AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce

Diabetes Mellitus, Type 2 Clinical Trial

— ADOPTION  

Official title:

AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05216172
• Other study ID #: 252155
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 21, 2020
• Est. completion date: August 1, 2023

Study information

• Verified date: January 2023
• Source: Queen Mary University of London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 50
• Est. completion date: August 1, 2023
• Est. primary completion date: May 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• End Stage Renal Disease
• Kidney Failure, Chronic
• Kidney Transplant; Complications
• Renal Transplant
• Type 2 Diabetes

Intervention

Drug:
• AZD1656
active drug
• Placebo
placebo

Locations

Country	Name	City	State
United Kingdom	Royal London Hospital Barts Health NHS Trust	London

Sponsors (2)

Lead Sponsor	Collaborator
Queen Mary University of London	AstraZeneca

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	12-month graft function (eGFR) and diabetic control (HbA1c; medication review) to assess legacy effect	1 year
Other	T cell profile	Differences in other peripheral T cell populations, measured by FACS analysis	3 months
Other	regulatory T cells in renal transplant: biopsy for cause	Histological staining for Treg cells in any renal biopsy taken for clinical indications between baseline and month 3 protocol biopsy	3 months
Other	regulatory T cells: functional assay	Differences in the functional phenotype of the Treg cells	3 months
Primary	peripheral regulatory T cells	Change in mean peripheral Treg cell number between baseline and 3 months measured using flow cytometry analysis (FACS) in AZD1656 and placebo arms	14 weeks
Secondary	regulatory T cells in renal transplant	Histological staining for Treg cells in renal biopsy tissue between baseline and 3 month protocol biopsy	3 months
Secondary	delayed graft function	Incidence of delayed graft function, defined as the need for dialysis within 1 week post-transplant	1 week
Secondary	glycemic control: HbA1c	Diabetic control between baseline and month 3 using change in HbA1c measurement	3 months
Secondary	number of participants with increase or decrease in concurrent anti-diabetic medication	Dose of other anti-diabetic medication between baseline and month 3 (descriptive)	3 months
Secondary	incidence of treatment emergent adverse events	safety endpoints including hypoglycaemic episodes	3 months
Secondary	change in HOMA-IR measurement between baseline and month 3	Insulin resistance: HOMA IR measurement at month 3	3 months
Secondary	kidney transplant function	Graft function: (eGFR) at month 3	3 months
Secondary	kidney transplant rejection	Episodes of acute rejection (defined as biopsy proven acute rejection)	3 months
Secondary	incidence of treatment emergent adverse events (with particular reference to episodes of infection)	Episodes of opportunistic infections: bacterial and viral (descriptive)	3 months