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

Phase 4

Not yet recruiting

• Conditions: Cardiovascular Diseases; Dyslipidemias; Pharmacogenic Myopathy; Statin Adverse Reaction
• Interventions: Other: Preemptive pharmacogenetic atorvastatin dose based on CPIC guidelines; Other: Standard of Care (SoC) dosing of atorvastatin; Other: Standard of Care (SoC) dosing of simvastatin; Other: Preemptive pharmacogenetic simvastatin dose based on CPIC guidelines; Other: Preemptive pharmacogenetic pitavastatin dose based on CPIC guidelines; Other: Standard of Care (SoC) dosing of pitavastatin; Other: Standard of Care (SoC) dosing of rosuvastatin; Other: Preemptive pharmacogenetic rosuvastatin dose based on CPIC guidelines; Other: Preemptive pharmacogenetic pravastatin dose based on CPIC guidelines; Other: Standard of Care (SoC) dosing of prasavastatin; Other: Standard of Care (SoC) dosing of lovastatin; Other: Preemptive pharmacogenetic lovastatin dose based on CPIC guidelines; Other: Standard of Care (SoC) dosing of fluvastatin; Other: Preemptive pharmacogenetic fluvastatin dose based on CPIC guidelines

• Registration Number: NCT06262685
• Lead Sponsor: Instituto de Investigación Hospital Universitario La Paz

Brief 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

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 Timeline

• Status Verified: 2024-01
• Study First Submitted: 2024-01-09
• Study First Submitted QC: 2024-02-13
• Last Update Submitted: 2024-02-13
• Study First Posted: 2024-02-16
• Last Update Posted: 2024-02-16
• Study Start: 2024-03-04
• Primary Completion: 2025-02-10
• Study Completion: 2025-03-04

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 216

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental Group	Preemptive pharmacogenetic atorvastatin dose based on CPIC guidelines	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
Experimental Group	Preemptive pharmacogenetic pitavastatin dose based on CPIC guidelines	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
Control Group	Standard of Care (SoC) dosing of rosuvastatin	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
Experimental Group	Preemptive pharmacogenetic rosuvastatin dose based on CPIC guidelines	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
Experimental Group	Preemptive pharmacogenetic pravastatin dose based on CPIC guidelines	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
Control Group	Standard of Care (SoC) dosing of pitavastatin	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
Control Group	Standard of Care (SoC) dosing of fluvastatin	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
Control Group	Standard of Care (SoC) dosing of atorvastatin	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
Control Group	Standard of Care (SoC) dosing of simvastatin	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
Control Group	Standard of Care (SoC) dosing of lovastatin	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
Experimental Group	Preemptive pharmacogenetic simvastatin dose based on CPIC guidelines	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
Experimental Group	Preemptive pharmacogenetic lovastatin dose based on CPIC guidelines	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
Control Group	Standard of Care (SoC) dosing of prasavastatin	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
Experimental Group	Preemptive pharmacogenetic fluvastatin dose based on CPIC guidelines	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

Primary Outcome Measures

Name	Time	Method
Incidence of clinically relevant statin-associated musculoskeletal events	9-months	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.

Secondary Outcome Measures

Name	Time	Method
Cost of a statin preemptive pharmacogenetic prescription scheme	Though study completion, on average 18 months	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 .
Low density lipoprotein cholesterol (LDLc) serum concentration baseline reduction rate	9-months	Percentage of Baseline LDLc serum concentration reduction rate when compared to LDLc serum concentration values at 9 months.
Baseline change in statin therapy prescription	9-months	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.

Trial Locations

Locations (1)

Hospital La Paz; 🇪🇸 Madrid, Comunidad De Madrid, Spain