CIRTEN-Simultaneous Pancreas-Kidney Transplant Recipients

• ClinicalTrials.gov Identifier: NCT03769298
• Recruitment Status: Recruiting
• First Posted: December 7, 2018
• Last Update Posted: April 6, 2022
• Sponsor: University of Wisconsin, Madison
• Collaborator: Veloxis Pharmaceuticals
• Information provided by (Responsible Party): University of Wisconsin, Madison

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Kidney Pancreas Transplantation	Drug: Envarsus XR	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: 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 2 years prior, with a history of tremors following transplantation.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Conversion From Immediate Release Tacrolimus to Envarsus XR® in Simultaneous Pancreas-Kidney Recipients: Assessment of Functional, Safety and Quality of Life Outcomes (CIRTEN SPK)
• Actual Study Start Date: February 27, 2019
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2024

Arms and Interventions

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 Name: tacrolimus

Outcome Measures

Primary Outcome Measures :

1. Change in patient and physician-assessed degree of tremors based on Fahn-Tolosa-Marin Tremor Rating Scale [ Time Frame: Over 6 months ]
   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).
2. Change in patient and physician-assessed degree of tremors based on Quality of Life in Essential Tremor (QUEST) Questionnaire [ Time Frame: Over 6 months ]
   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.
3. Scores on Quality of Life in Essential Tremor Questionnaires [ Time Frame: Over 6 months ]
   Use QUEST (Quality of Life in Essential Tremor Questionnaire) scoring tool
4. Scores on Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD) Questionnaire [ Time Frame: Over 6 months ]
   MTSOSD Questionnaire scores will be used to assess the presence and distress of side effects associated with the use of immunosuppressive drugs after transplantation.

Secondary Outcome Measures :

1. Renal function by eGFR (estimated Glomerular Filtration Rate) [ Time Frame: Over 6 months ]
   Change between baseline and post-conversion as measured by eGFR
2. Renal function by serum creatinine [ Time Frame: Over 6 months ]
   Change between baseline and post-conversion as measured by serum creatinine
3. Comparable or improved glycemic control as measured by mixed meal tolerance test [ Time Frame: Over 6 months ]
   Change between baseline and post-conversion
4. Comparable or improved glycemic control as measured by HbA1c [ Time Frame: Over 6 months ]
   Change between baseline and post-conversion
5. Tacrolimus doses and levels [ Time Frame: Over 6 months ]
   Change between baseline and post-conversion
6. Mycophenolate doses and levels [ Time Frame: Over 6 months ]
   Change between baseline and post-conversion

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Jon S Odorico, MD; 6082639903; jon@surgery.wisc.edu

Locations

United States, Wisconsin

University of Wisconsin; Recruiting

Madison, Wisconsin, United States, 53792

Contact: Jon S Odorico, MD 608-263-4768 jon@surgery.wisc.edu

Sponsors and Collaborators

University of Wisconsin, Madison

Veloxis Pharmaceuticals

Investigators

• Principal Investigator: Jon S Odorico, MD; University of Wisconsin, Madison

More Information

Additional Information:

U.S. Food and Drug Administration. Drug Approval Package. 

Fahn S, Tolosa E, Marin C. Clinical Rating Scale of Tremor 

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. 

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.

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.

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.

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 × 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.

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.

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.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT03769298
• Other Study ID Numbers: 2018-0821; A539742 ( Other Identifier: UW Madison ); SMPH/SURGERY/TRANSPLANT ( Other Identifier: UW Madison ); Protocol Version 9/9/2020 ( Other Identifier: UW Madison )
• First Posted: December 7, 2018
• Last Update Posted: April 6, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by University of Wisconsin, Madison:

Tremors

Additional relevant MeSH terms:

Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action