An Open-Label, Multi-Centre, Randomised Study to Investigate Integrase Inhibitor Versus Boosted Protease Inhibitor Antiretroviral Therapy for Patients With Advanced HIV Disease
Overview
- Phase
- Phase 3
- Intervention
- Biktarvy
- Conditions
- HIV/AIDS
- Sponsor
- NEAT ID Foundation
- Enrollment
- 447
- Locations
- 53
- Primary Endpoint
- Treatment Failure
- Status
- Completed
- Last Updated
- 4 months ago
Overview
Brief Summary
The main purpose of this study is to compare two different types of HIV treatments, in terms of effectiveness and improvement of side effects, for patients who are diagnosed with a more advanced HIV infection. Patients with advanced HIV infections are otherwise known as 'late presenters'.
There are many effective treatments for HIV available; however, for late presenting patients the investigators do not know which type of treatment performs best. This is the first large study to compare treatments for patients in this situation, and the investigators hope that the results of this study will help doctors decide which treatments to use in the future.
The two different types of treatment the investigators are comparing both contain a mixture of drugs that work together to combat HIV:
The Boosted Protease Inhibitor combination (PI) which is a combination tablet containing: darunavir, cobicistat, emtricitabine and tenofovir alafenamide. It was approved for use in Europe under the brand name Symtuza®.
The Integrase Inhibitor combination (INI). Which is a combination tablet containing: bictegravir, emtricitabine and tenofovir alafenamide. This is a a newer combination which was approved for use in Europe in June 2018 under the brand name of Biktarvy®.
The main difference between the two treatments is how each one fights a HIV infection. They both stop a part of the virus from working (i.e. inhibit it), to prevent it from making copies of itself. The PI treatment contains drugs to stop the protease part of the virus, whereas the INI treatment contains drugs to stop the integrase part.
In recent studies, it appears that treatments containing integrase inhibitors may be better for late presenting patients. They have been shown to quickly bring down the amount of virus in the body, and the side effects may be more acceptable to late presenters.
To compare the two treatments, half of the participants on this study will be given the PI treatment, and the other half will be given the INI treatment.
Detailed Description
The effectiveness of HIV antiretroviral therapy (ART) has consistently improved over the years. This is largely due to newer drugs having improved antiviral effectiveness and more tolerable side effect profiles; resulting in better viral suppression and improved treatment adherence. On the other hand, most recent clinical trials look at the effectiveness of ART in patients with less advanced disease. These patients usually suffer from less related diseases, drug-drug interactions, and other risks for treatment failure. Outside of these trials, the number of patients who present to clinic with a more developed advanced HIV infection, known as 'late presenters', remains high across Europe. Trials for these patients have tended to focus on the time of starting treatment and the management of infections. Much less is known about which ART treatments perform best for these late presenting patients; particularly in terms of virus suppression, immune system recovery, side effects and improvement of AIDs related diseases. No specific drug combinations have been compared in appropriate clinical trials before, and the international guidelines for first line treatment judge all therapies as equal standard of care for these patients. The investigators anticipate that Integrase inhibitor containing regimes may be better suited to patients with advanced disease, due to their beneficial side-effect profile and ability to rapidly decrease viral load levels. Therefore the investigators are conducting this clinical trial to compare an integrase inhibitor regime, against a protease inhibitor regime in patients with advanced HIV infection. The aim of the study is to demonstrate the non-inferiority of Biktarvy® against Symtuza®. Patients will be recruited from sites across Europe, and randomized onto either arm of the study. After randomisation onto either treatment regime, patients will attend approximately 9 follow-up visits over the course of a year. During these visits, patients will be asked to complete two questionnaires, to assess their quality of life and HIV symptoms. They will also be asked to provide a number of blood samples. These samples are to ensure that the patient is not resistant to the study drug and that their disease is not worsening. Samples to test for study drug resistance will be shipped to a laboratory for analysis in the even that the patient experiences virological failure. Biktarvy® will be supplied from Gilead and Symtuza® will be provided by Janssen Pharmaceuticals.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The ability to understand and sign a written informed consent form (ICF) and must be willing to comply with all study requirements.
- •Male or non-pregnant, non-lactating females†.
- •Age ≥ 18 years.
- •Have documented, untreated HIV-1 infection with either:
- •AIDS with any CD4 cell count (AIDS-defining conditions are listed within Appendix 3).
- •Severe bacterial infection (BI)‡ and must have a CD4 cell count \< 200/μl within 28 days prior to study entry§.
- •Any symptoms or no symptoms and must have a CD4 cell count \< 100/μL within 28 days prior to study entry and must have an entry HIV viral load \> 1000 copies/mL.
- •Currently receiving treatment for OI\*\*. i. Subjects with other serious OIs, including other AIDS-defining and AIDS-related OIs for which appropriate therapy other than ART exists are eligible, but Investigator approval must be obtained. ii. Current OI treatment can have been discontinued prior to start of ART.
- •Have an entry HIV viral load \> 1000 copies/mL
- •Have the ability to take oral medications.
Exclusion Criteria
- •Any therapeutic ARV which commenced less than 2 weeks prior to screening and which was taken for more than 48 hours
- •Systemic cancer chemotherapy within 30 days prior to study entry, or current treatment for cancer (with the exception of Kaposi's sarcoma) or lymphoma.
- •Current or anticipated use of contraindicated medications (see Summary of Product Characteristics (SmPC) for Symtuza® and Biktarvy®) or anticipated systemic chemotherapy during study enrolment (administration of any contraindicated medication must be discontinued at least 30 days prior to the baseline visit and for the duration of the study).
- •Known resistance to the components of study medications (see section 6.1.3 for more details).
- •History or symptoms of advanced renal and/or hepatic impairment. Such as, kidney failure requiring dialysis; eGFR \<30 mL/min; hepatic transaminases (AST and ALT) \> 5 x upper limit of normal (ULN); or, platelet count \<50,
- •Current drug or alcohol use that, in the opinion of the Investigator, would cause interference with the study.
- •Cryptococcal meningitis or active TB, or current or expected treatment requiring Rifampicin or Rifabutin (patients with expected latent TB will have a TB test (IGRAs e.g. ELISPOT, QuantiFERON etc.) at their screening visit).
- •History or presence of allergy to the study drugs or their components, or drugs of their class.
- •Using any concomitant therapy disallowed as per the product labelling for the study drugs.
- •Any investigational drug within 30 days prior to the study drug administration.
Arms & Interventions
Biktarvy
Bictegravir is an inhibitor of HIV-1 integrase that is being evaluated for the treatment of HIV-1 infection. Biktarvy® received marketing authorisation valid throughout the European Union (EU) in June 2018. Biktarvy is a combination of bictegravir, emtricitabine, and tenofovir (B/F/TAF). Method of administration: One combined B 50mg/F 200mg/TAF 25mg tablet taken orally once daily for up to 48 weeks without regard to food.
Intervention: Biktarvy
Symtuza
Symtuza® is a boosted PI indicated for the treatment of HIV-1 infection. Symtuza® received marketing authorisation valid throughout the EU in September 2017. Symtuza is a combination of darunavir, cobicistat, emtricitabine and tenofovir alafenamide (D/C/F/TAF) Method of administration: One combined D 800mg/C 150mg/F 200mg/TAF 10mg tablet taken orally once daily for up to 48 weeks with the addition of food.
Intervention: Symtuza
Outcomes
Primary Outcomes
Treatment Failure
Time Frame: Earliest at 12 weeks, latest 48 weeks
Composite outcome: treatment failure due to either virological or clinical reasons. Virological reasons can either be insufficient virological response or viral rebound. Clinical reasons can be death related to HIV/AIDS/opportunistic infection or severe bacterial infection, new or recurrent AIDS defining event, any serious non-AIDS defining event or clinically relevant adverse events of any grade or immune reconstitution inflammatory syndrome requiring treatment
Secondary Outcomes
- Proportion of Patients With HIV-RNA Viral Load <50 Copies/mL(Week 24, 36 and 48)
- Time to Reach CD4 (Cluster of Differentiation 4) Count >200/µL(Through study completion, up to 48 weeks.)
- Proportion of Patients With CD4 Cell Count <200 and < 350μL at Week 4, 8, 12, 24, 36, 48(4, 8, 12, 24, 36, 48 weeks)
- CD4/CD8 (Cluster of Differentiation 8) Ratio(Week 4, 8, 12, 24, 36, 48)
- Incidence of Immune Reconstitution Inflammatory Syndrome(Week 48)
- Number of Participants With Hospitalisation or Relapse of Specific Opportunistic or Bacterial Infection(Week 48)
- Number of Participants With Treatment-related Adverse Events as Assessed by Division of AIDS Adverse Event (AE) Grading Table Corrected Version 2.1-July 2017(Week 48)
- ART and OI/BI Treatment Changes and Dose Modifications Due to Toxicities and DDI With ART, and IRIS Through Week 48(Week 48)
- Health Care Resource Use, Including Number of Participants With Critical Care and Emergency Room Visits(Week 48)
- QOL and Functional Status Outcomes, Including Overall Self-reported QOL and Functional Status Compared in the Two Groups at Week 48(Week 48)
- Discontinuation or Modification of Study Medication Due to Insufficient Virological Response or Resistance Mutation Development(Week 48)
- Duration of Hospitalisations(Week 48)