Clinical Trials

MainTitle

Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents

This study is ongoing, but not recruiting participants.
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)


Information provided by (Responsible Party)
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier
NCT01302847

First received: February 15, 2011
Last updated: April 22, 2020
Last Verified: April 2020
History of Changes
Purpose

Purpose

Dolutegravir (DTG) is an HIV drug in the integrase inhibitor drug class. This study will test the safety of and immune response to DTG in HIV-1 infected infants, children, and adolescents.

Condition Intervention Phase
HIV Infections

Drug : Dolutegravir (DTG) film-coated tablets
Drug : DTG granules for suspension
Drug : DTG dispersible tablets
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures

  • Toxicity [ Time Frame: From Week 0 to Week 24 ]
    Defined as all adverse events or lab toxicities of Grade 3 or higher severity, adverse events or lab toxicities of Grade 3 or higher severity judged to be at least possibly attributable to the study medication, termination from treatment due to a drug-related adverse event, or death
  • Pharmacokinetic parameters [ Time Frame: Over a single 24-hour period at the Day 5 (+5 days) study visit ]
    Drug concentration 24 hours after dosing and area under the curve (AUC), defined as the area under the drug plasma concentration profile over time of dosing interval (predose to 24 hours]
Secondary Outcome Measures:
  • Toxicity [ Time Frame: From Week 0 to Week 48 and beyond ]
    Defined as all adverse events or lab toxicities of Grade 3 or higher severity, adverse events or lab toxicities of Grade 3 or higher severity judged to be at least possibly attributable to the study medication, termination from treatment due to a drug-related adverse event, or death
  • Plasma HIV-1 RNA less than 400 copies/ml [ Time Frame: At Weeks 24 and 48 ]
  • Plasma HIV-1 RNA less than 50 copies/ml [ Time Frame: At Weeks 24 and 48 ]
  • Area-under-the-curve (AUC 0-24) [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ]
    Determined from plasma concentration-time profiles using non-compartmental methods
  • Plasma concentration observed at end of 24 hour dosing interval (C24h) [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ]
    Determined from plasma concentration-time profiles using non-compartmental methods
  • Plasma concentration observed immediately to dosing of 24 hour dosing interval (C0) [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ]
    Determined from plasma concentration-time profiles using non-compartmental methods
  • Minimum plasma concentration (Cmin) [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ]
    Determined from plasma concentration-time profiles using non-compartmental methods
  • Maximum plasma concentration (Cmax) [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ]
    Determined from plasma concentration-time profiles using non-compartmental methods
  • Apparent clearance (CL/F) [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ]
    Determined from plasma concentration-time profiles using non-compartmental methods
  • Apparent volume of distribution (Vz/F) [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ]
    Determined from plasma concentration-time profiles using non-compartmental methods
  • Terminal half-life (t1/2) [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ]
    Determined from plasma concentration-time profiles using non-compartmental methods
  • Change in CD4 counts [ Time Frame: From baseline to Weeks 24 and 48 ]
  • Change in CD4 percentages [ Time Frame: From baseline to Weeks 24 and 48 ]
  • Change in CD8 counts [ Time Frame: From baseline to Weeks 24 and 48 ]
  • Change in CD8 percentages [ Time Frame: From baseline to Weeks 24 and 48 ]
  • Genotypic and phenotypic measures of resistance [ Time Frame: At baseline and through study completion ]
  • Disease progression as measured by change in Centers for Disease Control and Prevention (CDC) category [ Time Frame: From baseline to Week 48 or through study completion ]

Estimated Enrollment: 300
Study Start Date: March 2011
Estimated Study Completion Date: October 24, 2023
Estimated Primary Completion Date: January 19, 2021 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Cohort I: Adolescents 12 to younger than 18 years of age
DTG film-coated tablets
Drug: Dolutegravir (DTG) film-coated tablets
  • Stage I: Initial starting dose of DTG tablet(s) at approximately 1 mg/kg, to be taken orally once or twice daily.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily.

Experimental: Cohort IIA: Children 6 to younger than 12 years of age
DTG film-coated tablets
Drug: Dolutegravir (DTG) film-coated tablets
  • Stage I: Initial starting dose of DTG tablet(s) at approximately 1 mg/kg, to be taken orally once or twice daily.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily.

Experimental: Cohort IIB: Children 6 to younger than 12 years of age
DTG granules for suspension or DTG dispersible tablets
Drug: DTG granules for suspension
  • Stage I: DTG granules for suspension, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily. (Note: Cohort IIB will not be included in Stage II of the study).

Drug: DTG dispersible tablets
  • Stage I: DTG dispersible tablets, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily.

Experimental: Cohort III: Children 2 to younger than 6 years of age
DTG granules for suspension or DTG dispersible tablets
Drug: DTG granules for suspension
  • Stage I: DTG granules for suspension, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily. (Note: Cohort IIB will not be included in Stage II of the study).

Drug: DTG dispersible tablets
  • Stage I: DTG dispersible tablets, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily.

Experimental: Cohort III-DT: Children 2 to younger than 6 years of age
DTG dispersible tablets
Drug: DTG dispersible tablets
  • Stage I: DTG dispersible tablets, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily.

Experimental: Cohort IV: Children 6 months to younger than 2 years of age
DTG granules for suspension or DTG dispersible tablets
Drug: DTG granules for suspension
  • Stage I: DTG granules for suspension, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily. (Note: Cohort IIB will not be included in Stage II of the study).

Drug: DTG dispersible tablets
  • Stage I: DTG dispersible tablets, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily.

Experimental: Cohort IV-DT: Children 6 months to younger than 2 years of age
DTG dispersible tablets
Drug: DTG dispersible tablets
  • Stage I: DTG dispersible tablets, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily.

Experimental: Cohort V-DT: Infants 4 weeks to younger than 6 months of age
DTG dispersible tablets
Drug: DTG dispersible tablets
  • Stage I: DTG dispersible tablets, to be taken orally once or twice daily. Dose will vary for each participant.
  • Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily.

Detailed Description:

DTG is an HIV medicine in the integrase inhibitor drug class. The purpose of this study is to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of DTG in HIV-1 infected infants, children, and adolescents.
Participation in this study will last approximately 48 weeks, followed by long-term safety follow-up that will last for about 3 years. Participants may be receiving other antiretroviral (ARV) medications while in this study; these medications will be prescribed by participants' doctors and will not be provided by the study. This study has two stages. Stage I will evaluate the short-term tolerability and safety of DTG, allowing the selection of a dose for further study in Stage II. Stage II will then provide long-term safety, tolerability, and efficacy data for DTG. Participants will be assigned to one of eight cohorts depending on age (4 weeks to younger than 18 years of age). Participants in cohorts I and IIA will receive DTG film-coated tablets; participants in cohort IIB will receive DTG granules for oral suspension or DTG dispersible tablets; participants in cohorts III and IV will receive DTG granules for oral suspension; and participants in cohorts III-DT, IV-DT, and V-DT will receive DTG dispersible tablets. Participants will receive DTG orally once or twice daily, depending on which other ARV medications they are receiving. (All eight cohorts will be included in Stage I of the study; however, Stage II of the study will not include cohort IIB).
Stage I participants will undergo a physical examination and have blood drawn at each of 10 study visits, occurring on Day 0; Day 5 (+5 days); and Weeks 4, 8, 12, 16, 24, 32, 40, and

  1. Stage I participants will also have their blood drawn 8 times over 24 hours during the
Day 5 (+5 days) study visit to measure the amount of drug in the blood stream. Stage II participants will undergo a physical examination and have blood drawn at each study visit (Day 0; Day 10; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48). Blood, plasma, and urine will also be stored and tested to measure immune response. Females of childbearing potential will undergo pregnancy testing at every study visit. Questionnaires and assessments will be performed at select study visits.
After 48 weeks, all participants will enter long-term safety follow-up and will continue to receive DTG. During this time, participants will undergo a physical examination, blood collection, and questionnaires at most study visits (every 12 weeks for about 3 years).
Note: In January 2018, all participants on DTG granules for oral suspension were recommended to transition to DTG dispersible tablets. Cohorts III and IV are closed to further enrollments.

Eligibility

Eligibility

Ages Eligible for Study: up to 17 Years  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • At least 4 weeks but younger than 18 years of age at study entry
  • Confirmed HIV-1 infection defined as positive results from two samples collected at different time points (see protocol for more information)
  • Participants must belong 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 currently taking ARVs:
    • Must have been off treatment for greater than or equal to 4 weeks prior to screening, OR
    • Currently taking ARVs for treatment but failing:
    • Must be 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). NOTE: To meet this criterion, two HIV RNA levels are required: one from a date between 4-12 weeks prior to study screening and a second one at study screening. The HIV RNA level at screening must be higher than, equal to, or less than or equal to 1 log lower than the prior HIV RNA level. NOTE: Dose adjustments for growth or formula substitutions (i.e., switching from single agent to fixed dose combination) during this 4 to 12 week period, substitutions of one ARV within the same class for toxicity or tolerability management, or discontinuation of ARVs are permitted between the HIV RNA measurements and screening or enrollment. 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 has received nevirapine (NVP) as prophylaxis to prevent perinatal transmission, he or she must have not received 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. NOTE: For participants enrolling into cohorts IV, IV-DT, and V-DT, the HIV RNA test performed at screening may be pending at the time of enrollment. If the screening HIV RNA is less than or equal to 1000 c/mL, the participant should discontinue study drug (see the protocol for more information).
  • Demonstrated ability or willingness to swallow assigned study medications. NOTE: Film coated tablets MAY NOT be crushed or dissolved. Dispersible tablets MAY NOT be cut and must be used in five milligram intervals.
  • Parent or legal guardian able and willing to provide signed informed consent.
  • Female participants of reproductive potential, defined as having reached menarche, and who are engaging in sexual activity that could lead to pregnancy, must agree 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 must use a condom.
  • Optimized background therapy (OBT):
    • Participants who are both greater than or equal to 2 years of age and ARV-treatment experienced (meeting entry criterion) must have available at least one fully active drug for the OBT to enroll. If screening genotype testing is inconclusive, historical genotypes obtained within 1 year of screening will be considered by the Protocol Team for determination of fully active drugs.
    • Participants who are greater than or equal to 2 years of age and ARV-treatment naive (meeting entry criterion) can enroll if genotype testing has been obtained with results pending.
    • Participants less than 2 years of age (either ARV-treatment experienced or ARV treatment naïve) can enroll if genotype testing has been obtained 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 is allowable, if the participant is on atazanavir (ATV).
  • ANY known Grade 4 laboratory toxicities within 30 days prior to study entry. NOTE: Grade 4 total bilirubin is allowable, if the participant is 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 is 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 are pregnant or breastfeeding.
  • Participant is currently participating in or has participated in a study with a compound or device that is not commercially available within 30 days of signing informed consent, unless permission from both Protocol Teams is granted
  • Participant is unlikely to adhere to the study procedures, keep appointments, or is 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
  • Participant has used, or anticipates 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) are permitted. (See protocol for more information on disallowed medications.)
  • Any condition that would, in the opinion of the site investigator, place 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 includes
rifampin at the time of the screening visit. However, participants who need rifampin treatment while on DTG will be allowed to continue in P1093 provided the DTG dose is adjusted according to the protocol.

contacts and locations

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: NCT01302847

Locations

United States, California
University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program
La Jolla, California, United States, 92093-0672
Miller Children's Hosp. Long Beach CA NICHD CRS
Long Beach, California, United States, 90806
David Geffen School of Medicine at UCLA NICHD CRS
Los Angeles, California, United States, 90095-1752
Univ. of California San Francisco NICHD CRS
San Francisco, California, United States, 94143
United States, Colorado
Univ. of Colorado Denver NICHD CRS
Aurora, Colorado, United States, 80045
United States, District of Columbia
Howard Univ. Washington DC NICHD CRS
Washington, District of Columbia, United States, 20060
United States, Florida
South Florida CDTC Ft Lauderdale NICHD CRS
Fort Lauderdale, Florida, United States, 33316
USF - Tampa NICHD CRS
Tampa, Florida, United States, 33606
United States, Illinois
Rush Univ. Cook County Hosp. Chicago NICHD CRS
Chicago, Illinois, United States, 60612
Lurie Children's Hospital of Chicago (LCH) CRS
Chicago, Illinois, United States, 60614-3393
United States, Massachusetts
Children's Hosp. of Boston NICHD CRS
Boston, Massachusetts, United States, 02115
Boston Medical Center Ped. HIV Program NICHD CRS
Boston, Massachusetts, United States, 02118
United States, New York
Bronx-Lebanon Hospital Center NICHD CRS
Bronx, New York, United States, 10457
Jacobi Med. Ctr. Bronx NICHD CRS
Bronx, New York, United States, 10461
Metropolitan Hosp. NICHD CRS
New York, New York, United States, 10029
United States, North Carolina
DUMC Ped. CRS
Durham, North Carolina, United States, 27710
United States, Washington
Seattle Children's Research Institute CRS
Seattle, Washington, United States, 98101
Botswana
Gaborone CRS
Gaborone, South-East District, Botswana
Molepolole CRS
Gaborone, Botswana
Brazil
SOM Federal University Minas Gerais Brazil NICHD CRS
Belo Horizonte, Minas Gerais, Brazil, 30.130-100
Hospital Federal dos Servidores do Estado NICHD CRS
Rio de Janeiro, Brazil, 20221-903
Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
Rio de Janeiro, Brazil, 21941-612
Hosp. Geral De Nova Igaucu Brazil NICHD CRS
Rio de Janeiro, Brazil, 26030
Univ. of Sao Paulo Brazil NICHD CRS
Sao Paulo, Brazil, 14049-900
Kenya
Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS
Kericho, Kenya, 20200
South Africa
Wits RHI Shandukani Research Centre CRS
Johannesburg, Gauteng, South Africa, 2001
Umlazi CRS
Durban, KwaZulu-Natal, South Africa, 4001
Famcru Crs
Tygerberg, Western Cape Province, South Africa, 7505
Tanzania
Kilimanjaro Christian Medical Centre (KCMC)
Moshi, Tanzania
Thailand
Siriraj Hospital ,Mahidol University NICHD CRS
Bangkok, Bangkoknoi, Thailand, 10700
Chiangrai Prachanukroh Hospital NICHD CRS
Chiang Mai, Thailand, 50100
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
Chiang Mai, Thailand, 50200
Uganda
MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
Kampala, Uganda
Zimbabwe
Harare Family Care CRS
Harare, Zimbabwe

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Study Chair: Andrew Wiznia, M.D. Jacobi Medical Center
Study Chair: Theodore Ruel, M.D. University of California, San Francisco
More Information

More Information


Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)  
ClinicalTrials.gov Identifier: NCT01302847   History of Changes  
Other Study ID Numbers: P1093  
  11773  
  2010-020988-20  
  IMPAACT P1093  
Study First Received: February 15, 2011  
Last Updated: April 22, 2020  

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Integrase Inhibitors
Infant
Child
Adolescent

Additional relevant MeSH terms:
HIV Infections
Dolutegravir

ClinicalTrials.gov processed this data on July 10, 2020
This information is provided by ClinicalTrials.gov.