Safety and Effectiveness of Raltegravir in HIV-Infected Children and Adolescents

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00485264
First received: June 11, 2007
Last updated: September 4, 2013
Last verified: September 2013
  Purpose

Integrase is a protein that HIV needs in order to reproduce in the human body. Raltegravir is a drug that prevents integrase from working properly. This drug has been tested for safety and effectiveness in adults, but this is the first study to examine raltegravir in children. The purpose of this study is to determine the safety and effectiveness of raltegravir in HIV-infected children and adolescents.


Condition Intervention Phase
HIV Infections
Drug: Raltegravir film-coated tablet
Drug: Raltegravir chewable tablet
Drug: Raltegravir oral granules for suspension
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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:


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

Primary Outcome Measures:
  • 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 ]

Estimated Enrollment: 160
Study Start Date: September 2007
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Participants between the ages of 12 and 18 years; receiving film-coated raltegravir tablets.
Drug: Raltegravir film-coated tablet
400-mg tablet taken orally every 12 hours
Other Name: Isentress
Experimental: Cohort 2A
Participants between the ages of 6 and 11 years, weighing at least 25 kg; receiving film-coated raltegravir tablets.
Drug: Raltegravir film-coated tablet
400-mg tablet taken orally every 12 hours
Other Name: Isentress
Experimental: Cohort 2B
Participants between the ages of 6 and 11 years; receiving chewable raltegravir tablets.
Drug: Raltegravir chewable tablet
Raltegravir chewable tablets with a starting dose of 6 mg/kg to a maximum dose of 300 mg, taken orally every 12 hours
Other Name: Isentress
Experimental: Cohort 3
Participants between the ages of 2 and 5 years; receiving chewable raltegravir tablets.
Drug: Raltegravir chewable tablet
Raltegravir chewable tablets with a starting dose of 6 mg/kg to a maximum dose of 300 mg, taken orally every 12 hours
Other Name: Isentress
Experimental: Cohort 4
Participants between the ages of 6 and 23 months; receiving oral granules for suspension.
Drug: Raltegravir oral granules for suspension
Raltegravir oral granules for suspension (20 mg/mL) at a starting dose of 6 mg/kg orally every 12 hours according to dosing table in protocol or the dose determined by review of all available data.
Other Name: Isentress
Experimental: Cohort 5
Participants between the ages of 4 weeks and 5 months; receiving oral granules for suspension.
Drug: Raltegravir oral granules for suspension
Raltegravir oral granules for suspension (20 mg/mL) at a starting dose of 6 mg/kg orally every 12 hours according to dosing table in protocol or the dose determined by review of all available data.
Other Name: Isentress

Detailed Description:

Integrase is one of three enzymes necessary for HIV replication. Integrase allows for the integration of HIV DNA into the human genome. 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. 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 months (defined as 180 days) and 23 months and will receive oral granules for suspension. Participants in Cohort 5 will be between the ages of 4 weeks (defined as 30 days) 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.

During Stage II of this study, participants will take raltegravir at the dosage determined as safe and effective by the Stage I data. The purpose of Stage II is to determine long-term safety of raltegravir once a safe and effective dose has been determined.

Stage I participants who have not had individual dose adjustments because of 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 at least 9 study visits for participants in this study, occurring during the 48-week raltegravir treatment period and then additional visits at least once every 12 months for the next 4 years (for a total of 5 years [240 weeks from initial raltegravir exposure]). 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.

Update: On December 21, 2011, raltegravir was approved by the FDA in combination with other antiretroviral drugs in children and adolescents ages 2 to 18. The FDA-approved formulations in adults, children, and adolescents are film-coated tablets and chewable tablets.

  Eligibility

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

Inclusion Criteria for All Participants:

  • Documentation of HIV-1 infection, defined as positive results from two samples collected at different time points. More information on this criterion can be found in the protocol.
  • For participants in Cohorts 1, 2A, 2B, and 3: On unchanged therapeutic regimen for at least 12 weeks, or treatment experienced (not including therapy to interrupt maternal-infant transmission) but on no treatment for 4 or more weeks prior to study entry. More information on this criterion can be found in the protocol.
  • HIV RNA of 1,000 copies/mL or greater at screening
  • Demonstrated ability or willingness to take assigned raltegravir preparation
  • Parent or legal guardian or participant able and willing to provide signed informed consent when applicable
  • Female participants who are sexually active and potentially able to become pregnant must use two methods of birth control while on study and for 3 months after stopping study drug. More information on this criterion can be found in the protocol. Male participants must not participate in sperm donation programs. Male participants engaging in sexual activity that could lead to pregnancy must use a condom.
  • Willing to be re-registered within same cohort if a dose change is recommended

Exclusion Criteria for All Participants:

  • Known Grade 3 or higher of any of the following laboratory tests within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lipase, serum creatinine
  • Clinical evidence of pancreatitis
  • Treatment for active tuberculosis (TB) infection or disease.
  • History of lactic acidosis in 3 months prior to study entry. More information on this criterion can be found in the protocol.
  • Diagnosis of new Centers for Disease Control Stage C criteria or opportunistic or bacterial infection diagnosed within 30 days prior to study screening and not considered clinically stable
  • Prior treatment with another experimental HIV integrase inhibitor
  • Immunosuppressive therapy within 30 days prior to beginning raltegravir study treatment. Participants taking short courses of corticosteroids are not excluded.
  • Current or anticipated use of any disallowed medications, listed in the protocol.
  • Any history of malignancy
  • Participants who are unlikely to adhere to the study procedures or keep appointments
  • Participants who are planning to relocate during study
  • Any clinically significant diseases (other than HIV) or findings during the screening medical history or physical examination that, in the opinion of the investigator, would compromise the outcome of the study
  • Current or past participation in an investigational study with a compound or device that is not commercially available within 30 days of signing informed consent
  • Participants who are pregnant or breastfeeding. Infants who are receiving breastmilk are allowed to enroll.
  • For participants in Cohorts 4 and 5, participant's caregiver is unable to access clean water supply (as defined by local standards) to re-suspend raltegravir oral granules

Exclusion Criteria for Stage I Participants:

  • Stage I mini cohort (initial 4 participants) only: current or anticipated use of antiretroviral regimen that includes atazanavir, tenofovir, or tipranavir during Stage I. Any other commercially available antiretroviral drugs are acceptable.
  • Stage I participants enrolling after initial 4 participants: use of atazanavir, tenofovir, or tipranavir prior to the intensive PK testing. More information on this criterion can be found in the protocol.

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
  • Total bilirubin value lower than Grade 4 but direct bilirubin or concurrent transaminase greater than 1.5 times the upper limit of normal and participant is symptomatic, within 30 days prior to study entry
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

  Hide Study Locations
Locations
United States, California
Children's Hospital of Los Angeles NICHD CRS
Los Angeles, California, United States, 90027-6062
UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS
Los Angeles, California, United States, 90095-1752
Usc La Nichd Crs
Los Angeles, California, United States, 90033
UCSD Mother-Child-Adolescent Program CRS
San Diego, California, United States, 92103
Univ. of California San Francisco NICHD CRS
San Francisco, California, United States, 94143
United States, Colorado
Univ. of Colorado Denver NICHD CRS
Aurora, Colorado, United States, 80045
United States, District of Columbia
Howard Univ. Washington DC NICHD CRS
Washington, District of Columbia, United States, 20060
Children's National Med. Ctr. Washington DC NICHD CRS
Washington, District of Columbia, United States, 20010
United States, Florida
South Florida CDTC Ft Lauderdale NICHD CRS
Fort Lauderdale, Florida, United States, 33316
Univ. of Florida Jacksonville NICHD CRS
Jacksonville, Florida, United States, 32209
USF - Tampa NICHD CRS
Tampa, Florida, United States, 33620
United States, Illinois
Chicago Children's CRS
Chicago, Illinois, United States, 60614
Rush Univ. Cook County Hosp. Chicago NICHD CRS
Chicago, Illinois, United States, 60612
United States, Louisiana
Tulane Univ. New Orleans NICHD CRS
New Orleans, Louisiana, United States, 70112-2699
United States, Maryland
Johns Hopkins Univ. Baltimore NICHD CRS
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Children's Hosp. of Boston NICHD CRS
Boston, Massachusetts, United States, 02115
Boston Medical Center Ped. HIV Program NICHD CRS
Boston, Massachusetts, United States, 02118
WNE Maternal Pediatric Adolescent AIDS CRS
Worcester, Massachusetts, United States, 01605
United States, New York
Bronx-Lebanon Hosp. IMPAACT CRS
Bronx, New York, United States, 10457
Jacobi Med. Ctr. Bronx NICHD CRS
Bronx, New York, United States, 10461
Nyu Ny Nichd Crs
New York, New York, United States, 10016
Metropolitan Hosp. NICHD CRS
New York, New York, United States, 10029
Columbia IMPAACT CRS
New York, New York, United States, 10032
SUNY Stony Brook NICHD CRS
Stony Brook, New York, United States, 11794
United States, North Carolina
DUMC Ped. CRS
Durham, North Carolina, United States, 27710
United States, Pennsylvania
The Children's Hosp. of Philadelphia IMPAACT CRS
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
St. Jude/UTHSC CRS
Memphis, Tennessee, United States, 38105
United States, Texas
Texas Children's Hosp. CRS
Houston, Texas, United States, 77030
United States, Washington
Seattle Children's Hospital CRS
Seattle, Washington, United States, 98105
Argentina
Hosp. General de Agudos Buenos Aires Argentina NICHD CRS
Ciudad de Buenos Aires, Buenos Aires, Argentina, C1221ADC
Botswana
Gaborone Prevention/Treatment Trials CRS
Gaborone, Botswana
Brazil
SOM Federal University Minas Gerais Brazil NICHD CRS
Belo Horizonte, Minas Gerais, Brazil, 30130-100
Hospital Nossa Senhora da Conceicao CRS
Porto Alegre, Rio Grande do Sul, Brazil, 91350-200
Hosp. dos Servidores Rio de Janeiro NICHD CRS
Rio de Janeiro, Brazil, 20221-903
Inst of Pediatrics Fed Univ Rio de Janeiro NICHD CRS
Rio de Janeiro, Brazil
Univ. of Sao Paulo Brazil NICHD CRS
Sao Paulo, Brazil, 14049-900
Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
Sao Paulo, Brazil, 01246-900
Puerto Rico
San Juan City Hosp. PR NICHD CRS
San Juan, Puerto Rico, 00936
South Africa
Shandukani Research CRS
Johannesburg, Gauteng, South Africa, 2001
Soweto IMPAACT CRS
Johannesburg, Gauteng, South Africa
Durban Paediatric HIV CRS
Durban, KwaZulu-Natal, South Africa, 4001
Stellenbosch Univ. CRS
Cape Town, South Africa, 7505
Sponsors and Collaborators
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

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00485264     History of Changes
Other Study ID Numbers: P1066, 10495, IMPAACT P1066, PACTG P1066
Study First Received: June 11, 2007
Last Updated: September 4, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases

ClinicalTrials.gov processed this record on July 24, 2014