Safety and Pharmacokinetics (PK) of Raltegravir in HIV (Human Immunodeficiency Virus)-Infected Children and Adolescents

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00485264
First received: June 11, 2007
Last updated: July 2, 2015
Last verified: July 2015
  Purpose

Integrase is 1 of 3 HIV (Human Immunodeficiency Virus)-1 enzymes required for viral replication. Raltegravir is a drug that prevents integrase from working properly. This drug has been tested for safety and efficacy in adults, but this is the first study to examine raltegravir in children and adolescents. The purpose of this study was to determine the appropriate dose for raltegravir across the pediatric age range from 4 weeks to 18 years of age, by acquiring short and long term safety data, intensive and population pharmacokinetic (PK) data, and efficacy experience with raltegravir in HIV-infected children and adolescents.


Condition Intervention Phase
HIV Infections
Drug: Raltegravir poloxamer film coated tablet
Drug: Raltegravir chewable tablet
Drug: Raltegravir oral granules for suspension (20 mg/mL)
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:
  • Percentage of Participants With Grade 3 or 4 Adverse Events (AEs) [ Time Frame: From study entry through Week 24 ] [ Designated as safety issue: Yes ]
    Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009, which is available on the RCC website at (http://rcc.tech-res.com/). All grade 3 and higher signs, symptoms, and laboratory toxicities were included.

  • Number of Participants Terminated From Treatment Due to Suspected Adverse Drug Reaction (SADR) Attributable to the Study Medication [ Time Frame: From study entry through Week 24 ] [ Designated as safety issue: Yes ]
    The attribution of relationship of serious adverse events to study drug for the purposes of employing the start, stop and pause rules was by consensus among the site investigator, study team (which includes representatives from Merck) and the Division of AIDS medical officer; if unanimous agreement between them cannot be established, the attribution made by the majority of these 3 persons or entities will be used. Gradation of relationship will use the following terminology: Not related, Probably not related, Possibly related, Probably related or Definitely related.

  • Number of Participants Who Died [ Time Frame: From study entry through Week 24 ] [ Designated as safety issue: Yes ]
  • Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC12h) [ Time Frame: Measured between days 5 and 12 of raltegravir initiation; Blood samples were drawn pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing. ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). AUC12h (area-under-the-curve from 0 to 12 hours) were determined using the linear-log trapezoidal rule.

  • PK Parameter: Maximum Plasma Concentration (Cmax) [ Time Frame: Measured between days 5 and 12 of raltegravir initiation; Blood samples were drawn pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing. ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Maximum plasma concentration (Cmax) was taken directly from the observed concentration-time data.

  • PK Parameter: Time to Half of Maximum Plasma Concentration Cmax (T1/2) [ Time Frame: Measured between days 5 and 12 of raltegravir initiation; Blood samples were drawn pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing. ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Time to half of maximum plasma concentration Cmax (T1/2) was taken directly from the observed concentration-time data.

  • PK Parameter: Concentration at 12 Hours Postdose (C12h) [ Time Frame: Measured between days 5 and 12 of raltegravir initiation; Blood samples were drawn pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing. ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Plasma concentration at 12 hours postdose (C12h) was taken directly from the observed concentration-time data.


Secondary Outcome Measures:
  • Percentage of Participants With Grade 3 or 4 Adverse Events (AEs) [ Time Frame: From study entry through Week 48 ] [ Designated as safety issue: Yes ]
    Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009, which is available on the RCC website at (http://rcc.tech-res.com/). All grade 3 and higher signs, symptoms, and laboratory toxicities were included.

  • Number of Participants Terminated From Treatment Due to Suspected Adverse Drug Reaction (SADR) Attributable to the Study Medication [ Time Frame: From study entry through Week 48 ] [ Designated as safety issue: Yes ]
    The attribution of relationship of serious adverse events to study drug for the purposes of employing the start, stop and pause rules was by consensus among the site investigator, study team (which includes representatives from Merck) and the Division of AIDS medical officer; if unanimous agreement between them cannot be established, the attribution made by the majority of these 3 persons or entities will be used. Gradation of relationship will use the following terminology: Not related, Probably not related, Possibly related, Probably related or Definitely related.

  • Number of Participants Who Died [ Time Frame: From study entry through Week 48 ] [ Designated as safety issue: Yes ]
  • Percentage of Participants With ≥1 log10 Drop From Baseline in HIV RNA or HIV RNA <400 Copies/mL [ Time Frame: Baseline, Week 24, 48 ] [ Designated as safety issue: No ]
    Plasma HIV RNA (RNA) concentrations were determined at entry and at regular intervals using the HIV-1 MONITOR Test, version 1.5 (Roche Molecular Diagnostics) or RealTime HIV-1 (Abbott Molecular).

  • Change of CD4 Count (Cells/µL) From Baseline [ Time Frame: Baseline, Week 24, 48 ] [ Designated as safety issue: Yes ]
  • Change of CD4 Percent From Baseline [ Time Frame: Baseline, Week 24, 48 ] [ Designated as safety issue: Yes ]

Enrollment: 153
Study Start Date: September 2007
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort I

Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet:

Stage I starting dose: Weight based dose of ~6 mg/kg based on protocol dosing table, taken orally twice daily.

Final Selected Dose: 400-mg tablet taken orally twice daily.

Drug: Raltegravir poloxamer film coated tablet
Final Selected Dose: 400-mg tablet taken orally twice daily.
Other Name: Isentress
Experimental: Cohort IIA

Participants between the ages of 6 and 11 years, receiving raltegravir poloxamer film coated tablet:

Stage I starting dose: Weight based dose of ~8 mg/kg based on protocol dosing table, taken orally twice daily.

Final Selected Dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg. Participants < 25 kg were switched to a weight-based dose of the chewable tablet.

Drug: Raltegravir poloxamer film coated tablet
Final Selected Dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg. Participants < 25 kg were switched to a weight-based dose of the chewable tablet.
Other Name: Isentress
Experimental: Cohort IIB

Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet:

Stage I starting dose: Weight based dose of ~8 mg/kg based on protocol dosing table, taken orally twice daily.

Final Selected Dose: Weight based dose of ~6 mg/kg according to the dosing table, to a maximum dose of 300 mg, taken orally twice daily.

Drug: Raltegravir chewable tablet
Final Selected Dose: Weight based dose of ~6 mg/kg according to the dosing table, to a maximum dose of 300 mg, taken orally twice daily.
Other Name: Isentress
Experimental: Cohort III

Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet:

Stage I starting dose: Weight based dose of ~6 mg/kg based on protocol dosing table, taken orally twice daily.

Final Selected Dose: Weight based dose of ~6 mg/kg according to the dosing table, to a maximum dose of 300 mg, taken orally twice daily.

Drug: Raltegravir chewable tablet
Final Selected Dose: Weight based dose of ~6 mg/kg according to the dosing table, to a maximum dose of 300 mg, taken orally twice daily.
Other Name: Isentress
Experimental: Cohort IV -data not included in this interim analysis.

Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL):

Stage I starting dose: Weight based 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.

Drug: Raltegravir oral granules for suspension (20 mg/mL)
Weight based 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 V -data not included in this interim analysis.

Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL):

Stage I starting dose: Weight based 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.

Drug: Raltegravir oral granules for suspension (20 mg/mL)
Weight based 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

  Show Detailed Description

  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 I, IIA, IIB, and III: On unchanged therapeutic regimen for at least 12 weeks, or treatment experienced (not including therapy to interrupt maternal-to-child-transmission (MTCT)) but on no treatment for 4 or more weeks prior to study entry. More information on this criterion can be found in the protocol.
  • Participants in Cohorts IV must have received therapy to either interrupt MTCT and/or to treat HIV infection and participants in Cohort V must have received therapy to interrupt MTCT but have not received other anti-HIV therapies.
  • HIV RNA (ribonucleic acid) 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 IV and V, 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

  Show 42 Study Locations
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:
Sharon Nachman, Edward Acosta, Nan Zheng, Hedy Tepler, Brenda Homony, Terence Fenton, Edward Handelsman, Carol Worrell, Bobbie Graham, Andrew Wiznia , and the P1066 Group. Interim Results for IMPAACT P1066 Raltegravir (RAL) Oral Chewable Tablet (CT) Formulation on Children 2-5 Years. CROI 2011, Boston, MA, Feb27-March2, 2011.
S. Nachman, E. Acosta, N. Zheng, H. Teppler, B. Homony, X. Xu, C. Alvero, E. Handelsman, C. Worrell, B. Graham, M. Toye, A. Wiznia, and the P1066 Group. IMPAACT P1066: Raltegravir (RAL) safety and efficacy in treatment experienced HIV infected (+) youth 2 to 18 years of age through week 48. XIX International AIDS Conference, July 22-27, 2012, Washington, DC.
Julie Nelson, A Loftis, K Below, D Cole, S Nachman, L Frenkel, C Alvero, N Zheng, J Eron, and S Fiscus. Absence of Integrase Inhibitor Resistance Mutations in Children Not Treated with Integrase Inhibitor. CROI 2012, Seattle, WA. March 2012.
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.

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
Results First Received: February 28, 2014
Last Updated: July 2, 2015
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on July 29, 2015