How Does Antiretroviral Therapy Affect Coronary Atherosclerosis: A Serial CT Study (HART CT)

• ClinicalTrials.gov Identifier: NCT03986697
• Recruitment Status: Not yet recruiting
• First Posted: June 14, 2019
• Last Update Posted: September 30, 2019
• Sponsor: Professor Saye Khoo MD, FRCP
• Information provided by (Responsible Party): Professor Saye Khoo MD, FRCP, University of Liverpool

Tracking Information

• First Submitted Date: May 30, 2019
• First Posted Date: June 14, 2019
• Last Update Posted Date: September 30, 2019
• Estimated Study Start Date: November 4, 2019
• Estimated Primary Completion Date: November 28, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 12, 2019)

• The rate of recruitment to the HART CT study [ Time Frame: 2 years ]
  Rate of recruitment to the main study expressed as a rate of eligible patients screened to those who undergo randomisation.
• Drop out rate [ Time Frame: 2 years ]
  Drop out rate of the main study. The number of participants not completing the study expressed as a percentage of those recruited.
• Change in total plaque volume (mm3) including the following derivatives: total non-calcified plaque volume (mm3), calcium volume (mm3). These derivatives will be combined to give a total plaque volume (mm3). [ Time Frame: 2 years ]
  CT based quantification of coronary artery disease burden. Assessed using summary statistics and parametric or non-parametric measures of significance.
• Change in Agatston Score (Agatston units). [ Time Frame: 2 years ]
  Agatston calcium scoring is a highly reproducible well validated scale outlining the burden of calcific coronary artery disease. Agatston score is a function of calcium volume and density. The volume is calculated in mm3 and multiplied by a density weighting factor depending on the haunsfied units. Change in Agatston scores will be assessed using summary statistics and parametric or non-parametric measures of significance.
• Change in segmental stenosis score [ Time Frame: 2 years ]
  Coronary segments are graded as normal (no stenosis), stenosis 1%-29%, 30%-49%, 50%-69%, ≥70% by visual semiquantification method, with assignment of scores of 0, 1, 2, 3, or 4, respectively. Stenosis is not measured when the vessel diameter was <2 mm. Total segment stenosis score (TSS) per person is calculated by summing all the 15 individual SSSs with a possible score ranging from 0 to 60. Change in segmental stenosis scores will be assessed using summary statistics and parametric or non-parametric measures of significance.
• Number of adverse plaque features [ Time Frame: 2 years ]
  The change in the number of coronary segments displaying an adverse plaque characterisitc. This is defined as any one of the following (low attenuation plaque (<30 hounsfield units), positive remodelling (remodelling index >1.1), spotty calcification or napkin ring sign). Change in number of adverse plaque features will be assessed using summary statistics and parametric or non-parametric measures of significance.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 12, 2019)

• Inter and intraobserver variability of CT based outcome measures [ Time Frame: 2 years ]
  To assess the inter and intraobserver variability of total plaque volume (mm3). This will be assessed for the first 20 vessels containing evidence of coronary artery disease between the two study reporters. The mean difference (%) will be reported.
• The incidence of subclinical cardiovascular disease in the study population [ Time Frame: 2 years ]
  Expressed as percentage of recruited patients.
• The change in in 10-year cardiovascular disease risk between the control group and intervention group using both prediction models. [ Time Frame: 2 years ]
  Summary statistics (mean) assessment of the change in 10 year cardiovascular disease risk as assessed by QRISK and ASTROCHARM risk prediction models. The 10 year cardiovascular risk will be reported as %. The intervention group and control group compared using parametric or non-parametric measures of significance.
• Change in total cholesterol (mmol/L) including the derivatives (which are combined to give the total cholesterol) high-density lipoprotein (mmol/L), low-density lipoprotein (mmol/L) and non-high-density lipoprotein (mmol/L). [ Time Frame: 2 years ]
  Intervention group and control group compared using parametric or non-parametric measures of significance. The range of cholesterol is 0-20 mmol/L
• Fibroscore (Kilopascals) [ Time Frame: 2 years ]
  Change from baseline to end fibroscan score. Intervention group and control group compared using parametric or non-parametric measures of significance. The range of KPa is 0-75.
• Change in HBA1C (mmol/mol) [ Time Frame: 2 years ]
  Intervention group and control group compared using parametric or non-parametric measures of significance. The range of HBA1C is 0-150mmol/mol.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: How Does Antiretroviral Therapy Affect Coronary Atherosclerosis: A Serial CT Study
• Official Title: In Patients Taking Protease Inhibitors Does Switching to a Bictegravir, Tenofovir Alafenamide and Emtricitabine Combination, Reduce Cardiovascular Risk: An Open-label, Randomised, Serial CT Pilot Study

Brief Summary

Combined antiretroviral therapy (cART) is thought to promote coronary artery disease via a number of mechanisms: abnormal lipid profiles, endothelial dysfunction, hypertension, insulin resistance and renal impairment are the main pathological mechanisms driving atherosclerosis as a consequence of cART. An association between protease inhibitors and increased cardiovascular disease risk has been shown in many large cohort trials.

CT Coronary Angiography (CTCA) is now widely used to assess for the presence of atherosclerosis, typically in patients presenting with chest pain. This imaging technique allows visualisation of the coronary arteries and quantification of any atherosclerotic disease that may be present. This technique is being increasingly used as a surrogate for cardiovascular disease risk.

HART CT is an open label, prospective, randomised-control pilot study to investigate the feasibility of performing a future appropriately powered multi-centred randomised control trial using CT based outcome data as a surrogate for cardiovascular disease risk.

Participants will be randomised to either continue their usual cART or switch to Biktarvy (a fixed dose combination of bictegravir, emtricitabine and tenofovir alafenamide). A baseline CT scan will be performed. If there is any evidence of atherosclerosis a further CT scan will be performed at the end of the study (approximately 48 weeks). This will allow quantification of any change in coronary artery plaque burden or characteristic. Participants will be also followed up for any changes in metabolic health.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Coronary Artery Disease
• Hiv

Intervention

Drug: Biktarvy

Fixed dose combination preparation containing bictegravir, tenofovir alafenamide and emtricitabine

Study Arms

• Active Comparator: Bictarvy
  Intervention group: those randomised to switch antiretroviral therapy to Bictegravir, Emtricitabine and Tenofovir Alafenamide fixed dose combination.
  Intervention: Drug: Biktarvy
• No Intervention: Usual therapy
  Control group: those randomised to continue their usual antiretroviral regime

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: June 12, 2019): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 29, 2021
• Estimated Primary Completion Date: November 28, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

• HIV positive
• Undetectable viral load on cART which contain protease inhibitors (duration >6 months at eligibility visit)
• Age>40 years
• Stable cART
• No previous documented cardiovascular disease
• No contraindication to study drug
• Ability to give informed consent
• Willingness to comply with all study requirements
• No symptoms of overt cardiovascular disease

A definition of stable cART is no change to the medication regime in the preceding 6 months.

Well controlled hypertension is considered acceptable for recruitment.

Exclusion Criteria:

• Active liver disease (previously diagnosed)
• Renal disease eGFR <30
• Any ongoing infection
• Significant ionising radiation in preceding 12 months
• Known or suspected cardiovascular disease
• High dose statin therapy (Atorvastatin 20mg or more, Rosuvastatin 20mg or more)
• Pregnancy or planned pregnancy
• Breast feeding
• Allergy to iodine based contrast agent
• Known drug resistance to NRTI or Integrase
• Any contraindication to BIC/FTC/TAF
• Current enrolment onto another CTIMP.

Significant ionising radiation should not exceed >25mSv from medical sources. A definition of cardiovascular disease includes documented angina, previous myocardial infarction or previous coronary revascularization.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT03986697
• Other Study ID Numbers: UoL001362; 2017-005033-22 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Professor Saye Khoo MD, FRCP, University of Liverpool
• Study Sponsor: Professor Saye Khoo MD, FRCP
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University of Liverpool
• Verification Date: September 2019