Cardiovascular Diseases (CVD), HIV Infection
Conditions
Keywords
Coronary artery inflammation, Atherosclerosis, Coronary computed tomography angiography, Fat attenuation index
Brief summary
The purpose of this study is to evaluate whether colchicine can reduce coronary artery inflammation in people living with HIV and high cardiovascular risk. Participants will be randomized 1:1 to receive either colchicine or placebo for 96 weeks in a double-blind, multicenter clinical trial. Neither participants nor researchers will know which treatment is assigned during the study. The primary endpoint is the change in coronary artery inflammation measured by coronary computed tomography angiography (CCTA) after 96 weeks.
Detailed description
Despite advances in antiretroviral therapy, people living with HIV (PWH) have an increased risk of cardiovascular disease compared with the general population. Persistent inflammation and immune activation are considered important contributors to accelerated atherosclerosis and coronary artery disease in this population. Coronary inflammation is associated with cardiovascular risk, but strategies targeting this mechanism in PWH remain limited. Colchicine is an anti-inflammatory drug that has demonstrated cardiovascular benefits in patients with coronary artery disease by reducing inflammatory pathways involved in atherosclerosis. However, the effect of colchicine on coronary artery inflammation in PWH has not been previously evaluated. The hypothesis of this study is that colchicine may reduce coronary artery inflammation in PWH with high cardiovascular risk. This phase II, randomized, double-blind, multicenter, placebo-controlled trial will include approximately 90 participants who will receive colchicine or placebo for 96 weeks. Changes in coronary artery inflammation will be assessed using coronary computed tomography angiography (CCTA) and the perivascular fat attenuation index (FAI), a non-invasive imaging biomarker of vascular inflammation. The study will also evaluate safety and changes in cardiovascular and inflammatory markers during follow-up.
Interventions
DRUGColchicine 0.5 mg
Colchicine 0.5 mg administered orally once daily for 96 weeks as an anti-inflammatory treatment to reduce coronary artery inflammation in people living with HIV and high cardiovascular risk.
DRUGPlacebo
Matching placebo administered orally once daily for 96 weeks.
Sponsors
Instituto de Investigación Hospital Universitario La Paz
Instituto de Salud Carlos III
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PWH \> 50 years old * High cardiovascular risk measured by SCORE-2 \> 5% * Stable antiretroviral therapy (ART) in the previous six months * Viral load \< 50 copies/mililiter for at least 1 year. One blip is allowed (Viral load between 20-200 copies/mililiter with a previous and after viral load determinations \< 20 copies per mililiter. * CD4 cell count \> 350 cells/mm3 * Stable dose of an intermediate or high intensity statin in the previous year (statin dose should not be modified throghout the study unless there is a robust clinical indication). In case the participant does not receive statins, all other hypolipemiants (bempedoic acid, ezetimibe) will need to be at a stable dose as well in the previous year. * No clinical indication for a change in treatment based on European Society of Cardiology Guidelines * Written informed consent obtained according to international guidelines and local laws * Ability to understand the nature of the trial and the trial related procedures and to comply with them
Exclusion criteria
* Severe Heart failure defined as LVEF \< 35%. * Previous MI, stroke or coronary by-pass surgery * History of non-cutaneus malignancy prior to enrollment * History of inflammatory bowel disease or chronic diarrhoea * Renal dysfunctions defined as eGFR \< 50 ml/min or serum creatinine levels \> 1.7 mg/dL * Severe hepatic impairments defined as a Child-Pugh category C * Participants with stomach ulcers or gastrointestinal bleeding * Levels of ALT over five times the upper limit of normal OR levels of ALT over three times the upper limit of normal AND bilirrubin levels over one point five times the upper limit of normal * Participant is receiving drugs that inhibit the CYP3A4 (e.g. Verapamil, Azithromycin, Clarithromycin, protease inhibitors, cobicistat), CYP2D6 or inhibitors of P-glycoprotein (see section 6.3.2 for more information) * Participant needs treatment with colchicine for any indication * Participants with highly elevated hsCRP \> 10 mg/dL at screening * Women of childbearing potential. For this trial, definitions of nonchildbearing potential includes: * Permanent sterilisation methods including hysterectomy, bilateral salpingectomy and bilateral oophorectomy. * Postmenopausal state, defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. * Male participants are considered fertile after puberty unless permanently sterile by bilateral orchiectomy. To prevent pregnancies in female partners of male participants, they must agree to use highly effective contraceptive methods or have practiced sexual abstinence during the treatment period and until the end of relevant systemic exposure, defined as 5 half-lives of the IMP (9 days approximately). * Known hypersensitivity to the active substances or any of the excipients * Known iodine contrast allergy with prior history of anaphylaxis * Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in coronary artery inflammation | Baseline to Week 96 | Percent change from baseline of the mean Fat Attenuation Index (FAI) score for the three main coronary arteries (right coronary artery \[RCA\], left anterior descending artery \[LAD\], and left circumflex artery \[LCX\]). The mean FAI score will be calculated as the average of analyzable FAI scores with valid baseline and post-baseline measurements across the three coronary arteries. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in coronary plaque volume | Baseline to Week 96 | Change from baseline in total coronary plaque volume assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Changes in coronary plaque burden | Baseline to Week 96 | Change from baseline in coronary plaque burden assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Change in non-calcified plaque volume | Baseline to Week 96 | Change from baseline in non-calcified coronary plaque volume assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Change in mixed plaque volume | Baseline to Week 96 | Change from baseline in mixed coronary plaque volume assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Change in calcified plaque volume | Baseline to Week 96 | Change from baseline in calcified coronary plaque volume assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Change in prevalence of positive remodeling plaques | Baseline to Week 96 | Change from baseline in the percentage of coronary plaques presenting positive remodeling assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Change in prevalence of spotty calcium plaques | Baseline to Week 96 | Change from baseline in the percentage of coronary plaques presenting spotty calcium assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Change in prevalence of napkin-ring sign plaques | Baseline to Week 96 | Change from baseline in the percentage of coronary plaques presenting a napkin-ring sign assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Change in prevalence of low attenuation plaques | Baseline to Week 96 | Change from baseline in the percentage of coronary plaques presenting low attenuation characteristics assessed by coronary computed tomography angiography (CCTA) at Week 96. |
| Change in serum hsCRP concentration | Baseline to Week 96 | Change from baseline in serum high-sensitivity C-reactive protein (hsCRP) concentration at Week 96. |
| Change in serum IL-6 concentration | Baseline to Week 96 | Change from baseline in serum interleukin-6 (IL-6) concentration at Week 96. |
| Change in serum IL-1β concentration | Baseline to Week 96 | Change from baseline in serum interleukin-1 beta (IL-1β) concentration at Week 96. |
| Change in serum IL-18 concentration | Baseline to Week 96 | Change from baseline in serum interleukin-18 (IL-18) concentration at Week 96. |
| Change in serum SuPAR concentration | Baseline to Week 96 | Change from baseline in soluble urokinase plasminogen activator receptor (SuPAR) concentration at Week 96. |
| Change in extracellular vesicle NLRP3 levels | Baseline to Week 96 | Change from baseline in NLRP3 levels in extracellular vesicles at Week 96. |
| Change in extracellular vesicle ASC levels | Baseline to Week 96 | Change from baseline in ASC levels in extracellular vesicles at Week 96. |
| Change in extracellular vesicle Caspase-1 levels | Baseline to Week 96 | Change from baseline in Caspase-1 levels in extracellular vesicles at Week 96. |
| Change in classical monocyte proportion | Baseline to Week 96 | Change from baseline in the proportion of classical monocytes (CD14++CD16-) at Week 96. |
| Change in intermediate monocyte proportion | Baseline to Week 96 | Change from baseline in the proportion of intermediate monocytes (CD14+CD16+) at Week 96. |
| Change in non-classical monocyte proportion | Baseline to Week 96 | Change from baseline in the proportion of non-classical monocytes (CD14++CD16++) at Week 96. |
| Changes in leukocyte count | Baseline to Week 96 | Percentage change of leukocyte count in week 96 |
| Changes in arterial inflammation in individual coronary vessels measured by Fat Attenuation Index (FAI) | Baseline to Week 96 | Change from baseline in FAI and FAI score, including mean absolute change and mean percent change, assessed in individual coronary vessels (right coronary artery \[RCA\], left anterior descending artery \[LAD\], and left circumflex artery \[LCX\]). |
| Mean arterial inflammation across analyzable coronary vessels measured by Fat Attenuation Index (FAI) | Baseline to Week 96 | Mean absolute change from baseline in mean FAI and FAI score calculated as the average of analyzable coronary vessels with valid baseline and post-baseline measurements. |
| Adverse events and serious adverse events | Over the whole period of patient study participation | Incidence of solicited and unsolicited adverse events (AEs) and serious adverse events (SAEs) during the study. |
Countries
Spain
Contacts
CONTACTJosé Ignacio Bernardino de la Serna, MD, PhD
PRINCIPAL_INVESTIGATORJosé Ignacio Bernardino de la Serna, MD, PhD
Hospital Universitario La Paz. IdiPAZ
Outcome results
None listed