Safety and Pharmacokinetics (PK) of Raltegravir in HIV (Human Immunodeficiency Virus)-Infected Children and Adolescents
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 Antiviral Activity of Raltegravir (Isentress, MK-0518) in HIV-1 Infected Children and Adolescents
3 other identifiers
interventional
153
6 countries
42
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1 hiv-infections
Started Sep 2007
Longer than P75 for phase_1 hiv-infections
42 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 11, 2007
CompletedFirst Posted
Study publicly available on registry
June 12, 2007
CompletedStudy Start
First participant enrolled
September 17, 2007
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 3, 2013
CompletedResults Posted
Study results publicly available
December 22, 2014
CompletedStudy Completion
Last participant's last visit for all outcomes
May 18, 2017
CompletedNovember 2, 2021
October 1, 2021
5.7 years
June 11, 2007
February 28, 2014
October 29, 2021
Conditions
Outcome Measures
Primary Outcomes (7)
Percentage of Participants With Grade 3 or 4 Adverse Events (AEs)
Adverse events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0. All grade 3 and higher signs, symptoms, and laboratory toxicities were included.
From study entry through Week 24
Number of Participants Terminated From Treatment Due to Suspected Adverse Drug Reaction (SADR) Attributable to the Study Medication
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.
From study entry through Week 24
Number of Participants Who Died
Number of participants who died were summarized.
From study entry through Week 24
Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC12h)
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.
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.
PK Parameter: Maximum Plasma Concentration (Cmax)
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.
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.
PK Parameter: Time to Half of Maximum Plasma Concentration Cmax (T1/2)
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.
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.
PK Parameter: Concentration at 12 Hours Postdose (C12h)
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.
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.
Secondary Outcomes (6)
Percentage of Participants With Grade 3 or 4 Adverse Events (AEs)
From study entry through Week 48
Number of Participants Terminated From Treatment Due to Suspected Adverse Drug Reaction (SADR) Attributable to the Study Medication
From study entry through Week 48
Number of Participants Who Died
From study entry through Week 48
Percentage of Participants With ≥1 log10 Drop From Baseline in HIV RNA or HIV RNA <400 Copies/mL
Baseline, Week 24, 48
Change of CD4 Count From Baseline
Baseline, Week 24, 48
- +1 more secondary outcomes
Study Arms (6)
Cohort I
EXPERIMENTALParticipants 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.
Cohort IIA
EXPERIMENTALParticipants 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.
Cohort IIB
EXPERIMENTALParticipants 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.
Cohort III
EXPERIMENTALParticipants 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.
Cohort IV
EXPERIMENTALParticipants 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.
Cohort V
EXPERIMENTALParticipants 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.
Interventions
Final Selected Dose: 400-mg tablet 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.
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.
Eligibility Criteria
You may qualify if:
- 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
You may not qualify if:
- 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
- +4 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (42)
Usc La Nichd Crs
Alhambra, California, 91803, United States
University of California, UC San Diego CRS
La Jolla, California, 92093-0672, United States
Children's Hospital of Los Angeles NICHD CRS
Los Angeles, California, 90027-6062, United States
David Geffen School of Medicine at UCLA NICHD CRS
Los Angeles, California, 90095-1752, United States
Univ. of California San Francisco NICHD CRS
San Francisco, California, 94143, United States
Univ. of Colorado Denver NICHD CRS
Aurora, Colorado, 80045, United States
Children's National Med. Ctr. Washington DC NICHD CRS
Washington D.C., District of Columbia, 20010, United States
Howard Univ. Washington DC NICHD CRS
Washington D.C., District of Columbia, 20060, United States
South Florida CDTC Ft Lauderdale NICHD CRS
Fort Lauderdale, Florida, 33316, United States
Univ. of Florida Jacksonville NICHD CRS
Jacksonville, Florida, 32209, United States
USF - Tampa NICHD CRS
Tampa, Florida, 33606, United States
Rush Univ. Cook County Hosp. Chicago NICHD CRS
Chicago, Illinois, 60612, United States
Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS
Chicago, Illinois, 60614-3393, United States
Tulane Univ. New Orleans NICHD CRS
New Orleans, Louisiana, 70112, United States
Johns Hopkins Univ. Baltimore NICHD CRS
Baltimore, Maryland, 21287, United States
Children's Hosp. of Boston NICHD CRS
Boston, Massachusetts, 02115, United States
Boston Medical Center Ped. HIV Program NICHD CRS
Boston, Massachusetts, 02118, United States
WNE Maternal Pediatric Adolescent AIDS CRS
Worcester, Massachusetts, 01605, United States
Nyu Ny Nichd Crs
New York, New York, 10016, United States
Metropolitan Hosp. NICHD CRS
New York, New York, 10029, United States
Columbia IMPAACT CRS
New York, New York, 10032, United States
SUNY Stony Brook NICHD CRS
Stony Brook, New York, 11794-8111, United States
Bronx-Lebanon Hospital Center NICHD CRS
The Bronx, New York, 10457, United States
Jacobi Med. Ctr. Bronx NICHD CRS
The Bronx, New York, 10461, United States
DUMC Ped. CRS
Durham, North Carolina, 27710, United States
Philadelphia IMPAACT Unit CRS
Philadelphia, Pennsylvania, 19104, United States
St. Jude Children's Research Hospital CRS
Memphis, Tennessee, 38105-3678, United States
Texas Children's Hospital CRS
Houston, Texas, 77030-2399, United States
Seattle Children's Research Institute CRS
Seattle, Washington, 98105, United States
Hosp. General de Agudos Buenos Aires Argentina NICHD CRS
Ciudad de Buenos Aires, Buenos Aires, C1221ADC, Argentina
Gaborone CRS
Gaborone, Botswana
SOM Federal University Minas Gerais Brazil NICHD CRS
Belo Horizonte, Minas Gerais, 30.130-100, Brazil
Hospital Nossa Senhora da Conceicao NICHD CRS
Porto Alegre, Rio Grande do Sul, 91350-200, Brazil
Hospital Federal dos Servidores do Estado NICHD CRS
Rio de Janeiro, 20221-903, Brazil
Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
Rio de Janeiro, 21941-612, Brazil
Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
São Paulo, 01246-900, Brazil
Univ. of Sao Paulo Brazil NICHD CRS
São Paulo, 14049-900, Brazil
San Juan City Hosp. PR NICHD CRS
San Juan, 00936, Puerto Rico
Soweto IMPAACT CRS
Johannesburg, Gauteng, 1862, South Africa
Shandukani Research CRS
Johannesburg, Gauteng, 2001, South Africa
Durban Paediatric HIV CRS
Durban, KwaZulu-Natal, 4001, South Africa
Family Clinical Research Unit (FAM-CRU) CRS
Tygerberg, Western Cape, 7505, South Africa
Related Publications (9)
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.
BACKGROUNDDayam R, Al-Mawsawi LQ, Neamati N. HIV-1 integrase inhibitors: an emerging clinical reality. Drugs R D. 2007;8(3):155-68. doi: 10.2165/00126839-200708030-00003.
PMID: 17472411BACKGROUNDMarkowitz 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. doi: 10.1097/QAI.0b013e31802b4956.
PMID: 17133211BACKGROUNDNair V, Chi G. HIV integrase inhibitors as therapeutic agents in AIDS. Rev Med Virol. 2007 Jul-Aug;17(4):277-95. doi: 10.1002/rmv.539.
PMID: 17503547BACKGROUNDSharon 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.
RESULTS. 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.
RESULTJulie 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.
RESULTNachman S, Zheng N, Acosta EP, Teppler H, Homony B, Graham B, Fenton T, Xu X, Wenning L, Spector SA, Frenkel LM, Alvero C, Worrell C, Handelsman E, Wiznia A; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1066 Study Team. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis. 2014 Feb;58(3):413-22. doi: 10.1093/cid/cit696. Epub 2013 Oct 21.
PMID: 24145879RESULTNachman S, Alvero C, Teppler H, Homony B, Rodgers AJ, Graham BL, Fenton T, Frenkel LM, Browning RS, Hazra R, Wiznia AA; IMPAACT 1066 study team. Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised, multicentre trial. Lancet HIV. 2018 Dec;5(12):e715-e722. doi: 10.1016/S2352-3018(18)30257-1.
PMID: 30527329DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Melissa Allen, Director, IMPAACT Operations Center
- Organization
- Family Health International (FHI 360)
Study Officials
- 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
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
June 11, 2007
First Posted
June 12, 2007
Study Start
September 17, 2007
Primary Completion
June 3, 2013
Study Completion
May 18, 2017
Last Updated
November 2, 2021
Results First Posted
December 22, 2014
Record last verified: 2021-10