AZD1656 in Transplantation with Diabetes tO PromoTe Immune TOleraNce: a single site, placebo-controlled, double-blind randomised clinical trial of AZD1656 in renal transplant patients with Type 2 diabetes

Transplant recipients with pre-existing Type 2 diabetes frequently experience a deterioration in glycaemic control in the early post-transplant period, largely due to the significant immunosuppression burden at this stage. Elevated glucose profiles have been associated with poorer graft outcomes. The glucokinase activator AZD1656 has been shown to be a potent anti diabetic medication and safe in patients with T2DM, including those with chronic kidney disease. Recent data has shown that glucokinase activation increases regulatory T cell (Treg) migration and trafficking. The investigators propose to study the safety and efficacy of AZD1656 in optimising the glycaemic control and in stimulating Treg migration to the transplant kidney in a population of renal transplant patients with pre-existing T2DM.

ADOPTION is a single site, placebo-controlled, double-blind randomised clinical trial of AZD1656 in patients with Type 2 diabetes who have received a new renal transplant. Eligible, consented patients are randomised to a 3 month course of either active drug or placebo within 24 hours of transplantation. Clinical and laboratory data will be collected and assessed at baseline and throughout their participation in the study. The study plans to enrol 50 patients. There are no interim analyses planned. The primary endpoint will be the mean change in peripheral Tregs between baseline and 3 months as analysed by flow cytometry.

Ethical approval was obtained from the East of England - Cambridge East Ethics Committee (REC 19/EE/0209) prior to commencing the study. All study-related data will be used by the Sponsor in accordance with local data protection law. Results of the trial will be submitted for publication in a peer-reviewed journal.

Inclusion Criteria:

1. Females or males aged 18 years and above

2. Having undergone renal transplantation at the Royal London Hospital within the previous 24 hours

3. A pre-transplant diagnosis of Type 2 diabetes

4. Provision of written, informed consent prior to any study specific procedures

5. In women of childbearing potential* documentation of a negative pregnancy test during admission for renal transplant.

   • Women of childbearing potential are defined as women following menarche until becoming post-menopausal, unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-menopausal state is defined as the absence of menses for 12 months without an alternative medical cause.

Exclusion Criteria:

1. Unable to consent

2. Known allergy/intolerance to AZD1656

3. Pregnant or breastfeeding women

4. Planning on becoming pregnant/unwilling to use highly effective contraception* during the 3 month treatment period and for 2 weeks afterwards (i) In the case of men with sexual partners who are women of childbearing potential: refusal to wear a condom and female partner planning on becoming pregnant/unwilling to use highly effective contraception* during the 3 month treatment period and for 2 weeks afterwards

5. Clinically significant history of abnormal physical and/or mental health as judged by the investigator other than conditions related to chronic kidney disease

6. Current or planned use of strong inhibitors of CYP2C8

7. Participation in an investigational drug trial in the 3 months prior to administration of the initial dose of study drug

   • Highly effective contraception methods are defined as those that can achieve a failure rate of <1% per year when used correctly and consistently. These include:

     • Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation - either oral, transvaginal or transdermal
     • Progestogen-only hormonal contraception associated with inhibition of ovulation - either oral, injectable or implantable
     • Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
     • Bilateral tubal occlusion
     • Vasectomised partner - provided that the partner is the sole sexual partner of the participant and that the vasectomised partner has received medical assessment of surgical success

Individual participant data that underlie the results reported in any published article, after de-identification (text, tables, figures, and appendices)

Beginning 9 months and ending 36 months following article publication

Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

The data may be used for individual participant data meta-analysis.

Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata. Information regarding submitting proposals and accessing data may be found at [email corresponding author??]

This is a double blind placebo study: both the patient and the study team will be blinded to the treatment intervention.

Pharmacy staff who dispense the study medication will not be blinded, nor will Sponsor Office staff responsible for reporting unblinded SUSAR reports to the MHRA.