SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT02938520

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A Phase III, Randomized, Multicenter, Parallel-group, Open-Label Study Evaluating the Efficacy, Safety, and Tolerability of Long-Acting Intramuscular Cabotegravir and Rilpivirine for Maintenance of Virologic Suppression Following Switch From an Integrase Inhibitor Single Tablet Regimen in HIV-1 Infected Antiretroviral Therapy Naive Adult Participants

The First Long-Acting Injectable Regimen (FLAIR) study is being conducted to establish if human immunodeficiency virus type-1 (HIV-1) infected adult participants whose virus is virologically suppressed on an integrase inhibitor single tablet regimen (INI STR) will remain suppressed after switching to a two-drug intramuscular (IM) long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In this study, the INI STR will be limited to abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). FLAIR is a Phase 3, multi-phase, randomized, open label, active-controlled, multicenter, parallel-group, non-inferiority study in HIV-1, anti-retroviral therapy (ART)-naïve adult participants. This study is designed to demonstrate the non-inferior antiviral activity of switching to a two drug CAB LA 400 mg + RPV LA 600 mg regimen every 4 weeks (Q4W: monthly) compared to remaining on ABC/DTG/3TC over 48 weeks (4 weeks oral CAB + RPV, 44 weeks LA therapy). Participants who are HLA-B*5701 positive at Screening may enroll into the study and receive DTG plus a non-abacavir containing dual nucleoside reverse transcriptase inhibitor (NRTI) regimen. Eligible participants will enroll into the Induction Phase of the study and receive ABC/DTG/3TC for 20 weeks (Week [-20] to Day 1). Participants who have an HIV 1 ribose nucleic acid (RNA) <50 copies per milliliter (c/mL) at Week (-4) will be randomized (1:1) into the Maintenance Phase at Day 1 to either continue ABC/DTG/3TC or to discontinue ABC/DTG/3TC and begin oral therapy with CAB 30 mg + RPV 25 mg once daily for approximately 4 Weeks, followed by monthly CAB LA + RPV LA injections from visit Week 4b until study completion or withdrawal. Participants who successfully complete Week 100 (without meeting study defined withdrawal criteria and who remain virologically suppressed through Week 96: HIV-1 RNA <50 c/mL) will be given the option to switch to the LA arm in the Extension Phase (using an optional oral lead-in with CAB + RPV) or be withdrawn from the study. Participants will continue to receive injections every 4 weeks during the Extension Phase until CAB LA and RPV LA are either locally approved and commercially available, the participant no longer derives clinical benefit, the participant meets a protocol-defined reason for discontinuation, or until development of either CAB LA or RPV LA is terminated.

NCT02938520 HIV Infections
MeSH: HIV Infections

6 Interventions

Name: Cabotegravir (CAB) tablet

Description: It is a white oval shaped film coated 30 mg tablets for oral administration. CAB Tablet is composed of cabotegravir sodium, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate, and white film-coat.

Type: Drug

CAB LA + RPV LA every 4 weeks

Name: Rilpivirine (RPV) tablet

Description: It is a 25 mg tablet with off-white, round, biconvex, film-coated and debossed on one side with "TMC" and the other side with "25". Each tablet contains RPV hydrochloride, and the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose.

Type: Drug

CAB LA + RPV LA every 4 weeks

Name: Cabotegravir - Injectable Suspension (CAB LA)

Description: It is a sterile white to slightly pink suspension containing 200 mg/mL of CAB as free acid for administration by intramuscular (IM) injection. Each vial is for single-dose use containing a withdrawable volume of 2.0 mL, and does not require dilution prior to administration. CAB LA is composed of cabotegravir free acid, polysorbate 20, polyethylene glycol 3350, mannitol, and water for injection.

Type: Drug

CAB LA + RPV LA every 4 weeks

Name: Rilpivirine - Injectable Suspension (RPV LA)

Description: It is a sterile white suspension containing 300 mg/mL of RPV as the free base. The route of administration is by intramuscular (IM) injection. Each vial contains a nominal fill of 2.0 mL, and does not require dilution prior to administration. RPV LA requires refrigeration and must be protected from light. RPV LA is composed of RPV free base, poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water for injection.

Type: Drug

CAB LA + RPV LA every 4 weeks

Name: ABC/DTG/3TC STR - Tablet

Description: It is a purple, biconvex, oval, tablet debossed with "572 Tri" on one side, film-coated tablet contains abacavir sulphate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg dolutegravir, and 300 mg of lamivudine. The inactive ABC/DTG/3TC tablet ingredients include D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.

Type: Drug

ABC / DTG / 3TC (600 mg/50mg/300mg) once daily

Name: DTG Tablet

Description: It is a yellow, round, biconvex, 50 mg film-coated tablet debossed with "SV 572" on one side and "50" on the other side. Each tablet of DTG also contains the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate.

Type: Drug

ABC / DTG / 3TC (600 mg/50mg/300mg) once daily


Primary Outcomes

Description: Virologic failure (HIV-1 RNA >= 50 c/mL) based on the FDA Snapshot algorithm for the Intent-to-Treat Exposed population (subjects randomized and receiving at least one dose of investigational product during the Maintenance Phase).

Measure: Proportion of participants with a 'virologic failure' endpoint as per Food and Drug Administration (FDA) Snapshot algorithm at Week 48 (Missing, Switch or Discontinuation = Failure, Intent-to-Treat Exposed [ITT-E] population).

Time: Week 48

Secondary Outcomes

Description: It will be assessed using the FDA Snapshot algorithm at Week 48 and is a key secondary endpoint.

Measure: Proportion of participants with Plasma HIV-1 RNA <50 c/mL at Week 48

Time: Week 48

Description: It will be assessed using the FDA Snapshot algorithm at Week 96.

Measure: Proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 96

Time: Week 96

Description: It will be assessed using the FDA Snapshot algorithm at Week 48.

Measure: Proportion of participants with plasma HIV-1 RNA <200 c/mL at Week 48

Time: Week 48

Description: It will be assessed using the FDA Snapshot algorithm at Week 96

Measure: Proportion of participants with plasma HIV-1 RNA <200 c/mL at Week 96

Time: Week 96

Description: Proportion of participants with a virologic failure based on the FDA Snapshot algorithm for the Intent-to-Treat Exposed population (subjects randomized and receiving at least one dose of investigational product during the Maintenance Phase) will be assessed.

Measure: Proportion of participants with plasma HIV-1 RNA >=50 c/mL at Week 96

Time: Week 96

Description: For the purposes of clinical management in this study, virologic failure is defined as any of the following: Non-response as indicated by a less than a 1.0 log10 c/mL decrease in plasma HIV-1 RNA after 4 weeks of starting the Induction Phase, which is subsequently confirmed, unless the plasma HIV-1 RNA is < 400 c/mL (Induction Phase criteria), Rebound as indicated by two consecutive plasma HIV-1 RNA that are > 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, where the lowest HIV-1 RNA value is >=200 c/mL (Induction Phase criteria), Rebound as indicated by two consecutive plasma HIV-1 RNA levels >=200 c/mL after prior suppression to < 200 c/mL

Measure: Proportion of participants with confirmed virologic failure at Week 48

Time: Week 48

Description: For the purposes of clinical management in this study, virologic failure is defined as any of the following: Non-response as indicated by a less than a 1.0 log10 c/mL decrease in plasma HIV-1 RNA after 4 weeks of starting the Induction Phase, which is subsequently confirmed, unless the plasma HIV-1 RNA is < 400 c/mL (Induction Phase criteria), Rebound as indicated by two consecutive plasma HIV-1 RNA that are > 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, where the lowest HIV-1 RNA value is >=200 c/mL (Induction Phase criteria), Rebound as indicated by two consecutive plasma HIV-1 RNA levels >=200 c/mL after prior suppression to < 200 c/mL

Measure: Proportion of participants with confirmed virologic failure at Week 96

Time: Week 96

Description: It will be analyzed overtime, including Week 48 and Week 96

Measure: Change from Baseline in plasma HIV-1 RNA

Time: Baseline (Day 1) and up to Week 96

Description: It will be analyzed overtime, including Week 48 and Week 96

Measure: Change from Baseline in CD4+ cell counts

Time: Baseline (Day 1) and up to Week 96

Description: It will be assessed overtime, including Week 48 and Week 96 (HIV-associated conditions, acquired immunodeficiency syndrome [AIDS] and death)

Measure: Number of participants with disease progression

Time: Baseline (Day 1) and up to Week 96

Description: An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as serious adverse event (SAE). Severity will be analyzed as mild, moderate and severe AEs. It will be assessed overtime, including Week 48 and Week 96.

Measure: Number of participants with adverse events (AEs), serious AEs (SAEs) and AEs by severity

Time: Up to Week 96

Description: It will be analyzed overtime, including Week 48 and Week 96

Measure: Number of participants with laboratory abnormalities

Time: Up to Week 96

Description: Laboratory parameters includes; 1. Hematology parameters-platelet count, red blood cell (RBC) count, white blood cell (WBC) count, hemoglobin, hematocrit, mean corpuscular volume, WBC differential (includes; neutrophils, lymphocytes, monocytes, eosinophils and basophils), 2. Clinical chemistry- blood urea nitrogen, creatinine, fasting glucose, sodium, potassium, chloride, total carbon dioxide, lipase, Aspartate aminotransferase , Alanine aminotransferase, alkaline phosphatase, phosphate, total bilirubin, albumin, creatine phosphokinase, creatinine clearance will be analyzed over time, including Week 48 and Week 96

Measure: Number of participants with abnormal change from Baseline in laboratory parameters.

Time: Baseline (Day 1) and up to Week 96

Description: Participants who discontinue treatment due to AEs will be analyzed overtime, including Week 48 and Week 96

Measure: Number of participants who discontinue treatment due to AEs

Time: Up to Week 96

Description: Genotypic and phenotypic resistance to treatments; CAB, RPV, and other on-study antiretroviral treatment (ART) over time, including Week 48 and Week 96

Measure: Number of participants with treatment emergent resistance

Time: Up to Week 96

Description: Fasting lipid panel includes; Total cholesterol, high density lipid (HDL) cholesterol, low density lipid (LDL) cholesterol and triglycerides will be analyzed over time, including Week 48 and Week 96

Measure: Change from Baseline in fasting lipids

Time: Baseline (Day 1) and up to Week 96

Description: Blood sample will be obtained from participants at the given time points. Pre dose sample will be collected at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100 and 108 in IM arm and at 101 and 104a (direct to inject arm), week 104b (oral lead-in arm) for participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC.

Measure: Plasma trough concentration (Ctrough) for CAB LA arm

Time: Pre-dose at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100, 101, 104a, 104b, 108.

Description: Blood sample will be obtained from participants at the given time points. Pre dose sample will be collected at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100 and 108 in IM arm and at 101 and 104a (direct to inject arm), week 104b (oral lead-in arm) for participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC.

Measure: Plasma trough concentration (Ctrough) for RPV LA arm

Time: Pre-dose at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100, 101, 104a, 104b, 108.

Description: Blood sample will be obtained to evaluate Cmax of CAB.

Measure: Maximum concentration (Cmax) in plasma for CAB LA arm

Time: At anytime post-dose at Weeks 5, 41 and 101

Description: Blood sample will be obtained to evaluate Cmax of RPV.

Measure: Maximum concentration (Cmax) in plasma for RPV LA arm

Time: At anytime post-dose at Weeks 5, 41 and 101

Description: Blood sample will be obtained from participants at the given time points. Pre dose sample will be collected at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100 and 108 in IM arm and at 101 and 104a (direct to inject arm), week 104b (oral lead-in arm) for participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC. Post-dose sample will be collected at Weeks 5, 41 and 101 in IM arm.

Measure: Plasma area under the concentration-time curve (AUC) for CAB LA arm

Time: Pre-dose at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100, 101, 104a, 104b, 108; At anytime post-dose at Weeks 5, 41 and 101

Description: Blood sample will be obtained from participants at the given time points. Pre dose sample will be collected at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100 and 108 in IM arm and at 101 and 104a (direct to inject arm), week 104b (oral lead-in arm) for participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC. Post-dose sample will be collected at Weeks 5, 41 and 101 in IM arm.

Measure: Plasma area under the concentration-time curve (AUC) for RPV LA arm

Time: Pre-dose at Weeks 4b, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 41, 44, 48, 52, 56, 60, 96, 100, 101, 104a, 104b, 108; At anytime post-dose at Weeks 5, 41 and 101

Description: The Perception of iNjection questionnaire (PIN) will be used to assess the following dimension scores: Bother of ISRs, Leg movement, Sleep, and Injection Acceptance. Additionally, individual PIN item scores will assess pain during injection, anxiety before and after injection, willingness to be injected in the future and overall satisfaction with mode of administration over time. PIN will be assessed at weeks 5, 41, 48, 96 (or Withdrawal).

Measure: Change from Week 5 in Dimension Scores

Time: Week 5 and up to Week 96

Description: The proportion of participants considering pain and local reactions following injection to be extremely or very acceptable based on the acceptability score after first injection and over time, and changes in the PIN acceptance score within the CAB LA + RPV LA arm over time will be assessed.

Measure: Proportion of participants considering pain and local reactions following injection to be extremely or very acceptable

Time: Week 5 to Week 96

Description: HR QoL will be assessed using the HIV/AIDS targeted quality of life questionnaire (HAT-QoL) short form at Baseline (Day 1), Week 24, Week 48, Week 96 (or Withdrawal).

Measure: Change from Baseline in health related quality of life (HR QoL)

Time: Baseline (Day 1) and up to Week 96

Description: The HIV Treatment Satisfaction Questionnaire-status-12 (HIVTSQs-12) will be used to assess the "Total Treatment Satisfaction" score and individual item scores of the HIV Treatment Satisfaction Questionnaire (status version) (HIVTSQs) at Week 4b, Week 24, Week 44, Week 96 (or Withdrawal). The change from baseline (Day 1) in HIVTSQs total score at Week 44 is a key secondary endpoint.

Measure: Change from Baseline in treatment satisfaction

Time: Day 1 up to Week 96

Description: Change in treatment satisfaction over time (using the HIVTSQ change version [HIVTSQc]) at Week 48 (or Withdrawal) will be assessed.

Measure: Change in treatment satisfaction at Week 48

Time: Baseline (Day 1) and up to Week 48

Description: Overall health status will be assessed using the 12-item Short Form Survey (SF-12) at Day 1 and weeks 24, 48, 96 (or Withdrawal).

Measure: Change from Baseline in health status

Time: Baseline (Day 1) and up to Week 96

Description: Overall treatment acceptance to chronic therapy will be assessed using the "General Acceptance" dimension of the Chronic Treatment Acceptance (ACCEPT) questionnaire. It will be assessed at Day 1 and weeks 8, 24, 48, 96 (or Withdrawal).

Measure: Change from Baseline in treatment acceptance

Time: Baseline (Day 1) and up to Week 96

Description: Patient reported injection tolerability will be assessed using the Numeric Rating Scale (NRS) within the CAB LA + RPV LA arm. NRS will be assessed at weeks 4b, 5, 40, 41, and 96.

Measure: Change in tolerability of injection (for CAB LA + RPV LA)

Time: Week 4b and up to Week 96

Description: Demographic parameters and laboratory parameters will be evaluated as potential predictors of inter- and intra-participant variability for pharmacokinetic parameters. Number of subjects with identified potential predictors will be assessed.

Measure: Number of participants with potential predictors of inter- and intra-subject variability for pharmacokinetic parameters

Time: Up to Week 96

Description: Proportion of participants with HIV-1 RNA >= 50 c/mL at Week 124, with and without oral lead-in (FDA Snapshot algorithm, Extension Switch population) will be assessed.

Measure: Proportion of participants with HIV-1 RNA >= 50 c/mL at Week 124 in extension phase

Time: Up to Week 124

Description: Proportion of participants with plasma HIV-1 RNA <50 c/mL over time will be assessed.

Measure: Proportion of participants with plasma HIV-1 RNA <50 c/mL over time in extension phase

Time: Up to Week 124

Description: Proportion of participants with plasma HIV-1 RNA <200 c/mL over time will be assessed.

Measure: Proportion of participants with plasma HIV-1 RNA <200 c/mL over time in extension phase

Time: Up to Week 124

Description: Proportion of participants with confirmed virologic failure at Week 124 will be assessed.

Measure: Proportion of participants with confirmed virologic failure over time in extension phase

Time: Up to Week 124

Description: Genotypic and phenotypic resistance to treatments CAB and RPV will be assessed at Week 124.

Measure: Number of participants with treatment emergent genotypic and phenotypic resistance to CAB and RPV over time in extension phase

Time: Up to Week 124

Description: Change from Baseline in CD4+ cell counts will be assessed at Week 124.

Measure: Change from Baseline in CD4+ cell counts in extension phase

Time: Up to Week 124

Description: An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE. Severity will be analyzed as mild, moderate and severe AEs.

Measure: Number of participants with AEs, SAEs and AEs by severity in extension phase

Time: Up to Week 124

Description: Number of participants with any laboratory abnormalities in extension phase will be assessed.

Measure: Number of participants with laboratory abnormalities in extension phase

Time: Up to Week 124

Description: Laboratory parameters includes; 1. Hematology parameters-platelet count, RBC count, WBC count, hemoglobin, hematocrit, mean corpuscular volume, WBC differential (includes; neutrophils, lymphocytes, monocytes, eosinophils and basophils), 2. Clinical chemistry- blood urea nitrogen, creatinine, fasting glucose, sodium, potassium, chloride, total carbon dioxide, lipase, Aspartate aminotransferase , Alanine aminotransferase, alkaline phosphatase, phosphate, total bilirubin, albumin, creatine phosphokinase, creatinine clearance will be analyzed.

Measure: Number of participants with abnormal change from Baseline in laboratory parameters in extension phase

Time: Up to Week 124

Description: Participants who discontinue treatment due to AEs will be analyzed up to Week 124.

Measure: Number of participants who discontinue treatment due to AEs in extension phase

Time: Up to Week 124

Description: It will be assessed for for participants switching from ABC/DTG/3TC in the Extension Phase (direct to inject without oral lead-in).

Measure: Plasma CAB and RPV concentrations in the Extension Phase (direct to inject without oral lead-in)

Time: Weeks 100, 101 and 104a

Description: It will be assessed for participants switching from ABC/DTG/3TC in the Extension Phase (oral lead-in participants).

Measure: Plasma CAB and RPV concentrations in the Extension Phase (oral lead-in participants)

Time: Week 104b

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 K103N

- Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 within 28 days of the first dose of IP. - Use of medications which are associated with Torsades de Pointes - Any evidence of primary resistance to non-nuclease reverse transcriptase inhibitors (NNRTIs) (except for K103N which is allowed), or any known resistance to INIs from historical resistance test results. --- K103N ---



HPO Nodes