Human Islet Transplantation in Brittle Type 1 Diabetes Mellitus. The GRAGIL 2 Study.

• Register: ClinicalTrials.gov
• Last refreshed on: 19 February 2015
• Main ID: NCT00321256
• Date of registration: 02/05/2006
• Prospective Registration: No
• Primary sponsor: University Hospital, Grenoble
• Public title: Human Islet Transplantation in Brittle Type 1 Diabetes Mellitus. The GRAGIL 2 Study.
• Scientific title: Transplantation d'Ilots Pancreatiques Allogeniques Adultes Pour le Traitement du Diabete Insulino-dependant: Etude GRAGIL 2.
• Date of first enrolment: July 2003
• Target sample size: 22
• Recruitment status: Completed
• URL: http://clinicaltrials.gov/show/NCT00321256
• Study type: Interventional
• Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: Phase 1/Phase 2

Countries of recruitment

France, Switzerland

Contacts

• Name: Pierre Y Benhamou, MD, PhD
• Affiliation: Universty Hospital, Grenoble, France

• Name: Alfred Penfornis, MD, PhD
• Affiliation: University Hospital, Besancon, France

• Name: Charles Thivolet, MD, PhD
• Affiliation: Hospices Civils de Lyon

• Name: Philippe Morel, MD, PhD
• Affiliation: University Hospital, Geneva, Switzerland

• Name: Eric Renard, MD, PhD
• Affiliation: University Hospital, Montpellier, France

• Name: Lionel Badet, MD, PhD
• Affiliation: Hospices Civils de Lyon

• Name: Laurence Kessler, MD, PhD
• Affiliation: University Hospital, Strasbourg, France

• Name: Cyrille Colin, MD, PhD
• Affiliation: Hospices Civils de Lyon

• Name: Thierry Berney, MD, PhD
• Affiliation: University Hospital, Geneva, Switzerland

Key inclusion & exclusion criteria

Inclusion criteria:

- Type 1 diabetes mellitus

- Disease duration > 5 years

- Despite intensive insulin therapy with tight endocrinologist supervision, persistence
of the following conditions : hypoglycemia unawareness (< 54 mg/dl) ; brittleness
with at least two episodes of severe hypoglycemia ((defined by the need for
assistance to correct the blood glucose level) or ketoacidosis per year , or often
enough that the diabetologist judges the frequency to be life-threatening, the risk
of transplantation and immunosuppression being judged to be less than the risk of the
spontaneous course of uncontrolled diabetes

- Basal and stimulated plasma C-peptide < 0.2 ng/ml

- Creatinine clearance = 50 ml/min/1.73 m2 and proteinuria < 0.5 g/24h

Exclusion criteria:

- Severe cardiovascular disease (recent myocardial infarction, unstable coronaropathy…)

- Severe systemic infection, including hepatitis C or B viral infection, HIV infection
or tuberculosis

- Past or present neoplasia (with the exception of non melanoma skin cancers)

- Body weight > 70 kg in women and BW > 75 kg in men or BMI > 26

- Stimulated C-peptide = 0.3 ng/ml upon Glucagon or Arginine stimulation

- Age < 18 years or > 65 years

- Creatinine clearance < 50 ml/min/1.73 m2

- Albuminuria > 300 mg /24h or proteinuria > 0.5 g/24h

- Hemoglobinemia < 120 g/l in women or < 130 g/l in men

- Liver disease (enzymes > 1.5 N) such as cirrhosis or hepatitis

- Liver hemangioma

- Untreated proliferating diabetic retinopathy

- Pregnancy, lactation, pregnancy project or absence of efficient contraception

- Previous transplantation or immunization as judged by anti-HLA antibodies (> 20%)

- Insulin needs > 0.7 IU/kg/d or > 50 IU

- HbA1c > 12 %

- Any medical condition needing the chronic use of steroids

- Addison disease

- Any hemostasis disorder needing a prolonged treatment with anticoagulation drugs.
Low-dose aspirin is permitted. coagulation disorders contraindicating the procedure,
such as platelet count < 100000/mm3.

- Serious life-threatening disease

- Medical or surgical history potentially influencing the absorption, distribution,
metabolism and clearance of drugs

- Uncontrolled hypercholesterolemia (> 350 mg/dl, 9.1 mmol/l) or hypertriglyceridemia
(> 500 mg/dl, 5.6 mmol/l)

- Leukocytes < 4500/mm3, neutrophils < 2000/mm3, platelets < 100000/mm3

- Any medical or psychosocial condition susceptible to interfere with the study, such
as drug abuse or recent alcohol abuse

- Poor therapeutic observance

- Failure to communicate or cooperate with the investigator



Age minimum: 18 Years
Age maximum: 65 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Type 1 Diabetes Mellitus

Intervention(s)

Procedure: human pancreatic islet transplantation

Primary Outcome(s)

post-prandial blood glucose < 180 mg/dl, mean amplitude of glycemic excursion (MAGE index)

The rate of insulin-independence, judged upon the following criteria : HbA1c < 6.1%,

and 12 months following transplantation.

< 60 mg/dl, basal C-peptide > 0.5 ng/ml. This insulin independent rate will be assessed 6 months

Secondary Outcome(s)

good metabolic control, defined by HbA1c = 6.5%; disappearance of hypoglycemic events; reduction in exogenous insulin needs = 30%.

Morbidity and quality of life will also be assessed.

The rate of success according to the DiaCell composite score defined by the following 4 items : functional islet graft, defined by a basal C-peptide > 0.5 ng/ml;

Secondary ID(s)

011226/DGS-2001/0195

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Alfediam