

than 3 years of age, with and without concomitant rifampin-containing anti-TB therapy.



This study will have two study cohorts, which will enroll at the same time. Participants in

Cohort I will be HIV infected infants without TB coinfection who are eligible for initiation

of ART. Cohort I will be administered EFV and two NRTIs. EFV dosage will range from 200 mg

to 600 mg once daily, based on weight. Treatment and study will last for 24 weeks.



Participants in Cohort II will be HIV/TB coinfected infants who are eligible for ART and

have been treated with and tolerated a rifampin-containing anti-TB treatment regimen for at

least 2 weeks prior to enrollment. Participants in Cohort II will be followed while taking

both rifampin-containing anti-TB and EFV therapy for up to 24 weeks; participants unable to

obtain EFV capsules from in-country sources at the conclusion of the study may remain on the

study longer than 24 weeks until discontinuing anti-TB therapy. An estimated 12 to 15 of

these participants from Cohort II will be followed every 4 weeks on study and provided study

drug (EFV) until completion of TB treatment for up to 36 weeks study duration.



Participants in both Cohorts will be stratified based on age. One stratification will

include children 3 months to younger than 24 months of age, and the second stratification

will include children 24 months to younger than 36 months of age. Participants will then be

further stratified by cytochrome P450 genotype. All participants will be treated with an

EFV-based ART regimen using the capsule formulation of EFV and two NRTIs. EFV capsules will

be opened into a small amount of compatible, familiar, and locally available food or liquid

(e.g., formula, expressed breast milk, mashed banana).



Two weeks after the start of study treatment, intensive pharmacokinetic sampling prior to

the observed dose at 2, 4, 8, 12, and 24 hours post-dose will be performed. Dried blood

spots (DBS) will be prepared from each sample and subsequently analyzed; plasma samples will

be stored as well. A urine specimen will also be obtained 3 to 5 hours post-dose.



This study is being conducted to look at the safety of EFV, blood levels of EFV, genetic

factors that may affect blood levels of EFV, and how easy it is for infants and young

children to take and tolerate EFV when it is given as a capsule that is opened and sprinkled

in food. This information will help recommend the best doses of EFV for children younger

than 3 years of age.An increasing number of children in resource-limited countries require treatment for both

HIV and tuberculosis (TB); however, the options for antiretroviral therapy (ART) that is

compatible with concurrent rifampin-containing anti-TB therapy are limited. As a result,

treatment of HIV/TB coinfected patients remains difficult with multiple drug interactions,

very high pill burdens, overlapping toxicities, and possible immune reconstitution affecting

treatment outcomes.



The use of efavirenz (EFV) in adults and older children has allowed them to maintain their

non-nucleoside reverse transcriptase inhibitor (NNRTI) backbone while receiving TB therapy

including rifampin. In younger children with TB/HIV coinfection, the first-line treatment

recommendation has been the triple nucleoside reverse transcriptase inhibitor (NRTI)

regimen. However, this regimen has been shown to be less effective than an EFV plus

NNRTI-based regimen. In addition, triple NRTI regimens in resource-limited settings are

costly and have limited data in patients with TB, and monitoring for drug-related

hypersensitivity reactions is difficult. All of these factors make EFV an attractive agent

for use in HIV infected pediatric patients with and without TB coinfection. This study is

designed to provide necessary Phase I and II data on the safety, tolerance, and

pharmacokinetics of EFV when administered as opened capsules to pediatric patients younger

than 3 years of age, with and without concomitant rifampin-containing anti-TB therapy.



This study will have two study cohorts, which will enroll at the same time. Participants in

Cohort I will be HIV infected infants without TB coinfection who are eligible for initiation

of ART. Cohort I will be administered EFV and two NRTIs. EFV dosage will range from 200 mg

to 600 mg once daily, based on weight. Treatment and study will last for 24 weeks.



Participants in Cohort II will be HIV/TB coinfected infants who are eligible for ART and

have been treated with and tolerated a rifampin-containing anti-TB treatment regimen for at

least 2 weeks prior to enrollment. Participants in Cohort II will be followed while taking

both rifampin-containing anti-TB and EFV therapy for up to 24 weeks; participants unable to

obtain EFV capsules from in-country sources at the conclusion of the study may remain on the

study longer than 24 weeks until discontinuing anti-TB therapy. An estimated 12 to 15 of

these participants from Cohort II will be followed every 4 weeks on study and provided study

drug (EFV) until completion of TB treatment for up to 36 weeks study duration.



Participants in both Cohorts will be stratified based on age. One stratification will

include children 3 months to younger than 24 months of age, and the second stratification

will include children 24 months to younger than 36 months of age. Participants will then be

further stratified by cytochrome P450 genotype. All participants will be treated with an

EFV-based ART regimen using the capsule formulation of EFV and two NRTIs. EFV capsules will

be opened into a small amount of compatible, familiar, and locally available food or liquid

(e.g., formula, expressed breast milk, mashed banana).



Two weeks after the start of study treatment, intensive pharmacokinetic sampling prior to

the observed dose at 2, 4, 8, 12, and 24 hours post-dose will be performed. Dried blood

spots (DBS) will be prepared from each sample and subsequently analyzed; plasma samples will

be stored as well. A urine specimen will also be obtained 3 to 5 hours post-dose.



This study is being conducted to look at the safety of EFV, blood levels of EFV, genetic

factors that may affect blood levels of EFV, and how easy it is for infants and young

children to take and tolerate EFV when it is given as a capsule that is opened and sprinkled

in food. This information will help recommend the best doses of EFV for children younger

than 3 years of age.

Criterios de inclusión

    :
    • HIV infected
    • Treatment eligible as defined by country-specific guidelines
    • Able to swallow the contents of EFV as opened capsules in food or liquid vehicle
    • Parent or guardian able and willing to provide informed consent as designated by
    country-specific guidelines and (participant) willing to be followed at clinical site -- Cohort II only
    • Clinically diagnosed with HIV/TB coinfection and requiring rifampin-containing
    therapy, in the clinical judgment of the site investigator
    • Participant is tolerating a rifampin-containing antituberculosis drug regimen for at
    least 2 weeks prior to study entry
    • Participant plans to continue antituberculosis and study treatment for at least 16
    weeks from initiation of study treatment

Criterios de exclusión

    :
    • Known hypersensitivity to any component of EFV capsule formulation
    • Severe malnutrition. More information on this criterion can be found in the study
    protocol.
    • Documented receipt of nevirapine (NVP) or efavirenz (EFV) therapy within the previous
    6 months, including single-dose NVP for prevention of mother-to-child transmission of HIV (PMTCT). Infants or children who already have been receiving NVP-based ART for at least 24 weeks, are virally suppressed and are about to initiate rifampin-based anti-TB treatment can be considered for enrollment in Cohort II if they meet all other eligibility criteria including requirement for 2 positive HIV assays and upon approval by the protocol chairs. More information on this criterion can be found in the protocol.
    • Infants whose mothers have documentation of receiving NVP or EFV as part of PMTCT
    unless they meet criteria under the exception above NOTE: If the infant was born prior to the mother's HIV diagnosis OR if the study nurse receives what he or she considers to be a highly reliable verbal report that the mother and infant did not receive NVP, the participant can be enrolled.
    • Infants younger than or equal to 6 months of age whose mothers have documentation of
    receiving NVP or EFV as part of PMTCT. More information on this criterion can be found in the study protocol.
    • Grade 2 or higher aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
    at screening
    • Grade 3 or higher laboratory toxicity at screening
    • Higher than Grade 3 clinical toxicity at screening
    • Acute, serious infections requiring active treatment, such as Pneumocystis jiroveci
    pneumonia (PCP), cryptococcal meningitis, and tuberculosis (applicable to Cohort I only). Prophylaxis against opportunistic infections, including isoniazid, will be allowed.
    • Chemotherapy for active malignancy
    • Active central nervous system (CNS) infection, such as TB meningitis or cryptococcal
    meningitis, and receiving primary therapy
    • Use of abacavir as a background NRTI during the first 6 weeks on study treatment
    • Breastfeeding infants whose mothers are receiving or plan to initiate efavirenz
    (EFV)-based HAART within 3 weeks following study entry. Note: Breastfeeding infants whose mothers are receiving postpartum nevirapine as part of HAART as well as those whose mothers will begin an EFV-based HAART regimen 3 weeks or more after enrollment are not excluded from the study.

Centros de estudio/contactos

Botswana

    Gaborone Prevention/Treatment Trials CRS, Gaborone, Botswana

Retirado

    Molepolole Prevention/Treatment Trials CRS (Molepolole PTT CRS), Molepolole, Botswana

Retirado

Maharashtra

    BJ Medical College CRS, Pune, Maharashtra, 411001, India

             Nishi Suryavanshi, PhD, 91-20-26052419, nishi@jhumitpune.com

Inscripciones abiertas

Gauteng

    Soweto IMPAACT CRS, Johannesburg, Gauteng, 2001, South Africa

             Nasreen Abrahams, 27-11-9899742, abrahamsn@phru.co.za

Inscripciones abiertas

    Shandukani Research CRS, Johannesburg, Gauteng, 2001, South Africa

             Hermien Gous, PharmD, 27-11-3585502, hgous@wrhi.ac.za

Inscripciones abiertas

KwaZulu-Natal

    Durban Paediatric HIV CRS, Durban, KwaZulu-Natal, 4001, South Africa

             Rosie Mngqibisa, MBBS, 27-31-2604669, mngqibisa@ukzn.ac.za

Inscripciones abiertas

    Stellenbosch Univ. CRS, Cape Town, KwaZulu-Natal, 7505, South Africa

             Joan Coetzee, 27-21-9384157, joan@sun.ac.za

Inscripciones abiertas

    Makerere University- JHU Research Collaboration {MUJHU CARE LTD} CRS, Kampala, KwaZulu-Natal, 7505, Uganda

             Carolyne Onyango, MD, 256-414-541044, carolonyango@mujhu.org

Inscripciones pendientes

    George Clinic CRS, Lusaka, KwaZulu-Natal, 10101, Zambia

             Felistas Mbewe, 260-966828341, felistas.mbewe@cidrz.org

Inscripciones pendientes

    UZ-Parirenyatwa CRS, Harare, KwaZulu-Natal, 10101, Zimbabwe

             Rachel Mahachi, 263-4-701356, rmahachi@uzcrc.co.zw

Inscripciones abiertas

Actualizado: 15 de junio del 2010

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