Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation

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

• a glycated hemoglobin (HbA1c) level <6.5%;
• fingerstick fasting blood glucose not exceeding 126 mg/dL more than three times in the past week (based on a minimum of one daily measurement;
• a 2 hour post-prandial blood glucose not exceeding 180 mg/dL more than four times in the past week (based on a minimum of one daily measurement);
• a laboratory fasting glucose in the non-diabetic range (<126 mg/dL).

AUC for the serum C-peptide level is calculated during the first 4 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg

AUC for the serum C-peptide level is calculated during the first 4 hours of a mixed meal tolerance test (MMTT), normalized by the number of Islet Equivalent (IEQ)/kg

Daily insulin is reported as IU/kg and intake averaged over the previous week.

Daily insulin is reported as IU/kg and intake averaged over the previous week.

Data of this outcome are reported as "model estimates over all timepoints".

This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively:

• basal; N=43; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).
• 15 min; N=42; 46
• 30 min; N=40; 46
• 60 min; N=40; 46
• 90 min; N=40; 46
• 120 min; N=41; 46
• 180 min; N=40; 46
• 240 min; N=39; 44

Data are reported as "model estimates over all timepoints"

This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively:

• basal; N=34; 42 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).
• 15 min; N=34; 41
• 30 min; N=34; 41
• 60 min; N=34; 41
• 90 min; N=34; 41
• 120 min; N=34; 41
• 180 min; N=33; 41
• 240 min; N=33; 41

Data are reported as "model estimates over all timepoints".

This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively:

• basal; N=44; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).
• 15 min; N=43; 47
• 30 min; N=41; 47
• 60 min; N=42; 47
• 90 min; N=42; 47
• 120 min; N=42; 47
• 180 min; N=41; 47
• 240 min; N=40; 44

Data are reported as "model estimates over all timepoints".

This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively:

• basal; N=33; 41 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).
• 15 min; N=34; 41
• 30 min; N=34; 41
• 60 min; N=33; 41
• 90 min; N=34; 41
• 120 min; N=34; 41
• 180 min; N=33; 40
• 240 min; N=33; 41

Data are reported as "model estimates over all timepoints".

This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively:

• basal; N=43; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).
• 15 min; N=43; 47
• 30 min; N=41; 47
• 60 min; N=41; 47
• 90 min; N=41; 47
• 120 min; N=42; 47
• 180 min; N=41; 47
• 240 min; N=40; 44

Data are reported as "model estimates over all timepoints".

This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively:

• basal; N=34; 41 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal)
• 15 min; N=34; 41
• 30 min; N=34; 41
• 60 min; N=34; 41
• 90 min; N=34; 41
• 120 min; N=34; 41
• 180 min; N=33; 41
• 240 min; N=33; 40

This variable is assessed by β-score (assessment of β-cell function after islet transplantation). The total score is calculated on a 0-8 scoring system (higher is a better outcome) that gives 0-2 points each for:

• fasting plasma glucose,
• HbA1c,
• stimulated C-peptide
• insulin requirement subscales. The higher the total score, the better the outcome.
• Fasting (or before breakfast) plasma glucose (mg/dL) : ≤99, Score 2; 100-124, Score 1; ≥ 125, Score 0 (the higher the subscore the better the outcome)
• HbA1c (%): ≤6.1, Score 2; 6.2-6.9, Score 1; ≥ 7.0, Score 0 (the higher the subscore the better the outcome)
• Daily average (previous week) insulin (IU/kg/day): ---, Score 2; 0.01-0.24, Score 1; ≥ 0.25, Score 0 (the higher the subscore the better the outcome)
• Stimulated C-peptide (ng/mL): ≥ 0.9, Score 2; 0.3-0.89, Score 1; ≤0.3, Score 0 (the higher the subscore the better the outcome)

This variable is assessed by β-score (assessment of β-cell function after islet transplantation). The total score is calculated on a 0-8 scoring system (higher is a better outcome) that gives 0-2 points each for glucose, HbA1c, stimulated C-peptide and insulin requirement subscales.

The higher the total score the better the outcome.

• Fasting (or before breakfast) plasma glucose (mg/dL) : ≤99, Score 2; 100-124, Score 1; ≥ 125, Score 0 (the higher the subscore the better the outcome)
• HbA1c (%): ≤6.1, Score 2; 6.2-6.9, Score 1; ≥ 7.0, Score 0 (the higher the subscore the better the outcome)
• Daily average (previous week) insulin (IU/kg/day): ---, Score 2; 0.01-0.24, Score 1; ≥ 0.25, Score 0 (the higher the subscore the better the outcome)
• Stimulated C-peptide (ng/mL): ≥ 0.9, Score 2; 0.3-0.89, Score 1; ≤0.3, Score 0 (the higher the subscore the better the outcome)

Percentage of patients with a glycated haemoglobin (HbA1c) <6.5% at day 365±14 after the transplant.

A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.

Percentage of patients with an HbA1c <6.5% at day 365±14 after the transplant AND free of severe hypoglycemic events from day 75±14 to day 365±14 after the transplant inclusive.A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.

The percentages of patients with any treatment emergent adverse events (TEAE, serious and non serious) and with serious TEAE by severity are presented.

Patients with multiple events within a particular system organ class or preferred term were counted only under the category of their most severe event within that system organ class or preferred term.

A serious AE was defined as any untoward medical occurrence that at any dose:

• Resulted in death
• Was life-threatening (ie, the patient was at risk of death at the time of the event)
• Required inpatient hospitalization or prolongation of existing hospitalization
• Resulted in persistent or significant disability/incapacity
• Was a congenital anomaly/birth defect
• Was an important medical event that, based upon appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above

Malnutrition risk levels are defined as:

• Poor prognosis = pre-albumin level <5.0 mg/dL
• Significant risk = pre-albumin level 5.0 to 10.9 mg/dL
• Increased risk = pre-albumin level 11.0 to 15.0 mg/dL
• Normal = pre-albumin level > 15.0 (up to 35.0) mg/dL

Malnutrition risk levels are defined as:

• Poor prognosis = pre-albumin level <5.0 mg/dL
• Significant risk = pre-albumin level 5.0 to 10.9 mg/dL
• Increased risk = pre-albumin level 11.0 to 15.0 mg/dL
• Normal = pre-albumin level > 15.0 (up to 35.0) mg/dL

Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as:

• No steatorrhea;
• Steatorrhea few times per week;
• Steatorrhea daily;
• Stool incontinence.

Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as:

• No steatorrhea;
• Steatorrhea few times per week;
• Steatorrhea daily;
• Stool incontinence.

The following definition applies:

• Asymptomatic hypoglycemia = An event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration <70mg/dL.

The following definition applies:

• Documented symptomatic hypoglycemia = An event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <70mg/dL.

A diabetic ketoacidosis event is defined as the presence of:

• hyperglycemia (blood glucose >200 mg/dL);
• pH <7.3 or HCO3 <15;
• ketones positive in the serum or urine.

Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.

Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.

The time-to-peak value in minutes was computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test Case Report Form.

The time to peak value in minutes will be computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test CRF.

Data are reported as "model estimates over all timepoints".

This safety parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively:

• baseline; N=50; 52
• Day 2 post-transplant; N=49; 51
• Day 3 post-transplant; N=47; 50
• Day 7 post-transplant; N=47; 50
• Day 75 post-transplant; N=44; 47

Data are reported as "model estimates over all timepoints".

This safety parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively:

• baseline; N=50; 52
• Day 2 post-transplant; N=49; 51
• Day 3 post-transplant; N=47; 50
• Day 7 post-transplant; N=47; 50
• Day 75 post-transplant; N=44; 47

Treatment emergent adverse events - possibly, probably and highly probably - related to investigational product are called "Adverse reactions" (ADR).

An adverse reaction is defined as any untoward medical occurrence in a patient or clinical investigation patient, which has a causal relationship with the administered medicinal product.

Serious Treatment emergent adverse events - possibly, probably and highly probably - related to investigational product are called serious "Adverse reactions".

A serious adverse reaction is defined as any untoward medical occurrence with a causal relationship with the administered medicinal product, that at any dose:

• Resulted in death
• Was life-threatening (ie, the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.)
• Required patient hospitalization or prolongation of existing hospitalization
• Resulted in persistent or significant disability/incapacity
• Was an important medical event that, based upon appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above