PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions

Adverse Drug Reaction Clinical Trial

— PREPARE  

Official title:

PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03093818
• Other study ID #: 668353 (U-PGx)
• Status: Completed
• Phase: N/A
• Start date: March 20, 2017
• Est. completion date: May 1, 2021

Study information

• Verified date: April 2024
• Source: Leiden University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6950
• Est. completion date: May 1, 2021
• Est. primary completion date: September 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Adverse Drug Reaction
• Drug-Related Side Effects and Adverse Reactions

Intervention

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).

Locations

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

Sponsors (16)

Lead Sponsor

Collaborator

J.J.Swen

Andaluz Health Service, Bio.Logis Genetic Information Management, Centro di Riferimento Oncologico - Aviano, Federal Institute for Drugs and Medical Devices, Karolinska Institutet, Medical University of Vienna, Robert Bosch Gesellschaft für Medizinische Forschung mbH, Royal Dutch Pharmacists Association (KNMP), St. Antonius Hospital, The Golden Helix Foundation, University of Liverpool, University of Ljubljana, University of Patras, University Paul Sabatier of Toulouse, Uppsala University

Countries where clinical trial is conducted

Austria,  Greece,  Italy,  Netherlands,  Slovenia,  Spain,  United Kingdom, 

Outcome

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

External Links

•   Ubiquitous Pharmacogenomics (U-PGx) Consortium Official Website