A Phase III or IV factorial randomised double-blind trial to compare the addition of dapagliflozin versus placebo, and rosuvastatin or ezetimibe versus pitavastatin, in patients with HIV on integrase strand transfer inhibitor-based antiretroviral therapy with elevated metabolic risk(the OPTIMAR Study). OPTImising Metabolic Management on Integrase based ART-OPTIMAR

A Phase III/IV factorial randomized double-blind trial to compare the addition of dapagliflozin versus placebo, and rosuvastatin/ezetimibe versus pitavastatin, inpatients with HIV on integrase strand transfer inhibitor-based antiretroviral therapy with elevated metabolic risk (the OPTIMAR study).

People with HIV have an increased cardiovascular disease (CVD) risk compared to the general population due to HIV and treatment effects. Preferred HIV treatments, Integrase strand transfer inhibitors (INSTIs), are linked to higher CVD and metabolic concerns, including weight gain and elevations in blood pressure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown to reduce CVD events and heart failure hospitalisations in people with or without type 2 diabetes, while also reducing weight and blood pressure. Pitavastatin has also been shown to lower CVD events in those with HIV, although it is not widely available. The benefit of pitavastatin is likely a class effect of statins, although this remains unproven. The overall objective of the study is to examine the impact of dapagliflozin vs. placebo on metabolic parameters in PWH with high metabolic risk who are on INSTI-based ART.

Study  Design:

A 2x2 factorial, randomised, placebo-controlled, double-blind, phase III/IV trial, stratified by site.

Study Treatment:

Participants will be randomised to one of the following 4 arms:

a. Dapagliflozin 10mg + pitavastatin 4mg

b. Dapagliflozin 10mg + rosuvastatin 10mg/ezetimibe 10mg

c. Placebo + pitavastatin 4mg

d. Placebo + rosuvastatin 10mg/ezetimibe 10mg

ENDPOINTS

PRIMARY:

• To assess the impact of dapagliflozin vs. placebo on absolute weight change from baseline to wk24 (arms a+b vs. c+d)

SECONDARY:

• To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe on LDL concentration change from baseline to wk24 (a+c vs. b+d).

Population:

Adults aged 40-75 years with HIV with elevated metabolic risk who have been virologically stable on INSTI-based ART for over 12 months.

Sample size

The total sample size required is 300 participants (allowing for 5% lost to follow-up).

Randomization:

Participants will be randomized 1:1 to dapagliflozin 10mg vs. placebo; this randomization will be blinded.

Participants will also be randomized 1:1 within each group to pitavastatin 4mg vs. rosuvastatin 10mg/ezetimibe 10mg; this randomization will be open label.

Clinical assessments:

Clinical assessments with routine laboratory testing and safety assessments will be scheduled at screening, randomization (week 0), and weeks 4, 12, 24, and 48.

Academic Trial

As per CDSCO’s New Drugs and Clinical Trial Rules 2019,  if the Ethics Committee has granted approval for conduct of academic clinical trial of a permitted drug formulation for a new indication or new route of administration or new dose or new dosage form and the drug is to be imported for conducting the academic clinical trial in accordance with Rule 28 of the said Rules, no import license is required from CDSCO.

Rule 28. Academic clinical trial.― (1) No permission for conducting an academic clinical trial shall be required for any drug from the Central Licencing Authority where,― (i) the clinical trial in respect of the permitted drug formulation is intended solely for academic research purposes for a new indication or new route of administration or new dose or new dosage form; and (ii) the clinical trial referred to in clause (i) has been initiated after prior approval by the Ethics Committee for clinical trial; and (iii) the observations generated from such clinical trial are not required to be submitted to the Central Licencing Authority; and (iv) the observations of such clinical trial are not used for promotional purposes.

In case, the Ethics Committee has granted approval for conduct of academic clinical trial of a permitted drug formulation for a new indication or new route of administration or new dose or new dosage form and the drug is to be imported for conducting the academic clinical trial in accordance with Rule 28 of the said Rules, no import license is required, if copy of the ethics committee approval for the said clinical trial of the drug to be imported is furnished to the concerned Port office at the time of import along with an undertaking mentioning the quantity of the drug being imported will be used exclusively for the academic clinical trial.