PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions (PREPARE)

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.

Study Overview

• Status: Completed
• Conditions: Adverse Drug Reaction
• Intervention / Treatment: Other: Pharmacogenomic testing

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).

• Study Type: Interventional
• Enrollment (Actual): 6950
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • Medical University of Vienna
• Greece
  • Patras, Greece
    • University of Patras
• Italy
  • Aviano, Italy
    • Centro di Riferimento Oncologico
• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center
• Slovenia
  • Ljubljana, Slovenia
    • University of Ljubljana
• Spain
  • Granada, Spain
    • Servicio Andaluz de Salud
• United Kingdom
  • Liverpool, United Kingdom
    • University of Liverpool

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pharmacogenomic testing arm; 4,050 patients will provide a DNA sample. A pharmacogenomic test is performed. Results of this test are incorporated in the (electronic) medical record and combined with a clinical decision support system. Physicians and pharmacists may choose to use these results to guide drug and dose selection as per the Dutch Pharmacogenomics Working Group guidelines. Patients will receive a "Safety-Code card" containing their personal pharmacogenomics results, which can be used by other physicians or pharmacists during subsequent prescriptions.	Other: Pharmacogenomic testing; 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).
No Intervention: Standard of care arm; 4,050 patients will provide a DNA sample. However, no pharmacogenomic test is performed until the study is completed. Physicians and pharmacists will prescribe and dispense drugs routinely, without using pharmacogenomic test results to guide drug and dose selection. Patients will receive a mock "Safety-Code card", which does not contain personal pharmacogenomics results.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physician and pharmacist adherence to Dutch Pharmacogenomics Working Group guidelines	Defined as adhering to the guidelines or not adhering to the guidelines	18 months
Healthcare expenditure related to adverse events	Any costs made as a result of an adverse event	18 months
Incidence of drug discontinuation due to an adverse event	Related to the drug of inclusion	18 months
Incidence of discontinuation due to lack of efficacy	Related to the drug of inclusion	18 months
Quality of life	Time trade-off question	18 months
Incidence of dose adjustments	Related to the drug of inclusion	18 months
Attitudes towards and knowledge of pharmacogenomics	Composite outcome: a list of seven questions regarding pharmacogenomics	18 months

Collaborators and Investigators

• Sponsor: J.J.Swen
• Collaborators: Karolinska Institutet; Medical University of Vienna; Uppsala University; St. Antonius Hospital; University of Liverpool; Andaluz Health Service; University of Patras; Centro di Riferimento Oncologico - Aviano; University of Ljubljana; University Paul Sabatier of Toulouse; Robert Bosch Gesellschaft für Medizinische Forschung mbH; The Golden Helix Foundation; Royal Dutch Pharmacists Association (KNMP); Bio.Logis Genetic Information Management; Federal Institute for Drugs and Medical Devices
• Investigators: Principal Investigator: Jesse J. Swen, PharmD PhD, Leiden University Medical Center; Principal Investigator: Munir Pirmohamed, MB ChB(Hons) PhD, University of Liverpool; Principal Investigator: Giuseppe Toffoli, MD, Centro di Riferimento Oncologico; Principal Investigator: Cristina Lucía Dávila Fajardo, PharmD PhD, Andaluz Health Service; Principal Investigator: George P. Patrinos, PhD, University of Patras; Principal Investigator: Vita Dolzan, MD PhD, University of Ljubljana; Principal Investigator: Gere Sunder-Plassmann, MD, Medical University of Vienna

Publications and helpful links

General Publications

• Psarias G, Iliopoulou E, Liopetas I, Tsironi A, Spanos D, Tsikrika A, Kalafatis K, Tarousi D, Varitis G, Koromina M, Siamoglou S, Patrinos GP. Development of Rapid Pharmacogenomic Testing Assay in a Mobile Molecular Biology Laboratory (2MoBiL). OMICS. 2020 Nov;24(11):660-666. doi: 10.1089/omi.2020.0168. Epub 2020 Oct 16.

Helpful Links

• Ubiquitous Pharmacogenomics (U-PGx) Consortium Official Website

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2017
• Primary Completion (Actual): September 30, 2020
• Study Completion (Actual): May 1, 2021

Study Registration Dates

• First Submitted: March 6, 2017
• First Submitted That Met QC Criteria: March 22, 2017
• First Posted (Actual): March 28, 2017

Study Record Updates

• Last Update Posted (Estimated): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Drug-Related Side Effects and Adverse Reactions
• Other Study ID Numbers: 668353 (U-PGx)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The data management plan has been written to comply to FAIR principles.

Findable:

We will indicate the existence of the data in our scientific publications and at our website (www.upgx.eu).

Accessible:

The datasets will not be made openly accessible, but will become available upon request after publications of the main paper by the U-PGx consortium.

Interoperable:

We will make use of standardized scores and standardized methodologies for example the star allele nomenclature and rs-numbering for genetic variants.

Reusable:

We do not intend to licence our data. A data dictionary is available for the entire eCRF.

• IPD Sharing Time Frame: The datasets will not be made openly accessible, but will become available upon request after publications of the main paper by the U-PGx consortium.
• IPD Sharing Access Criteria: Requests to re-use the data sets by third parties will be addressed to U-PGx Executive Board including the coordinator, i.e. Leiden University Medical Center, the Netherlands.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No