Safety of and Immune Response to Dolutegravir (GSK1349572) in HIV-1 Infected Infants, Children, and Adolescents

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01302847
First received: February 15, 2011
Last updated: September 8, 2014
Last verified: September 2014
  Purpose

Dolutegravir (DTG) (also known as GSK1349572) is a new drug that may slow HIV replication. It works by blocking a protein named integrase, which HIV needs in order to make copies of itself in the human body. This drug has been tested for safety and effectiveness in adults but not in children. 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) tablet formulation
Drug: DTG oral pediatric granules taken as suspension or granules
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity of GSK1349572, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants, Children and Adolescents

Resource links provided by NLM:


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 ] [ Designated as safety issue: Yes ]
    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 suspected adverse drug reaction (SADR), or death

  • Pharmacokinetics as assessed by the area under the curve (AUC) [ Time Frame: Over a single 24-hour period at the Day 5 (+5 days) study visit ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 an SADR, or death

  • Plasma HIV-1 RNA less than 400 copies/ml [ Time Frame: At Weeks 24 and 48 ] [ Designated as safety issue: No ]
  • Plasma HIV-1 RNA less than 50 copies/ml [ Time Frame: At Weeks 24 and 48 ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters [ Time Frame: At Day 5 (+5 days) and Weeks 4, 12, and 24 ] [ Designated as safety issue: No ]
    Drug concentration before dosing, after 24 hours, minimal observed concentration, maximum observed concentration, amount of time to clear the drug from the body, volume of distribution after terminal phase, and drug half-life

  • Change in CD4 and CD8 counts and percentages [ Time Frame: From baseline to Weeks 24 and 48 ] [ Designated as safety issue: No ]
  • Genotypic and phenotypic measures of resistance [ Time Frame: At baseline and at virologic failure ] [ Designated as safety issue: No ]
  • Disease progression as measured by change in Centers for Disease Control and Prevention (CDC) category [ Time Frame: From baseline to Week 48 or until virologic failure ] [ Designated as safety issue: No ]

Estimated Enrollment: 160
Study Start Date: March 2011
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort I: Adolescents 12 to younger than 18 years of age
DTG tablet formulation
Drug: Dolutegravir (DTG) tablet formulation

Stage I: Target dose of 1 mg/kg (maximum daily dose 100 mg), tablet(s) to be taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving

Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving

Experimental: Cohort IIA: Children 6 to younger than 12 years of age
DTG tablet formulation
Drug: Dolutegravir (DTG) tablet formulation

Stage I: Target dose of 1 mg/kg (maximum daily dose 100 mg), tablet(s) to be taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving

Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving

Experimental: Cohort IIB: Children 6 to younger than 12 years of age
DTG oral pediatric granules taken either as a suspension or as granules
Drug: DTG oral pediatric granules taken as suspension or granules

Stage I: Oral pediatric granules taken either as a suspension (1.6 mg/mL) or as granules, at a dose of approximately 0.64 mg/kg (maximum daily dose 64 mg) taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving. Exact dose will vary, based on participants' weight.

Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving

Experimental: Cohort III: Children 2 to younger than 6 years of age
DTG oral pediatric granules taken either as a suspension or as granules
Drug: DTG oral pediatric granules taken as suspension or granules

Stage I: Oral pediatric granules taken either as a suspension (1.6 mg/mL) or as granules, at a dose of approximately 0.64 mg/kg (maximum daily dose 64 mg) taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving. Exact dose will vary, based on participants' weight.

Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving

Experimental: Cohort IV: Children 6 months to younger than 2 years of age
DTG oral pediatric granules taken either as a suspension or as granules
Drug: DTG oral pediatric granules taken as suspension or granules

Stage I: Oral pediatric granules taken either as a suspension (1.6 mg/mL) or as granules, at a dose of approximately 0.64 mg/kg (maximum daily dose 64 mg) taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving. Exact dose will vary, based on participants' weight.

Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving

Experimental: Cohort V: Infants 4 weeks to younger than 6 months
DTG oral pediatric granules taken either as a suspension or as granules
Drug: DTG oral pediatric granules taken as suspension or granules

Stage I: Oral pediatric granules taken either as a suspension (1.6 mg/mL) or as granules, at a dose of approximately 0.64 mg/kg (maximum daily dose 64 mg) taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving. Exact dose will vary, based on participants' weight.

Stage II: Stage I-approved dose of DTG to be taken orally once or twice daily, depending on which other antiretroviral medications participants are receiving


Detailed Description:

Highly active antiretroviral therapy (HAART) combines multiple drugs from at least two different drug classes. Combining multiple drug types targets key points in the HIV life cycle and reduces the development of resistance mutations. Integrase, a viral enzyme essential for HIV replication, catalyzes the incorporation of the viral DNA into the host chromosome. Currently there is only one Food and Drug Administration (FDA)-approved integrase inhibitor. DTG is an investigational integrase inhibitor that has been tested for safety and efficacy in both treatment-naive and treatment-experienced adults. The purpose of this study is to determine the safety, best dose of, and immune response to 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 at least 3 years. Participants may be receiving other antiretroviral 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 sequential stages. Stage I will determine the safety and best dose of DTG. Stage II will then continue to study the safety of DTG at the dose chosen during Stage I and will begin to evaluate the immune response to the drug. Participants, in both stages, will be assigned to one of six cohorts depending on age. Participants in cohorts I and IIA will receive DTG tablets orally once or twice daily, depending on which other antiretroviral medications they are receiving; participants in cohorts IIB through V will receive DTG oral suspension or granules once or twice daily, depending on which other antiretroviral medications they are receiving.

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 48. 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. During this visit, blood will be drawn through a catheter so as to minimize the number of needle sticks. 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 drawn, in both stages, will be used to evaluate participants' health and pharmacokinetics. 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 8 weeks for a minimum of 3 years).

  Eligibility

Ages Eligible for Study:   up to 17 Years
Genders Eligible for Study:   Both
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)
  • For antiretroviral (ARV) treatment-experienced participants (includes those who have received therapy to interrupt maternal-infant transmission) currently not on antiretroviral therapy (ART):

    1. Must be off treatment for at least 4 weeks, AND
    2. Must have an HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening
  • For ARV treatment-experienced participants currently on ART:

    1. Must be on an unchanged, failing therapeutic regimen for at least 8 to 12 weeks before screening (less than or equal to 1 log drop in HIV-1 RNA within the previous 8 to 12 weeks before screening), AND
    2. Must have an HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening.

(Note: Dose adjustments for growth or formula substitutions [i.e., switching from single agent to fixed dose combination] are permitted during this 8 to 12 week time frame. Substitutions of one ARV within the same class for toxicity or tolerability management, or discontinuation of ARVs are also allowed during within 8 to 12 weeks.)

  • Demonstrated ability or willingness to swallow assigned study medications (tablets or pediatric formulation) (Note: Tablets MAY NOT be crushed or dissolved)
  • Parent or legal guardian able and willing to provide signed informed consent
  • Female participants who are of childbearing potential and who are engaging in sexual activity that could lead to pregnancy must use two adequate birth control methods while on study and for 2 weeks after stopping study drug; hormonal birth control alone (e.g., pills, shots, or slow-release inserts placed under/on the skin) would not be considered adequate; an effective, medically accepted barrier method of contraception (e.g., female/male condoms, diaphragm or cervical cap with a cream or gel that kills sperm [excluding nonoxydyl-9], intrauterine device [IUD], others) also must be used during the study; condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV-1 transmission
  • Males engaging in sexual activity that could lead to HIV-1 transmission must use a condom
  • Participants must have available at least one fully active drug for the planned optimized background regimen (OBR). Historical genotypes obtained within 1 year of screening will be considered by the study team for determination of fully active drugs if screening genotype testing is inconclusive.

Exclusion Criteria:

  • Presence of any active AIDS-defining opportunistic infection
  • 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, total bilirubin. A single repeat within the 30 days is allowed for eligibility determination. (Note: Grade 3 or greater total bilirubin is allowable if the participant is on 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 one 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 greater than 2X the 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 (more information can be found in the protocol)
  • 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
  • Pregnancy or breastfeeding (Note: Infants who are receiving breast milk are eligible to enroll)
  • 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 study 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
  • Any ARV-treatment naïve participant
  • 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 the study provided the DTG dose is adjusted according to the protocol.
  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

  Show 40 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Rolando Viani, MD University of California, San Diego
  More Information

Publications:
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: September 8, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Integrase Inhibitors
Infant
Child
Adolescent

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Dolutegravir
Integrase Inhibitors
HIV Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 16, 2014