Safety and Effectiveness of Raltegravir (MK-0518) in Treatment-Experienced, HIV-Infected Children and Adolescents

• Grade 3 or 4 adverse events (AEs) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: Yes ]
  
• Termination from treatment due to suspected adverse drug reaction (SADR) attributable to the study medication [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: Yes ]
  
• Death [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: Yes ]
  
• Pharmacokinetic (PK) parameter: area under the curve (AUC) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
  
• PK parameter: maximum plasma concentration (Cmax) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
  
• PK parameter: time to Cmax (Tmax) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
  
• PK parameter: minimum plasma concentration (Cmin) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
  

Integrase is one of three enzymes necessary for HIV replication. Integrase allows for the integration of HIV DNA into the human genome. Currently, no Food and Drug Administration (FDA)-approved drugs exist that prevent integrase from working properly. Raltegravir is a strong and selective inhibitor of HIV integrase. In adults, raltegravir has shown significant antiretroviral activity in clinical trials and is well tolerated. However, there no data exist on the drug's safety and effectiveness in children and adolescents. The purpose of this study is to determine the safety and effectiveness of raltegravir in treatment-experienced, HIV-infected children and adolescents.

This study will take place in two stages. Stage I will last for a minimum of 48 weeks, Stage II will last for 48 weeks, and a long-term follow-up period will last for 5 years from initial exposure (i.e. 48 weeks of treatment plus 4 years of follow-up). Participants will be stratified by age and will be assigned to one of six cohorts. Participants in Cohort 1 will be between the ages of 12 and 18 years and will receive film-coated raltegravir tablets. Participants in Cohort 2A will be between the ages of 6 and 11 years, will weigh at least 25 kg, and will receive film-coated raltegravir tablets. Participants in Cohort 2B will be between the ages of 6 and 11 years and will receive chewable raltegravir tablets. Participants in Cohort 3 will be between the ages of 2 and 5 years and will receive chewable raltegravir tablets. Participants in Cohort 4 will be between the ages of 6 and 23 months and will receive oral granules for suspension. Participants in Cohort 5 will be between the ages of 4 weeks and 5 months and will receive oral granules for suspension.

Enrollment for Stage I of this study will begin with Cohort 1 and progress to the younger cohorts once preliminary dosage has been determined and safety data have been reviewed. When this information has been determined for Cohort 1, Cohorts 2A and 2B will begin enrollment. Once safety and dose data for these cohorts have been reviewed, enrollment into Cohort 3 will begin. Once safety and dose data for Cohort 3 have been reviewed, enrollment into Cohorts 4 and 5 will begin.

Stage I will begin with enrollment of 4 participants into Cohort 1. On Days 5 to 12, an intensive pharmacokinetic (PK) evaluation will be performed. If these PK data are acceptable and safety data at Week 4 are acceptable, Cohort 1 will open to a full enrollment of 10 participants. The purpose of Stage II is to determine long-term safety of raltegravir once a safe and effective dose has been determined. During Stage II of this study, participants will take raltegravir at the dosage determined as safe and effective by the Stage I data. Ten additional participants will be enrolled into each cohort. The remaining 50 to 70 additional participants will be enrolled into Stage II without restriction to age.

Stage I participants who have not had individual dose adjustments due to extreme PK values will have their raltegravir dose changed to the selected Stage II dose once it is determined. Participants will continue to follow the same visit schedule after the dose modification, with an additional safety visit 4 weeks after the dose modification.

There will be between 9 and 16 study visits for participants in this study, with visits occurring during the 48-week raltegravir treatment period and then at least once every 12 months for the next 4 years (for a total of 5 years). At each visit, a physical exam, blood collection, and determination of treatment adherence will occur. At some visits, urine collection and Tanner staging will occur. Select cohorts will undergo a taste evaluation at 1 of 2 visits. Participants in Cohort 3 will be asked to participate in a therapeutic drug monitoring visit in which blood will be collected two times over a 12-hour visit (or, if more convenient, this visit may be completed in 2 separate visits). Participants may be re-registered into the same cohort if a dose change is recommended.