CIRTEN-Simultaneous Pancreas-Kidney Transplant Recipients

Conversion From Immediate Release Tacrolimus to Envarsus XR® in Simultaneous Pancreas-Kidney Recipients: Assessment of Functional, Safety and Quality of Life Outcomes (CIRTEN SPK)

This is a Phase II/III, Single-center, Prospective, Open-label, Single Arm Study of 30 Simultaneous Kidney Pancreas recipients who received a transplant at least 3 months, but no more than 5 years prior, with a history of tremors following transplantation.

Study Overview

• Status: Recruiting
• Conditions: Kidney Pancreas Transplantation
• Intervention / Treatment: Drug: Envarsus XR

Detailed Description

Accrual objective: Enrollment of 2-3 participants per month and all participants within an 18 month period. With minimum of 1 year follow-up post-conversion, we anticipate the entire study would be completed within 2 ½ years.

Study design: This is a Phase II/III, Single-center, Prospective, Open-label, Single Arm Study of 30 Simultaneous Kidney Pancreas recipients who received a transplant at least 3 months, but no more than 5 years prior, with a history of tremors following transplantation.

Study duration: There will be a minimum of 1 year follow-up post-conversion, and it is expected that the entire study would be completed within 2 ½ years.

Study aims:

• Determine if EnvarsusXR® reduces tremor severity compared to IR tacrolimus
• Determine if EnvarsusXR® improves renal function or glycemic control compared to IR tacrolimus
• Compare the efficacy of EnvarsusXR® by comparing the outcomes (patient, pancreas graft and kidney graft survival) of patients treated with Envarsus XR to those of contemporary and historical controls at our center treated with IR tacrolimus, with the goal of showing non-inferiority.
• Compare insulin resistance and insulin sensitivity by defined measures post conversion between T1D and T2D recipients.

Primary Endpoint:

1. Improvement in patient and physician-assessed degree of tremors based on FTM (Fahn-Tolosa-Martin Tremor Rating Scale) and QUEST (Quality of Life in Essential Tremor Questionnaire) scoring tools
2. Scores on Quality of Life in Essential Tremor and Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD) Questionnaires

Secondary Endpoints:

1. Renal function - eGFR (estimated glomerular filtration rate) and serum creatinine
2. Glycemic control - AUC by MMTT, fasting BG, fasting C-peptide, calculated C-peptide/glucose ratio, calculated 20/(fasting Cpeptide x fasting BG) as a measure of insulin resistance, calculated HOMA-IR (fasting insulin x fasting BG)/22.5 as a measure of insulin sensitivity/resistance, calculated BETA-2 score to sensitive estimate beta cell function, and HbA1c.
3. Tacrolimus and Mycophenolate doses as well as TAC and MPA levels

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Jon S Odorico, MD; Phone Number: 6082639903; Email: jon@surgery.wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • University of Wisconsin
      • Contact: Jon S Odorico, MD; Phone Number: 608-263-4768; Email: jon@surgery.wisc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult, 18-70 years of age
• Participant must be able to understand and provide consent
• History of Diabetes Type 1 or Insulin-Dependent Diabetes Type 2 with Chronic Kidney Disease (CKD)
• Recipient of a Simultaneous Pancreas Kidney (SPK) transplant, 3- 60 months prior to screening, per Principal Investigator's discretion.
• Have a history of tremors following transplantation
• Stable pancreas allograft function as evidenced by no requirement of exogenous insulin or oral anti-diabetic agents and stable pancreatic enzymes
• Stable kidney allograft function
• Currently taking Immediate-Release (IR) tacrolimus
• Women of child-bearing potential (WOCP) must have a negative pregnancy test at the time of study entry

Exclusion Criteria:

• Currently maintained on an extended-release tacrolimus immunosuppressive regimen
• Previous history of tremors prior to transplantation
• Solitary pancreas transplant recipients
• History of solid organ transplant other than a kidney or pancreas
• Uncontrolled concomitant infection at the discretion of the investigator
• Presence of Donor Specific Antibodies

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: Envarsus XR; Envarsus XR (extended release) will be administered orally, once-daily, for 6 months.	Drug: Envarsus XR; The Envarsus XR® drug will be administered to study participants once daily, orally. The dosage can be 0.75 mg, 1 mg or 4 mg. The tacrolimus whole blood trough concentrations will be monitored and titrate Envarsus XR® dosage to achieve target whole blood trough concentration.; Other Names: tacrolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in patient and physician-assessed degree of tremors based on Fahn-Tolosa-Marin Tremor Rating Scale	FTM-TRS will be used as a tool for essential tremor scoring. (0: no tremor, 1: barely perceptible tremor, 2: < 2 cm, 3: 2-4 cm, and 4: > 4 cm).	Over 6 months
Change in patient and physician-assessed degree of tremors based on Quality of Life in Essential Tremor (QUEST) Questionnaire	QUEST Questionnaire, a scoring tool will be used to measure the quality of life among patients with Essential Tremor. It consists of 30 items which are rated on a five-point scale (score 0-4), corresponding to the frequency (never, rarely, sometimes, frequently, always) with which tremor was perceived to affect a function or to be associated with various feelings and attitudes. A few items (e.g. 'I had to quit my job because of tremor') could only be answered at the extremes (yes/no; true/false), and these were scored either 0 or 4.	Over 6 months
Scores on Quality of Life in Essential Tremor Questionnaires	Use QUEST (Quality of Life in Essential Tremor Questionnaire) scoring tool	Over 6 months
Scores on Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD) Questionnaire	MTSOSD Questionnaire scores will be used to assess the presence and distress of side effects associated with the use of immunosuppressive drugs after transplantation.	Over 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal function by eGFR (estimated Glomerular Filtration Rate)	Change between baseline and post-conversion as measured by eGFR	Over 6 months
Renal function by serum creatinine	Change between baseline and post-conversion as measured by serum creatinine	Over 6 months
Comparable or improved glycemic control as measured by mixed meal tolerance test	Change between baseline and post-conversion	Over 6 months
Comparable or improved glycemic control as measured by HbA1c	Change between baseline and post-conversion	Over 6 months
Tacrolimus doses and levels	Change between baseline and post-conversion	Over 6 months
Mycophenolate doses and levels	Change between baseline and post-conversion	Over 6 months

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: Veloxis Pharmaceuticals
• Investigators: Principal Investigator: Jon S Odorico, MD, University of Wisconsin, Madison

Publications and helpful links

General Publications

• Langone A, Steinberg SM, Gedaly R, Chan LK, Shah T, Sethi KD, Nigro V, Morgan JC; STRATO Investigators. Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. Clin Transplant. 2015 Sep;29(9):796-805. doi: 10.1111/ctr.12581. Epub 2015 Aug 6.
• Gutch M, Kumar S, Razi SM, Gupta KK, Gupta A. Assessment of insulin sensitivity/resistance. Indian J Endocrinol Metab. 2015 Jan-Feb;19(1):160-4. doi: 10.4103/2230-8210.146874.
• Stacy MA, Elble RJ, Ondo WG, Wu SC, Hulihan J; TRS study group. Assessment of interrater and intrarater reliability of the Fahn-Tolosa-Marin Tremor Rating Scale in essential tremor. Mov Disord. 2007 Apr 30;22(6):833-8. doi: 10.1002/mds.21412.
• Baraldo M. Meltdose Tacrolimus Pharmacokinetics. Transplant Proc. 2016 Mar;48(2):420-3. doi: 10.1016/j.transproceed.2016.02.002.
• Kerstenetzky L, Descourouez JL, Jorgenson MR, Felix DC, Mandelbrot DA, Redfield RR, Odorico JS. A Single-Center Experience With Tacrolimus LCP (Envarsus XR) in Pancreas Transplant Recipients. Ann Pharmacother. 2018 Apr;52(4):392-396. doi: 10.1177/1060028017749076. Epub 2017 Dec 14. No abstract available.
• Ohkura T, Shiochi H, Fujioka Y, Sumi K, Yamamoto N, Matsuzawa K, Izawa S, Kinoshita H, Ohkura H, Kato M, Taniguchi S, Yamamoto K. 20/(fasting C-peptide x fasting plasma glucose) is a simple and effective index of insulin resistance in patients with type 2 diabetes mellitus: a preliminary report. Cardiovasc Diabetol. 2013 Jan 22;12:21. doi: 10.1186/1475-2840-12-21.
• Forbes S, Oram RA, Smith A, Lam A, Olateju T, Imes S, Malcolm AJ, Shapiro AM, Senior PA. Validation of the BETA-2 Score: An Improved Tool to Estimate Beta Cell Function After Clinical Islet Transplantation Using a Single Fasting Blood Sample. Am J Transplant. 2016 Sep;16(9):2704-13. doi: 10.1111/ajt.13807. Epub 2016 Apr 21.

Helpful Links

• U.S. Food and Drug Administration. Drug Approval Package.
• 5. West-Thielke P, Brennan D, Stevens D. Pharmacokinetics of once-daily Envarsus XR in diabetic vs. non-diabetic kidney transplant recipients: a pooled subgroup analysis. [abstract] Kidney Week. Nov 2016, Chicago IL.
• Fahn S, Tolosa E, Marin C. Clinical Rating Scale of Tremor

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2019
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: November 16, 2018
• First Submitted That Met QC Criteria: December 5, 2018
• First Posted (Actual): December 7, 2018

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 26, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Tremors
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 2018-0821; A539742 (Other Identifier: UW Madison); Protocol Version 9/9/2020 (Other Identifier: UW Madison); SMPH/SURGERY/TRANSPLANT (Other Identifier: UW Madison)

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