IMPAACT P1058A: Pharmacokinetic Effects of New Antiretroviral Drugs on Children, Adolescents and Young Adults

Study Overview
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Brief Summary
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This study will examine drug and body interactions in children receiving anti-HIV treatment regimens using new medications. Drug regimens to be examined will feature the medications raltegravir (RAL), maraviroc (MVC), and etravirine (ETV). These drugs will not be provided through the study.

Detailed Description
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Antiretroviral (ARV) medication regimens for children, adolescents and young adults are often prescribed based on drug resistance because of previous treatment history. In order to find an effective regimen, clinicians must often turn to newer drugs before they have been fully tested in adolescent or pediatric clinical trials. One of the first steps in testing these drugs is to assess the drug pharmacokinetics (PK), or interaction between drugs and body. This study, a follow-on protocol to the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) P1058 study, will test children, adolescents and young adults who have already been prescribed treatment regimens with new drugs. The study will examine the PK of medication combinations featuring raltegravir, a new drug in the new ARV class of entry inhibitors (EIs); maraviroc, a new drug in the new class of fusion inhibitors (FIs); and etravirine, a new drug in the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Older medications may also be used to complete these regimens. Participation in this study will last between 1 and 7 weeks and involve at least two clinic visits. The first is a screening and entry visit at which a medical history will be taken and a physical exam and blood test will be completed. The second visit will measure PK of the medications. During this visit, participants will complete the same measures as before-medical history, physical exam, blood test-and then be given a dose of their anti-HIV medication regimen. After receiving the medications, participants will be monitored and give blood samples after 1, 2, 4, 6, 8, and 12 hours. For Groups G, H, I, J, K and L an intensive 12-hour PK study will be scheduled after at least 30 days on the combination of interest. For all Groups, the intensive 12-hour PK study should be performed within 35 days (5 weeks) of screening/entry evaluations. Medications will not be provided through this study. Results of the 12-hour medication monitoring tests will be delivered to participants' physicians within 6 weeks. If, based on these results, a physician decides to change the dosage of a participant's medication, that participant may be asked to complete a second PK visit. Participants must have received the revised dose for at least 14 days before the PK study can be repeated.

Official Title
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IMPAACT P1058A: Intensive Pharmacokinetic Studies of New Classes of Antiretroviral Drug Combinations in Children, Adolescents and Young Adults

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Raltegravir (RAL)
* Drug: Atazanavir (ATV)
* Drug: Ritonavir (RTV)
* Drug: Tenofovir (TDF)
* Drug: Etravirine (ETV)
* Drug: Darunavir (DRV)
* Drug: Maraviroc (MVC)
* Drug: Lopinavir/ritonavir (LPV/r)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Certain laboratory values received within 5 weeks of the date of the screening or entry evaluations HIV infected Stable on the specified antiretroviral (ARV) regimen for 30 days prior to screening and entry. ARVs will not be provided through this protocol. Prescribed one of the regimens described in the study details by clinician on the basis of clinical need (although the availability of drug levels may have been a factor in clinical decision-making). The decision to initiate the regimen must have been solely that of the prescribing physician. On the ARV combination of interest for at least 14 days and within 5 weeks (35 days) of the date of screening results Body surface area (BSA) of at least 0.85 m2 Participants in P1058 Version 1.0 and Version 2.0 who have switched to a regimen specified in the entry criteria are eligible for P1058A. Any licensed formulation that achieves these dosages, but without including a disallowed drug, may be used. Participants who have enrolled in P1058A (Groups G-L) and who subsequently switch to a different regimen specified in the entry criteria are eligible to re-register to a subsequent step of P1058A (re-consent required) Females must agree to use two reliable methods of contraception, one of which must be a barrier method, while taking study medications and for 6 weeks after study testing Documentation of presence of an R5-tropic virus at the start of treatment with maraviroc (MVC) Exclusion Criteria: Pregnant or breastfeeding Hemoglobin level less than 8.5 g/dL Clinical evidence of pancreatitis as defined by moderate clinical symptoms Treatment with any anti-HIV or non-ARV drug that could interact with drugs under pharmacokinetic (PK) study in the 14 days prior to study entry Known allergy, sensitivity, or hypersensitivity to components of two or more study-specified drugs or their formulation

Ages Eligible for Study
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Minimum Age: 6 Years
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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group G<br>Participants will receive a medication regimen including RAL + ATV + RTV. | Drug: Raltegravir (RAL)<br>* 400 mg twice daily (BID)<br>* Other names: Isentress;Drug: Atazanavir (ATV)<br>* 300 mg daily<br>* Other names: Reyataz;Drug: Ritonavir (RTV)<br>* 100 mg daily, dosing by weight in Group I<br>* Other names: Norvir;|
| Group H<br>Participants will receive a medication regimen including RAL + TDF. | Drug: Raltegravir (RAL)<br>* 400 mg twice daily (BID)<br>* Other names: Isentress;Drug: Tenofovir (TDF)<br>* 300 mg daily<br>* Other names: Viread;|
| Group I<br>Participants will receive a medication regimen including ETV + DRV + RTV. | Drug: Ritonavir (RTV)<br>* 100 mg daily, dosing by weight in Group I<br>* Other names: Norvir;Drug: Etravirine (ETV)<br>* 200 mg BID<br>* Other names: Intelence;Drug: Darunavir (DRV)<br>* Dosing by weight<br>* Other names: Prezista;|
| Group J<br>Participants will receive a medication regimen including MVC + ATV + RTV. | Drug: Atazanavir (ATV)<br>* 300 mg daily<br>* Other names: Reyataz;Drug: Ritonavir (RTV)<br>* 100 mg daily, dosing by weight in Group I<br>* Other names: Norvir;Drug: Maraviroc (MVC)<br>* 150 mg BID in groups J and K; 600 mg BID in group L<br>* Other names: Selzentry;|
| Group K<br>Participants will receive a medication regimen including MVC + LPV + RTV. | Drug: Ritonavir (RTV)<br>* 100 mg daily, dosing by weight in Group I<br>* Other names: Norvir;Drug: Maraviroc (MVC)<br>* 150 mg BID in groups J and K; 600 mg BID in group L<br>* Other names: Selzentry;Drug: Lopinavir/ritonavir (LPV/r)<br>* Coformulation of 400 mg lopinavir and 100 mg ritonavir, taken twice daily<br>* Other names: Kaletra;|
| Group L<br>Participants will receive a medication regimen including MVC + RAL + ETV. | Drug: Raltegravir (RAL)<br>* 400 mg twice daily (BID)<br>* Other names: Isentress;Drug: Etravirine (ETV)<br>* 200 mg BID<br>* Other names: Intelence;Drug: Maraviroc (MVC)<br>* 150 mg BID in groups J and K; 600 mg BID in group L<br>* Other names: Selzentry;|
| Arm M<br>Participants will receive a medication regimen of DRV | |
| Arm N<br>Participants will receive a medication regimen of DRV | |
| Arm O<br>Participants will receive a medication regimen of unboosted ATV | |
| Arm P<br>Participants will receive a medication regimen of RPV | |
| Arm Q<br>Participants will receive a medication regimen of RPV | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steady state pharmacokinetics (PK) of raltegravir administered in combination with atazanavir/ritonavir or tenofovir or maraviroc/etravirine to older children, adolescents and young adults |  | Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing | 
| Steady state PK of etravirine administered to older children, adolescents and young adults |  | Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing | 
| Steady state PK of maraviroc administered in combination with atazanavir/ritonavir or lopinavir/ritonavir to older children, adolescents and young adults |  | Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing | 
| Steady state PK of maraviroc (600 mg twice daily [BID]) given in combination with raltegravir and etravirine (a protease inhibitor [PI]-sparing regimen) to older children, adolescents and young adults |  | Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship between Tanner stage and the PK of the regimens of interest in children and adolescents |  | Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing | 
| Relationships between the PK parameters and polymorphisms that may affect the antiretrovirals (ARVs) of interest in older children, adolescents and young adults |  | Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing | 
| Adverse events associated with the ARVs of interest |  | Measured throughout | 
| Steady state PK of darunavir/ritonavir administered to older children, adolescents and young adults |  | Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment, Children, Integrase Inhibitors, Entry Inhibitors, Treatment Experienced