Reparixin in Pancreatic Islet Transplantation

Reparixin + Immunosuppression

Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration.

Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour.

For immunosoppression regimen see the other arm description.

• REP

Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:

• HbA1c level of less than 7%;
• glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period);
• glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).

Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:

• HbA1c level of less than 7%;
• glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period);
• glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).

Total time of insulin-independence after the transplant. This was defined as the number of days between the onset and loss of insulin-independence and was calculated as the date of loss of insulin-independence minus the date of onset of insulin-independence.

Of the 3 patients who achieve insulin-independence after transplant 2, only 2 remained insulin-independent up to 1 year and the mean (SD) total time of insulin-independence after the second transplant was 276 (96.2) days with a range between 208 and 344 days.

Safety was assessed by monitoring the incidence and severity of adverse events (AEs) and serious AEs (SAEs) throughout the study up to 1 year after last transplant.

A serious adverse event is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.

Glucose level reflects the metabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.

AUC was calculated using the trapezoidal rule.

C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.

AUC was calculated using the trapezoidal rule.

Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.

AUC was calculated using the trapezoidal rule.

For Transplant 1 (patients on reparixin), the mean C-Peptide AUC (derived from the MMTT) corrected by IEQ/kg values were calculated.

AUC was calculated using the trapezoidal rule and normalized by the actual number of islet equivalents (IEQ) per kilo infused (IEQ/kg).

The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function.

Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function.