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

Study Overview
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Brief Summary
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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.

Detailed Description
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DTG is an HIV medicine in the integrase inhibitor drug class. The purpose of this study was to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of DTG when used concurrently with OBT in HIV-1 infected infants, children, and adolescents. Participants in this study were evaluated for PK, safety and tolerability through 48 weeks, followed by additional long-term study follow-up that lasted for approximately 144 weeks (3 years), for a total of 192 weeks on study. This study had two stages. Stage I provided pharmacokinetics, short-term tolerability and safety data on DTG on a limited number of participants to permit dose selection for further study in Stage II. Once a Stage I dose was accepted, enrollment to Stage II began to complete enrollment to the cohort. Stage II provided longer-term safety and antiviral activity data among a larger number of participants. Infants, children and adolescents with HIV-1, aged ≥ 4 weeks to < 18 years enrolled in the age and formulation cohorts specified below: Cohort I: Adolescents ≥ 12 to <18 years of age (film-coated tablets) Cohort IIA: Children ≥ 6 to <12 years of age (film-coated tablets) Cohort IIB: Children ≥ 6 to <12 years of age (granules for suspension) Cohort III: Children ≥ 2 to < 6 years of age (granules for suspension) Cohort IV: Children ≥ 6 months to < 2 years of age (granules for suspension) Cohort III-DT: Children ≥ 2 to < 6 years of age (dispersible tablets) Cohort IV-DT: Children ≥ 6 months to < 2 years of age (dispersible tablets) Cohort V-DT: Infants ≥ 4 weeks to < 6 months (dispersible tablets) Cohorts were opened sequentially according by age group (starting with the older age group), DTG formulation, and study stage, i.e. Initial study enrollment was for Cohort I and progressed to Cohort IIA once Cohort I Stage I met the PK and safety criteria, followed by opening of Cohort IIB. Each cohort enrolled in two sequential stages: Stage I and II (the only exception is Cohort IIB, which only enrolled through Stage I). Sequential enrollment for Cohort III and IV proceeded in the same manner. Cohort V never enrolled because of the recommended changes in dosing and inclusion of enrollment weight band in the criteria for dose finding. Stage I participants had physical examinations and had blood draws for safety assessments at study visits: Day 0; Day 5 (+5 days); and Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Stage I participants also had intensive PK sampling with blood samples collected at time 0 (pre-dose), and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing. Once a Stage I treatment dose was accepted, enrollment to Stage II began to complete enrollment to the cohort. Stage II participants had physical examinations and blood draws for safety assessment at study visits: Day 0; Day 10; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Blood, plasma, and urine were collected and tested to measure immune response. Females of childbearing potential underwent pregnancy testing at screening and at every study visit. After 48 weeks, all Stage I and Stage II participants entered the long-term study follow-up and continued to receive DTG. During this time, participants had safety and/or antiviral activity assessments every 12 weeks for up to 3 years. The study was able to determine a proposed dose (i.e. optimal dose) for Cohorts I, IIA, III-DT, IV-DT, and V-DT but not for Cohorts IIB, III, and IV. Participants on the proposed dose had intensive PK sampling between days 5 and10 of DTG initiation with blood samples collected at time 0 (pre-dose), and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing. The study is closed to accrual but study follow-up for some participants in Cohorts III-DT, IV-DT and V-DT is ongoing. Summary tables were generated based on interim data freeze (March 24, 2021) for this primary submission and will be updated upon study completion.

Official Title
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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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: DTG film-coated tablets
* Drug: DTG granules for suspension
* Drug: DTG dispersible tablets
* Drug: DTG dispersible tablets
* Drug: DTG dispersible tablets


Participation Criteria
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Eligibility Criteria
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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: 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. 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.

Ages Eligible for Study
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Minimum Age: 4 Weeks
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort I<br>Adolescents 12 to younger than 18 years of age who received DTG film-coated tablets | Drug: DTG film-coated tablets<br>* 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.<br>|
| Experimental: Cohort IIA<br>Children 6 to younger than 12 years of age who received DTG film-coated tablets | Drug: DTG film-coated tablets<br>* 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.<br>|
| Experimental: Cohort IIB<br>Children 6 to younger than 12 years of age who received DTG granules for suspension | Drug: DTG granules for suspension<br>* DTG granules for suspension initial starting dose at  0.64 mg/kg with a maximum dose of 32 mg; orally once daily.<br>|
| Experimental: Cohort III<br>Children 2 to younger than 6 years of age who received DTG granules for suspension | Drug: DTG granules for suspension<br>* DTG granules for suspension initial starting dose at  0.64 mg/kg with a maximum dose of 32 mg; orally once daily.<br>|
| Experimental: Cohort IV<br>Children 6 months to younger than 2 years of age who received DTG granules for suspension | Drug: DTG granules for suspension<br>* DTG granules for suspension initial starting dose at  0.64 mg/kg with a maximum dose of 32 mg; orally once daily.<br>|
| Experimental: Cohort III-DT<br>Children 2 to younger than 6 years of age who received DTG dispersible tablets | Drug: DTG dispersible tablets<br>* 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.<br>|
| Experimental: Cohort IV-DT<br>Children 6 months to younger than 2 years of age who received DTG dispersible tablets | Drug: DTG dispersible tablets<br>* 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.<br>|
| Experimental: Cohort V-DT<br>Infants 4 weeks to younger than 6 months of age who received DTG dispersible tablets | Drug: DTG dispersible tablets<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) | 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. | From treatment initiation through Weeks 24 and 48 | 
| Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug | 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. | From treatment initiation through Weeks 24 and 48 | 
| Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug | Number of participants with permanent discontinuation of study drug due to AEs assessed by the site investigator as related to the study drug. | From treatment initiation through Weeks 24 and 48 | 
| Number of Participants Who Died | Number of participants who died were summarized | From treatment initiation through Weeks 24 and 48 | 
| PK Parameter: Area-under-the-curve From 0 to 24 Hours (AUC0-24) | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) | 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. | From treatment initiation through Week 192 | 
| Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug | 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. | From treatment initiation through Week 192 | 
| Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug | 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. | From treatment initiation through Week 192 | 
| Number of Participants Who Died | Number of participants who died were summarized. The study is ongoing. Results for extended long term safety will be posted upon study completion. | From treatment initiation through Week 192 | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 400 Copies/ml | 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. | Week 24 and Week 48 | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/ml | 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. | Week 24 and Week 48 | 
| PK Parameter: Plasma Concentration Observed at End of 24 Hour Dosing Interval (C24h) | 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. | 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 | 
| PK Parameter: Plasma Concentration Observed Immediately to Dosing of 24 Hour Dosing Interval (C0h) | 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. | 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 | 
| PK Parameter: Minimum Plasma Concentration (Cmin) | 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. | 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 | 
| PK Parameter: Maximum Plasma Concentration (Cmax) | 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. | 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 | 
| PK Parameter: Apparent Clearance (CL/F) | 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. | 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 | 
| PK Parameter: Apparent Volume of Distribution (Vz/F) | 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). | 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 | 
| PK Parameter: Terminal Half-life (t1/2) | 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. | 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 | 
| Summary of Changes in CD4 Count From Baseline | The median differences between CD4 count at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented. | Measured at Day 0, Week 24, and Week 48 | 
| Summary of Changes in CD4 Percent From Baseline | The median differences between CD4 percent at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented. | Measured at Day 0, Week 24, and Week 48 | 
| Summary of Changes in CD8 Count From Baseline | The median differences between CD8 count at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented. | Measured at Day 0, Week 24, and Week 48 | 
| Summary of Changes in CD8 Percent From Baseline | The median differences between CD8 percent at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented. | Measured at Day 0, Week 24, and Week 48 | 
| Genotypic and Phenotypic Measures of Resistance | Genotypic and phenotypic measures of resistance. The study is ongoing. Results for extended long term safety will be posted upon study completion. | From baseline through Week 192 | 
| Disease Progression as Measured by Change in Centers for Disease Control and Prevention (CDC) Category | 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. | From baseline through Week 192 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Integrase Inhibitors, Infant, Child, Adolescent