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

Cardiovascular Diseases Clinical Trial

— PREVESTATGx  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06262685
• Other study ID #: 2023-509418-12-00
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: March 4, 2024
• Est. completion date: March 4, 2025

Study information

• Verified date: January 2024
• Source: Instituto de Investigación Hospital Universitario La Paz
• Contact: Alberto M. Borobia Pérez, MD, PhD
• Phone: +34 912071466
• Email: alberto.borobia[@]salud.madrid.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 216
• Est. completion date: March 4, 2025
• Est. primary completion date: February 10, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Dyslipidemias
• Malignant Hyperthermia
• Statin Adverse Reaction

Intervention

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/
• 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/
• 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/
• 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/
• 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/
• 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/
• 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/
• 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
• 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
• 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
• 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
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Spain	Hospital La Paz	Madrid	Comunidad De Madrid

Sponsors (2)

Lead Sponsor	Collaborator
Instituto de Investigación Hospital Universitario La Paz	Instituto de Salud Carlos III

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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