Dolutegravir Study in HIV-1 Participants Completing IMPAACT Studies P1093 and P2019

Study Overview
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Brief Summary
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Dolutegravir is a potent integrase strand transfer inhibitor. Abacavir/dolutegravir/lamivudine (ABC/DTG/3TC) is a fixed dose combination regimen containing two nucleoside reverse transcriptase inhibitors and dolutegravir. This is a phase 3b, non-randomized, open-label, multi-center, two treatment rollover study. The primary objective of this pediatric interventional study is to provide continued access to age appropriate formulations of investigational product (dolutegravir), either as Tivicay or as part of fixed dose combination ABC/DTG/3TC, for eligible participants who previously participated in parent studies P1093 (NCT01302847) or P2019 (NCT03760458) and who cannot locally access age appropriate formulations of dolutegravir or ABC/DTG/3TC in the public sector. The P1093 study was designed to evaluate the pharmacokinetics (PK), safety, tolerability and antiviral activity of dolutegravir in combination with optimized background regimens in human immunodeficiency virus type 1 (HIV-1) experienced adolescents and children as well as treatment naïve infants and toddlers. The P2019 study was designed to evaluate PK, safety, tolerability and antiviral activity of ABC/DTG/3TC dispersible and immediate release tablets in HIV-1-infected children. Participants who have tolerated investigational product in the parent studies without any significant toxicity or signs of virologic failure leading to the permanent discontinuation of investigational product and withdrawal from the parent study will be considered for this open label continued access study. Participants will receive their age/weight appropriate dose of investigational product as defined in the parent study. The duration of participation in the study will extend until age appropriate formulations of Tivicay or ABC/DTG/3TC receive local (by country) regulatory approval and are available in those countries from another source (e.g. government programs, aid programs, assistance programs, etc.) or the participant is no longer deriving benefit from treatment or meets a protocol defined reason for discontinuation. Participants will be enrolled after all screening procedures have been completed. In most cases, the Screening visit will overlap with the participants penultimate visit on the parent study (at Week 180 of P1093, or Week 36 of the P2019 study). Participants who meet all entry criteria may enroll and will be seen in the clinic every 12 weeks for a safety evaluation and to receive investigational product. It is estimated that no more than 300 participants will be enrolled in this study. Tivicay is a registered trademark of ViiV Healthcare.

Official Title
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Open-label Access to Dolutegravir for HIV-1 Infected Children and Adolescents Completing IMPAACT Studies P1093 and P2019

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Dolutegravir film-coated tablets
* Drug: Dolutegravir film-coated dispersible tablets
* Drug: ABC/DTG/3TC immediate release tablets
* Drug: ABC/DTG/3TC film-coated dispersible tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have completed participation in one of the following parent studies, for the duration noted, with continued benefit from investigational product: P1093 parent study through at least Week 180; P2019 parent study through at least Week 48. Participant with evidence of Virological Failure in either parent study must have eligibility for this rollover study discussed and agreed with the ViiV Healthcare Medical Monitor. Virological control: Participants in parent study P1093 must have virological control defined as HIV-1 ribonucleic acid (RNA) <400 copies per milliliter (c/mL) at their penultimate visit (on or after the Week 180 visit); Participants in parent study P2019 must have virological control defined as HIV-1 RNA <200 c/mL at their penultimate visit (on or after Week 36). Evidence of continued benefit from IP during the subject's participation in the parent study (P1093 or P2019) At screening, Investigators will submit a clinical summary verifying evidence of continued benefit from IP during the subject's participation in the parent study (P1093 or P2019). The summary will be submitted via the PPD ePIP system to the Study Medical Monitor who will review and confirm if the inclusion criterion has been met. Confirmation from the Study Medical Monitor is required to meet this eligibility criterion Males and Females: All participants who are engaging in sexual activity should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (example [e.g.] male condom) and on the risk of HIV transmission to an uninfected partner. Females: Female participants who are of child- bearing potential and who are engaging in sexual activity that could lead to pregnancy, must agree to use one of the acceptable birth control methods until the last dose of study medication and completion of the follow-up visit (4 weeks after the last dose). Condoms are recommended in addition, because their appropriate use is the only contraception method effective for preventing HIV-1 transmission. Parent or legal guardian or participant >=18 years of age is able and willing to provide signed informed consent. Exclusion Criteria: Confirmed virologic failure with evidence of resistance to: DTG in the P1093 parent study, or ABC, DTG or 3TC (with the exception of M184V) in the P2019 parent study Presence of any active AIDS defining opportunistic infection. Known >=grade 3 laboratory toxicities prior to study entry (e.g. neutrophil count, hemoglobin, platelets, aspartate aminotransferase [AST], alanine aminotransferase [ALT], lipase, serum creatinine and total bilirubin) would be considered exclusionary if identified at or after the penultimate parent study visit, prior to enrollment in the study... Repeat testing is allowed for eligibility determination. Previous permanent discontinuation from investigational product in the parent study due to toxicity, intolerance or pregnancy. Known ALT >=5 times the upper limit of normal (ULN), or ALT >=3 times ULN and bilirubin >=1.5 times ULN (with >35 percent [%] direct bilirubin) would be considered exclusionary if identified at or after the penultimate parent study visit, prior to enrolment in the study.. Participants with moderate to severe hepatic impairment (Class B or greater) as determined by Child-Pugh classification should be excluded. Participants positive for hepatitis B virus at any time prior to entry (hepatitis B virus surface antigen positive). Females who are pregnant or plan to become pregnant or breastfeed during the study. 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 the sponsor's medical monitor is granted. Presence of any history of allergy/sensitivity to any of the study drugs. Participants transitioning from the P2019 study (taking ABC/DTG/3TC) have evidence of being Human Leukocyte Antigen-B*5701- positive based on documented testing at any time prior to entry. Use of any disallowed medications at time of Screening. Anticipated need for Hepatitis C virus therapy with interferon or any drugs that have potential for adverse drug: drug interactions with study treatment throughout the entire study period. Participant is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study. Clinical or symptomatic evidence of pancreatitis, as determined by the clinician. Any condition (including but not limited to alcohol and drug use) 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.

Ages Eligible for Study
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Maximum Age: 25 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: Dolutegravir (Tivicay)<br>All participants will receive dolutegravir film-coated tablets or film-coated dispersible tablets at appropriate doses selected as per their age and weight bands. For those participants who were previously receiving dolutegravir in study P1093 (parent study), dolutegravir will be supplied as film-coated tablets containing 50 mg; and 5 mg film-coated dispersible tablets of dolutegravir. Participants will receive dolutegravir until age-appropriate formulations are available to them from some other source, or until participant is no longer deriving benefit from treatment, or participant is discontinued, or until development of dolutegravir is terminated. | Drug: Dolutegravir film-coated tablets<br>* Dolutegravir film-coated tablets will be provided as 50 mg tablets.<br>Drug: Dolutegravir film-coated dispersible tablets<br>* Dolutegravir film-coated dispersible tablets will be provided as 5 mg dispersible tablets. It will be administered at the appropriate dose as determined by results of the parent protocol to participants as per their age and weight band.<br>|
| Experimental: ABC/DTG/3TC<br>All participants will receive ABC/DTG/3TC immediate release tablets or film-coated dispersible tablets at appropriate doses selected as per their weight bands. For those participants who were previously receiving ABC/DTG/3TC in study P2019 (parent study), ABC/DTG/3TC will be supplied as immediate release tablets containing 600 mg, 50 mg and 300 mg of ABC, DTG, and 3TC respectively and film-coated dispersible tablets containing 60 mg, 5 mg and 30 mg of ABC, DTG, and 3TC respectively. Participants will receive ABC/DTG/3TC until age-appropriate formulations are available to them from some other source, until participant is no longer deriving benefit from treatment, or until participant is discontinued, or until development of ABC/DTG/3TC is terminated. | Drug: ABC/DTG/3TC immediate release tablets<br>* ABC/DTG/3TC immediate release tablets will be provided as biconvex, oval tablets containing 600 mg ABC, 50 mg DTG and 300 mg 3TC.<br>Drug: ABC/DTG/3TC film-coated dispersible tablets<br>* ABC/DTG/3TC dispersible tablets will be provided as biconvex, oval, film-coated tablets containing 60 mg ABC, 5 mg DTG and 30 mg 3TC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with continued access to age appropriate formulation of dolutegravir | To provide access to age appropriate formulation of investigational product (dolutegravir), either as Tivicay or as fixed dose combination ABC/DTG/3TC in an open-label protocol to eligible participants who have completed P1093 and P2019 studies respectively. | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with serious adverse events (SAEs) as a measure of safety | An SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function. | Up to 2 years | 
| Number of participants with SAEs based on the severity | An SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function. The Division of acquired immunodeficiency syndrome (DAIDS) table for grading the severity of adult and pediatric adverse events will be used to assess severity. | Up to 2 years | 
| Number of participants with any clinical or laboratory adverse events leading to discontinuation of investigational product | An adverse event is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the investigational product. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dolutegravir, Continued access study, HIV-1, ABC/DTG/3TC, Pediatric