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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 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: August 17, 2016
Last verified: August 2016
  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
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 Dolutegravir, 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 drug-related adverse event, 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 a drug-related adverse event, 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: May 2018 (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
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).

Experimental: Cohort III: Children 2 to younger than 6 years of age
DTG granules for suspension
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).

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
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).

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: Infants 4 weeks to younger than 6 months of age
DTG granules for suspension
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).

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 at least 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 nine 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 orally once or twice daily, depending on which other ARV medications they are receiving; participants in cohorts IIB, III, IV, and V will receive DTG granules for oral suspension once or twice daily, depending on which other ARV medications they are receiving; and participants in cohorts III-DT, IV-DT, and V-DT will receive DTG dispersible tablets orally once or twice daily, depending on which other ARV medications they are receiving. (All nine 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 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. 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 a minimum of 3 years).

  Eligibility

Ages Eligible for Study:   up to 17 Years   (Child)
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)
  • Subjects must belong to one of the ARV exposure groups below:
  • 1) ARV-treatment experienced (not including receipt of ARVs as prophylaxis or PMTCT)

    • Previously took ARVs as treatment, but not currently taking ARVs:
    • Must have been off treatment for greater than or equal to 4 weeks, 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: Dose adjustments for growth or formula substitutions (i.e., switching from single agent to fixed dose combination) are permitted 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 also allowed within the 4 to 12 weeks period. OR
    • For subjects 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 PMTCT)

    • Age less than 2 years
  • If an infant has received nevirapine (NVP) as prophylaxis to prevent mother to child transmission (PMTCT), 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 subjects enrolling into cohorts IV, IV-DT, V, 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 subject 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 subjects who are of child bearing 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 two 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.
  • Optimized background therapy (OBT):

    • Subjects aged greater than or equal to 2 years of age (Cohorts I, II, III, and III-DT) must have available at least one fully active drug for the OBT to enroll. Historical genotypes obtained within 1 year of screening will be considered by the Protocol Team for determination of fully active drugs if screening genotype testing is inconclusive.
    • Subjects less than 2 years of age (Cohorts IV, IV-DT, V, and V-DT) can enroll if genotype testing has been obtained with results pending. Note: Subjects enrolled with genotype results pending but found to have no active drugs per genotype performed at screening should discontinue study drug (more information can be found in the protocol). However, such subjects who have a greater than 1 log drop in HIV RNA by 4 weeks can continue study drug with approval by the Protocol Team.

Exclusion Criteria:

  • Presence of any active AIDS-defining opportunistic infection
  • At enrollment, subject weighs 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 or greater total bilirubin is allowable, if the subject 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 subject 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 subject or subject's mother prior to delivery/cessation of breastfeeding
  • Known resistance to an integrase inhibitor
  • Women who are pregnant or breastfeeding.
  • Subject 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
  • Subject 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
  • Subject 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 subject at an unacceptable risk of injury or render the subject 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, subjects 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
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 56 Study Locations
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

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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: August 17, 2016
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
HIV Integrase Inhibitors
Anti-HIV Agents
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Dolutegravir
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on August 25, 2016