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

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ClinicalTrials.gov Identifier: NCT01302847
Recruitment Status : Recruiting
First Posted : February 24, 2011
Last Update Posted : July 24, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
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 or disease Intervention/treatment Phase
HIV Infections Drug: Dolutegravir (DTG) film-coated tablets Drug: DTG granules for suspension Drug: DTG dispersible tablets Phase 1 Phase 2

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 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 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
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
Study Start Date : March 2011
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
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.





Primary Outcome Measures :
  1. 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

  2. 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 :
  1. 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

  2. Plasma HIV-1 RNA less than 400 copies/ml [ Time Frame: At Weeks 24 and 48 ]
  3. Plasma HIV-1 RNA less than 50 copies/ml [ Time Frame: At Weeks 24 and 48 ]
  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. Change in CD4 counts [ Time Frame: From baseline to Weeks 24 and 48 ]
  13. Change in CD4 percentages [ Time Frame: From baseline to Weeks 24 and 48 ]
  14. Change in CD8 counts [ Time Frame: From baseline to Weeks 24 and 48 ]
  15. Change in CD8 percentages [ Time Frame: From baseline to Weeks 24 and 48 ]
  16. Genotypic and phenotypic measures of resistance [ Time Frame: At baseline and through study completion ]
  17. 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 ]


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Ages Eligible for Study:   up to 17 Years   (Child)
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01302847


  Show 58 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

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 ( Registry Identifier: DAIDS-ES )
2010-020988-20 ( EudraCT Number )
IMPAACT P1093
First Posted: February 24, 2011    Key Record Dates
Last Update Posted: July 24, 2018
Last Verified: July 2018

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

Additional relevant MeSH terms:
HIV Infections
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
HIV Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents