Mycophenolate-Based Therapy for Kidney Transplant Recipients Without HLA-DQ Mismatch (MyQURE)

Safety of Calcineurin-Inhibitor Withdrawal in Zero-HLA DQ-Mismatched Kidney Transplant Recipients on a Concentration Controlled Mycophenolate Dose: A Prospective, Single Arm Pilot Study

The goal of this clinical trial is to learn if calcineurin-inhibitor therapy (a drug commonly used to prevent rejection) can be safely stopped in kidney transplant recipients with a relatively low risk of rejection (being recipients of a first transplant, without any signs of pre-existing immunity against the graft, and having a good HLA match with the donor (no mismatch in HLA-DQ)). Before stopping the calcineurin-inhibitors, the remaining therapy with mycophenolate mofetil and corticosteroids will be optimized.The main questions it aims to answer are:

Is this approach safe, in terms of preventing rejection? Is this approach well tolerated? Will this approach lead to better kidney function and/or other beneficial effects?

Study Overview

• Status: Recruiting
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Withdrawal of calcineurin-inhibitor, continue on concentration-controlled mycophenolate mofetil and corticosteroids.

Detailed Description

In summary, this pilot, prospective, single-arm open interventional study the investigators will include immune-quiescent zero-DQ mismatched kidney transplant recipients between 3-12 months post-transplant who are on a CNI-based regimen with corticosteroids and MMF. After optimization of MMF dose, targeted at an MPA AUC12 of 60 (±15) mg.h/L, CNIs will be tapered and stopped over a 4 week peri-od. Prednisolon dose will be temporarily increased to 10 mg/day at the day of CNI withdrawal for 14 days, and continued at 5 mg/d thereafter. The primary outcome is biopsy-proven rejection at 6 months after CNI withdrawal. Secondary outcomes will look at other markers of alloreactivity (dnD-SA without clinical or histological signs of rejection), tolerability of MMF in the defined range, infec-tious complications, and possible favorable effects of CNI withdrawal (on GFR, tubular function, blood pressure, lipid profile and diabetes).

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Rachel Hellemans, MD PhD; Phone Number: +3238213435; Email: rachel.hellemans@uza.be
• Study Contact Backup: Name: Hans de Fijter, MD PhD; Phone Number: +3238213435; Email: nefrologie@uza.be

Study Locations

• Belgium
  • Antwerp
    • Edegem, Antwerp, Belgium, 2650
      • Recruiting
      • University Hospital Antwerp
      • Contact: Rachel Hellemans, MD PhD; Phone Number: +3238213435; Email: rachel.hellemans@uza.be
      • Principal Investigator: Rachel Hellemans, MD PhD
      • Principal Investigator: Hans de Fijter, MD PhD
      • Sub-Investigator: Vicky De Meyer, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• Adults ≥ 18 years old who received a first, zero-HLA-DQ mismatched kidney transplant between 3 and 12 months before screening. ((mis)matching based on the broad Eurotransplant Match determinant for DQA1 and on the split Eurotransplant Match determinant for DQB1
• Maintenance immunosuppressive therapy should consist of a calcineurin-inhibitor (tacrolimus or cyclosporine), MMF and corticosteroids
• subjects capable of giving informed consent
• eGFR ≥ 20 ml/min/1.73m² based on CKD-EPI Creatinine-Cystatin Equation at screening
• Recent HLA antibody testing (<6 weeks before screening)
• Absence of DSA (MFI > 500) at screening and in all historical samples
• Absence of subclinical rejection on a protocol kidney transplant biopsy according to latest Banff criteria (excl. borderline lesions)
• Recent assessment of CNI and MPA AUC (performed at least 8 weeks after transplantation, but <12 weeks before screening, )
• Recent OGTT in patients not on antidiabetic therapy (<3 months ago)

Exclusion Criteria:

• Receipt of a non-renal transplant
• HLA identical sibling donor transplant
• ABO incompatible kidney transplantation
• cdc-PRA at transplantation > 50%
• Ongoing treatment with immunosuppressive drugs other than CNI, MMF/MPA and cortico-steroids
• Prophylactic therapy with valganciclovir
• History of biopsy-proven acute rejection
• Unexplained rise in creatininemia >20% over the last 6 weeks
• Albuminuria > 1g/day ( based on latest 24h urine collection max 6 weeks ago)
• Chronic diarrhea or gastrointestinal disorders that interfere with the absorption or oral medi-cation
• Active peptic ulcer disease
• Active hepatitis B, hepatitis C or human immunodeficiency virus infection at the day of trans-plantation
• New diagnosis of malignancy since transplantation, except successfully treated nonmetastatic basal or squamous cell carcinoma of the skin
• Pregnancy or lactation
• Patients unwilling to use reliable anticonception during the study (Male patients or their untreated female partner must use reliable contraception during my-cophenolate treatment and for at least 90 days after stopping MMF treatment. Female patients who can get pregnant must use at least one reliable form of contraception before, during and for 6 weeks after stopping MMF treatment)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Withdrawal of calcineurin-inhibitors in zero-HLA DQ-mismatched kidney transplant recipients; calcineurin-inhibitor withdrawal, continue on a concentration controlled mycophenolate dose (AUC12 target 60 h.mg/L)	Drug: Withdrawal of calcineurin-inhibitor, continue on concentration-controlled mycophenolate mofetil and corticosteroids.; Mycophenolate mofetil dose will be optimized to an AUC12 of 60 h.mg/L, thereafter the calcineurin inhibitor will be withdrawn.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of biopsy proven rejection	Biopsy will be performed as clinically indicated, or in case DSA develop (directed against HLA -A, HLA-B, HLA-DR or HLA-DQ with a MFI > 500 and remaining present in a repeated test after 6 weeks (± 2 weeks)) to exclude subclinical rejection.	at 26 weeks after CNI withdrawal

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of biopsy proven rejection	Biopsy will be performed as clinically indicated, or in case DSA develop (directed against HLA -A, HLA-B, HLA-DR or HLA-DQ with a MFI > 500 and remaining present in a repeated test after 6 weeks (± 2 weeks)) to exclude subclinical rejection.	at 14 weeks and 1 year after CNI withdrawal
Incidence of de novo donor specific HLA antibodies (dnDSA)	• HLA antibody testing (Luminex SAB): at baseline (unless performed < 6 weeks ago), day 98, day 182, day 364 (and in case of suspected rejection)	at 14 weeks, 26 weeks and 1 year after CNI withdrawal
Tolerability of MMF in the defined range	Gastro-intestinal Symptom Rating Scale and Adverse events	up to 1 year after CNI withdrawal
Change in eGFR	eGFR (CKDepi-cystatine formula)	Comparing day 0 (day of CNI withdrawal) to 14 weeks, 26 weeks and 1 year after CNI withdrawal
Change in creatinine clearance	24h creatinine clearance	Comparing day 0 (day of CNI withdrawal) to 14 weeks, 26 weeks and 1 year after CNI withdrawal
Change in albuminuria	Albuminuria in mg/day	Comparing day 0 to 14 weeks, 26 weeks and 1 year after CNI withdrawal
Change in albumin/creatinine ratio in urine	Albumine/creatinine ratio in urine	Comparing day 0 to 14 weeks, 26 weeks and 1 year after CNI withdrawal
Change in beta-2 microglobulinuria	beta-2 microglobulinuria in mg/day	Comparing day 0 to 14 weeks, 26 weeks and 1 year after CNI withdrawal
Change in beta-2 microglobulin/creatinine ratio in urine	beta-2 microglobuline/creatinine ratio in urine	Comparing day 0 to 14 weeks, 26 weeks and 1 year after CNI withdrawal
Change in arterial hypertension	Blood pressure in mmHg	Comparing baseline to 1 year after CNI withdrawal
Change in number of antihypertensive drugs	number of antihypertensive drugs	Comparing baseline to 1 year after CNI withdrawal
Change in serum total cholesterol	total cholesterol levels (mg/dl)	Comparing baseline to 1 year after CNI withdrawal
Change in serum LDL cholesterol	LDL cholesterol levels (mg/dl)	Comparing baseline to 1 year after CNI withdrawal
Change in serum HDL cholesterol	HDL cholesterol levels (mg/dl)	Comparing baseline to 1 year after CNI withdrawal
Change in serum fasting triglycerides	fasting triglyceride levels (mg/dl)	Comparing baseline to 1 year after CNI withdrawal
Change in need for statin therapy	type and dose of statin therapy	Comparing baseline to 1 year after CNI withdrawal
Change in HbA1C	HbA1C (%)	Comparing baseline to 1 year after CNI withdrawal
Change in need for antidiabetic medication	number and type of antidiabetic drugs	Comparing baseline to 1 year after CNI withdrawal
Change in fasting glucose levels	fasting glucose level (mg/dL)	Comparing baseline to 1 year after CNI withdrawal
Change in body weight	Body weight in kg	Comparing baseline to 1 year after CNI withdrawal

Collaborators and Investigators

• Sponsor: University Hospital, Antwerp
• Investigators: Principal Investigator: Rachel Hellemans, MD PhD, Antwerp University Hospital, Department of Nephrology, Drie Eikenstraat 655, 2650 Edegem, BELGIUM; Principal Investigator: Hans de Fijter, MD PhD, Antwerp University Hospital, Department of Nephrology, Drie Eikenstraat 655, 2650 Edegem, BELGIUM

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: June 18, 2024
• First Submitted That Met QC Criteria: July 1, 2024
• First Posted (Actual): July 10, 2024

Study Record Updates

• Last Update Posted (Actual): August 21, 2024
• Last Update Submitted That Met QC Criteria: August 20, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: rejection; pharmacokinetic; mycophenolate mofetil; withdrawal; Calcineurin Inhibitor; area under the curve; calcineurin inhibitor withdrawal; HLA-DQ; concentration-controlled; mismatches
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid; Calcineurin Inhibitors
• Other Study ID Numbers: UZA-6402

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No