Clinical trial NCT03093818: PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions
Official title: PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Adverse Drug Reaction
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: University of Liverpool
name: Medical University of Vienna
name: Centro di Riferimento Oncologico - Aviano
name: Andaluz Health Service
name: University of Patras
name: University of Ljubljana
name: Karolinska Institutet
name: The Golden Helix Foundation
name: Royal Dutch Pharmacists Association (KNMP)
name: Bio.Logis Genetic Information Management
name: University Paul Sabatier of Toulouse
name: Uppsala University
name: Robert Bosch Gesellschaft für Medizinische Forschung mbH
name: Federal Institute for Drugs and Medical Devices
name: St. Antonius Hospital
First posted: 2017-03-28
Enrollment: 6950
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

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).

Eligibility 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)

Primary outcomes:
measure: 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.
timeFrame: 12 weeks
Secondary outcomes:
measure: Physician and pharmacist adherence to Dutch Pharmacogenomics Working Group guidelines
timeFrame: 18 months
measure: Healthcare expenditure related to adverse events
timeFrame: 18 months
measure: Incidence of drug discontinuation due to an adverse event
timeFrame: 18 months
measure: Incidence of discontinuation due to lack of efficacy
timeFrame: 18 months
measure: Quality of life
timeFrame: 18 months
measure: Incidence of dose adjustments
timeFrame: 18 months
measure: Attitudes towards and knowledge of pharmacogenomics
timeFrame: 18 months
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Patras
country: Greece
facility: University of Patras
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Ljubljana
country: Slovenia
facility: University of Ljubljana
city: Granada
country: Spain
facility: Servicio Andaluz de Salud
city: Liverpool
country: United Kingdom
facility: University of Liverpool
Study officials:
affiliation: Leiden University Medical Center
name: Jesse J. Swen, PharmD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Liverpool
name: Munir Pirmohamed, MB ChB(Hons) PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Vienna
name: Gere Sunder-Plassmann, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro di Riferimento Oncologico
name: Giuseppe Toffoli, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Andaluz Health Service
name: Cristina Lucía Dávila Fajardo, PharmD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Patras
name: George P. Patrinos, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Ljubljana
name: Vita Dolzan, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.