Efficacy, Safety and Cost-efficacy of a Pre-emptive Genotyping Strategy in Patients Receiving Statins

A Multicenter, Controlled, Randomized, Single-blind Phase IV Trial Assesses Efficacy, Safety, and Cost of Pre-emptive Genotyping in a Cardiovascular Risk Population Eligible for High/Moderate-intensity Statins

This is a Phase IV multicentre adaptive single-blinded randomized clinical trial if preemptively genotyping populations at risk of cardiovascular disease susceptible of receiving high or moderate doses of statin therapy is efficacious, cost-efficacious, and feasible within the Spanish National Health System when compared to the current standard of care. This trial is nested within the iPHARMGx master protocol

This is a nation-wide, multicentre, randomised, controlled, and adaptive phase IV clinical trial that aims to assess the efficacy and cost-efficacy of pre-emptive pharmacogenetic testing strategies, including those impacted by genetic variants associated with adverse drug reactions (ADRs) or limited efficacy. Populations at high-risk of developing clinically relevant outcomes will be enrolled in nested trials within this master protocol. The clinical trials will evaluate the efficacy and cost-efficacy of pre-emptive genotyping by defining a drug-gene-endpoint triad. Study subjects will be pre-emptively genotyped and, if found to have an actionable gene variant, randomly allocated to either a test group where guideline-based treatment modifications will be initiated or a control group that will be managed according to healthcare provider standard of care (SoC). Subsequently, subjects will be prospectively followed at prespecified timepoints. Detailed information on drug-gene-endpoint triads, allocation schemes, and follow-up visits will be provided in each of the subprotocols. A Data Monitoring Committee (DMC), composed of physician experts, will be appointed for each nested trial to review the data on an ongoing basis, ensuring the safety of participants and scientific validity of the study.

Inclusion Criteria:

Each potential participant must satisfy all of the following criteria to be enrolled in the study:

1. Ability of the participant to understand the purpose and risks of the study, to provide informed consent, and to authorize the use of confidential health information in accordance with national and local privacy regulations.

2. Subject has voluntarily signed the ICF.

3. Subject must be ≥ 18 years old at the time of signing ICF.

4. Subject is able and willing to take part and be followed-up for the majority of the study duration.

5. Participants are susceptible to be prescribed any of the following:

   1. Atorvastatin ≥40 mg/day p.o.
   2. Simvastatin ≥20mg/day p.o.
   3. Pitavastatin≥2mg/day p.o.
   4. Rosuvastatin ≥40mg/day p.o.
   5. Pravastatin ≥40mg/day p.o.
   6. Lovastatin ≥40mg/day p.o.
   7. Fluvastatin ≥80 mg/day p.o.

6. Subjects must be naïve to any genotyping test of the following genes: SCLO1B1, ABCG2, CYP2C9, CYP3A4, CYP3A5 and HMGCR.

7. Subjects must be willing to comply and adhere to any treatment plan modifications established and to the procedures specified in this protocol.

8. Women of childbearing potential must commit not to become pregnant. Subjects must be willing to use highly effective contraceptive methods or have practiced sexual abstinence during the study.

Exclusion Criteria:

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Subject is currently taking ubiquinone (Q10) supplements.

2. Known personal or family history of statin-associated autoimmune myopathy or HMG-CoA reductase disorder.

3. Pregnant or breastfeeding women

4. Subject has a personal history or analytical evidence of one of the following disorders:

   1. Any contraindications to statin administration as revealed in the summary of product characteristics (SmPCs) for statins.
   2. Prior SAMS if subject is not statin-naïve.

5. Any condition or situation deemed by the investigator precluding or interfering with the present study.