Sirolimus vs Mycophenolate With Tacrolimus in Simultaneous Pancreas and Kidney Transplantation

Effect of Sirolimus or Mycophenolate With Tacrolimus on Survival of Pancreas and Kidney Grafts in Type 1 Diabetic Recipients After Simultaneous Pancreas and Kidney Transplantation

This is prospective randomized open single center clinical study to compare effect of sirolimus vs mycophenolate tacrolimus based protocol on pancreas and kidney graft survival in simultaneous pancreas and kidney recipients.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Mycophenolate Mofetil; Drug: Sirolimus Oral Product

Detailed Description

MTOR (mammalian target of rapamycin) inhibitors represent group of immunosuppressive drugs with mechanism of T-cell blockade complementary to calcineurin inhibitors. The investigators presume that combination of sirolimus with tacrolimus will result in better survival of pancreatic and kidney grafts in simultaneous pancreas and kidney transplantations.

The study is proposed as a single-center extension of EUROSPK 002 trial originally started in 2004 by the EUROSPK Study Group. Recruitment of recipients started in 2004 with approval of EUROSPK 002. The patient recruitment has continued in a single center (Institute for Clinical and Experimental Medicine in Prague, Czech Republic) using the same inclusion and exclusion criteria. The recipients of primary kidney and pancreas transplantation have been randomized into 2 arms.

• In the intervention arm sirolimus is added to protocol at a dose of 5 mg immediately before transplantation, the dose is adjusted to maintained trough sirolimus trough levels between 5-10ng/ml.
• In the control arm mycophenolate mofetil was added to tacrolimus. Starting with 1g before transplantation, the dose has been increased to 1g bid afterwards.

Induction protocol at day 0. consists of ATG (antithymocyte globulin)induction 8mg/kg , Tacrolimus 0.05mg/kg, Methylprednisolone 125mg. Dosing of tacrolimus has been adjusted to maintain trough levels between 5-10ng/ml. ATG was administered at 3mg/kg on days 1.-3. Steroids have been gradually tapered from a dose of 20 mg prednison orally and withdrawn by 6w after transplantation.

• Study Type: Interventional
• Enrollment (Actual): 238
• Phase: Phase 4

Contacts and Locations

Study Locations

• Czechia
  • Prague, Czechia, 14021
    • Institute for Clinical and Experimental Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 1 diabetes mellitus
• End stage kidney failure
• Negative CDC crossmatch
• Female patients of childbearing age must have a negative pregnancy test
• Patient must have signed the Patient Informed Consent Form.
• Patient must receive a primary simultaneous pancreas/kidney (SPK) cadaver transplant,

Exclusion Criteria:

• Patient is pregnant or breastfeeding.
• Patient is allergic or intolerant to Mycophenolate Mofetil, Sirolimus, ATG, Tacrolimus
• Patient has malignancy or history of malignancy, with the exception of adequately treated localized squamous cell or basal cell carcinoma, without recurrence.
• Patient has been included in another clinical trial protocol for any investigational drug within 4 weeks prior to randomization.
• Patient has any form of substance abuse or psychiatric disorder or condition, which invalidate communication.
• Severe cardiac failure or severe liver failure diagnosed at the time of transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: mycophenolate mofetil; mycophenolate mofetil dosing 1g before transplantation and 1g bid afterwards	Drug: Mycophenolate Mofetil; Mycophenolate Mofetil dosing 1g before transplantation and 1g bid afterwards; Other Names: CellCept
Experimental: Sirolimus; Sirolimus oral product Dosing 5mg orally 2-6h before transplantation Target trough levels between 5-10ng/ml	Drug: Sirolimus Oral Product; Oral form of sirolimus, daily dosing to achieve target trough levels between 5-10ng/ml since 1.day of transplantation; Other Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pancreas graft survival	Number of failed pancreatic grafts, failure is defined as graft removal, death, retransplantation or return to intensified insulin regimen.	10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recipient survival	Long-term recipient survival evaluated with Kaplan-Meyer method	10 years
Wound healing time	The number of days from transplantation to date of completely healed wound	1year
Kidney graft survival	Number of failed kidneys evaluated with Kaplan-Meyer method. Failure defined as return to dialysis, death, retransplantation or graft removal	10 years

Collaborators and Investigators

• Sponsor: Institute for Clinical and Experimental Medicine
• Investigators: Principal Investigator: Frantisek Saudek, MD, Institute for Clinical and Experimental Medicine

Publications and helpful links

General Publications

• Girman P, Lipar K, Kocik M, Voska L, Koznarova R, Marada T, Lanska V, Saudek F. Sirolimus vs mycophenolate mofetil (MMF) in primary combined pancreas and kidney transplantation. Results of a long-term prospective randomized study. Am J Transplant. 2020 Mar;20(3):779-787. doi: 10.1111/ajt.15622. Epub 2019 Oct 23.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2004
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): January 1, 2019

Study Registration Dates

• First Submitted: April 25, 2018
• First Submitted That Met QC Criteria: June 27, 2018
• First Posted (Actual): July 11, 2018

Study Record Updates

• Last Update Posted (Actual): April 26, 2021
• Last Update Submitted That Met QC Criteria: April 22, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid; Sirolimus
• Other Study ID Numbers: SiroMMFStudy 1

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