Optimising Metabolic Management for People With Human Immunodeficiency Virus (HIV) on Integrase Based Antiretroviral Therapy (ART)

Phase 3Active Not RecruitingNCT06317051

Kirby Institute300 enrolled

Overview

People with HIV are at a higher risk of cardiovascular diseases (CVD) due to the effects of the virus and its treatment. Integrase strand transfer inhibitors (INSTIs), a common HIV treatment, are associated with increased CVD risk and metabolic issues, such as weight gain and high blood pressure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, however, have been working well in reducing CVD events and hospitalizations due to heart failure, irrespective of diabetes presence. They also help in reducing weight and blood pressure. Pitavastatin has shown to work in lowering CVD events in people with HIV, but its availability is limited. This benefit is thought to be common to all statins, but this has not yet been confirmed. This study will examine the impact of dapagliflozin vs. placebo on metabolic parameters in people with HIV with high metabolic risk who are on INSTI-based ART.

This is a 2x2 factorial, randomised, placebo-controlled, double-blind, phase III/IV trial with two randomisations performed centrally via an on-line system, stratified by site. Participants will be randomised 1:1 to dapagliflozin 10mg vs. Placebo; this randomisation will be blinded. Participants will also be randomised 1:1 within each group to pitavastatin 4mg vs. rosuvastatin 10mg/ezetimibe 10mg; this randomisation will be open label. Therefore, participants will be randomised to one of 4 groups: 1. Dapagliflozin 10mg + pitavastatin 4mg 2. Dapagliflozin 10mg + rosuvastatin 10mg/ezetimibe 10mg 3. Placebo + pitavastatin 4mg 4. Placebo + rosuvastatin 10mg/ezetimibe 10mg With the following 2-arm randomised comparisons: * Primary analysis hypothesis: a+b vs c+d (dapagliflozin vs placebo) * Secondary analysis hypothesis: a+c vs b+d (pitavastatin vs rosuvastatin 10mg/ezetimibe 10mg) The study's primary and secondary endpoints described will assess both efficacy and safety/tolerability across randomisation arms. Follow up will continue to 48 weeks and endpoint measures will be obtained at 4, 12, 24, and 48 weeks. Primary endpoint is at 24 weeks. The total number of participants is 300, with 75 randomised to each of the groups as listed above.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Interventions

Dapagliflozin 10mg TabDRUG

Dapagliflozin will be administered as a comparator to the placebo to assess its effects on weight reduction

Pitavastatin 4 Mg Oral TabletDRUG

Pitavastatin tablets will be administered as a comparator to Rosuvastatin/Ezetimibe 10mg/10mg tablets to assess and compare their effects on LDL concentrations

Rosuvastatin and EzetimibeDRUG

Rosuvastatin/Ezetimibe 10mg/10mg tablets will be administered as a comparator to pitavastatin to assess and compare their effects on LDL concentrations

PlaceboDRUG

The placebo tablets are visually identical to the active drug tablets and will be administered as a comparator to Dapagliflozin.

Eligibility

Sex: ALLMin age: 40 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age 40-75 years and at least one of the following risk factors: 1. BMI \> 7% increase or \> 5kg weight gain since INSTI commencement, or 2. BMI ≥ 30 kg/m2 2. BMI ≥18 kg/m2 prior to INSTI commencement 3. Currently taking INSTI-based ART 4. Sustained virologic response, defined as viral load \<200 copies/mL for at least 12 months 5. Current CD4 \>250 cells/mm3 6. Informed consent for trial participation Exclusion Criteria: 1. Currently taking a protease inhibitor 2. Indicated to take or already taking high intensity statin 3. estimated glomerular filtration rate (eGFR) \< 30 ml/min/1.73m2 4. Currently taking an SGLT-2 inhibitor or glucagon-like peptide 1 (GLP-1) agonist 5. Absolute contraindication or absolute indication to SGLT2 inhibitor therapy 6. Absolute contraindication to pitavastatin, rosuvastatin, ezetimibe or combination of rosuvastatin/ezetimibe 7. Pregnant or breast feeding 8. Severe hepatic impairment (Child Pugh B or C) 9. Participants receiving any excluded/contraindicated medication 10. Participants who are enrolled into an additional interventional study. 11. Expected inability or unwillingness to participate in study procedures. 12. In the opinion of the investigator, participation in a trial is not in the best interest of the patient.

Locations (10)

Hospital Ramos Mejía

Buenos Aires, Argentina

St Vincent's Hospital

Sydney, New South Wales, Australia

Austin Health

Melbourne, Victoria, Australia

CART-CRS

Chennai, Tamil Nadu, India

Universiti Malaya Medical Centre

Kuala Lumpur, Malaysia

Institute of Human Virology, Nigeria

Abuja, Nigeria

Desmond Tutu Health Foundation

Cape Town, South Africa

HIV-NAT

Bangkok, Thailand

Infectious Diseases Institute, Makerere University

Kampala, Uganda

University of Zimbabwe Clinical Research Centre

Harare, Zimbabwe

Outcomes

Primary Outcomes

To assess the impact of dapagliflozin vs. placebo on weight reduction

Mean reduction change in body weight across treatment arms at 24 weeks, defined as absolute body weight change.

Time frame: 24 weeks

To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe on low-density lipoproteins (LDL) concentration

Mean change in LDL as absolute change from baseline to 24 weeks across treatment arms

Time frame: 24 weeks

Secondary Outcomes

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on body mass index (BMI )- weight and height will be combined to report BMI in kg/m^2

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on waist (cm) to hip (cm) ratio

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on waist (cm) to height (cm) ratio

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on systolic and diastolic blood pressure (mm Hg)

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on Atherosclerotic cardiovascular disease risk score (ASCVD) - calculation of a person's10-year risk (%) of having a cardiovascular problem.

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on fasting lipids including: Total Cholesterol (mmol/L), LDL (mmol/L), High-Density Lipoproteins (HDL) (mmol/L), Triglycerides (mmol/L)

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on fasting glucose (mmol/L)

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on haemoglobin A1C (%)

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on measures of fatty liver disease: Liver Function Tests - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (U/L), FibroScan (kPa)

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on inflammatory biomarkers (tested centrally on stored research samples)

Time frame: 48 weeks

To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on Serious adverse events.

Time frame: 48 weeks

To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on fasting lipids including: Total Cholesterol (mmol/L), LDL (mmol/L), High-Density Lipoproteins (HDL) (mmol/L), Triglycerides (mmol/L)

Time frame: 48 weeks

To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on Atherosclerotic cardiovascular disease risk score (ASCVD) - calculation of a person's10-year risk (%) of having a cardiovascular problem.

Time frame: 48 weeks

To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on inflammatory biomarkers (tested centrally on stored research samples)

Time frame: 48 weeks

To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on serious adverse events

Time frame: 48 weeks

Optimising Metabolic Management for People With Human Immunodeficiency Virus (HIV) on Integrase Based Antiretroviral Therapy (ART)

Overview

Conditions

Interventions

Eligibility

Locations (10)

Outcomes

Primary Outcomes

Secondary Outcomes