Adverse Drug Reaction
Conditions
Brief summary
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.
Detailed description
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).
Interventions
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).
Sponsors
University of Liverpool
Medical University of Vienna
Centro di Riferimento Oncologico - Aviano
Andaluz Health Service
University of Patras
University of Ljubljana
Karolinska Institutet
The Golden Helix Foundation
Royal Dutch Pharmacists Association (KNMP)
Bio.Logis Genetic Information Management
University Paul Sabatier of Toulouse
Uppsala University
Robert Bosch Gesellschaft für Medizinische Forschung mbH (RBMF)
Federal Institute for Drugs and Medical Devices
St. Antonius Hospital
J.J.Swen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
A 10% random sample will be re-assessed for causality and severity of recorded ADE will by a second independent, blinded (unaware of patient allocation) assessor. Drug-genotype association of the ADE as per the Dutch Pharmacogenomics Working Group guideline will be assessed by a blinded review committee
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 12 weeks | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Healthcare expenditure related to adverse events | 18 months | Any costs made as a result of an adverse event |
| Incidence of drug discontinuation due to an adverse event | 18 months | Related to the drug of inclusion |
| Incidence of discontinuation due to lack of efficacy | 18 months | Related to the drug of inclusion |
| Physician and pharmacist adherence to Dutch Pharmacogenomics Working Group guidelines | 18 months | Defined as adhering to the guidelines or not adhering to the guidelines |
| Incidence of dose adjustments | 18 months | Related to the drug of inclusion |
| Attitudes towards and knowledge of pharmacogenomics | 18 months | Composite outcome: a list of seven questions regarding pharmacogenomics |
| Quality of life | 18 months | Time trade-off question |
Countries
Austria, Greece, Italy, Netherlands, Slovenia, Spain, United Kingdom
Outcome results
None listed