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Islet transplantation using brain-dead donors and donors after cardiac death for patients with insulin-dependent diabetes mellitus suffering from complicating hypoglycemia unawareness (Islet transplantation for insulin-dependent diabetes mellitus )

Islet transplantation using brain-dead donors and donors after cardiac death for patients with insulin-dependent diabetes mellitus suffering from complicating hypoglycemia unawareness (Islet transplantation for insulin-dependent diabetes mellitus )

Takeishi Yasuchika

Feb. 10, 2020

9

Target disease: Insulin-dependent diabetes mellitus with severe hypoglycemic unawareness 1) Disease state: Insulin-dependent diabetes mellitus with severe hypoglycemic unawareness 2) Age: 20 to 65 years old. 3) Eligibility criteria 1.The patient must be able to give written consent to participate in the clinical trial. 2. Able to follow the protocol procedures of the clinical trial. 3. The patient must have been insulin dependent for more than 5 years at the time of study entry. 4. Depletion of endogenous insulin secretion. 5. On insulin therapy for diabetes mellitus. 6. At least one severe hypoglycemic unawareness attack in the past 12 months. 7. The patient must have data on Clark Score, HYPO Score, and Lability Index. -In the case of islet transplantation after renal transplantation (IAK), the following selection criteria will be added. IAK-1. At least 6 months have passed since kidney transplantation. IAK-2. Creatinine less than 1.8 mg/dl and serum creatinine less than 0.2 mg/dl with no persistent increase in the last 6 months. IAK-3. Steroid medication dose less than 10mg/day.

According to the study implementation plan, the posterior probability of the achievement rate was to be estimated in a Bayesian manner for each case in which the primary endpoint was determined, and if the probability of the achievement rate exceeding 40% exceeded 90%, interim monitoring was to be conducted in order to consider early discontinuation (effective discontinuation) of the study. As the prior distribution, it was decided to adopt Beta distribution Beta(12,5) considering that 12 out of 17 islet transplants performed up to 2009, when this study was planned, were considered to be successful cases regarding the primary endpoint of this clinical trial. The primary endpoint of the last case was determined, and interim monitoring was conducted,in terms of subject information, the number of primary enrollment cases (those enrolled in this clinical trial for transplantation) was 20, the number of secondary enrollment first transplantation cases was 9, the number of secondary enrollment second transplantation cases was 5, and the number of secondary enrollment third transplantation cases was 2. Of the 9 first transplant patients, there were 2 cases of treatment discontinuation, but 8 patients with evaluation data at one year after the first transplant were included in the efficacy analysis population. Efficacy analysis was performed, and the primary endpoint of "the proportion of patients with HbA1c <7.4% (NGSP) at 1 year after the first transplant and resolution of severe hypoglycemic attacks between 90 days and 365 days after the first transplant" was 75% (6/8 patients). The Beta distribution Beta(12,5) was adopted as the prior distribution, and the posterior probability of achievement percentage was estimated in Bayesian fashion. The probability of exceeding the achievement rate of 40% was 99.9%, which exceeded the target of 90%. Based on this result, an independent data monitoring committee was convened and recommended early effective discontinuation.

One case each of Grade 4 leukopenia and neutropenia was reported and has been reported separately.

The results of the interim monitoring showed that the primary endpoint, the proportion of patients with HbA1c <7.4% (NGSP level) 1 year after the first transplant and resolution of severe hypoglycemic attacks between 90 days and 365 days after the first transplant, was 75% (6/8 patients). The Beta distribution Beta(12,5) was adopted as the prior distribution, and the posterior probability of achievement percentage was estimated in Bayesian fashion. The probability of exceeding the achievement rate of 40% was 99.9%, exceeding the target of 90%. The secondary endpoint of insulin withdrawal was confirmed in 25% (2/8) of the cases.

This study suggests that islet transplantation from brain-dead or cardiac arrest donors for insulin-dependent diabetes mellitus with severe hypoglycemic attacks is a treatment that eliminates severe hypoglycemic attacks and stabilizes blood glucose levels.

Feb. 24, 2022

Feb. 24, 2022

https://center6.umin.ac.jp/cgi-openbin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000004768&language=J

No

No plan

https://jrct.mhlw.go.jp/latest-detail/jRCTa021190016

Marubashi Shigeru

Fukushima Medical University Hospital

1 Hikarigaoka, Fukushima-shi, Fukushima, Japan

s-maru@fmu.ac.jp

Kanou Takashi

Fukushima Medical University

1 Hikarigaoka Fukushima-shi, Fukushima, Japan

+81-24-547-1825

tkano@fmu.ac.jp

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Male or female; 20 to 65 years of age.
2. Ability to provide written informed consent.
3. Mentally stable and able to comply with the procedures of the study protocol.
4. Clinical history compatible with type 1 diabetes with insulin dependence for > 5 years at the time of the registration.
5. Absent stimulated C-peptide (< 0.3 ng/mL)
6. Involvement in intensive diabetes management defined as the self monitoring of glucose values no less than a mean of three times each day, averaged over each week, and the administration of three or more insulin injections each day or insulin pump therapy. Such management must have been subjected to at least 3 clinical evaluations during the previous 12 months.
7. At least one episode of severe hypoglycemia in the past 12 months defined as an event with symptoms compatible with hypoglycemia in which the subject required the assistance of another person and which was associated with either a blood glucose level < 54 mg/dL (3.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.
8. At least once evaluated glycemic lability status by a Clarke score, a HYPO score and a glycemic lability index (LI) score.

1. BMI > 25 kg/m2 or weight > 80 kg.
2. Insulin requirement of > 0.8 IU/kg/day or 55 U/day.
3. Mean HbA1c value of several measurements in the previous 12 months > 10%.
4. Untreated proliferative diabetic retinopathy.
5. Blood pressure: SBP > 160 mmHg or DBP > 100 mmHg.
6. Creatinine clearance < 60 mL/min (applied only to islet transplantation alone case)
7. Presence of proteinuria > 1 g/day.
8. For female participants: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 3 months after discontinuation. For male participants: Intent to procreate during the duration of the study or within 3 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant, Depo-Provera, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
9. Active infection including hepatitis B, hepatitis C, HIV, or TB as determined by a positive skin test or clinical presentation, or under treatment for suspected TB. Positive tests are acceptable only if associated with a history of previous vaccination in the absence of any sign of active infection. Positive tests are otherwise not acceptable, even in the absence of any active infection at the time of evaluation.
10. Negative screen for Epstein-Barr Virus (EBV) by IgG determination.
11. Difficulty of administration for laboratory and physical tests for evaluation or regular outpatient visits.
12. Mental abnormalities to hinder medical procedure under protocol (Assessment by psychiatrists is required and final decision is made by investigators in charge)
13. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial.

Both

Insulin-dependent diabetes mellitus suffering from complicating hypoglycemia unawareness

Immunosuppressant

Insulin-dependent diabetes mellitus

The proportion of subjects with HbA1c<7.4% and who are free of severe hypoglycemic events (from day 90 to day 365) one years after the first islet cell infusion.

1. Proportion of patients with HbA1c (NGSP) <7.4% and severe hypoglycemic unawareness disappears 2 years after the first transplantation.
2. Proportion of patients with severe hypoglycemic attack unawareness.
3. Proportion of patients with HbA1c value (NGSP)<7.4% two years after the first transplantation.
4. Proportion of patients with HbA1c value (NGSP value) <6.9% two years after the first transplantation.
5. Percentage of patients with insulin withdrawal by 2 years after the first transplantation.

Complete

+81-75-753-4680

Aug. 09, 2019