Clinical trial NCT01302847: Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents
Official title: Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants, Children and Adolescents
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Keywords: Integrase Inhibitors
Infant
Child
Adolescent
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2011-02-24
Enrollment: 181
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Dolutegravir (DTG) is an HIV drug in the integrase inhibitor drug class. This study evaluated the pharmacokinetics (PK), safety, tolerability of and immune response to DTG when used concurrently with optimized background therapy (OBT) in HIV-1 infected infants, children, and adolescents.

Detailed description: DTG is an HIV medicine in the integrase inhibitor drug class. The purpose of this study was to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of DTG when used concurrently with OBT in HIV-1 infected infants, children, and adolescents.

Participants in this study were evaluated for PK, safety and tolerability through 48 weeks, followed by additional long-term study follow-up that lasted for approximately 144 weeks (3 years), for a total of 192 weeks on study. This study had two stages. Stage I provided pharmacokinetics, short-term tolerability and safety data on DTG on a limited number of participants to permit dose selection for further study in Stage II. Once a Stage I dose was accepted, enrollment to Stage II began to complete enrollment to the cohort. Stage II provided longer-term safety and antiviral activity data among a larger number of participants.

Infants, children and adolescents with HIV-1, aged ≥ 4 weeks to \< 18 years enrolled in the age and formulation cohorts specified below:

* Cohort I: Adolescents ≥ 12 to \<18 years of age (film-coated tablets)
* Cohort IIA: Children ≥ 6 to \<12 years of age (film-coated tablets)
* Cohort IIB: Children ≥ 6 to \<12 years of age (granules for suspension)
* Cohort III: Children ≥ 2 to \< 6 years of age (granules for suspension)
* Cohort IV: Children ≥ 6 months to \< 2 years of age (granules for suspension)
* Cohort III-DT: Children ≥ 2 to \< 6 years of age (dispersible tablets)
* Cohort IV-DT: Children ≥ 6 months to \< 2 years of age (dispersible tablets)
* Cohort V-DT: Infants ≥ 4 weeks to \< 6 months (dispersible tablets)

Cohorts were opened sequentially according by age group (starting with the older age group), DTG formulation, and study stage, i.e. Initial study enrollment was for Cohort I and progressed to Cohort IIA once Cohort I Stage I met the PK and safety criteria, followed by opening of Cohort IIB. Each cohort enrolled in two sequential stages: Stage I and II (the only exception is Cohort IIB, which only enrolled through Stage I). Sequential enrollment for Cohort III and IV proceeded in the same manner. Cohort V never enrolled because of the recommended changes in dosing and inclusion of enrollment weight band in the criteria for dose finding.

Stage I participants had physical examinations and had blood draws for safety assessments at study visits: Day 0; Day 5 (+5 days); and Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Stage I participants also had intensive PK sampling with blood samples collected at time 0 (pre-dose), and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing. Once a Stage I treatment dose was accepted, enrollment to Stage II began to complete enrollment to the cohort. Stage II participants had physical examinations and blood draws for safety assessment at study visits: Day 0; Day 10; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Blood, plasma, and urine were collected and tested to measure immune response. Females of childbearing potential underwent pregnancy testing at screening and at every study visit.

After 48 weeks, all Stage I and Stage II participants entered the long-term study follow-up and continued to receive DTG. During this time, participants had safety and/or antiviral activity assessments every 12 weeks for up to 3 years.

The study was able to determine a proposed dose (i.e. optimal dose) for Cohorts I, IIA, III-DT, IV-DT, and V-DT but not for Cohorts IIB, III, and IV. Participants on the proposed dose had intensive PK sampling between days 5 and10 of DTG initiation with blood samples collected at time 0 (pre-dose), and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing.

The study is closed to accrual and study follow-up was completed on Oct 18, 2023.

Eligibility criteria: Inclusion Criteria:

* Confirmed HIV-1 infection, defined as positive results from two samples collected at different time points (see protocol for more information)
* Participant belonged to one of the ARV exposure groups below:

  1. ARV-treatment experienced (not including receipt of ARVs as prophylaxis or for prevention of perinatal transmission)

     * Previously took ARVs for treatment, but not taking ARVs at study screening.
     * Had been off treatment for greater than or equal to 4 weeks prior to screening, OR
     * At screening, taking ARVs for treatment but failing.
     * Was on an unchanged, failing therapeutic regimen within the 4 to 12 weeks prior to screening (less than or equal to 1 log drop in HIV-1 RNA within the 4 to 12 weeks prior to screening). OR
     * For participants less than 2 years of age, initiated ARVs for treatment less than 4 weeks prior to screening.
  2. ARV treatment naive (no exposure to ARVs for treatment; could have received ARVs for prophylaxis or prevention of perinatal transmission)
* If an infant had received nevirapine (NVP) as prophylaxis to prevent perinatal transmission, he or she did not receive NVP for at least 14 days prior to enrollment into Stage I or II.
* HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening.
* Demonstrated ability or willingness to swallow assigned study medications.
* Parent or legal guardian were able and willing to provide signed informed consent.
* Female participants of reproductive potential, defined as having reached menarche, and who were engaging in sexual activity that could lead to pregnancy, agreed to use two contraceptive methods while on study and for two weeks after stopping study drug.
* Males engaging in sexual activity that could lead to HIV-1 transmission agreed to use a condom.
* Agreed to stay on optimized background therapy (OBT) while on study:

  * Participants who at screening were greater than or equal to 2 years of age and ARV-treatment experienced, had at screening at least one fully active drug for the OBT.
  * Participants who were greater than or equal to 2 years of age and ARV-treatment naïve, had genotype testing at screening/entry even with results pending.
  * Participants less than 2 years of age (either ARV-treatment experienced or ARV treatment naïve), had genotype testing at screening/entry even with results pending.

Exclusion Criteria:

* Presence of any active AIDS-defining opportunistic infection
* At enrollment, participant less than 3.0 kg
* Known Grade 3 or greater of any of the following laboratory toxicities within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine transaminase (ALT), lipase, serum creatinine and total bilirubin. A single repeat within the 30 days is allowed for eligibility determination. NOTE: Grade 3 total bilirubin was allowable, if the participant was on atazanavir (ATV).
* ANY known Grade 4 laboratory toxicities within 30 days prior to study entry. NOTE: Grade 4 total bilirubin was allowable, if the participant was on ATV.
* The following liver toxicities within 30 days prior to study entry: ALT greater than 3x the upper limit of normal (ULN) AND direct bilirubin was greater than 2x ULN
* Any prior history of malignancy, with the exception of localized malignancies such as squamous cell or basal cell carcinoma of the skin
* Clinical or symptomatic evidence of pancreatitis, as determined by the clinician
* Use of any disallowed medications at time of screening (see the protocol for a complete list of disallowed medications)
* Known history of exposure to integrase inhibitor treatment by the participant or participant's mother prior to delivery/cessation of breastfeeding
* Known resistance to an integrase inhibitor
* Women who were pregnant or breastfeeding
* At screening/entry, participating in or had participated in a study with a compound or device that was not commercially available within 30 days of signing informed consent, unless permission from both Protocol Teams was granted
* Participant was unlikely to adhere to the study procedures, keep appointments, or was planning to relocate during the study to a non-IMPAACT study site
* Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study
* At screening/entry had used, or anticipated using, chronic systemic immunosuppressive agents or systemic interferon (e.g., for treatment of hepatitis C virus \[HCV\] infection) within 30 days prior to beginning DTG study treatment. Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses (less than or equal to 30 days) were permitted. (See protocol for more information on disallowed medications.)
* Any condition that in the opinion of the site investigator, placed the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol.
* Active tuberculosis (TB) disease and/or requirement for treatment that included rifampin at the time of the screening visit. However, participants who needed rifampin treatment while on DTG were allowed to continue in P1093 provided the DTG dose was adjusted according to the protocol.

Primary outcomes:
measure: Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)
timeFrame: From treatment initiation through Weeks 24 and 48
measure: Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug
timeFrame: From treatment initiation through Weeks 24 and 48
measure: Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug
timeFrame: From treatment initiation through Weeks 24 and 48
measure: Number of Participants Who Died
timeFrame: From treatment initiation through Weeks 24 and 48
measure: PK Parameter: Area-under-the-curve From 0 to 24 Hours (AUC0-24)
timeFrame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Secondary outcomes:
measure: Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)
timeFrame: From treatment initiation through Week 192. AEs after that time were censored.
measure: Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug
timeFrame: From treatment initiation through Week 192. AEs after that time were censored.
measure: Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug
timeFrame: From treatment initiation through Week 192. AEs after that time were censored.
measure: Number of Participants Who Died
timeFrame: From treatment initiation through Week 192. AEs after that time were censored.
measure: Percentage of Participants With Plasma HIV-1 RNA Less Than 400 Copies/ml
timeFrame: Week 24 and Week 48
measure: Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/ml
timeFrame: Week 24 and Week 48
measure: PK Parameter: Plasma Concentration Observed at End of 24 Hour Dosing Interval (C24h)
timeFrame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
measure: PK Parameter: Plasma Concentration Observed Immediately to Dosing of 24 Hour Dosing Interval (C0h)
timeFrame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
measure: PK Parameter: Minimum Plasma Concentration (Cmin)
timeFrame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
measure: PK Parameter: Maximum Plasma Concentration (Cmax)
timeFrame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
measure: PK Parameter: Apparent Clearance (CL/F)
timeFrame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
measure: PK Parameter: Apparent Volume of Distribution (Vz/F)
timeFrame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
measure: PK Parameter: Terminal Half-life (t1/2)
timeFrame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
measure: Summary of Changes in CD4 Count From Baseline
timeFrame: Measured at Day 0, Week 24, and Week 48
measure: Summary of Changes in CD4 Percent From Baseline
timeFrame: Measured at Day 0, Week 24, and Week 48
measure: Summary of Changes in CD8 Count From Baseline
timeFrame: Measured at Day 0, Week 24, and Week 48
measure: Summary of Changes in CD8 Percent From Baseline
timeFrame: Measured at Day 0, Week 24, and Week 48
measure: Genotypic Measures of Resistance to Integrase
timeFrame: At baseline
measure: Genotypic Measures of Resistance to Integrase
timeFrame: at virological failure visit at or prior to Week 192
measure: Genotypic Measures of Resistance to Protease
timeFrame: at baseline
measure: Genotypic Measures of Resistance to Protease
timeFrame: at virological failures at or prior to Week 192
measure: Genotypic Measures of Resistance to Reverse Transcriptase
timeFrame: at baseline
measure: Genotypic Measures of Resistance to Reverse Transcriptase
timeFrame: at virologic failure at or prior to Week 192
measure: Phenotypic Measures of Resistance
timeFrame: Whenever virological failures took place from baseline to week 192
measure: Worst Case CDC HIV Classification Status
timeFrame: From baseline through Week 192
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program (Site ID: 4601)
state: California
city: Long Beach
country: United States
facility: Miller Children's Hosp. Long Beach CA NICHD CRS (Site ID: 5093)
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA NICHD CRS (Site ID: 5112)
state: California
city: San Francisco
country: United States
facility: Univ. of California San Francisco NICHD CRS (Site ID: 5091)
state: California
city: Aurora
country: United States
facility: Univ. of Colorado Denver NICHD CRS (Site ID: 5052)
state: Colorado
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS (Site ID: 5044)
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: South Florida CDTC Ft Lauderdale NICHD CRS (Site ID: 5055)
state: Florida
city: Tampa
country: United States
facility: USF - Tampa NICHD CRS (Site ID: 5018)
state: Florida
city: Chicago
country: United States
facility: Rush Univ. Cook County Hosp. Chicago NICHD CRS (Site ID: 5083)
state: Illinois
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago (LCH) CRS (Site ID: 4001)
state: Illinois
city: Boston
country: United States
facility: Children's Hosp. of Boston NICHD CRS (Site ID: 5009)
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD CRS (Site ID: 5011)
state: Massachusetts
city: Bronx
country: United States
facility: Bronx-Lebanon Hospital Center NICHD CRS (Site ID: 5114)
state: New York
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS (Site ID: 5013)
state: New York
city: New York
country: United States
facility: Metropolitan Hosp. NICHD CRS (Site ID: 5003)
state: New York
city: Durham
country: United States
facility: DUMC Ped. CRS (Site ID: 4701)
state: North Carolina
city: Seattle
country: United States
facility: Seattle Children's Research Institute CRS (Site ID: 5017)
state: Washington
city: Gaborone
country: Botswana
facility: Gaborone CRS (Site ID: 12701)
state: South-East District
city: Gaborone
country: Botswana
facility: Molepolole CRS (Site ID: 12702)
city: Belo Horizonte
country: Brazil
facility: SOM Federal University Minas Gerais Brazil NICHD CRS (Site ID: 5073)
state: Minas Gerais
city: Rio de Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS (Site ID: 5072)
city: Rio de Janeiro
country: Brazil
facility: Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS (Site ID: 5071)
city: Rio de Janeiro
country: Brazil
facility: Hosp. Geral De Nova Igaucu Brazil NICHD CRS (Site ID: 5097)
city: Sao Paulo
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS (Site ID: 5074)
city: Kericho
country: Kenya
facility: Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS (Site ID: 5121)
city: Johannesburg
country: South Africa
facility: Wits RHI Shandukani Research Centre CRS (Site ID: 8051)
state: Gauteng
city: Durban
country: South Africa
facility: Umlazi CRS (Site ID: 30300)
state: KwaZulu-Natal
city: Tygerberg
country: South Africa
facility: FAMCRU CRS (Site ID: 8950)
state: Western Cape Province
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118)
city: Bangkok
country: Thailand
facility: Siriraj Hospital, Mahidol University NICHD CRS (Site ID: 5115)
state: Bangkoknoi
city: Chiang Mai
country: Thailand
facility: Chiangrai Prachanukroh Hospital NICHD CRS (Site ID: 5116)
city: Chiang Mai
country: Thailand
facility: Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (Site ID: 31784)
city: Harare
country: Zimbabwe
facility: Harare Family Care CRS (Site ID: 31890)
Study officials:
affiliation: Jacobi Medical Center
name: Andrew Wiznia, M.D.
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Theodore Ruel, M.D.
role: STUDY_CHAIR
References:
citation: Bennetto-Hood C, Tabolt G, Savina P, Acosta EP. A sensitive HPLC-MS/MS method for the determination of dolutegravir in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jan 15;945-946:225-32. doi: 10.1016/j.jchromb.2013.11.054. Epub 2013 Dec 3.
citation: Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, Steimers D, Min S, Wiznia A; P1093 Study Team. Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093. Pediatr Infect Dis J. 2015 Nov;34(11):1207-13. doi: 10.1097/INF.0000000000000848.
citation: Viani RM, Ruel T, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, Palumbo P, Buchanan AM, Vavro C, Singh R, Graham B, Anthony P, George K, Wiznia A; P1093 Study Team. Long-Term Safety and Efficacy of Dolutegravir in Treatment-Experienced Adolescents With Human Immunodeficiency Virus Infection: Results of the IMPAACT P1093 Study. J Pediatric Infect Dis Soc. 2020 Apr 30;9(2):159-165. doi: 10.1093/jpids/piy139.
citation: Ruel TD, Acosta EP, Liu JP, Gray KP, George K, Montanez N, Popson S, Buchanan AM, Bartlett M, Dayton D, Anthony P, Brothers C, Vavro C, Singh R, Koech L, Vhembo T, Mmbaga BT, Pinto JA, Dobbels EFM, Archary M, Chokephaibulkit K, Ounchanum P, Deville JG, Hazra R, Townley E, Wiznia A; IMPAACT P1093 team. Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial. Lancet HIV. 2022 May;9(5):e332-e340. doi: 10.1016/S2352-3018(22)00044-3.
citation: Singh RP, Adkison KK, Baker M, Parasrampuria R, Wolstenholme A, Davies M, Sewell N, Brothers C, Buchanan AM. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children. Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366.
citation: Vavro C, Ruel T, Wiznia A, Montanez N, Nangle K, Horton J, Buchanan AM, Stewart EL, Palumbo P. Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0164521. doi: 10.1128/AAC.01645-21. Epub 2021 Oct 25.