PRE-EMPTIVE PHARMACOGENOMICS IN ACUTE CARE SETTINGS WITH HEALTH ECONOMIC EVALUATIONS (PHOENIX TRIAL)

PHOENIX TRIAL - A PILOT RANDOMISED CONTROLLED TRIAL OF PRE-EMPTIVE PHARMACOGENOMICS IN ACUTE CARE SETTINGS WITH HEALTH ECONOMIC EVALUATIONS

It is known that individuals respond differently to the same medicine with some people benefitting, some experiencing no effect and others suffering side-effects or even coming to harm. Some of the differences in response to medications can be explained by our genes. Genes are short sections of DNA. Each individual has over 20,000 different genes. Genes carry instructions for making the proteins needed to build things within the body including the sites where medicines act. Pharmacogenomics is the study of how our genes affect the way our body responds to medications.

Doctors can test for gene variations that might put an individual at risk of severe side-effects or mean that they are likely to receive no benefit from a specific medicine. Though not widely available in the NHS, testing allows doctors and patients to chose a different dose or avoid the medicine completely. It is estimated that almost everyone in the population (>95%) carries at least one gene variation that affects our response to medicines.

The PHOENIX study will recruit 4,000 participants who are admitted to hospital or attend an outpatient clinic who require a new drug prescription. The new drug prescription will be one who known pharmacogenomic implications. A cheek (buccal) swab will be taken which can be used to test a large number of genes known to alter the response to medicines. Around half of the participants will be tested immediately whilst the other half will have the test after three months. The results of the test relevant to each patients new prescription will enable the doctor prescribing to determine if any changes to that medicine would be beneficial. Information will be collected about participants quality of life, subsequent admissions to hospital, medication changes and side-effects. An assessment of cost saving to the NHS will also be made.

PHOENIX is a pilot two-group parallel randomised trial aimed at generating preliminary evidence on the effectiveness of a pharmacogenomics (PGx) intervention in reducing adverse drug reactions (ADR) and treatment failures in patients (hospitalised or attending secondary care specialist clinics). Additionally, it will provide early insights into health-economic impact of such PGx-guided care. Pharmacogenomic analysis will be conducted on DNA extracted from buccal swab samples taken at consent. This Trial will be performed according to the UK Policy Framework for Health and Social Care Research (2023).

The trial will recruit adult participants, admitted to wards or attending specialist outpatient clinics in Queen Elizabeth University Hospital (QEUH), Glasgow, where the selected PGx drugs are frequently prescribed: General Medicine (all specialities and receiving areas), Medicine for the Elderly, Cardiology, Stroke, Diabetes and Endocrinology, Infectious Diseases, Rheumatology, Neurology, General Surgery, Vascular Surgery, Urology, ENT and Orthopaedics.

Potential participants will be identified by the prescription of a new medicine with pharmacogenomic implications on the HEPMA electronic prescribing system, trial team visit to ward areas, treating clinician or patients self identifying on inpatient ward areas. Drug caps will be in place throughout the trial to prevent over-recruitment of one or more commonly prescribed medications. Potential participants approached by study team and offered PIS/invite. Potential participants contact study team to opt-in or study team return to ask if interested in study +/- further discussion. Written informed consent will be given by each participant or their legal representative is they are deemed to be lacking capacity.

Maximum Total 4000 Intervention arm: 1000 to 2000 Standard of care arm: 1000 to 2000

All participants will provide a buccal swab (mouth swab) for genetic testing. All samples will have DNA extracted on receipt of the sample. Pharmacogenomic testing will be performed immediately for those in the intervention arm or stored and tested at six month in the standard of care arm.

The pharmacogenomic report will be returned to the clinician with responsibility for the patients care (at baseline for intervention or three months for standard of care) with a recommendation regarding the medicine if changes are suggested. This will unblind the treating clinician and potentially the patient if medication changes are made for the intervention group.

All participants will be asked to complete questionnaires on quality of life (monthly for three months), medication adherence and adverse drug reactions (monthly for three months).

Blood testing will be carried out for safety (usual clinical care) at approximately four weeks, dependent on the index drug.

Further information will be collected through West of Scotland Safe Haven on new medication prescriptions, hospital admissions and deaths. This will require the participants CHI (community health index) number to be linked to their Safe Haven data but data will be returned to the researchers in anonymised form.

Inclusion Criteria INPATIENTS Age ≥18 years

• Capable of giving informed consent directly or via a legal representative (e.g., next of kin, welfare guardian, health care power of attorney).
• Participants who are newly prescribed one of the trial-eligible index drugs during their hospital stay may be approached for consent. Consent should be obtained within 3 days of the first dose of the index drug being administered. If there is a clear clinical plan documented on HEPMA indicating that the patient will be started on an eligible drug (but has not yet received the first dose), consent may be obtained in anticipation. However, formal trial enrolment will only occur once the first dose of the index drug has been administered.
• Participant is able to provide a cheek swab
• Participant is able to take part and be followed-up for at least 12 weeks.
• Participant is resident in NHSGGC health board area OUTPATIENTS
• Age ≥18 years
• Capable of giving informed consent directly or via a legal representative (e.g., next of kin, welfare guardian, health care power of attorney).
• Participants who are expected to be prescribed a trial-eligible drug during their outpatient clinic visit may be approached for consent prior to starting the medication. In these cases, formal trial enrolment will only occur once the patient has confirmed that they have received and started the prescribed medication
• Participant must not have a prescription for this drug in the previous 3 months.
• Participant is able to provide a cheek swab
• Participant is able to take part and be followed-up for at least 12 weeks.
• Participant is resident in NHSGGC health board area.

Exclusion Criteria INPATIENTS

• Inability to give informed consent directly or via a legal representative.
• Non-English speakers without translation support.
• Participants co-enrolled in other trials where a medication is one of the index drug is part of the trial protocol.
• Inability to give informed consent directly or via a legal representative.
• Non-English speakers without translation support.
• Participants co-enrolled in other trials where a medication is one of the index drug is part of the trial protocol.
• Life expectancy estimated to be less than 6 months by treating clinical team.
• Severe illness limiting participation (investigator discretion).
• Duration of index drug total treatment length is planned to be less than five consecutive days.
• Not registered with a General Practitioner.
• No fixed address.
• Participant is, in the opinion of the Investigator, not suitable to participate in the trial.
• Participant has existing impaired hepatic or renal function for which a lower dose of the index drug or alternate selection of the index drug is already part of current routine care.
• Estimated glomerular filtration rate greater than 15 ml/min/1.73m2 (except for participants with a renal transplant commenced on tacrolimus, who may be included regardless of eGFR, provided they are not on dialysis).eGFR result obtained at screening or within the last 6 months or patients record confirming history of CKD 5
• Participants on any form of dialysis.
• Participant with advanced liver failure (stage Child-Pugh C).
• Participants with liver transplant.
• Participants with allogeneic haematopoietic stem cell transplant.
• Participants previously enrolled in the PHOENIX trial.
• Participant who has declined participation and has declined reapproach for subsequent drugs.
• Index drug exceeding trial drug cap. OUTPATIENTS
• Inability to give informed consent directly or via a legal representative.
• Non-English speakers without translation support.
• Participants co-enrolled in other trials where a medication is one of the index drug is part of the trial protocol.
• Life expectancy estimated to be less than 6 months by treating clinical team.
• Severe illness limiting participation (investigator discretion).
• Duration of index drug total treatment length is planned to be less than seven consecutive days.
• Not registered with a General Practitioner.
• No fixed address.
• Participant is, in the opinion of the Investigator, not suitable to participate in the trial.
• Participant has existing impaired hepatic or renal function for which a lower dose or alternate drug selection is already part of current routine care.
• Estimated glomerular filtration rate greater than 15 ml/min/1.73m2 (except for participants with a renal transplant commenced on tacrolimus, who may be included regardless of eGFR, provided they are not on dialysis)..eGFR result obtained at screening or within the last 6 months or patients record confirming history of CKD 5.
• Participants on any form of dialysis.
• Participant with advanced liver failure (stage Child-Pugh C).
• Participants with liver transplant.
• Participants with allogeneic haematopoietic stem cell transplant.
• Participants previously enrolled in the PHOENIX trial.
• Participant who has declined participation and has declined reapproach for subsequent drugs.
• Index drug exceeding trial drug cap.

Re-approach Criteria: Previously declined patients will only be re-approached in subsequent admissions six-months after the first approach.

* We wish to ensure that no more than 20% of participants are included on the basis of any single index drug. The numbers recruited on each index drug will be monitored and recruitment on specific drugs may be limited, or paused, at times throughout the study. This process will be administered by the Trial Management group, and monitored by the Trial Steering Committee.