PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions

J.J.Swen6,950 enrolled

Overview

PREPARE is an international, prospective, multi-center, open, randomized, cross-over implementation study assessing the impact of pre-emptive pharmacogenomic testing, of a panel of actionable pharmacogenomic variants, on adverse event incidence. Additional outcomes include, healthcare expenditure, process indicators for implementation and provider adoption of pharmacogenomics.

Pre-emptive pharmacogenomic testing will be implemented in clinical sites across seven European countries (United Kingdom, The Netherlands, Austria, Greece, Slovenia, Italy and Spain). The 36-month study is split into two (19 and 18-month) time-blocks. The participating countries are randomized to start with either implementing pharmacogenomics guided prescribing or with standard of care in the first block. In the pharmacogenomics guided prescribing arm, results of the pharmacogenomic test will be incorporated in the (electronic) medical record and may be used by physicians and pharmacists to guide drug and dose selection for 39 routinely prescribed drugs, as per the Dutch Pharmacogenomics Working Group guidelines. In the standard of care arm, patients will not receive pharmacogenomic testing. After this 19-month block, the countries switch to implementing the opposite strategy and will recruit new patients for a period of 18 months. Patients are eligible for participation when they receive a first prescription for one or more of 39 drugs for which a Dutch Pharmacogenomic Working Group guideline is available (acenocoumarol, amitriptyline, aripiprazole, atomoxetine, atorvastatin, azathioprine ,capecitabine, citalopram, clomipramine, clopidogrel, codeine, doxepin, efavirenz, escitalopram, flecainide, flucloxacillin, fluorouracil, haloperidol, imipramine, irinotecan, mercaptopurine, metoprolol, nortryptiline, paroxetine, phenprocoumon, phenytoin, pimozide, propafenon, sertraline, simvastatin, tacrolimus, tamoxifen, tegafur, thioguanine, tramadol, venlafaxine, voriconazole, warfarin or zuclopenthixol). All patients will be followed for a minimum of three months and a maximum of 18 months. In total, 8,100 patients will be recruited; 4,050 will receive pharmacogenomic testing, and 4,050 will receive standard of care. Each implementation site will concentrate on, but is not limited to, recruiting patients within a specific therapeutic area. Therapeutic areas include primary care, general medicine, cardiology, oncology, psychiatry, neurology, and transplantation. It is hypothesized that implementing pharmacogenomics guided drug and dose selection will decrease incidence of clinically relevant adverse drug reactions by 30% (from 4% to 2.8% among those with actionable drug-gene interactions).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

SINGLE

Enrollment

6,950

Conditions

Adverse Drug Reaction

Interventions

Pharmacogenomic testingOTHER

The pharmacogenomic panel to be used incorporates 48 genetic variants for the following 13 "pharamacogenes": CYP2B6 (cytochrome P450), CYP2C19, CYP2C9, CYP2D6,CYP3A4, DPYD (dihydropyrimidine dehydrogenase), FVL (factor five Leiden), HLA-B (human leukocyte antigen), NUDT15 (Nudix hydrolase), SLCO1B1 (solute carrier organic anion transporter), TPMT (thiopurine methyltransferase), UGT1A1 (UDP-glucuronosyltransferase), and VKORC1 (vitamin K epoxide reductase complex).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Subject must be ≥ 18 years old * Subject must receive a first prescription (meaning no known prescription for this drug in the preceding 12 months) for one or more of 42 drugs, for which a Dutch Pharmacogenomic Working Group guideline is available, which is prescribed to them in routine care * Subject is able and willing to take part and be followed-up for at least 12 weeks * Subject is able to donate blood or saliva * Subject has signed informed consent * The study limit of enrolment (200 per arm, per 18-month block) for that drug has not been reached Exclusion Criteria: * Subject has previous (direct-to-consumer, or clinical) genetic testing for a gene important to the drug of inclusion * Subject is pregnant or lactating * Subject has a life expectancy estimated to be less than three months by treating clinical team * Duration of the drug of inclusion total treatment length is planned to be less than seven consecutive days. A drug whose route of administration changes during the first seven days (e.g. intravenous to oral flucloxacillin) but whose total treatment duration is seven days or longer, is still eligible. * For inpatients: hospital admission is expected to be less than 72 hours * Subject is unable to consent to the study * Subject is unwilling to take part * Subject has no fixed address * Subject has no current general practitioner * Subject is, in the opinion of the Investigator, not suitable to participate in the study * Subject has existing impaired hepatic or renal function for which a lower dose or alternate drug selection are already part of current routine care. This would not apply to any drugs specifically given to manage liver/renal impairment/transplantation. * Subject has an estimated glomerular filtration rate (MDRD) of less than 15 ml/min per 1,73m2 in a subject with a functioning graft * Subject has advanced liver failure (stage Child-Pugh C)

Locations (7)

Medical University of Vienna

Vienna, Austria

University of Patras

Pátrai, Greece

Centro di Riferimento Oncologico

Aviano, Italy

Leiden University Medical Center

Leiden, Netherlands

Outcomes

Primary Outcomes

Occurrence of a clinically relevant adverse drug reaction which is caused by the drug of inclusion. For oncology patients only hematological toxicities (grade 4-5) and non-hematological toxicities (grade 3-5) will be considered clinically relevant.

Defined as an adverse drug reaction which is causally related to the drug of inclusion (definite, probable or possible), clinically relevant (CTCAE Grade 2,3,4 or 5) and associated with a drug-genotype interaction (as per the Dutch Pharmacogenomics Working Group guidelines)

Time frame: 12 weeks

Secondary Outcomes

Physician and pharmacist adherence to Dutch Pharmacogenomics Working Group guidelines

Defined as adhering to the guidelines or not adhering to the guidelines

Time frame: 18 months

Healthcare expenditure related to adverse events

Any costs made as a result of an adverse event

Time frame: 18 months

Incidence of drug discontinuation due to an adverse event

Related to the drug of inclusion

Time frame: 18 months

Incidence of discontinuation due to lack of efficacy

Related to the drug of inclusion

Time frame: 18 months

Quality of life

Time trade-off question

Time frame: 18 months

Incidence of dose adjustments

Related to the drug of inclusion

Time frame: 18 months

Data from ClinicalTrials.gov

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