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NCT00485264

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

Last Updated: 2021-11-02

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

153 participants

Study Classification

INTERVENTIONAL

Study Start Date

2007-09-17

Study Completion Date

2017-05-18

Brief Summary

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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.

Detailed Description

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Integrase is one of three enzymes necessary for HIV replication. Integrase allows for the integration of HIV DNA (deoxyribonucleic acid) 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 was to determine the appropriate dose for raltegravir across the pediatric age range from 4 weeks (30 days) to 18 years of age, by acquiring short and long term safety data, intensive and population PK data, and efficacy experience with raltegravir in treatment-experienced, HIV-infected children and adolescents.

The study consisted of two sequential Stages: I and II. The dose finding period of Stage I was intended to examine the pharmacokinetics and short term tolerability and safety of raltegravir in a limited number of participants to permit dose selection for further study in Stage II. The dose finding algorithm required a preliminary assessment of data from the first 4 patients of each cohort (termed a "mini-cohort"). Failure to meet PK targets required dose adjustments, contingent upon the mini-cohort's dose having met safety criteria, followed by reassessment of safety and PK data from the new mini-cohort dose. When a mini-cohort dose had passed both safety and PK criteria, further accrual to and an assessment of results from the full cohort could occur. Again, failure to meet PK targets required dose adjustments contingent upon the full cohort's dose having met safety criteria with subsequent PK and safety evaluation of data from a new cohort taking the new dose.

Chronic dosing, which includes Stage I extension (the period after Stage I dose finding) and Stage II (additional participants enrolled), was intended to provide longer term safety and antiviral activity data in a larger sample of participants. Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all patients received only the final selected doses for their respective cohorts. This group is denoted as the Final Dose Population, and results from this group are considered primary, since they reflect only the age-specific doses proposed for commercial use. The group with all participants exposed to raltegravir (at any dose) is denoted as the All Treated Population.

Stage I lasted for a minimum of 48 weeks, Stage II was for 48 weeks, and a long-term follow-up period lasted for 5 years from initial exposure (i.e., 48 weeks of treatment plus 4 years of follow-up). Participants were stratified by age and assigned to one of six cohorts. Participants in Cohort I were between the ages of 12 and 18 years and received poloxamer film coated raltegravir tablets. Participants in Cohort IIA were between the ages of 6 and 11 years, weighed at least 25 kg, and received poloxamer film coated raltegravir tablets. Participants in Cohort IIB were between the ages of 6 and 11 years and received chewable raltegravir tablets. Participants in Cohort III were between the ages of 2 and 5 years and received chewable raltegravir tablets. Participants in Cohort IV were between the ages of 6 months (defined as 180 days) and 23 months and received oral granules for suspension. Participants in Cohort V were between the ages of 4 weeks (defined as 30 days) and 5 months and received oral granules for suspension.

Enrollment for Stage I of this study began with Cohort I and progressed to the other cohorts once preliminary dosage had been determined and safety data were reviewed. When this information had been determined for Cohort I, Cohorts IIA and IIB began enrollment. Once safety and dose data for these cohorts were reviewed, enrollment into Cohort III began. Once safety and dose data for Cohort III were reviewed, enrollment into Cohort IV began and once safety and dose data for Cohort IV were reviewed, enrollment into Cohort V began.

During Stage II of this study, participants took raltegravir at the dosage determined as safe and reaching PK targets based on the the Stage I data. The purpose of Stage II was to determine long-term safety of raltegravir once a safe dose meeting PK targets has been determined.

Participants whose Stage I dose was different from the dose determined for Stage II and who had not had individual dose adjustments because of extreme PK values had their raltegravir dose changed to the selected Stage II dose once it was determined. If individualizing the dose for participants in this manner resulted in a dose increase, these participants had an additional safety visit 4 weeks after the dose modification, and then continued on study visits with no further changes in the visit schedule.

There were at least 9 study visits for participants in this study, occurring during the 48-week raltegravir treatment period. For participants who completed 48 weeks of study and appeared to have benefited from receiving study drug, raltegravir was provided until five years after initial raltegravir exposure. For participants who opted to continue on study-provided raltegravir, extended provision of drug was implemented as part of a protocol extension involving visits every 4 months for five years after initial raltegravir exposure. Participants who did not continue on study-provided raltegravir were followed with annual visits for five years after initial raltegravir exposure (i.e. 48 weeks of raltegravir treatment plus 4 years follow-up). At each visit, a physical exam, blood collection, and determination of treatment adherence occurred. At some visits, urine collection and Tanner staging occurred. Selected cohorts underwent a taste evaluation at 1 of 2 visits. Participants aged 2 to less than 6 years of age were asked to participate in an additional PK substudy in which blood was collected two times over a 12-hour visit (or, if more convenient, this assessment may have been completed in 2 separate visits) in order to collect additional Cmin PK data. Participants were re-registered into the same cohort if a dose change was recommended.

Current pediatric Food and Drug Administration approval and dosing recommendations are based upon evaluations in 122 Final Dose participants aged ≥4 weeks to 18 years enrolled in this study.

The results present safety and efficacy results of the complete 5 year follow up data (primary and key secondary endpoints) of the participants from IMPAACT P1066, the Final Dose Population. By the date on which most of the data were frozen, 24 July 2017, all participants enrolled had Week 24 data (i.e., had either completed the Week 24 visit, or, for those who discontinued before Week 24, had the potential to have experienced the Week 24 visit), had also completed (or had the potential to have experienced) the Week 48 visit, and had either completed 240 weeks of study and were subsequently taken off study, or had prematurely discontinued study and were no longer in follow up.

Conditions

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HIV Infections

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type DRUG

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.

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Inclusion Criteria

* 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

* 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

* 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.

* 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

Minimum Eligible Age

30 Days

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Sharon A. Nachman, MD

Role: STUDY_CHAIR

State University of New York at Stony Brook, Health Science Center

Andrew Wiznia, MD

Role: STUDY_CHAIR

Jacobi Medical Center, Albert Einstein College of Medicine

Explore related publications, articles, or registry entries linked to this study.

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.

Reference Type BACKGROUND

Dayam 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.

Reference Type BACKGROUND

PMID: 17472411 (View on PubMed)

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. doi: 10.1097/QAI.0b013e31802b4956.

Reference Type BACKGROUND

PMID: 17133211 (View on PubMed)

Nair 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.

Reference Type BACKGROUND

PMID: 17503547 (View on PubMed)

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.

Reference Type RESULT

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.

Reference Type RESULT

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.

Reference Type RESULT

Nachman 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.

Reference Type RESULT

PMID: 24145879 (View on PubMed)

Nachman 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.

Reference Type DERIVED

PMID: 30527329 (View on PubMed)

Other Identifiers

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10495

Identifier Type: REGISTRY

Identifier Source: secondary_id

IMPAACT P1066

Identifier Type: OTHER

Identifier Source: secondary_id

P1066

Identifier Type: -

Identifier Source: org_study_id

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

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Study Design

Study Groups

Cohort I

Raltegravir poloxamer film coated tablet

Cohort IIA

Raltegravir poloxamer film coated tablet

Cohort IIB

Raltegravir chewable tablet

Cohort III

Raltegravir chewable tablet

Cohort IV

Raltegravir oral granules for suspension (20 mg/mL)

Cohort V

Raltegravir oral granules for suspension (20 mg/mL)

Interventions

Raltegravir poloxamer film coated tablet

Raltegravir chewable tablet

Raltegravir oral granules for suspension (20 mg/mL)

Raltegravir poloxamer film coated tablet

Other Intervention Names

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Allergy and Infectious Diseases (NIAID)

Responsible Party

Principal Investigators

Sharon A. Nachman, MD

Andrew Wiznia, MD

Locations

Usc La Nichd Crs

University of California, UC San Diego CRS

Children's Hospital of Los Angeles NICHD CRS

David Geffen School of Medicine at UCLA NICHD CRS

Univ. of California San Francisco NICHD CRS

Univ. of Colorado Denver NICHD CRS

Children's National Med. Ctr. Washington DC NICHD CRS

Howard Univ. Washington DC NICHD CRS

South Florida CDTC Ft Lauderdale NICHD CRS

Univ. of Florida Jacksonville NICHD CRS

USF - Tampa NICHD CRS

Rush Univ. Cook County Hosp. Chicago NICHD CRS

Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS

Tulane Univ. New Orleans NICHD CRS

Johns Hopkins Univ. Baltimore NICHD CRS

Children's Hosp. of Boston NICHD CRS

Boston Medical Center Ped. HIV Program NICHD CRS

WNE Maternal Pediatric Adolescent AIDS CRS

Nyu Ny Nichd Crs

Metropolitan Hosp. NICHD CRS

Columbia IMPAACT CRS

SUNY Stony Brook NICHD CRS

Bronx-Lebanon Hospital Center NICHD CRS

Jacobi Med. Ctr. Bronx NICHD CRS

DUMC Ped. CRS

Philadelphia IMPAACT Unit CRS

St. Jude Children's Research Hospital CRS

Texas Children's Hospital CRS

Seattle Children's Research Institute CRS

Hosp. General de Agudos Buenos Aires Argentina NICHD CRS

Gaborone CRS

SOM Federal University Minas Gerais Brazil NICHD CRS

Hospital Nossa Senhora da Conceicao NICHD CRS

Hospital Federal dos Servidores do Estado NICHD CRS

Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS

Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS

Univ. of Sao Paulo Brazil NICHD CRS

San Juan City Hosp. PR NICHD CRS

Soweto IMPAACT CRS

Shandukani Research CRS

Durban Paediatric HIV CRS

Family Clinical Research Unit (FAM-CRU) CRS

Countries