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

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00485264

Purpose

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.

Condition	Intervention	Phase
HIV Infections	Drug: Raltegravir (MK-0518)	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Parallel Assignment, Safety/Efficacy Study
Official Title:	A Phase I/II, Multicenter, Open-Label, Noncomparative Study of the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Group to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiretroviral Activity of Raltegravir (Isentress, MK-0518) in HIV-1 Infected Children and Adolescents

Resource links provided by NLM:

MedlinePlus related topics: AIDS

Drug Information available for: Raltegravir

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Termination from treatment due to suspected drug reaction attributable to the study medication [ Time Frame: Through Week 48 ] [ Designated as safety issue: Yes ]
Grade 3 or 4 adverse events [ Time Frame: Through Week 48 ] [ Designated as safety issue: Yes ]
Pharmacokinetic parameters [ Time Frame: Through Week 48 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

HIV viral load [ Time Frame: Through Week 48 ] [ Designated as safety issue: No ]
CD4 count and percentage [ Time Frame: Through Week 48 ] [ Designated as safety issue: No ]
Genotypic and phenotypic resistance measures [ Time Frame: Weeks 12, 24, 36, and 48 ] [ Designated as safety issue: No ]

Estimated Enrollment:	140
Study Start Date:	September 2007
Estimated Study Completion Date:	August 2011
Estimated Primary Completion Date:	August 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Cohort 1: Experimental Participants between the ages of 12 and 18; receiving raltegravir tablets.	Drug: Raltegravir (MK-0518) 400 mg tablet taken orally twice daily
Cohort 2A: Experimental Participants between the ages 6 and 11; receiving raltegravir tablets.	Drug: Raltegravir (MK-0518) 400 mg tablet taken orally twice daily
Cohort 2B: Experimental Participants between the ages 6 and 11; receiving chewable raltegravir tablets.	Drug: Raltegravir (MK-0518) 6 mg/kg with a maximum dose of 300 mg every 12 hours, tablets taken orally twice daily
Cohort 3: Experimental Participants between the ages 2 and 5; receiving chewable raltegravir tablets.	Drug: Raltegravir (MK-0518) Dosage and formulation is dependent on weight and age
Cohort 4: Experimental Participants between the ages of 6 and 23 months; receiving an age appropriate formulation of raltegravir that is currently in development.	Drug: Raltegravir (MK-0518) Dosage and formulation is dependent on weight and age
Cohort 5: Experimental Participants between the ages of 4 weeks and 5 months; receiving an age appropriate formulation of raltegravir that is currently in development.	Drug: Raltegravir (MK-0518) Dosage and formulation is dependent on weight and age

Detailed Description:

Integrase is one of three enzymes necessary for HIV replication. Integrase allows for the integration of HIV DNA into the human genome. Currently, there are no FDA approved drugs 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 is no data 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 last at least 2 years and will take place in two stages. 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 and will receive raltegravir tablets. Participants in Cohort 2A will be between ages 6 and 11 and will receive raltegravir tablets. Participants in Cohort 2B will be between the ages 6 and 11 and will receive chewable raltegravir tablets. Participants in Cohort 3 will be between the ages 2 and 5 and will receive a chewable raltegravir tablets. Participants in Cohort 4 will be between the ages of 6 and 23 months and will receive an age appropriate formulation that is currently in development. Participants in Cohort 5 will be between the ages of 4 weeks and 5 months and will receive an age appropriate formulation that is currently in development.

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 has 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. Participants will continue to follow the same visit schedule after the dose modification, with an additional safety visit 4 weeks after the dose modification. For example, if a subject's dose is modified to the Stage II selected dose at Week 24 visit, a safety visit will be conducted at week 28 and then continue with the next scheduled visit for that subject at week 36.

There will be about 16 study visits for this study split up into stages. At each visit, a physical exam, blood collection and determinations of treatment adherence will occur. At some visits, urine collection and Tanner staging will also occur. Cohorts 2B and 3 will undergo a taste evaluation at one of two visits. Participants may be re-registered into the same cohort if a dose change is recommended.

Eligibility

Ages Eligible for Study:	2 Years to 18 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00485264

Show 29 Study Locations

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Study Chair:	Sharon A. Nachman, MD	State University of New York at Stony Brook, Health Science Center
Study Chair:	Andrew Wiznia, MD	Jacobi Medical Center, Albert Einstein College of Medicine

More Information

Additional Information:

Click here for more information about raltegravir (MK-0518) This link exits the ClinicalTrials.gov site

Haga clic aquí para ver información sobre este ensayo clínico en español. This link exits the ClinicalTrials.gov site

Publications:

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]

Responsible Party:	DAIDS ( Rona Siskind )
Study ID Numbers:	IMPAACT P1066, PACTG P1066
Study First Received:	June 11, 2007
Last Updated:	January 20, 2010
ClinicalTrials.gov Identifier:	NCT00485264 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Treatment Experienced

Additional relevant MeSH terms:

Virus Diseases
Sexually Transmitted Diseases, Viral
RNA Virus Infections
Slow Virus Diseases
Immune System Diseases
HIV Infections

Sexually Transmitted Diseases
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Infection
Retroviridae Infections
Immunologic Deficiency Syndromes

ClinicalTrials.gov processed this record on February 08, 2010