Cardiovascular Diseases, Dyslipidemias, Pharmacogenic Myopathy, Statin Adverse Reaction
Conditions
Keywords
Statin, Statin Associated Muscle Symptoms, Cardiovascular disease, Cost-effectiveness, Phase IV Clinical Trial, Pharmacogenetic
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.
Interventions
OTHERPreemptive 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/
OTHERPreemptive 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/
OTHERPreemptive 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/
OTHERPreemptive 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/
OTHERPreemptive 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/
OTHERPreemptive 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/
OTHERPreemptive 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/
OTHERStandard 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
OTHERStandard 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
OTHERStandard 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
OTHERStandard 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
OTHERStandard 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.
OTHERStandard 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.
OTHERStandard 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.
Sponsors
Instituto de Salud Carlos III
Instituto de Investigación Hospital Universitario La Paz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Subjects will remain blinded to arm assigned because pharmacogenetic phenotype and statin/dose-guidance will only be exclusively accesible to the attending physician
Intervention model description
Phase IV, multicentre, controlled, randomized, parallel and single-blind adaptive clinical trial nested within the iPHARMGx master protocol study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 . |
Other
| Measure | Time frame | Description |
|---|---|---|
| Novel prognostic and predictive genetic biomarkers of statin-related adverse events and efficacy identification | Though study completion, on average 18 months | 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. |
| Death from cardiovascular causes, nonfatal myocardial infarction or hospitalization for unstable angina or resuscitated cardiac arrest | 9-months | 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 |
| Difference in percentage in the eight-item Morisky Medication Adherence Scale (MMAS-8) questionnaire score between intervention and control arm | 9-months | A score \<6 indicates low adherence A score of 6-8 indicates medium adherence A score \>8 indicates high adherence |
| SAMS intensity reduction of a statin preemptive pharmacogenetic prescription scheme | 9-months | 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. |
Countries
Spain
Contacts
Primary ContactAlberto M. Borobia Pérez, MD, PhD
Outcome results
None listed