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 July 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: July 11, 2016
Last verified: July 2016

February 15, 2011
July 11, 2016
March 2011
May 2018   (final data collection date for primary outcome measure)
  • 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)
  • 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)
Complete list of historical versions of study NCT01302847 on ClinicalTrials.gov Archive Site
  • 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 ]
  • 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 24 or until virologic failure ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents
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
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.

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).

Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
HIV Infections
  • 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.

  • 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 I: Adolescents 12 to younger than 18 years of age
    DTG film-coated tablets
    Intervention: Drug: Dolutegravir (DTG) film-coated tablets
  • Experimental: Cohort IIA: Children 6 to younger than 12 years of age
    DTG film-coated tablets
    Intervention: Drug: Dolutegravir (DTG) film-coated tablets
  • Experimental: Cohort IIB: Children 6 to younger than 12 years of age
    DTG granules for suspension
    Intervention: Drug: DTG granules for suspension
  • Experimental: Cohort III: Children 2 to younger than 6 years of age
    DTG granules for suspension
    Intervention: Drug: DTG granules for suspension
  • Experimental: Cohort III-DT: Children 2 to younger than 6 years of age
    DTG dispersible tablets
    Intervention: Drug: DTG dispersible tablets
  • Experimental: Cohort IV: Children 6 months to younger than 2 years of age
    DTG granules for suspension
    Intervention: Drug: DTG granules for suspension
  • Experimental: Cohort IV-DT: Children 6 months to younger than 2 years of age
    DTG dispersible tablets
    Intervention: Drug: DTG dispersible tablets
  • Experimental: Cohort V: Infants 4 weeks to younger than 6 months of age
    DTG granules for suspension
    Intervention: Drug: DTG granules for suspension
  • Experimental: Cohort V-DT: Infants 4 weeks to younger than 6 months of age
    DTG dispersible tablets
    Intervention: Drug: DTG dispersible tablets

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
160
Not Provided
May 2018   (final data collection date for primary outcome measure)

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.
Both
up to 17 Years   (Child)
No
United States,   Argentina,   Botswana,   Brazil,   Puerto Rico,   South Africa,   Tanzania,   Thailand,   Zimbabwe
 
NCT01302847
P1093, 11773, 2010-020988-20, IMPAACT P1093
Yes
Not Provided
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Not Provided
Study Chair: Andrew Wiznia, M.D. Jacobi Medical Center
Study Chair: Theodore Ruel, M.D. University of California, San Francisco
National Institute of Allergy and Infectious Diseases (NIAID)
July 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP