Clinical trial NCT05216172: AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce
Official title: AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes
Diabetes Mellitus, Type 2
Renal Transplant
Kidney Transplant; Complications
End Stage Renal Disease
Keywords: Type 2 Diabetes Mellitus
Diabetes Mellitus
Renal transplantation
Regulatory T cells
AZD1656
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2022-01-31
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single site, placebo controlled, double blind randomised clinical trial
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: peripheral regulatory T cells
timeFrame: 14 weeks
Secondary outcomes:
measure: regulatory T cells in renal transplant
timeFrame: 3 months
measure: delayed graft function
timeFrame: 1 week
measure: glycemic control: HbA1c
timeFrame: 3 months
measure: number of participants with increase or decrease in concurrent anti-diabetic medication
timeFrame: 3 months
measure: incidence of treatment emergent adverse events
timeFrame: 3 months
measure: change in HOMA-IR measurement between baseline and month 3
timeFrame: 3 months
measure: kidney transplant function
timeFrame: 3 months
measure: kidney transplant rejection
timeFrame: 3 months
measure: incidence of treatment emergent adverse events (with particular reference to episodes of infection)
timeFrame: 3 months
Other outcomes:
measure: Comparison of patient and placebo group at 1 year post transplant: number of participants experiencing episodes of infection, rejection; comparison of renal function and diabetic control
timeFrame: 1 year
measure: T cell profile
timeFrame: 3 months
measure: regulatory T cells in renal transplant: biopsy for cause
timeFrame: 3 months
measure: regulatory T cells: functional assay
timeFrame: 3 months
Locations:
city: London
country: United Kingdom
facility: Royal London Hospital Barts Health NHS Trust
Study officials:
affiliation: Barts Health NHS Trust; Queen Mary University London
name: Kieran McCafferty, M.B., B.Chir
role: PRINCIPAL_INVESTIGATOR
References: