PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions (PREPARE)

• ClinicalTrials.gov Identifier: NCT03093818
• Recruitment Status: Active, not recruiting
• First Posted: March 28, 2017
• Last Update Posted: August 19, 2020
• Sponsor: J.J.Swen
• Collaborators: 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; Federal Institute for Drugs and Medical Devices; St. Antonius Hospital
• Information provided by (Responsible Party): J.J.Swen, Leiden University Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Adverse Drug Reaction	Other: Pharmacogenomic testing	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6950 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• 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

• Primary Purpose: Prevention
• Official Title: PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions
• Actual Study Start Date: March 20, 2017
• Estimated Primary Completion Date: October 1, 2020
• Estimated Study Completion Date: October 1, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. 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. [ Time Frame: 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 Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

Austria

Medical University of Vienna

Vienna, Austria

Greece

University of Patras

Patras, Greece

Italy

Centro di Riferimento Oncologico

Aviano, Italy

Netherlands

Leiden University Medical Center

Leiden, Netherlands

Slovenia

University of Ljubljana

Ljubljana, Slovenia

Spain

Servicio Andaluz de Salud

Granada, Spain

United Kingdom

University of Liverpool

Liverpool, United Kingdom

Sponsors and Collaborators

J.J.Swen

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

Federal Institute for Drugs and Medical Devices

St. Antonius Hospital

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: Gere Sunder-Plassmann, MD; Medical University of Vienna
• 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

  Study Documents (Full-Text)

Documents provided by J.J.Swen, Leiden University Medical Center:

Statistical Analysis Plan  [PDF] June 29, 2020

More Information

Additional Information:

Ubiquitous Pharmacogenomics (U-PGx) Consortium Official Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: J.J.Swen, Associate Professor of Pharmacogenetics, Section Chair Laboratory, Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center
• ClinicalTrials.gov Identifier: NCT03093818
• Other Study ID Numbers: 668353 (U-PGx)
• First Posted: March 28, 2017
• Last Update Posted: August 19, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• 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.
• 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.
• URL: https://cordis.europa.eu/project/id/668353/results

• 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

Additional relevant MeSH terms:

Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders