HIV Infections, Weight Gain
Conditions
Keywords
HIV
Brief summary
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.
Detailed description
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. All randomised participants who have not withdrawn from the study will be invited to attend an optional observational follow-up visit at Week 96 (±6 weeks). The visit will collect longer-term post-treatment clinical, metabolic, cardiovascular risk, liver-related, medication use and safety data. No study drug will be supplied beyond Week 48, and no Week 96 CT coronary angiogram is planned. Week 96 data will be analysed separately as exploratory observational post-treatment follow-up data and will not alter the primary Week 24 or Week 48 analyses.
Interventions
DRUGDapagliflozin 10mg Tab
Dapagliflozin will be administered as a comparator to the placebo to assess its effects on weight reduction
DRUGPitavastatin 4 Mg Oral Tablet
Pitavastatin tablets will be administered as a comparator to Rosuvastatin/Ezetimibe 10mg/10mg tablets to assess and compare their effects on LDL concentrations
Rosuvastatin/Ezetimibe 10mg/10mg tablets will be administered as a comparator to pitavastatin to assess and compare their effects on LDL concentrations
DRUGPlacebo
The placebo tablets are visually identical to the active drug tablets and will be administered as a comparator to Dapagliflozin.
Sponsors
Kirby Institute
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To assess the impact of dapagliflozin vs. placebo on weight reduction | 24 weeks | Mean reduction change in body weight across treatment arms at 24 weeks, defined as absolute body weight change. |
| To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe on low-density lipoproteins (LDL) concentration | 24 weeks | Mean change in LDL as absolute change from baseline to 24 weeks across treatment arms |
Secondary
| Measure | Time frame |
|---|---|
| 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 | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on waist (cm) to hip (cm) ratio | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on waist (cm) to height (cm) ratio | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on systolic and diastolic blood pressure (mm Hg) | 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. | 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) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on fasting glucose (mmol/L) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on haemoglobin A1C (%) | 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) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on inflammatory biomarkers (tested centrally on stored research samples) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on Serious adverse events. | 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) | 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. | 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) | 48 weeks |
| To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on serious adverse events | 48 weeks |
Countries
Argentina, Australia, India, Malaysia, Nigeria, South Africa, Thailand, Uganda, Zimbabwe
Contacts
PRINCIPAL_INVESTIGATORGail Matthews, MD
Kirby Institute
Outcome results
None listed