Phase 2b, Open-label, Multicenter, Rollover Study to Assess Antiviral Activity and Safety of Long-acting (LA) Cabotegravir (CAB) Plus LA Rilpivirine (RPV), Administered Every 2 Months (Q2M), in Human Immunodeficiency Virus (HIV)-Positive Participants From the LATTE Study

ViiV Healthcare

Status and phase: Completed; Phase 2

Conditions: HIV Infections

Treatments: Drug: DTG; Drug: CAB LA; Drug: RPV LA; Drug: RPV

Study type: Interventional

Funder types: Industry

Identifiers

NCT03639311

209035

Details and patient eligibility

About

This study (POLAR), is designed to assess the antiviral activity and safety of CAB LA plus RPV LA, administered Q2M, in approximately 100 adult HIV-1 infected, antiretroviral therapy (ART) experienced participants. Participants will rollover from the NCT01641809 (LATTE) study, who have completed minimum duration of Week 312 and with demonstrated HIV-1 ribonucleic acid (RNA) suppression (less than [<]50 copies (c) per milliliter [mL]), while receiving a two-drug regimen consisting of once-daily oral CAB at 30 milligram (mg) plus RPV at 25 mg. The participants will be offered the option to switch to the LA, intramuscular injections of CAB LA plus RPV LA, Q2M or the oral fixed dose combination (FDC) of dolutegravir (DTG) plus RPV, for the continued maintenance of HIV-1 RNA suppression, known as the Maintenance Phase (From Day 1 to Commercial Approval). Duration of study will vary from country to country, until regimen receives regulatory approval and becomes commercially available. The study plans to enroll approximately 100 participants. Any participant who receives at least one dose of CAB LA and/or RPV LA and discontinues the CAB LA plus RPV LA regimen for any reason will enter a 52-week Long-Term Follow-Up (LTFU) phase. Those participants must remain on suppressive highly active antiretroviral therapy (HAART) for at least 52 weeks after the last dose of CAB LA and or RPV LA.

Enrollment: 97 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Aged 18 years or older (or >=19 where required by local regulatory agencies), at the time of signing the informed consent.

• A female participant is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin [hCG] test at Day 1), not lactating, and at least with one of following conditions:

  (a) Non-reproductive potential defined as: (i) Pre-menopausal females with one of the conditions as documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy.

(ii) 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 (refer to laboratory reference ranges for confirmatory levels)]. 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 enrolment.

(b) 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, 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 the methods of contraception.
• Capable of giving signed informed consent.
• Must have been on oral CAB 30 mg plus RPV 25 mg regimen through at minimum Week 300 of the LATTE study as per LATTE protocol dosing requirements and until Day 1 of the POLAR study. Any disruptions in dosing during LATTE must be discussed with the Medical Monitor for a final determination of eligibility.
• Plasma HIV-1 RNA <50 c/mL at Week 300. If participant has plasma HIV-1 RNA >= 50 c/mL at Week 300 in LATTE, a single repeat to determine eligibility may be allowed ONLY after consultation with the medical monitor.

Exclusion criteria

• During the last 6 months of participation in LATTE, consecutive (2 or more sequential) plasma HIV-1 RNA measurements >=50 c/mL.
• During the last 6 months of participation in LATTE, any HIV-1 RNA measurement >=200 c/mL.
• Any evidence of a current Center for Disease Control and Prevention (CDC) Stage 3 disease [CDC, 2014], except cutaneous Kaposi's sarcoma not requiring systemic therapy.
• Participants with moderate to severe hepatic impairment determined by Child-Pugh classification.
• Any pre-existing physical or mental condition (including substance use 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 enrolment if the Investigator believes the risk of seizure recurrence is low.
• Participants who, in the investigator's judgment, pose a significant suicide risk. Participant's recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk.
• Participants 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 for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B surface antibody (anti-HBs) and HBV 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 within 12 months must be excluded. (HCV treatment on study may be permitted, following consultation with the medical monitor).
• Participants with HCV co-infection will be allowed entry into this study if: Liver enzymes meet entry criteria; HCV Disease has undergone appropriate work-up, and is not advanced.
• 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 inconclusive, the fibrosis- 4 (Fib-4) score will be used to verify eligibility where Fib-4 score >3.25 is exclusionary; Fib-4 scores 1.45 - 3.25 requires Medical Monitor consultation where the Fibrosis 4 Score Formula: age multiplied by aspartate amino transferase (AST) divided by platelets multiplied by square of alanine aminotransferase (ALT).
• Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or cirrhosis), 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.
• 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.
• Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the participant prior to randomization.
• 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.
• 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 with the exception of the use of low dose acetylsalicylic acid (less than or equal to [<=]325 mg) or hereditary coagulation and platelet disorders such as hemophilia or Von Willebrand Disease.
• Corrected QT interval (QTc (Bazett)) >450 millisecond (msec) or QTc (Bazett) >480 msec for participants with bundle branch block.
• Any verified Grade 4 laboratory abnormality over the last 6 months in LATTE. A single repeat test is allowed to verify a result.
• Any acute laboratory abnormality over the last 6 months in LATTE, which, in the opinion of the investigator, would preclude the participant's participation in the study of an investigational compound.
• ALT>=5 times upper limit of normal (ULN) or ALT >= 3 times ULN and bilirubin >= 1.5 times ULN (with >35 percent [%] direct bilirubin) over the last 6 months in LATTE.
• Exposure to an experimental drug (with the exception of those in the LATTE study including CAB and RPV) or experimental vaccine within either 30 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to Day 1 of this study.
• Treatment with any of the following agents within 28 days of Day 1: radiation therapy, cytotoxic chemotherapeutic agents, tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid [INH]); anti-coagulation agents.
• Immunomodulators that alter immune responses such as chronic systemic corticosteroids, interleukins, or interferons.
• Use of medications which are associated with Torsade de Pointes must be discussed with the Medical Monitor to determine eligibility.
• Participants receiving any prohibited medication and who are unwilling or unable to switch to an alternate medication.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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97 participants in 3 patient groups

CAB LA + RPV LA Q2M

Experimental group

Description:

Eligible participants from LAI116482 (NCT01641809 \[LATTE\]) study who were administered oral CAB 30 milligrams (mg) plus RPV 25 mg and who successfully completed Week 300 received their first dose CAB LA (600 mg) plus RPV LA (900 mg) injections within 2 hours of the final oral dose of LATTE given on the same day. The second loading injections were administered 1 month after initial loading dose, with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring Q2M thereafter. Participants continued to receive the treatment until the study intervention was locally approved and commercially available. Participants who received at least one dose of CAB LA and/or RPV LA and discontinued the CAB LA + RPV LA regimen for any reason entered a 52-week long-term follow-up (LTFU) Phase.

Treatment:

Drug: RPV LA

Drug: CAB LA

DTG + RPV

Experimental group

Description:

Eligible participants from LAI116482 (NCT01641809 \[LATTE\]) study who were administered oral CAB 30 mg plus RPV 25 mg and who successfully completed Week 300 received their first dose of the Dolutegravir (DTG) 50 mg plus RPV 25 mg, once daily as oral regimen on Day 1 until Month 12 in the current study. These participants were not eligible for the LTFU phase.

Treatment:

Drug: RPV

Drug: DTG

LTFU: CAB LA+RPV LA Q2M Group

Experimental group

Description:

This group included the participants who received at least one dose of CAB LA and/or RPV LA and discontinued the CAB LA + RPV LA regimen for any reason before end of Maintenance Period. The participants entered a 52-week LTFU period.

Treatment:

Drug: RPV LA

Drug: CAB LA