Safety and Effectiveness of Emtricitabine, Efavirenz, and Didanosine in HIV Infected Children Who Have Taken Few or No Anti-HIV Drugs

Study Overview
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Brief Summary
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Treatment of HIV-infected patients involves combining drugs from different classes of anti-HIV drugs. One preferred regimen for adults is 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 protease inhibitor (PI). For children, this regimen may be too complicated or the drugs may be too difficult to take by mouth. The purpose of this study was to determine the long-term safety and effectiveness of daily didanosine (ddI), efavirenz (EFV), and emtricitabine (FTC) in pediatric patients who had taken few or no anti-HIV drugs.

Detailed Description
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Anti-HIV treatment options are limited for pediatric patients because combination therapies recommended for adults may not be appropriate for children or adolescents. Few PIs are available in formulations appropriate for pediatric patients, and complex dosing schedules and food requirements may be detrimental to treatment adherence. A once-daily regimen of the NRTIs ddI and FTC and the nonnucleoside reverse transcriptase inhibitor (NNRTI) EFV has been shown safe and well tolerated in adults. This Phase I/II open label study evaluated the long-term safety and efficacy of a ddI, FTC, and EFV regimen in pediatric patients. All study patients were either absolutely naive to antiretroviral therapy or had received less than or equal to 56 days perinatal prophylaxis or less than 7 days of cumulative antiretroviral therapy prior to study entry, and had a plasma screening plasma HIV-1 RNA levels >= 5000 copies/mL. This study was written to characterize the disposition of FTC, determine the PK data for ddI-EC QD, comparing the bio-availability of the enteric coated formulation with ddI pediatric powder for oral solution, and to provide insight into the age related pharmacokinetics differences observed in this and other studies. HIV infected pediatric patients were stratified into three age Groups: Group 1: 90 days to <3 years of age; Group 2: 3 years to 12 years of age (inclusive); and Group 3: 13 to 21 years of age (inclusive). The initial study doses for the triple drug regimen was FTC, 6 mk/kg up to a maximum of 200 mg once daily, for EFV, the dose for age Group 1 was determined in PACTG 382 and dose adjusted for body size, and the doses for age Groups 2 and 3 were defined in the dosing table of the protocol of up to a maximum of 600 mg once daily as a capsule or 720 mg as an oral solution; for ddI, 240 mg/m2 up to a maximum of 400 mg once daily. Comparison of age groups was not required as per the protocol. Patients were followed for a maximum of 192 weeks; all patients were to receive ddI, EFV, and FTC together once daily. Study visits occurred at study entry, Weeks 2,and 4, and every 4 weeks thereafter. Blood collection, medical history assessment, and a physical exam occurred at all visits; urine collection occurred at selected visits. Intensive pharmacokinetic (PK) studies was done at Weeks 2 and 12 to determine if dose adjustments were required for any of the drugs. If virologic failure was determined, PK studies was repeated 4 weeks after adjustments in therapy. Parents or guardians were asked to complete treatment adherence questionnaires at some visits. Some patients were also asked to participate in an additional PK study after Week 16 or week 96.

Official Title
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An Open-Label Study to Evaluate the Safety, Tolerance, Antiviral Activity, and Pharmacokinetics of Emtricitabine in Combination With Efavirenz and Didanosine in a Once-Daily Regimen in HIV Infected, Antiretroviral Therapy Naive or Very Limited Antiretroviral Exposed Pediatric Subjects

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Didanosine (ddI)
* Drug: Efavirenz (EFV)
* Drug: Emtricitabine (FTC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV infected Antiretroviral naive OR have received no more than 56 days of drugs to prevent mother-to-child transmission of HIV OR have received less than 7 total days of antiretroviral therapy Viral load of 5,000 copies/ml or more Any Center for Disease Control (CDC) classification and immune status Able to swallow study medications Parent or guardian willing to provide informed consent, if applicable Willing to use acceptable forms of contraception female subjects of childbearing potential with a negative serum beta human chronic gonadotropin Exclusion Criteria: Allergic to study medications or their formulations Kidney disease Positive for hepatitis B or C Acute opportunistic infection (OI) or bacterial infection requiring treatment at study entry Taking drugs to treat tuberculosis Taking anti-HIV drugs other than those included in this study Hemoglobin >= grade 3 at screening Absolute Neutrophil counts >= grade 2 at screening Platelets >= Grade 2 at screening Bilirubin >= Grade 2 at screening SGOT (AST), SGPT(ALT) >= Grade 2 at screening Non-fasting triglycerides >= Grade 2 at screening. Confirmed by a 2nd determination >=100 mg/dl at fasting state Pancreatic amylase or total amylase+ lipase >= Grade 2 at screening Taking any investigational drugs Anti-cancer drugs within 1 year of study screening Serious medical event within 21 days of study screening Active or history of pancreatitis Require certain medications. Patients requiring short courses of steroids (less than 14 days) for asthma are not excluded. Active or history of significant peripheral neuropathy Difficulty with food or severe chronic diarrhea within 30 days before study entry Unable to eat at least 1 meal per day (or to feed at least 3 times per day, for infants) because of chronic nausea, vomiting, swallowing problems, or stomach upset Unable to swallow oral medications Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 90 Days
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Age Group 1: 90 days to < 3 years of age (FTC, EFV, ddI)<br>Emtricitabine (FTC), Efavirenz (EFV) and Didanosine (ddI) together once daily | Drug: Didanosine (ddI)<br>* Antiretroviral Didanosine (ddI) : 240 mg/m^2 up to a maximum of 400 mg once daily<br>* Other names: Videx, Videx EC;Drug: Efavirenz (EFV)<br>* Antiretroviral For Age Group 1 Efavirenz (EFV): dose adjusted for body size and for Age Groups 2 and 3 Efavirenz (EFV): up to a maximum of 600 mg once daily as a capsule ot 720 mg as an oral solution<br>* Other names: Sustiva;Drug: Emtricitabine (FTC)<br>* Antiretroviral Emtricitabine (FTC): 6 mg/Kg up to a maximum of 200 mg once daily<br>* Other names: Emtriva;|
| Experimental: Age Group 2: 3 to 12 years of age (FTC, EFV, ddI)<br>Emtricitabine (FTC), Efavirenz (EFV) and Didanosine (ddI) together once daily | Drug: Didanosine (ddI)<br>* Antiretroviral Didanosine (ddI) : 240 mg/m^2 up to a maximum of 400 mg once daily<br>* Other names: Videx, Videx EC;Drug: Efavirenz (EFV)<br>* Antiretroviral For Age Group 1 Efavirenz (EFV): dose adjusted for body size and for Age Groups 2 and 3 Efavirenz (EFV): up to a maximum of 600 mg once daily as a capsule ot 720 mg as an oral solution<br>* Other names: Sustiva;Drug: Emtricitabine (FTC)<br>* Antiretroviral Emtricitabine (FTC): 6 mg/Kg up to a maximum of 200 mg once daily<br>* Other names: Emtriva;|
| Experimental: Age Group 2: 13 to 21 years of age (FTC, EFV, ddI)<br>Emtricitabine (FTC), Efavirenz (EFV) and Didanosine (ddI) together once daily | Drug: Didanosine (ddI)<br>* Antiretroviral Didanosine (ddI) : 240 mg/m^2 up to a maximum of 400 mg once daily<br>* Other names: Videx, Videx EC;Drug: Efavirenz (EFV)<br>* Antiretroviral For Age Group 1 Efavirenz (EFV): dose adjusted for body size and for Age Groups 2 and 3 Efavirenz (EFV): up to a maximum of 600 mg once daily as a capsule ot 720 mg as an oral solution<br>* Other names: Sustiva;Drug: Emtricitabine (FTC)<br>* Antiretroviral Emtricitabine (FTC): 6 mg/Kg up to a maximum of 200 mg once daily<br>* Other names: Emtriva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Who Developed Grade 3 or 4 Adverse Events Attributed to the Study Treatment. | Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009, which is available on the RCC website at (http://rcc.tech-res.com/). Adverse Events of Grade 3 or 4 laboratory abnormalities or signs and symptoms that were judged by the study team to be possibly or probably related to the study treatment. Comparisons between age groups were not required as per protocol. | At study entry, weeks 2 and 4, every 4 weeks up to week 96 and every 6 weeks thereafter for Group 1 participants and at study entry, weeks 2 and 4, every 4 weeks up to week 144 and every 12 weeks thereafter for Groups 2 and 3 | 
| Proportion of Participants With Suppression of HIV Viral Load to Less Than 400 Copies/ml at Week 16 | Proportion was calculated as number of participants with HIV-1 RNA <= 400 copies/ml relative to the number of participants with HIV-1 RNA measured at that time point. | At week 16 | 
| Proportion of Participants With Suppression of HIV Viral Load to Less Than 50 Copies/ml at Week 16 | Proportion was calculated as number of participants with HIV-1 RNA <= 50 copies/ml relative to the number of participants with HIV-1 RNA measured at that time point. | At week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Didanosine, Drug Therapy, Combination, Drug Administration Schedule, Reverse Transcriptase Inhibitors, Anti-HIV Agents, Pharmacokinetics, Deoxycytidine, Efavirenz, Treatment Naive