Clinical trial NCT03769298: CIRTEN-Simultaneous Pancreas-Kidney Transplant Recipients
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Kidney Pancreas Transplantation
Keywords: Tremors
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: Veloxis Pharmaceuticals
First posted: 2018-12-07
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a Phase II/III, Single-center, Prospective, Open-label, Single Arm Study of 20 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.
Primary purpose: TREATMENT

Brief summary: This is a Phase II/III, Single-center, Prospective, Open-label, Single Arm Study of 20 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.

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 20 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

Eligibility 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

Primary outcomes:
measure: Change in patient and physician-assessed degree of tremors based on Fahn-Tolosa-Marin Tremor Rating Scale
timeFrame: Over 6 months
measure: Change in patient and physician-assessed degree of tremors based on Quality of Life in Essential Tremor (QUEST) Questionnaire
timeFrame: Over 6 months
measure: Scores on Quality of Life in Essential Tremor Questionnaires
timeFrame: Over 6 months
measure: Scores on Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD) Questionnaire
timeFrame: Over 6 months
Secondary outcomes:
measure: Renal function by eGFR (estimated Glomerular Filtration Rate)
timeFrame: Over 6 months
measure: Renal function by serum creatinine
timeFrame: Over 6 months
measure: Comparable or improved glycemic control as measured by mixed meal tolerance test
timeFrame: Over 6 months
measure: Comparable or improved glycemic control as measured by HbA1c
timeFrame: Over 6 months
measure: Tacrolimus doses and levels
timeFrame: Over 6 months
measure: Mycophenolate doses and levels
timeFrame: Over 6 months
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Jon S Odorico, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Baraldo M. Meltdose Tacrolimus Pharmacokinetics. Transplant Proc. 2016 Mar;48(2):420-3. doi: 10.1016/j.transproceed.2016.02.002.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.