EASI-KIDNEY Randomisation letter

EASI-KIDNEY^TM 
Clinical Trial Service Unit                                              
Richard Doll Building
University of Oxford
Old Road Campus
Roosevelt Drive
Oxford OX3 7LF, UK                                                                                                                                          

Tel: 01865 743868
Fax 01865 743988
Freephone 0808 164 4060
cco.easukidney@ndph.ox.ac.uk

Ref XXXXXXX/XXXXXXXXX 

3 December 2024

[dr_title] [dr_initial] [dr_sname]

[address] 

[pt_title] [pt_fname] [pt_sname] DoB [dob]

[address1], [address2], [address3], [address4], [address5], [postcode]

EASi-KIDNEY Trial Ref: [study_ref]     Centre ID: [centre]

Dear [dr_title] [dr_sname],

What is EASi-KIDNEY?

EASi-KIDNEY is an international randomised trial initiated and co-ordinated by the Oxford Population Health Research Unit within the Clinical Trial Service Unit at the University of Oxford. It is testing the effects of BI 690517 10mg versus placebo, together with study-provided empagliflozin 10mg once daily, on kidney disease progression, hospitalisation for heart failure and cardiovascular death among patients at risk of progressive chronic kidney disease. The study aims to recruit about 11,000 such patients from about 450 hospitals internationally, including about 1250 participants in the UK. There are two phases to the trial which are outlined below. 

1. Run-in

Your patient will be started on or switched to study-provided empagliflozin 10mg daily and has been given a supply of study treatment to try for at least 8-15 weeks.

2. Randomisation and Follow-up

Provided there are no problems during the Run-in phase and he/she agrees to continue, your patient will then be seen again at least 8 weeks after the initial Screening visit. Eligibility will be re-checked and, if your patient remains willing to continue, he/she will then be randomised to receive either BI 690517 10mg once daily or matching placebo once daily, and a study-provided supply of empagliflozin 10mg once daily. An appointment will be scheduled for local blood tests in about 1-3 weeks’ time. Study visits will occur at 1, 3 and 6 months after Randomisation and then every 6 months after that. After about 3-4 years, he/she will stop their study treatment and study-provided empagliflozin and the trial results will be analysed and published. 

If your patient is randomised, we shall write to you again after he/she is randomised. The study is double-blind so participants and investigators do not know which treatment participants are allocated. 

Individualised standard of care: During the study we ask that appropriate management of risk of kidney disease progression, risk of cardiovascular disease, and other conditions which are common in CKD (such as mineral-bone disorder, renal anaemia, metabolic acidosis) are managed in the context of prevailing local, national or international guidance. Support for this can be provided by their normal nephrology or diabetes hospital clinic appointments, but primary care would be the normal place to co-ordinate care of diabetes, blood pressure, and dyslipidaemia. 

BI 690517 increases potassium. This will be monitored in the trial, and may require changes to their non-study medication (e.g. to improve glycaemic or acidosis control, alter other potassium increasing medication, start potassium binders). This is the responsibility of the local investigators at the participant’s trial site (but you may be asked to help with long-term prescriptions etc.). 

Additional Notes:

Interacting drugs: There are no known interacting drugs with empagliflozin. Exploratory analyses in the Phase II study revealed that neither empagliflozin affected BI 690517 exposure levels or vice versa. BI 690517 is glucuronidated by uridine 5′-diphosphate glucuronyltransferases (UGT) UGT2B7 and UGT2B4. As such, concomitant administration of medications that are known to inhibit UGT (probenecid, valproic acid, fluconazole, amitriptyline, clomipramine) should be used with caution (but are not contraindicated). Also note that rifampicin and phenytoin can induce UGT, potentially decreasing BI 690517 concentrations (again such treatments are not contraindicated). 

Relevant side effects: BI 690517 is a newly developed medication which has only been tested in a limited number of people to date and so has not yet been approved as a treatment for any disease. It is explained to participants when they consent for the trial that:

• BI 690517 has been tested in clinical trials with healthy volunteers and in over 500 patients with kidney disease to determine the most appropriate dosage to use in large trials like EASi-KIDNEY
• There is a risk of hyperkalaemia, a predictable effect of inhibiting the aldosterone pathway, and it may be necessary for participants to modify their diet (Dietary Potassium Leaflet has been provided)
• Hypotension may occur, and it may be necessary to change blood pressure medication to compensate
• Participants’ cortisol levels may be affected. No symptomatic episodes of low serum cortisol and no adrenal crises were reported in the phase II trial in over 500 participants with CKD. Participants’ cortisol levels will be monitored early in the trial
• A kidney function decrease on starting study treatment may be noticed. This may not be a bad thing as it may be a sign of the protective effect of BI 690517 (or perhaps just natural changes in the participants’ kidney function). 

Empagliflozin is a marketed drug and more complete details are available in the Summary of Product Characteristics. It is explained to participants when they consent for the trial that:

• Empagliflozin has already been tested in thousands of people in trials of a range of conditions and has been generally well-tolerated
• There is a risk of polyuria, increased thirst and other symptoms of dehydration, and that it may be necessary to change blood pressure/diuretic medication to compensate
• There is an increased risk of a urine or fungal genital tract infection, like candidiasis. These are usually easily treated with a course of antibiotics or antifungals respectively, but be aware that necrotizing fasciitis has been reported. If the patient develops perineal pain, please ensure rapid assessment and care.
• Hypoglycaemia may also occur, particularly in people on insulin or sulphonylureas
• For people with diabetes, ketoacidosis can develop without blood sugars being particularly high (“normoglycaemic” ketoacidosis). Those at highest risk are those with type 1 diabetes and those with type 2 requiring insulin.
• A kidney function decrease on starting study treatment may be noticed. This may not be a bad thing as it may be a sign of the protective effect of empagliflozin and BI 690517 (or perhaps just natural changes in the participants’ kidney function).