Clinical trial NCT05896748: Study to Assess the Effects of Cabotegravir (CAB) and Rilpivirine (RPV) Long-Acting (LA) Injections Following Sub-cutaneous (SC) Administration Compared With Intramuscular (IM) Administration in Adult Participants Living With Human Immunodeficiency Virus (HIV-1) Infection in the FLAIR Study
Official title: An Amendment to the FLAIR Study to Evaluate the Pharmacokinetics, Safety, Tolerability, Maintenance of Virological Suppression and Patient Reported Outcomes for Participants Receiving Cabotegravir (CAB 200 mg/mL) and Rilpivirine (300 mg/mL) Long-Acting Injections Following Sub-cutaneous (SC) Administration in the Anterior Abdominal Wall SC Tissue Compared With Intramuscular (IM) Administration in the Gluteus Medius Muscle in Adult Participants Living With HIV-1 Infection in the FLAIR Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Human Immunodeficiency Virus Type 1 (HIV-1)
Keywords: Antiretroviral agent
Rilpivirine
Cabotegravir
FLAIR
Human immunodeficiency virus
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Janssen Pharmaceuticals
name: GlaxoSmithKline
First posted: 2023-06-09
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will assess the pharmacokinetics, safety, tolerability, maintenance of virological suppression and patient reported outcomes for participants receiving CAB and RPV LA injections following SC administration in the anterior abdominal wall SC tissue compared with IM administration in the gluteus medius muscle in adult participants living with HIV-1 infection in the FLAIR study (NCT02938520).


Eligibility criteria: Inclusion Criteria:

* Capable of giving signed informed consent (FLAIR and Sub-study specific informed consent)
* Eligible participants must have been on CAB LA + RPV LA regimen for a minimum of 12 months while on the FLAIR study. Any disruptions in dosing during FLAIR must be discussed with the Medical Monitor for a final determination of eligibility into the sub-study.
* Plasma HIV-1 RNA \<50 c/mL at Sub-Study Screening.
* History of Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) vaccination (or booster dosing) is allowed prior to sub study screening and will be allowed during the conduct of the sub-study as long as the vaccine (or boosters) are not administered within 14 days of virologic load (VL) assessments.
* HIV-1 infected antiretroviral therapy (ART)-naive men or women aged 18 years or greater at the time of signing the informed consent.
* HIV-1 infection as documented by Screening plasma HIV-1 RNA \>=1000 cubic (c)/mL
* Antiretroviral-naive (less than or equal to (\<=10) days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection). Any previous exposure to an HIV integrase inhibitor or non-nucleoside reverse transcriptase inhibitor will be exclusionary
* Female Participants: A female participant is eligible to participate if she is not pregnant at Screening and first day of Induction Phase (as confirmed by a negative serum human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies

  1. Non-reproductive potential defined as:

     * Pre-menopausal females with one of the following:
     * Documented tubal ligation;
     * Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion;
     * Hysterectomy; Documented Bilateral Oophorectomy;
     * Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment.
  2. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication, throughout the study, and for at least 30 days after discontinuation of all oral study medications and for at least 52 weeks after discontinuation of CAB LA and RPV LA.
* The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception.
* All participants in the study 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.
* In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

* More than 1 plasma HIV-1 RNA measurement 50 c/mL to \<200 c/mL (virologic blip) within 24 weeks prior to sub-study Screening visit that was investigated and found NOT to be associated with alternative causes including recent vaccinations received within 4 weeks of the viral blip or NOT associated with intercurrent illness that developed within 2-4 weeks of the viral blip.
* All viral blips that occurred within 24 weeks prior to screening should be discussed with the Medical Monitor to assess whether such a participant can enroll into the sub-study.
* Any Suspected Virologic Failure (HIV-RNA 200 c/mL) as defined during FLAIR study.
* Participants planning to require oral bridging during participation in the FLAIR sub study.
* The participant has a tattoo or any dermatological condition overlying the abdominal or gluteal regions which may interfere with interpretation of injection site reactions.
* Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the participant unable to receive study medication.
* Any woman of childbearing potential who is pregnant at screening will be excluded from entering the sub-study.
* Any women of childbearing potential who gets pregnant while on the sub-study will have to be withdrawn from the sub-study but will be allowed to transition back to the parent FLAIR study if a pregnancy specific Informed Consent Form (ICF) is signed, and commercial access is not available at the time of pregnancy
* Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed during the study.
* Any evidence at Screening of an active Centers for Disease and Prevention Control (CDC) Stage 3 disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy or historic or current cluster of differentiation 4+ (CD4+) cell count \<200 cells/ cubic millimeter (mm\^3) are not exclusionary.
* Participants with known moderate to severe hepatic impairment.
* Any pre-existing physical or mental condition (including substance abuse disorder) which, in the opinion of the Investigator, may interfere with the participant's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participant.
* Participants determined by the Investigator to have a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder. A participant with a prior history of seizure may be considered for enrollment if the Investigator believes the risk of seizure recurrence is low. All cases of prior seizure history should be discussed with the Medical Monitor prior to enrollment.
* Participant who, in the investigator's judgment, poses a significant suicide risk. Participant's recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk.
* The participant has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.
* Evidence of Hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti HBc), Hepatitis B surface antibody (anti-HBs) and HBV Deoxyribonucleic acid (DNA) as follows:

  * Participants positive for HBsAg are excluded;
  * Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.
* Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded, however Investigators must carefully assess if therapy specific for HCV infection is required; participants who are anticipated to require HCV treatment prior to Week 48 of the Maintenance Phase must be excluded. HCV treatment on study may be permitted post Week 48, following consultation with the Medical Monitor. Participants with HCV co-infection will be allowed entry into Phase 3 studies if:

  * Liver enzymes meet entry criteria;
  * HCV Disease has undergone appropriate work-up, HCV is not advanced, and will not require treatment prior to the Week 48 visit. Additional information (where available) on participants with HCV co-infection at screening should include results from any liver biopsy, fibroscan, ultrasound, or other fibrosis evaluation, history of cirrhosis or other decompensated liver disease, prior treatment, and timing/plan for HCV treatment.
  * In the event that recent biopsy or imaging data is not available or is inconclusive, the Fib-4 score will be used to verify eligibility.
  * A Fib-4 score \> 3.25 is exclusionary;
  * Fib-4 scores 1.45 - 3.25 requires Medical Monitor consultation. Fibrosis 4 Score Formula: (Age \* AST)/ (Platelets \* \[square root of ALT\]).
* Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
* History of liver cirrhosis with or without hepatitis viral co-infection.
* Ongoing or clinically relevant pancreatitis.
* All participants will be screened for syphilis (rapid plasma reagin \[RPR\]). Participants with untreated syphilis infection, defined as a positive RPR without clear documentation of treatment, are excluded. Participants with a positive RPR test who have not been treated may be rescreened at least 30 days after completion of antibiotic treatment for syphilis.
* Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the study Medical Monitor for inclusion of the participant prior to enrollment.
* Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug or render the participant unable to receive study medication.
* History or presence of allergy or intolerance to the study drugs or their components or drugs of their class. In addition, if heparin is used during pharmacokinetic (PK) sampling, participants with a history of sensitivity to heparin or heparin-induced thrombocytopenia must not be enrolled.
* Current or anticipated need for chronic anti-coagulation.
* ALT \>=3 times upper limit normal (ULN).
* Clinically significant cardiovascular disease, as defined by history/evidence of congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically significant cardiac disease.
* Exposure to an experimental drug and/or experimental vaccine within 28 days or 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of investigational product (IP).
* Treatment with any of the following agents within 28 days of Screening:

  * radiation therapy;
  * cytotoxic chemotherapeutic agents;
  * tuberculosis (TB) therapy, with the exception of treatment of latent TB with isoniazid;
  * Immunomodulators that alter immune responses (such as chronic systemic corticosteroids, interleukins, or interferons).
* Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
* 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 Integrase inhibitors from historical resistance test results.
* Participants who are human leukocyte antigen (HLA)-B\*5701 positive and are unable to use an NRTI backbone that does not contain abacavir (participants who are HLA-B\*5701 positive may be enrolled if they use a nuclease reverse transcriptase inhibitors (NRTI) backbone that does not contain abacavir; HLA-B\*5701 positive participants may be excluded from the study if local provision of an alternate NRTI backbone is not possible).
* Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening Phase to verify a result.
* Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the participant's participation in the study of an investigational compound.
* Participant has estimated creatinine clearance \<50 mL/minute (min)/1.73 meter square (m\^2) via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
* Participants who are currently participating in or anticipate to be selected for any other interventional study.

Primary outcomes:
measure: Concentrations at the End of the Dosing Interval (Ctau) of CAB LA 400 mg Following Administration CAB LA + RPV LA
timeFrame: At screening Week-4; Day 1, Week 4, Week 8 for SC injections; and Week 12 for Return to IM gluteal injection
measure: Ctau of RPV LA 600 mg Following Administration of CAB LA + RPV LA
timeFrame: At screening Week-4; Day 1, Week 4, Week 8 for SC abdominal injections; and Week 12 for Return to IM gluteal injection
measure: Maximum Plasma Concentration (Cmax) One Week Post Dose of CAB LA 400 mg Following Administration of CAB LA + RPV LA
timeFrame: At screening week -3; Week 1, Week 5, Week 9 for SC abdominal injections; and Week 13 for Return to IM gluteal injection
measure: Cmax One Week Post Dose of RPV LA 600 mg Following Administration of CAB LA + RPV LA
timeFrame: At screening Week -3; Week 1, Week 5, Week 9 for SC abdominal injections; and Week 13 for Return to IM gluteal injection
measure: Area Under the Plasma Concentration-time Curve From 0 Through the End of Dosing Interval (AUC[0-tau]) of CAB LA 400 mg Following Administration of CAB LA + RPV LA
timeFrame: At screening Week-4; Day 1, Week 4, Week 8 for SC abdominal injections; and Week 12, for Return to IM gluteal injection
measure: AUC[0-tau] of RPV LA 600 mg Following Administration of CAB LA + RPV LA
timeFrame: At screening Week-4; Day 1, Week 4, Week 8 for SC abdominal injections; and Week 12 for Return to IM gluteal injection
Secondary outcomes:
measure: Number of Participants With Injection Site Reactions (ISRs) and by Maximum Severity - SC Injection Phase
timeFrame: From Day 1 Up to Week 12
measure: Number of Participants With Adverse Events of Special Interest (AESI) Based on Maximum Severity Grade - SC Injection Phase
timeFrame: From Day 1 Up to Week 12
measure: Number of Participants Who Discontinue Treatment Due to ISRs and AESIs - SC Injection Phase
timeFrame: From Day 1 Up to Week 12
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) From the Last IM Gluteal Injection in Screening Phase to the End of the SC Injection Phase
timeFrame: From Week -4 Up to Week 12
measure: Change From Baseline in Chemistry Parameters Following Administration of SC Injection: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Creatine Phosphokinase
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Chemistry Parameters Following Administration of SC Injection: Creatinine, Total Bilirubin
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Chemistry Parameters Following Administration of SC Injection: Glucose, Potassium, Sodium, Blood Urea Nitrogen, Carbon Dioxide, Chloride, Phosphate
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Chemistry Parameter Following Administration of SC Injection: Albumin
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Chemistry Parameters Following Administration of SC Injection: Lipase
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Chemistry Parameters Following Administration of SC Injection: Creatinine Clearance
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Fasting Lipid Panels Following Administration of SC Injection: Total Cholesterol, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, Triglycerides
timeFrame: Baseline (screening Week -4), and CFB at Week 12
measure: Change From Baseline in Hematology Parameters Following Administration of SC Injection: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelet Count
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Hematology Parameter Following Administration of SC Injection: Red Blood Cell (RBC) Count
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Hematology Parameter Following Administration of SC Injection: Hemoglobin
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Hematology Parameter Following Administration of SC Injection: Hematocrit
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Change From Baseline in Hematology Parameter Following Administration of SC Injection: Mean Corpuscular Volume
timeFrame: Baseline (screening Week -4), Change from baseline (CFB) at Week 4, CFB at Week 8, and CFB at Week 12
measure: Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) Less Than (<) 50 Copies Per Milliliter (c/mL) Using the Food and Drug Administration (FDA) Snapshot Algorithm - SC Injection Phase
timeFrame: Baseline (Day 1) and at Weeks 4, 8, 12
measure: Percentage of Participants With Plasma HIV RNA Greater Than Equal to (>=) 50 c/mL as Per FDA Snapshot Algorithm - SC Injection Phase
timeFrame: Baseline (Day 1) and at Weeks 4, 8, 12
measure: Percentage of Participants With Protocol Defined Confirmed Virologic Failure (CVF) of >=200 c/mL - SC Injection Phase
timeFrame: From Day 1 Up to Week 12
measure: Number of Participants With Treatment Emergent Phenotypic Resistance - SC Injection Phase
timeFrame: From Day 1 Up to Week 12
measure: Number of Participants With Treatment Emergent Genotypic Resistance - SC Injection Phase
timeFrame: From Day 1 Up to Week 12
measure: Number of Participants With Post-injection Pain Assessment Using Numeric Rating Scale (NRS) on Week-3 - Screening/IM Gluteal Injection Phase
timeFrame: Week -3 (Baseline)
measure: Number of Participants With Post-injection Pain Assessment Using Numeric Rating Scale (NRS) on Week 1 - SC Injection Phase
timeFrame: Day 1
measure: Number of Participants With Post-injection Pain Assessment Using NRS on Week 9- SC Injection Phase
timeFrame: Week 9
measure: Number of Participants With Post-injection Pain Assessment Using NRS on Week 13- Return to IM Gluteal Injection Phase
timeFrame: Week 13
measure: HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) Total Score -Screening/IM Gluteal Injection Phase
timeFrame: Week -3 (Baseline)
measure: HIVTSQs Total Score -SC Injection Phase
timeFrame: At Week 9
measure: HIVTSQs Total Score -Return to IM Gluteal Injection Phase
timeFrame: At Week 17
measure: Change From Baseline in HIVTSQs Individual Item Scores at Indicated Time Points -SC Injection Phase
timeFrame: Baseline (Week -3) and up to Week 9
measure: Change From Baseline in HIVTSQs Individual Item Scores at Indicated Time Points - Return to IM Gluteal Injection Phase
timeFrame: Baseline (Week -3) and up to Week 17
measure: Change From Study Week 9 to Study Week 17 in HIVTSQs Individual Item Scores at Indicated Time Points - Return to IM Gluteal Injection Phase
timeFrame: Week 9 and Week 17
measure: HIV Treatment Satisfaction Questionnaire - Change Version (HIVTSQc) Individual Item Score at Indicated Time Points -SC Injection Phase
timeFrame: From Week -4 up to Week 9
measure: HIVTSQc Total Score at Indicated Time Points -SC Injection Phase
timeFrame: From Week -4 up to Week 9
measure: Perception of Injection (PIN) Questionnaire in Domain Scores and Individual Item Scores- Screening/IM Gluteal Injection Phase
timeFrame: At Week -3 (Baseline)
measure: PIN Questionnaire in Domain Scores and Individual Item Scores at Indicated Time Points - SC Injection Phase
timeFrame: At Week 1 and Week 9
measure: PIN Questionnaire in Domain Scores and Individual Item Scores - Return to IM Gluteal Injection Phase
timeFrame: At Week 13
measure: Change From Baseline to the PIN Questionnaire in Domain Scores and Individual Item Scores at Indicated Time Points - SC Injection Phase
timeFrame: Change from Baseline (Week -3) at Week 1 and Week 9
measure: Change From Baseline to the PIN Questionnaire in Domain Scores and Individual Item Scores at Indicated Time Points - Return to IM Gluteal Injection Phase
timeFrame: Change from Baseline (Week -3) at Week 13
measure: Number of Participants With Their Treatment Preference Assessed Using Preference Questionnaire on Week 9 - SC Injection Phase
timeFrame: Up to Week 9
measure: Number of Participants With Their Treatment Preference Assessed Using Preference Questionnaire on Week 17 - Return to IM Gluteal Injection Phase
timeFrame: Up to Week 17
Other outcomes:
Locations:
city: Macon
country: United States
facility: GSK Investigational Site
state: Georgia
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Bellaire
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Fort Worth
country: United States
facility: GSK Investigational Site
state: Texas
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Bloemfontein
country: South Africa
facility: GSK Investigational Site
state: Free State
city: Wentworth
country: South Africa
facility: GSK Investigational Site
state: KwaZulu- Natal
city: Durban
country: South Africa
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Bilbao
country: Spain
facility: GSK Investigational Site
city: Elche
country: Spain
facility: GSK Investigational Site
city: Ferrol
country: Spain
facility: GSK Investigational Site
city: Granada
country: Spain
facility: GSK Investigational Site
city: La Laguna-Tenerife
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Murcia
country: Spain
facility: GSK Investigational Site
city: Murcia
country: Spain
facility: GSK Investigational Site
city: Palma De Mallorca
country: Spain
facility: GSK Investigational Site
city: San Sebastian de los Reyes
country: Spain
facility: GSK Investigational Site
city: Santa Cruz de Tenerife
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: Leeds
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: