Safety and Pharmacokinetics Evaluation of Fostemsavir + (OBT) in HIV-1 Infected Children and Adolescents Who Are Failing Their cART and Have Dual- or Triple-class Antiretroviral Resistance

Study Overview
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Brief Summary
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In the SHIELD study, the study sponsor seeks to assess safety, PK and antiviral activity for children and adolescents with dual or triple class resistance. It will also assess the acceptability and swallowability of formulation among the pediatric population. The dose selection of FTR for children and adolescents ≥20kg utilized a population pharmacokinetic (POP PK) model-based approach to achieve similar adult TMR exposures following FTR 600mg BID administration with combination therapy that was demonstrated to be safe and effective in the FTR Phase 3 BRIGHTE study in HTE patients.

Official Title
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A Multicenter, Open-label, Single-arm Trial to Evaluate the Safety, Pharmacokinetics and Antiviral Activity of Fostemsavir in Combination With Optimized Background Therapy (OBT) in HIV-1 Infected Children and Adolescents Who Are Failing Their Current Combination Antiretroviral Therapy (cART) and Have Dual- or Triple-class Antiretroviral (ARV) Resistance

Conditions
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HIV Infections With Multi Drug Resistant Virus

Intervention / Treatment
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* Drug: Fostemsavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female HIV-1 infected paediatric participants from 6 years old and weighing at least 20 kg to less than 18 years of age. Antiretroviral-experienced with documented historical or baseline resistance to one or more agents in at least two classes. All resistance has to be properly documented. Failing current antiretroviral regimen with a confirmed plasma HIV-1 RNA ≥ 1000 c/mL (first value from Investigator within 6 months of screening visit, with the second value obtained from Screening labs, without a decline greater than 1 log10, and no value <1000 in between). Documented resistance to at least one component of the current failing regimen per screening resistance testing. Must have at least 1 fully active and available agent in 2 or more ARV classes, based on current and/or documented historical resistance testing, taking into account tolerability, and other safety concerns. At least two fully active agents must be a part of the initial OBT to be paired with FTR. Girls who have reached menarche must have a negative pregnancy test at screening, not be breastfeeding, and be willing to adhere to effective methods of contraception if sexually active. All participants (male or female) have to agree with recommendations for effective contraception. Exclusion Criteria: Medical History and Concurrent Diseases: Unable to comply with dosing requirements (to swallow solid pharmaceutical form of the investigational medicinal product) Unable to comply with study visits Presence of a malabsorption syndrome or other gastrointestinal dysfunction which might interfere with drug absorption or render the participant unable to take oral medication. Any clinical condition (including but not limited to recreational drug use) or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study Pregnancy and breastfeeding Physical and Laboratory Test Findings: Chronic untreated Hepatitis B virus (HBV) (however, participants with chronic treated HBV or spontaneously remitted HBV are eligible) HIV-2 infection Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), OR ALT ≥3xULN and bilirubin ≥1.5xULN (with>35% direct bilirubin) History of unstable liver disease, decompensated cirrhosis, or known biliary disorder History of congestive heart failure, or congenital/acquired prolonged QT syndrome/other cardiac diseases predisposing to prolonged QTc Hemoglobin < 8.0 g/dL Platelets < 50,000 cells/mm3 Confirmed QTcF value > 450 msec, regardless of sex, at Screening or Day 1 Current (defined as taking the medication within 14 days of Day 1) or anticipated treatment with medication considered prohibited or restricted as per Appendix II. Certain medication will be carefully evaluated as acceptable, see Appendix II. Participation in an experimental drug and/or HIV-1 vaccine trial(s) within the previous 30 days Child in governmental care, e.g. child is a ward of the state. Note: This criterion does not apply if the child is officially adopted by a family/guardian.

Ages Eligible for Study
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Minimum Age: 6 Years
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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fostemsavir<br>Fostemsavir in combination with optimized background therapy (OBT) in HIV-1 infected children and adolescents who are failing their current combination antiretroviral therapy (cART) and have dual- or triple-class ARV resistance | Drug: Fostemsavir<br>* fostemsavir in combination with optimized background therapy (OBT) in HIV-1 infected children and adolescents who are failing their current combination antiretroviral therapy (cART) and have dual- or triple-class ARV resistance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of the following events through Week 24 |  | 24 weeks | 
| AUC(0-tau) |  | at week 1, 4, 12, 24, 48 | 
| Cmax |  | at week 1, 4, 12, 24, 48 | 
| Ctau of temsavir across weight bands |  | at week 1, 4, 12, 24, 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with HIV-1 RNA <50 copies/mL | To evaluate the antiviral activity of fostemsavir + OBT | at 24 weeks and 48 weeks | 
| Change in log10 HIV-1 RNA from baseline |  | at 24 weeks and 48 weeks | 
| Occurrence of: AEs, treatment-related AEs, AEs of Grade 3 or higher, serious AEs, and AEs leading to premature study treatment discontinuation. |  | at Week 48 and at the end of Study | 
| Occurrence of WHO 3 or 4 defining events, or death |  | up to 156 weeks | 
| efficacy of fostemsavir plus OBT | changes from baseline in CD4+ T cell counts and the percentage of CD4 + T-cells | up to 156 weeks | 
| Emergence of genotypic or phenotypic resistance to Temsavir and components of OBT |  | up to 156 weeks |