We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01302847
Recruitment Status : Active, not recruiting
First Posted : February 24, 2011
Results First Posted : March 22, 2022
Last Update Posted : March 22, 2022
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 evaluated the pharmacokinetics (PK), safety, tolerability of and immune response to DTG when used concurrently with optimized background therapy (OBT) in HIV-1 infected infants, children, and adolescents.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: DTG film-coated tablets Drug: DTG granules for suspension Drug: DTG dispersible tablets Phase 1 Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 181 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
Actual Study Start Date : April 20, 2011
Actual Primary Completion Date : January 20, 2021
Estimated Study Completion Date : January 20, 2024

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 who received DTG film-coated tablets
Drug: DTG film-coated tablets
DTG film-coated tablets initial starting dose at ~1 mg/kg with a maximum dose of 50 mg; orally once daily. Participants weighing ≥ 35kg received the proposed dose of 50 mg of DTG film-coated tablets.

Experimental: Cohort IIA
Children 6 to younger than 12 years of age who received DTG film-coated tablets
Drug: DTG film-coated tablets
DTG film-coated tablets initial starting dose at ~1 mg/kg with a maximum dose of 50 mg; orally once daily. Participants weighing ≥ 35kg received the proposed dose of 50 mg of DTG film-coated tablets.

Experimental: Cohort IIB
Children 6 to younger than 12 years of age who received DTG granules for suspension
Drug: DTG granules for suspension
DTG granules for suspension initial starting dose at ~0.64 mg/kg with a maximum dose of 32 mg; orally once daily.

Experimental: Cohort III
Children 2 to younger than 6 years of age who received DTG granules for suspension
Drug: DTG granules for suspension
DTG granules for suspension initial starting dose at ~0.64 mg/kg with a maximum dose of 32 mg; orally once daily.

Experimental: Cohort IV
Children 6 months to younger than 2 years of age who received DTG granules for suspension
Drug: DTG granules for suspension
DTG granules for suspension initial starting dose at ~0.64 mg/kg with a maximum dose of 32 mg; orally once daily.

Experimental: Cohort III-DT
Children 2 to younger than 6 years of age who received DTG dispersible tablets
Drug: DTG dispersible tablets

DTG dispersible tablets initial starting dose of ~0.8 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was:

Weight band 3 to <6 kg: 5 mg DTG dispersible tablets; Weight band 6 to <10 kg: 15 mg DTG dispersible tablets; Weight band 10 to <14 kg: 20 mg DTG dispersible tablets; Weight band 14 to <20 kg: 25 mg DTG dispersible tablets; Weight band ≥20 kg: 30 mg DTG dispersible tablets.


Experimental: Cohort IV-DT
Children 6 months to younger than 2 years of age who received DTG dispersible tablets
Drug: DTG dispersible tablets

DTG dispersible tablets initial starting dose of ~1.25 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was:

Weight band 3 to <6 kg: 5 mg DTG dispersible tablets; Weight band 6 to <10 kg: 15 mg DTG dispersible tablets; Weight band 10 to <14 kg: 20 mg DTG dispersible tablets; Weight band 14 to <20 kg: 25 mg DTG dispersible tablets; Weight band ≥20 kg: 30 mg DTG dispersible tablets.


Experimental: Cohort V-DT
Infants 4 weeks to younger than 6 months of age who received DTG dispersible tablets
Drug: DTG dispersible tablets

DTG dispersible tablets initial starting dose of ~1.25 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was:

Weight band 3 to <6 kg: 5 mg DTG dispersible tablets; Weight band 6 to <10 kg: 15 mg DTG dispersible tablets.





Primary Outcome Measures :
  1. Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) [ Time Frame: From treatment initiation through Weeks 24 and 48 ]

    All grade 3 or higher signs/symptoms, diagnoses, and laboratory AEs were included.

    AE grading was based on DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009).

    A 2-sided 95% Confidence Interval (CI) was calculated for the percentage using the binominal exact method.


  2. Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug [ Time Frame: From treatment initiation through Weeks 24 and 48 ]

    All grade 3 or higher signs/symptoms, diagnoses, and laboratory AEs were included.

    AE grading was based on DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009).

    A 2-sided 95% Confidence Interval (CI) was calculated for the percentage using the binominal exact method.


  3. Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug [ Time Frame: From treatment initiation through Weeks 24 and 48 ]
    Number of participants with permanent discontinuation of study drug due to AEs assessed by the site investigator as related to the study drug.

  4. Number of Participants Who Died [ Time Frame: From treatment initiation through Weeks 24 and 48 ]
    Number of participants who died were summarized

  5. PK Parameter: Area-under-the-curve From 0 to 24 Hours (AUC0-24) [ Time Frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing ]
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). AUC0-24 was determined using linear up-log down estimation in WinNonlin.


Secondary Outcome Measures :
  1. Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) [ Time Frame: From treatment initiation through Week 192 ]

    Percentage and exact 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs. AEs were graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009 (see References). All grade 3 or higher signs, symptoms, and laboratory toxicities were included.

    The study is ongoing. Results for extended long term safety will be posted upon study completion.


  2. Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug [ Time Frame: From treatment initiation through Week 192 ]

    Percentage and exact 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs assessed by the site investigator as related to the study drug.

    The study is ongoing. Results for extended long term safety will be posted upon study completion.


  3. Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug [ Time Frame: From treatment initiation through Week 192 ]

    Number of participants with permanent discontinuation of study drug due to AEs assessed by the site investigator as related to the study drug.

    The study is ongoing. Results for extended long term safety will be posted upon study completion.


  4. Number of Participants Who Died [ Time Frame: From treatment initiation through Week 192 ]
    Number of participants who died were summarized. The study is ongoing. Results for extended long term safety will be posted upon study completion.

  5. Percentage of Participants With Plasma HIV-1 RNA Less Than 400 Copies/ml [ Time Frame: Week 24 and Week 48 ]
    Virologic responses were assessed at weeks 24 and 48 as percentages of participants and exact 95% Confidence Interval (CI). The virologic response or virologic failure was defined and calculated according to FDA's Snapshot algorithm.

  6. Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/ml [ Time Frame: Week 24 and Week 48 ]
    Virologic responses were assessed at weeks 24 and 48 as percentages of participants and exact 95% Confidence Interval (CI), The virologic response or virologic failure was defined and calculated according to FDA's Snapshot algorithm.

  7. PK Parameter: Plasma Concentration Observed at End of 24 Hour Dosing Interval (C24h) [ Time Frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing ]
    Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). C24h was taken directly from the observed concentration-time data or estimated using the elimination rate constant.

  8. PK Parameter: Plasma Concentration Observed Immediately to Dosing of 24 Hour Dosing Interval (C0h) [ Time Frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing ]
    Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). C0h was taken directly from the observed concentration-time data.

  9. PK Parameter: Minimum Plasma Concentration (Cmin) [ Time Frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing ]
    Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ) and were performed in real-time. Cmin was taken directly from the observed concentration-time data.

  10. PK Parameter: Maximum Plasma Concentration (Cmax) [ Time Frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing ]
    Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). Cmax was taken directly from the observed concentration-time data.

  11. PK Parameter: Apparent Clearance (CL/F) [ Time Frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing ]
    Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). CL/F was calculated as Dose/AUC.

  12. PK Parameter: Apparent Volume of Distribution (Vz/F) [ Time Frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing ]
    Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). Vz/F was calculated as Dose/(ke x AUC).

  13. PK Parameter: Terminal Half-life (t1/2) [ Time Frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing ]
    Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). t1/2 was calculated as ln(2)/ke.

  14. Summary of Changes in CD4 Count From Baseline [ Time Frame: Measured at Day 0, Week 24, and Week 48 ]
    The median differences between CD4 count at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.

  15. Summary of Changes in CD4 Percent From Baseline [ Time Frame: Measured at Day 0, Week 24, and Week 48 ]
    The median differences between CD4 percent at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.

  16. Summary of Changes in CD8 Count From Baseline [ Time Frame: Measured at Day 0, Week 24, and Week 48 ]
    The median differences between CD8 count at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.

  17. Summary of Changes in CD8 Percent From Baseline [ Time Frame: Measured at Day 0, Week 24, and Week 48 ]
    The median differences between CD8 percent at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.

  18. Genotypic and Phenotypic Measures of Resistance [ Time Frame: From baseline through Week 192 ]
    Genotypic and phenotypic measures of resistance. The study is ongoing. Results for extended long term safety will be posted upon study completion.

  19. Disease Progression as Measured by Change in Centers for Disease Control and Prevention (CDC) Category [ Time Frame: From baseline through Week 192 ]

    Disease progression as measured by change in Centers for Disease Control and Prevention (CDC) category.

    The study is ongoing. Results for extended long term safety will be posted upon study completion.




Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   4 Weeks to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed HIV-1 infection, defined as positive results from two samples collected at different time points (see protocol for more information)
  • Participant belonged 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 taking ARVs at study screening.
      • Had been off treatment for greater than or equal to 4 weeks prior to screening, OR
      • At screening, taking ARVs for treatment but failing.
      • Was 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). 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 had received nevirapine (NVP) as prophylaxis to prevent perinatal transmission, he or she did not receive 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.
  • Demonstrated ability or willingness to swallow assigned study medications.
  • Parent or legal guardian were able and willing to provide signed informed consent.
  • Female participants of reproductive potential, defined as having reached menarche, and who were engaging in sexual activity that could lead to pregnancy, agreed 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 agreed to use a condom.
  • Agreed to stay on optimized background therapy (OBT) while on study:

    • Participants who at screening were greater than or equal to 2 years of age and ARV-treatment experienced, had at screening at least one fully active drug for the OBT.
    • Participants who were greater than or equal to 2 years of age and ARV-treatment naïve, had genotype testing at screening/entry even with results pending.
    • Participants less than 2 years of age (either ARV-treatment experienced or ARV treatment naïve), had genotype testing at screening/entry even 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 was allowable, if the participant was on atazanavir (ATV).
  • ANY known Grade 4 laboratory toxicities within 30 days prior to study entry. NOTE: Grade 4 total bilirubin was allowable, if the participant was 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 was 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 were pregnant or breastfeeding
  • At screening/entry, participating in or had participated in a study with a compound or device that was not commercially available within 30 days of signing informed consent, unless permission from both Protocol Teams was granted
  • Participant was unlikely to adhere to the study procedures, keep appointments, or was 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
  • At screening/entry had used, or anticipated 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) were permitted. (See protocol for more information on disallowed medications.)
  • Any condition that in the opinion of the site investigator, placed 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 included rifampin at the time of the screening visit. However, participants who needed rifampin treatment while on DTG were allowed to continue in P1093 provided the DTG dose was 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


Locations
Show Show 33 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Layout table for investigator information
Study Chair: Andrew Wiznia, M.D. Jacobi Medical Center
Study Chair: Theodore Ruel, M.D. University of California, San Francisco
  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):
Study Protocol: Protocol V5.0  [PDF] July 12, 2018
Informed Consent Form  [PDF] July 12, 2018

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01302847    
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
Results First Posted: March 22, 2022
Last Update Posted: March 22, 2022
Last Verified: February 2022
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Integrase Inhibitors
Infant
Child
Adolescent
Additional relevant MeSH terms:
Layout table for MeSH terms
HIV Infections
Blood-Borne Infections
Communicable Diseases
Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases