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

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

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiovascular Diseases; Dyslipidemias; Statin Adverse Reaction; Pharmacogenic Myopathy
• Intervention / Treatment: Other: Preemptive pharmacogenetic atorvastatin dose based on CPIC guidelines; Other: Preemptive pharmacogenetic simvastatin dose based on CPIC guidelines; Other: Preemptive pharmacogenetic pitavastatin dose based on CPIC guidelines; Other: Preemptive pharmacogenetic rosuvastatin dose based on CPIC guidelines; Other: Preemptive pharmacogenetic pravastatin dose based on CPIC guidelines; Other: Preemptive pharmacogenetic lovastatin dose based on CPIC guidelines; Other: Preemptive pharmacogenetic fluvastatin dose based on CPIC guidelines; Other: Standard of Care (SoC) dosing of atorvastatin; Other: Standard of Care (SoC) dosing of simvastatin; Other: Standard of Care (SoC) dosing of pitavastatin; Other: Standard of Care (SoC) dosing of rosuvastatin; Other: Standard of Care (SoC) dosing of prasavastatin; Other: Standard of Care (SoC) dosing of lovastatin; Other: Standard of Care (SoC) dosing of fluvastatin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 216
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alberto M. Borobia Pérez, MD, PhD; Phone Number: +34 912071466; Email: alberto.borobia@salud.madrid.org

Study Locations

• Spain
  • Comunidad De Madrid
    • Madrid, Comunidad De Madrid, Spain, 28046
      • Hospital La Paz
      • Contact: Stefan Mark Stewart Balbás, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Group; Patients in this Experimental Group will receive any of the statins authorized in Spain for lipid-lowering, both for primary and secondary prevention. Subjects in the Experimental Group will be administered the specific type and dosage of statins recommended by the Clinical Pharmacogenetics Consortium's genotype guidelines, utilizing the patient's pharmacogenetic information and characteristics	Other: Preemptive pharmacogenetic atorvastatin dose based on CPIC guidelines; Atorvastatin at the dosage reccomended by the 2022 "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and considerations for Statin-Associated Musculoskeletal Symptoms" based on the subjects pharmacogenetic phenotype. A comprehensive description of said doses are can be accessed at: https://cpicpgx.org/guidelines/cpic-guideline-for-statins/; Other: Preemptive pharmacogenetic simvastatin dose based on CPIC guidelines; Simvastatin at the dosage reccomended by the 2022 "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and considerations for Statin-Associated Musculoskeletal Symptoms" based on the subjects pharmacogenetic phenotype. A comprehensive description of said doses are can be accessed at: https://cpicpgx.org/guidelines/cpic-guideline-for-statins/; Other: Preemptive pharmacogenetic pitavastatin dose based on CPIC guidelines; Pitavastatin at the dosage reccomended by the 2022 "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and considerations for Statin-Associated Musculoskeletal Symptoms" based on the subjects pharmacogenetic phenotype. A comprehensive description of said doses are can be accessed at: https://cpicpgx.org/guidelines/cpic-guideline-for-statins/; Other: Preemptive pharmacogenetic rosuvastatin dose based on CPIC guidelines; Rosuvastatin at the dosage reccomended by the 2022 "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and considerations for Statin-Associated Musculoskeletal Symptoms" based on the subjects pharmacogenetic phenotype. A comprehensive description of said doses are can be accessed at: https://cpicpgx.org/guidelines/cpic-guideline-for-statins/; Other: Preemptive pharmacogenetic pravastatin dose based on CPIC guidelines; Pravastatin at the dosage reccomended by the 2022 "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and considerations for Statin-Associated Musculoskeletal Symptoms" based on the subjects pharmacogenetic phenotype. A comprehensive description of said doses are can be accessed at: https://cpicpgx.org/guidelines/cpic-guideline-for-statins/; Other: Preemptive pharmacogenetic lovastatin dose based on CPIC guidelines; Lovastatin at the dosage reccomended by the 2022 "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and considerations for Statin-Associated Musculoskeletal Symptoms" based on the subjects pharmacogenetic phenotype. A comprehensive description of said doses are can be accessed at: https://cpicpgx.org/guidelines/cpic-guideline-for-statins/; Other: Preemptive pharmacogenetic fluvastatin dose based on CPIC guidelines; Fluvastatin at the dosage reccomended by the 2022 "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and considerations for Statin-Associated Musculoskeletal Symptoms" based on the subjects pharmacogenetic phenotype. A comprehensive description of said doses are can be accessed at: https://cpicpgx.org/guidelines/cpic-guideline-for-statins/
Active Comparator: Control Group; Patients in this Control Group will receive any of the authorized statins in Spain for lipid-lowering, whether for primary or secondary prevention. They will be administered statins according to clinical practice and the drug's product labeling, without exceeding the already authorized dosages	Other: Standard of Care (SoC) dosing of atorvastatin; Subject allocated to this arm will receive the atorvastatin according to clinical practice and the drug's product labelling, and never exceeding the already authorized dosages. These subject will not receive a personalised dosed/prescription based on their pharmacogenetic phenotype; Other: Standard of Care (SoC) dosing of simvastatin; Subject allocated to this arm will receive the simvastatin according to clinical practice and the drug's product labelling, and never exceeding the already authorized dosages. These subject will not receive a personalised dosed/prescription based on their pharmacogenetic phenotype; Other: Standard of Care (SoC) dosing of pitavastatin; Subject allocated to this arm will receive the pitavastatin according to clinical practice and the drug's product labelling, and never exceeding the already authorized dosages. These subject will not receive a personalised dosed/prescription based on their pharmacogenetic phenotype; Other: Standard of Care (SoC) dosing of rosuvastatin; Subject allocated to this arm will receive the rosuvastatin according to clinical practice and the drug's product labelling, and never exceeding the already authorized dosages. These subject will not receive a personalised dosed/prescription based on their pharmacogenetic phenotype; Other: Standard of Care (SoC) dosing of prasavastatin; Subject allocated to this arm will receive the prasavastatin according to clinical practice and the drug's product labelling, and never exceeding the already authorized dosages. These subject will not receive a personalised dosed/prescription based on their pharmacogenetic phenotype.; Other: Standard of Care (SoC) dosing of lovastatin; Subject allocated to this arm will receive the lovastatin according to clinical practice and the drug's product labelling, and never exceeding the already authorized dosages. These subject will not receive a personalised dosed/prescription based on their pharmacogenetic phenotype.; Other: Standard of Care (SoC) dosing of fluvastatin; Subject allocated to this arm will receive the fluvastatin according to clinical practice and the drug's product labelling, and never exceeding the already authorized dosages. These subject will not receive a personalised dosed/prescription based on their pharmacogenetic phenotype.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of clinically relevant statin-associated musculoskeletal events	As defined by the a composite endpoint: Patients with a clinically relevant statin-associated musculoskeletal symptom defined as a combination of a SAMS-CI (Statin Associated Muscular Symptoms Clinical Index) score ≥7 points and a NPRS (Numerical Pain Rating Scale) score ≥3) in the 9-month follow-up period Serum creatin phosphokinase (CPK) [UI/L] greater than three times the upper limit of normality prespecified by each centre's laboratory, in relation to the statin.	9-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Low density lipoprotein cholesterol (LDLc) serum concentration baseline reduction rate	Percentage of Baseline LDLc serum concentration reduction rate when compared to LDLc serum concentration values at 9 months.	9-months
Baseline change in statin therapy prescription	Percentage of patients that require either a statin dose modification/withdrawal or additional lipid-lowering therapy after 9 months in order to meet LDLc goals.	9-months
Cost of a statin preemptive pharmacogenetic prescription scheme	To quantify economic burden a cost-benefit analysis defined as the difference [in monetary units, euros] between the costs of the intervention [pharmacogenetic analysis] and all its surrounding procedures [personnel, geneticist report, clinical pharmacologist report] combined with the costs derived from the events [blood sample analysis, hospital admission, follow-up visits, lipid-lowering therapy modification] in the intervention arm when compared to the costs derived from the events in the control arm alone Monetary units requiered to prevent a event will be calculated through an incremental cost effectiveness ratio (ICER) between intervention and control arm .	Though study completion, on average 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Novel prognostic and predictive genetic biomarkers of statin-related adverse events and efficacy identification	All participants DNA sample will be susceptible of deep sequencing analysis at CNIO (National Centre of Oncological Investigations) to assess novel prognostic and predictive biomarkers for statin induced muscle symptoms such as fibroblast growth factor 21 (FGF21), MicroRNA-499 or IL-6.	Though study completion, on average 18 months
Death from cardiovascular causes, nonfatal myocardial infarction or hospitalization for unstable angina or resuscitated cardiac arrest	Combined incidence of participants who experience a 4-component exploratory endpoint consisting of: Cardiovascular death Nonfatal myocardial infarction (MI) Resuscitated cardiac arrest Hospitalization for unstable angina	9-months
Difference in percentage in the eight-item Morisky Medication Adherence Scale (MMAS-8) questionnaire score between intervention and control arm	A score <6 indicates low adherence A score of 6-8 indicates medium adherence A score >8 indicates high adherence	9-months
SAMS intensity reduction of a statin preemptive pharmacogenetic prescription scheme	Difference in Numeric Pain Rating Scale (NPRS) score between intervention and control arm. Categories will be as follow: 0-3 no pain; 3-5 moderate pain; 5-7 intense pain; 7-9 very intense pain; 9-10 extreme pain.	9-months

Collaborators and Investigators

• Sponsor: Instituto de Investigación Hospital Universitario La Paz
• Collaborators: Instituto de Salud Carlos III

Study record dates

Study Major Dates

• Study Start (Estimated): March 4, 2024
• Primary Completion (Estimated): February 10, 2025
• Study Completion (Estimated): March 4, 2025

Study Registration Dates

• First Submitted: January 9, 2024
• First Submitted That Met QC Criteria: February 13, 2024
• First Posted (Actual): February 16, 2024

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Cost-effectiveness; Statin; Pharmacogenetic; Statin Associated Muscle Symptoms; Phase IV Clinical Trial
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Postoperative Complications; Lipid Metabolism Disorders; Body Temperature Changes; Intraoperative Complications; Hyperthermia; Cardiovascular Diseases; Dyslipidemias; Malignant Hyperthermia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Pravastatin; Simvastatin; Lovastatin; L 647318; Dihydromevinolin; Pitavastatin
• Other Study ID Numbers: 2023-509418-12-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: A copy of the database of data collected during the clinical trial will be attached as an appendix to the publication resulting from this clinical trial.
• IPD Sharing Time Frame: Data will be available at the same time as the results will be published, and will be kept available to everyone without any time limit.
• IPD Sharing Access Criteria: Data will be available indefinitely on the publisher's website, as long as it is kept by the Publisher, for anyone who wishes to access the data, for non-commercial purposes
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No