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 ]

• Grade 3 or 4 adverse events [ Time Frame: throughout the study ]
• Termination from treatment due to suspected drug reaction attributable to the study medication [ Time Frame: throughout the study ]
• Pharmacokinetic parameters [ Time Frame: throughout the study ]

• HIV viral load [ Time Frame: throughout the study ]
• CD4 count and percentage [ Time Frame: throughout the study ]
• Genotypic and phenotypic resistance measures [ Time Frame: Weeks 12, 24, 36, and 48 ]

Integrase is a protein that HIV needs in order to reproduce in the human body. Raltegravir is a new drug that prevents integrase from working properly. This drug has been tested for safety and effectiveness in adults but not in children. The purpose of this study is to determine the safety and effectiveness of raltegravir in treatment-experienced HIV-infected children and adolescents.

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.

• Drug: Raltegravir (MK-0518)
  Dosage and formulation are dependent on weight and age
  Other Name: Isentress
• Drug: Raltegravir (MK-0518)
  400-mg tablet taken orally twice daily
  Other Name: Isentress
• Drug: Raltegravir (MK-0518)
  6 mg/kg with a maximum dose of 300 mg every 12 hours, tablets taken orally twice daily
  Other Name: Isentress

• Experimental: Cohort 1
  Participants between the ages of 12 and 18 years; receiving film-coated raltegravir tablets.
  Intervention: Drug: Raltegravir (MK-0518)
• Experimental: Cohort 2A
  Participants between the ages of 6 and 11 years, weighing at least 25 kg; receiving film-coated raltegravir tablets.
  Intervention: Drug: Raltegravir (MK-0518)
• Experimental: Cohort 2B
  Participants between the ages of 6 and 11 years; receiving chewable raltegravir tablets.
  Intervention: Drug: Raltegravir (MK-0518)
• Experimental: Cohort 3
  Participants between the ages of 2 and 5 years; receiving chewable raltegravir tablets.
  Intervention: Drug: Raltegravir (MK-0518)
• Experimental: Cohort 4
  Participants between the ages of 6 and 23 months; receiving oral granules for suspension.
  Intervention: Drug: Raltegravir (MK-0518)
• Experimental: Cohort 5
  Participants between the ages of 4 weeks and 5 months; receiving oral granules for suspension.
  Intervention: Drug: Raltegravir (MK-0518)

• Cooper D, Gatell J, Rockstroh J, Katlama C, Yeni P, Lazzarin A, Chen J, Isaacs R, Teppler H, Nguyen B, and for the BENCHMRK-1 Study Group. Results of BENCHMRK-1, a Phase III Study Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 105aLB, 2007.
• Dayam R, Al-Mawsawi LQ, Neamati N. HIV-1 Integrase Inhibitors : An Emerging Clinical Reality. Drugs R D. 2007;8(3):155-68.
• Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, Liporace R, Schwartz R, Isaacs R, Gilde LR, Wenning L, Zhao J, Teppler H. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006 Dec 15;43(5):509-15. Erratum in: J Acquir Immune Defic Syndr. 2007 Apr 1;44(4):492.
• Nair V, Chi G. HIV integrase inhibitors as therapeutic agents in AIDS. Rev Med Virol. 2007 May 15; [Epub ahead of print]

Inclusion Criteria for All Participants:

• HIV infected
• On steady antiretroviral therapy regimen for at least 12 weeks prior to study entry
• HIV viral load of 1,000 copies/mL or greater at study entry
• Parent or legal guardian willing to provide informed consent, if necessary
• Willing to use acceptable forms of contraception
• Willing to be re-registered within same cohort if a dose change is recommended

Exclusion Criteria for All Participants:

• Grade 3 or higher abnormal laboratory values
• Pancreatitis
• Lactic acidosis within 3 months prior to study entry
• Diagnosis of new Stage C criteria or opportunistic or bacterial infection within 30 days prior to study screening
• Prior treatment with another experimental HIV integrase inhibitor
• Immunosuppressive therapy within 30 days prior to study entry. Participants taking short courses of corticosteroids are not excluded.
• Current or anticipated use of phenobarbital, phenytoin, rifampin, and investigational agents, or use of certain medications. More information is available in the protocol.
• History of cancer
• Active hepatitis B or C virus infection
• Consume breastmilk from HIV-infected person
• Planning to relocate during study
• Any clinically significant diseases or findings that, in the opinion of the investigator, would interfere with the study
• Current or past participation in an investigational study with a compound or device that is not commercially available within 30 days of study entry
• Pregnancy or breastfeeding. Infants who are breastfeeding are allowed to enroll.

Exclusion Criteria for Stage I Participants:

• Use of atazanavir, tenofovir, or tipranavir prior to the intensive PK testing

Exclusion Criteria for Stage II Participants Taking Atazanavir as Part of Their Background Regimen:

• Total bilirubin of Grade 4 or higher within 30 days of study entry
• Direct bilirubin or concurrent transaminase greater than 1.5 x the upper limit of normal with symptoms within 30 days of study entry