To determine whether implementing pre-emptive PGx testing of an entire panel of clinically relevant PGx markers, to guide the dose and drug selection for over 39 commonly prescribed drugs, will result in an overall reduction in the number of…
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Health condition
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Research involving
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Intervention
Outcome measures
Primary outcome
The primary endpoint of PREPARE is a composite endpoint of clinically relevant
drug-genotype associated ADRs.
Secondary outcome
Secondary outcomes include other clinical outcome measures (e.g. total number
of ADEs, dose changes, drug cessations etc.), a cost-effectiveness evaluation,
and process metrics for implementation; the latter includes physician and
pharmacist adherence to the DPWG guidelines, and the acceptance of PGx-informed
prescribing to health care professionals and patients.
Background summary
In recent years, multiple randomized controlled trials for a variety of
drug-gene combinations have strongly indicated that pharmacogenomics (PGx)
testing prior to prescribing, to guide the dose and drug selection, can improve
patient outcomes. Almost 15% of medicinal products evaluated by the European
Medicines Agency between 1995 and 2014 contain PGx information in their product
label. PGx-guided therapeutic dose and drug selection recommendations have also
been created and published by the Dutch Pharmacogenetics Working Group (DPWG).
However, despite these major scientific and clinical advances in PGx, and the
availability of several commercially available PGx tests, the application of
PGx into routine care remains very limited. PREPARE will implement pre-emptive
genotyping of an entire panel of clinically relevant PGx markers (for which
DPWG guidelines are available: *pharmacogenes*) across seven countries within
the European Union, in a prospective clinical study and investigate its
collective impact on patient outcomes and cost-effectiveness.
Study objective
To determine whether implementing pre-emptive PGx testing of an entire panel of
clinically relevant PGx markers, to guide the dose and drug selection for over
39 commonly prescribed drugs, will result in an overall reduction in the number
of clinically relevant drug-genotype associated adverse drug reactions (ADRs).
We hypothesize that the implementation of PGx-guided drug prescribing will
reduce both the occurrence and severity of drug-genotype associated ADRs in
comparison to patients receiving standard of care treatment.
Study design
A multi-center, open, randomized, cross-over implementation study conducted in
seven countries across Europe. Countries will be randomised to start with
either PGx-guided prescribing (study arm) or standard of care (control arm).
After this period, a new set of patients will be recruited and the opposite
strategy will implemented. All study patients will be followed-up for a minimum
of 12 weeks; maximum follow-up is limited to 22 months per patient.
Intervention: All patients will donate a DNA sample that will be genotyped for
a panel of 48 genetic variants in 13 pharmacogenes. For patients within the
study arm, their results will be: 1) recorded in the (electronic) medical
record and 2) provided to the patient in the form of plastic card, akin to a
credit card. Genetic results and DPWG guidelines can used by physicians and
pharmacists to guide the dose and drug selection for the initial drug of
inclusion, and for the prescription of any subsequent drugs that are newly
started during follow-up and are on the list of drugs eligible for inclusion in
PREPARE (i.e. a DPWG guideline is available for the drug). Physicians and
pharmacists are given PGx test results but are not forced to adhere to the DPWG
guidelines.
Study burden and risks
When a patient chooses to participate in this study, genetic information
concerning 48 genetic variants in 13 pharmacogenes will be determined. Burdens
to the patient are: 1) the supply of a blood or saliva sample for DNA
collection, 2) being contacted four times at regular intervals by a research
nurse (at baseline, four weeks and 12 weeks and at the end of the arm*s
follow-up period), and 3) being asked to complete online surveys (at two weeks,
and eight weeks). Patients who endure an ADR which is categorized as an
*extreme phenotype* will be asked to provide an additional blood spot sample
within 24 hours of the ADR. In a sub-study, patients included in the study for
a first prescription of voriconazole, metoprolol, simvastatin, atorvastatin,
fluorouracil or capecitabine will be asked to provide additional blood spot
samples at multiple time points and at the time of a serious ADR. Benefits to
patients in the study arm include a potential reduced risk of ADRs. Overall,
minimal risks are expected for included patients due to the fact that all of
the drugs included within this study have previously been licensed for routine
use and thus have been evaluated as having a positive benefit/risk ratio.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
1. Subject must be >= 18 years old
2. Subject must receive a 1st prescription (meaning no known prescription for
this drug in the preceding 12 months) for a drug of interest (Flecainide,
Propafenon, Codeine, Tramadol, Capecitabine, Fluorouracil, Irinotecan,
Tamoxifen, Tegafur, Acenocoumarol, Clopidrogel , Phenprocoumon, Warfarin,
Citalopram , Escitalopram, Paroxetine, Sertraline, Venlafaxine, Amitriptyline,
Clomipramine, Doxepine, Imipramine, Nortryptiline, Phenytoin, Metoprolol,
Efavirenz, Flucloxacillin, Voriconazole, Aripiprazole, Haloperidol, Pimozide,
Zuclopenthixol, Atorvastatin, Simvastatin, Azathioprine, Mercaptopurine,
Tacrolimus, Thioguanine or Atomoxetine), which is prescribed to them in routine
care.
3. Subject is able and willing to take part and be followed-up for at least 12
weeks
4. Subject is able to donate blood or saliva
5. Subject has signed informed consent
Exclusion criteria
1. Previous (direct-to-consumer, or clinical) genetic testing for a gene
important to the index drug
2. Pregnancy or lactating
3. Life expectancy estimated to be less than three months by treating clinical
team
4. Duration of index drug 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.
5. For inpatients: hospital admission is expected to be less than 72 hours (to
facilitate acting upon the PGX results)
6. Unable to consent to the study
7. Unwilling to take part
8. Subject has no fixed address
9. Subject has no current general practitioner
10. Subject is, in the opinion of the Investigator, not suitable to participate
in the study
11. Patient 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.
12. Estimated glomerular filtration rate (MDRD) of less than 15 ml/min per
1,73m2 in a subject with a functioning graft
13. Patients with advanced liver failure (stage Child-Pugh C)
Design
Recruitment
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| CCMO | NL60069.058.16 |