Clinical trial NCT06535542: Integrating Whole Genome Sequencing and Digital Twins Into the Management of Hypercholesterolemia in Emiratis
Official title: A Randomized Trial of Integrating Whole Genome Sequencing and Digital Twins Into the Management of Hypercholesterolemia in Emiratis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Hypercholesterolemia, Autosomal Dominant
Hypercholesterolemia, Autosomal Recessive
Familial Combined Hypercholesterolemia
Keywords: LDH
Familial Hypercholesterolemia
Whole Genome Sequencing
Digital Twins
Management of Hypercholesterolemia
Emirati
Randomized Controlled Trial
Sanger Sequencing
Predictiv Care
Genomic Medicine
Precision Medicine
Pharmacogenomics
Lead sponsor: Abu Dhabi Health Services Company
Sponsor class: OTHER_GOV
Collaborators: name: Predictiv Care, Inc.
First posted: 2024-08-02
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized controlled clinical trial of whole-genome sequencing.
Primary purpose: DIAGNOSTIC

Brief summary: This pilot study investigates integrating whole genome sequencing and digital twin technology for managing hypercholesterolemia in Abu Dhabi clinics. It aims to establish protocols for larger future studies and incorporate genomic insights into routine medical care.

Detailed description: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in the Middle East, with hypercholesterolemia being a significant contributor. Genetic mechanisms of hypercholesterolemia in this region are not well understood. Autosomal dominant hypercholesterolemia is a major factor, yet only \~7% of Emiratis with familial hypercholesterolemia (FH) have these mutations. In 2013, Talmud et al. identified common variants through genome-wide association studies (GWAS) that suggest a polygenic cause for hypercholesterolemia in mutation-negative FH patients. A polygenic risk score based on 12 SNPs was validated in White European populations and is used in the UK's NHS diagnostic pipeline. Distinguishing polygenic hypercholesterolemia from FH without genetic testing is challenging. These patients exhibit familial moderate hypercholesterolemia and early coronary heart disease, with elevated LDL-C, normal triglycerides, and no tendon xanthoma. Their cardiovascular risk is similar to monogenic FH with age.

Statins, though commonly prescribed for ASCVD prevention, can cause musculoskeletal symptoms leading to poor adherence, discontinuation, elevated cholesterol, and increased cardiovascular risk. Many patients fail to achieve target LDL-C levels due to suboptimal dosing. Certain gene variants increase the risk of statin side effects.

This study seeks to integrate whole genome sequencing (WGS) technology in a clinical setting through an innovative digital twin platform. This platform allows clinicians to assess monogenic and polygenic risks in real-time and make informed statin prescribing and management decisions.

Eligibility criteria: Inclusion Criteria:

* Patients with 2 or more LDL-C levels greater than 190 mg/dL or 5.0 mmol/L in the past 12 months
* Undiagnosed patients meeting Possible, Probable or Definitive FH criteria according to Dutch Lipid Clinic Network (DLCN) criteria (Eur Heart J. 2011 Jul;32(14):1769-818. doi: 10.1093/eurheartj/ehr158. Epub 2011 Jun 28.)
* Patients who have not been on anti-lipidemic medication in the past 3 months
* Ages 18-55
* Emirati national
* All patients must be fluent in English or Arabic

Exclusion Criteria:

* - Patients who do not meet the above criteria
* Patients with a previous diagnosis of FH
* Patients with a progressive debilitating illness
* Patient with untreated hypothyroidism, history of proteinuria, obstructive liver disease, chronic renal failure, human immunodeficiency virus infection, or on immunosuppressant or steroid or psychiatric medications
* Patients with untreated clinical anxiety or depression (as measured by a Hospital Anxiety and Depression Scale (HADS) score of ≥ 16 on the depression subscale)
* Patients who are pregnant

Primary outcomes:
measure: Diagnostic capabilities
timeFrame: From consent date until first documented report, up to 6 months
Secondary outcomes:
measure: Prognostic capabilities of standard-of-care
timeFrame: Baseline to End of Study, up to 12 months
measure: Resources Implementation for WGS in a clinical setting
timeFrame: Baseline to End of Study, up to 12 months
measure: Participant characteristics
timeFrame: Baseline
measure: Change in Perceived Utility
timeFrame: Baseline, post-disclosure of results (approximately 2-3 months after enrollment), 6 months post-enrollment
measure: Changes in Health Care Utilization
timeFrame: Baseline to End of Study, up to 12 months
measure: Clinician Attitudes About WGS
timeFrame: Baseline
Other outcomes:
Locations:
city: Abu Dhabi
country: United Arab Emirates
facility: Abu Dhabi Health Research Center
Study officials:
affiliation: Abu Dhabi Health Services Co. -SEHA
name: Abdulmajeed BS Alzubaidi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Abu Dhabi Health Services Co. -SEHA
name: Erik J Koornneef, PHD
role: STUDY_DIRECTOR
affiliation: Predictiv Care, Inc.
name: Mhy-Lanie Adduru, MD
role: STUDY_DIRECTOR
affiliation: Abu Dhabi Health Services Co. -SEHA
name: Salah Eldin HM Hu, MD
role: STUDY_CHAIR
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citation: Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dube MP, Lettre G, Tardif JC, Hegele RA. Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. doi: 10.1161/ATVBAHA.116.308027. Epub 2016 Oct 20.
citation: Futema M, Bourbon M, Williams M, Humphries SE. Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia. Atherosclerosis. 2018 Oct;277:457-463. doi: 10.1016/j.atherosclerosis.2018.06.006.
citation: Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA, Harrison SC, Li K, Drenos F, Karpe F, Neil HA, Descamps OS, Langenberg C, Lench N, Kivimaki M, Whittaker J, Hingorani AD, Kumari M, Humphries SE. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013 Apr 13;381(9874):1293-301. doi: 10.1016/S0140-6736(12)62127-8. Epub 2013 Feb 22.
citation: Rimbert A, Daggag H, Lansberg P, Buckley A, Viel M, Kanninga R, Johansson L, Dullaart RPF, Sinke R, Al Tikriti A, Kuivenhoven JA, Barakat MT. Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates. Front Genet. 2022 Jan 3;12:809256. doi: 10.3389/fgene.2021.809256. eCollection 2021.
citation: Bamimore MA, Zaid A, Banerjee Y, Al-Sarraf A, Abifadel M, Seidah NG, Al-Waili K, Al-Rasadi K, Awan Z. Familial hypercholesterolemia mutations in the Middle Eastern and North African region: a need for a national registry. J Clin Lipidol. 2015 Mar-Apr;9(2):187-94. doi: 10.1016/j.jacl.2014.11.008. Epub 2014 Nov 29.