Clinical trial NCT00485264: Safety and Pharmacokinetics (PK) of Raltegravir in HIV (Human Immunodeficiency Virus)-Infected Children and Adolescents
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 Antiviral Activity of Raltegravir (Isentress, MK-0518) in HIV-1 Infected Children and Adolescents
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2007-06-12
Enrollment: 153
Sex: ALL
Minimum age (years): 30
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Grade 3 or 4 Adverse Events (AEs)
timeFrame: From study entry through Week 24
measure: Number of Participants Terminated From Treatment Due to Suspected Adverse Drug Reaction (SADR) Attributable to the Study Medication
timeFrame: From study entry through Week 24
measure: Number of Participants Who Died
timeFrame: From study entry through Week 24
measure: Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC12h)
timeFrame: 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.
measure: PK Parameter: Maximum Plasma Concentration (Cmax)
timeFrame: 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.
measure: PK Parameter: Time to Half of Maximum Plasma Concentration Cmax (T1/2)
timeFrame: 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.
measure: PK Parameter: Concentration at 12 Hours Postdose (C12h)
timeFrame: 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:
measure: Percentage of Participants With Grade 3 or 4 Adverse Events (AEs)
timeFrame: From study entry through Week 48
measure: Number of Participants Terminated From Treatment Due to Suspected Adverse Drug Reaction (SADR) Attributable to the Study Medication
timeFrame: From study entry through Week 48
measure: Number of Participants Who Died
timeFrame: From study entry through Week 48
measure: Percentage of Participants With ≥1 log10 Drop From Baseline in HIV RNA or HIV RNA <400 Copies/mL
timeFrame: Baseline, Week 24, 48
measure: Change of CD4 Count From Baseline
timeFrame: Baseline, Week 24, 48
measure: Change of CD4 Percent From Baseline
timeFrame: Baseline, Week 24, 48
Other outcomes:
Locations:
city: Alhambra
country: United States
facility: Usc La Nichd Crs
state: California
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS
state: California
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles NICHD CRS
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA NICHD CRS
state: California
city: San Francisco
country: United States
facility: Univ. of California San Francisco NICHD CRS
state: California
city: Aurora
country: United States
facility: Univ. of Colorado Denver NICHD CRS
state: Colorado
city: Washington
country: United States
facility: Children's National Med. Ctr. Washington DC NICHD CRS
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: South Florida CDTC Ft Lauderdale NICHD CRS
state: Florida
city: Jacksonville
country: United States
facility: Univ. of Florida Jacksonville NICHD CRS
state: Florida
city: Tampa
country: United States
facility: USF - Tampa NICHD CRS
state: Florida
city: Chicago
country: United States
facility: Rush Univ. Cook County Hosp. Chicago NICHD CRS
state: Illinois
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ. New Orleans NICHD CRS
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Univ. Baltimore NICHD CRS
state: Maryland
city: Boston
country: United States
facility: Children's Hosp. of Boston NICHD CRS
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD CRS
state: Massachusetts
city: Worcester
country: United States
facility: WNE Maternal Pediatric Adolescent AIDS CRS
state: Massachusetts
city: Bronx
country: United States
facility: Bronx-Lebanon Hospital Center NICHD CRS
state: New York
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: New York
country: United States
facility: Nyu Ny Nichd Crs
state: New York
city: New York
country: United States
facility: Metropolitan Hosp. NICHD CRS
state: New York
city: New York
country: United States
facility: Columbia IMPAACT CRS
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook NICHD CRS
state: New York
city: Durham
country: United States
facility: DUMC Ped. CRS
state: North Carolina
city: Philadelphia
country: United States
facility: Philadelphia IMPAACT Unit CRS
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital CRS
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital CRS
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Research Institute CRS
state: Washington
city: Ciudad de Buenos Aires
country: Argentina
facility: Hosp. General de Agudos Buenos Aires Argentina NICHD CRS
state: Buenos Aires
city: Gaborone
country: Botswana
facility: Gaborone CRS
city: Belo Horizonte
country: Brazil
facility: SOM Federal University Minas Gerais Brazil NICHD CRS
state: Minas Gerais
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao NICHD CRS
state: Rio Grande Do Sul
city: Rio de Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
city: Sao Paulo
country: Brazil
facility: Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
city: Sao Paulo
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
city: Johannesburg
country: South Africa
facility: Soweto IMPAACT CRS
state: Gauteng
city: Johannesburg
country: South Africa
facility: Shandukani Research CRS
state: Gauteng
city: Durban
country: South Africa
facility: Durban Paediatric HIV CRS
state: KwaZulu-Natal
city: Tygerberg
country: South Africa
facility: Family Clinical Research Unit (FAM-CRU) CRS
state: Western Cape Province
Study officials:
affiliation: State University of New York at Stony Brook, Health Science Center
name: Sharon A. Nachman, MD
role: STUDY_CHAIR
affiliation: Jacobi Medical Center, Albert Einstein College of Medicine
name: Andrew Wiznia, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.