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

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

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.


Condition or disease Intervention/treatment Phase
Coronary Artery Disease Hiv Drug: Biktarvy Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : August 6, 2019
Estimated Primary Completion Date : November 28, 2020
Estimated Study Completion Date : March 29, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Bictarvy
Intervention group: those randomised to switch antiretroviral therapy to Bictegravir, Emtricitabine and Tenofovir Alafenamide fixed dose combination.
Drug: Biktarvy
Fixed dose combination preparation containing bictegravir, tenofovir alafenamide and emtricitabine

No Intervention: Usual therapy
Control group: those randomised to continue their usual antiretroviral regime



Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.


  5. 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.


  6. 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.



Secondary Outcome Measures :
  1. 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.


  2. The incidence of subclinical cardiovascular disease in the study population [ Time Frame: 2 years ]
    Expressed as percentage of recruited patients.

  3. 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.


  4. 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

  5. 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.


  6. 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.




Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


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Responsible Party: Professor Saye Khoo MD, FRCP, Professor, University of Liverpool
ClinicalTrials.gov Identifier: NCT03986697     History of Changes
Other Study ID Numbers: UoL001362
2017-005033-22 ( EudraCT Number )
First Posted: June 14, 2019    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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

Keywords provided by Professor Saye Khoo MD, FRCP, University of Liverpool:
HIV
Coronary Artery Disease
Atherosclerosis
Antiretroviral therapy
Computed tomography

Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Atherosclerosis
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Tenofovir
Emtricitabine
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents