Steroid-free and Long-term Calcineurin-free Trial in Islet Cell Transplantation

STUDY DESIGN:

The initial proposal submitted to the JDRFI was to compare 3 different groups of patients receiving islet cell transplants utilizing steroid-free, calcineurin-free protocols. The 3 groups were as follows:

• Zenapax, Rapamycin & MMF
• Campath, Rapamycin & MMF, and
• Thymoglobulin, Rapamycin & MMF.

The grant was awarded in December 2003, however the recommendations were to focus on a single group (group 3 or 4) in order to determine the relative efficacy and toxicity of a new immunosuppressive drug combination. We elected to perform the group utilizing Campath, since we have a similar protocol utilizing the same immunosuppressive regimen with the addition of CD34+ enriched donor bone marrow cells (2000/0024). The results of this trial utilizing a steroid-free/calcineurin-free protocol will be compared with the standard "Edmonton Protocol" (2000/0196), which we are currently conducting (14 patients have been transplanted). In addition, the results will be compared with those in 2000/0024.

Protocol 2000/0024 (utilizing the same immunosuppressive regimen; Campath, Rapamycin, Tacrolimus-switched to MMF at 3 months) is being followed by a DSMB established at the NIH.

We propose to evaluate 12 patients with steroid free, long term calcineurin inhibitor free immunosuppression regimens which can be directly compared to our historical group of patients who underwent the Miami version of the Edmonton protocol (Islet Cell Transplantation Alone in Patients with Type 1 Diabetes Mellitus: Steroid-Free Immunosuppression - Protocol # 2000/196) and with the concurrent tolerogenic protocol (Islet Cell Transplantation Alone and CD34+ Enriched Donor Bone Marrow Cell Infusion in Patients with Type 1 Diabetes Mellitus; Steroid Free Regimen - Protocol # 2000/0024) which uses the same immunosuppressive regimen combined with CD34+ stem cell enriched donor bone marrow infusions.

The regimen will consist of Campath 1-H induction, maintenance immunosuppression with sirolimus and tacrolimus for 3 months with subsequent introduction of mycophenolate mofetil (MMF) and removal of tacrolimus completely and TNF-alpha inhibition (etanercept) in the peri-transplant period.

Inclusion criteria

Potential candidates must have type 1 diabetes mellitus and fulfill one or more of the following:

• Manifest signs and symptoms that are severe enough to be incapacitating. Incapacitating signs and symptoms include hypoglycemic episodes requiring assistance by others and hypoglycemia unawareness (the inability to recognize low blood glucoses; glucoses < 54 mg/dl). These patients are at high risk for involvement in accidents (they can lose consciousness or act irrationally), thus causing harm to themselves and/or others.
• Patients with poor diabetes control (HbA1c > 8.0% but < 12%), despite intensive insulin therapy, as defined by: self monitoring of blood glucose ≥ 4 times/day, multiple insulin injections (≥ 3/day) or insulin pump, and close monitoring of blood glucose control by an endocrinologist. These patients can experience acute, rapid hyperglycemia secondary to several stress factors, that can lead to dehydration, disorientation, and in some instances, ketoacidosis.
• Progressive diabetic complications. These patients with chronically poor glycemic control are at higher risk for the development of a wide variety of complications (retinopathy, neuropathy, nephropathy, and cardiovascular disease) associated with diabetes.

Exclusion criteria

Potential candidates will be excluded as per the following criteria:

• Age < 18 or > 65 years
• Duration of diabetes < 5 years
• Do not have a physician that is monitoring diabetes for > 6 months
• Body mass index > 26
• Weight > 80 kg
• Insulin requirement > 1.0 u/kg/d
• HbA1c > 12%
• Stimulated or basal C-peptide > 0.3 ng/ml
• Corrected creatinine clearance < 60 ml/min
• Serum creatinine consistently above 1.6 mg/dl
• Macroalbuminuria (> 300 mg/24 hours)
• Anemia (hemoglobin < 12.0 g/dl for males; < 11 g/dl for females)
• Hyperlipidemia (fasting low-density lipoprotein [LDL] cholesterol > 130 mg/dl and/or fasting triglycerides > 200 mg/dl)
• Abnormal liver function tests (consistently > 1.5 x normal range)
• Serological evidence of HIV, HBsAg and/or HBcAb, HBsAb without history of vaccination, human t cell lymphotropic virus 1 (HTLV-1), or hepatitis C virus (HCV)
• Negative serology for Epstein-Barr virus (EBV) or evidence of acute or chronic infection (IgM ≥ IgG)
• Lack of updated immunizations per current Centers for Disease Control (CDC) guidelines (including lack of immunization against hepatitis B, pneumococcus and influenza - during season)
• Presence of panel reactive antibodies > 20%
• Prostate-specific antigen (PSA) > 4 ng/ml unless malignancy is ruled out
• Positive tuberculin test (unless proof of adequate treatment for latent tuberculosis can be provided)
• X-ray evidence of pulmonary infection or other significant pathology
• Gall stones and/or portal hypertension and/or hemangioma on liver ultrasound
• Abnormal abdominal or pelvic ultrasound (evidence of masses that are considered suspicious for malignancy or adenopathy)
• Active peptic ulcer disease
• Active infections
• Unstable cardiovascular status (including positive stress echocardiography if age > 35)
• Untreated or unstable proliferative diabetic retinopathy
• Previous/concurrent organ transplantation (except for failed islet cell or pancreas transplantation)
• Malignancy or previous malignancy
• Any medical condition requiring chronic use of steroids
• Active alcohol or substance abuse; smoking in the last 6 months.
• Sexually active females who are not:

• post-menopausal,
• surgically sterile, or
• not using an acceptable method of contraception (oral contraceptives, Norplant, Depo-Provera, and barrier devices with spermicide are acceptable; condoms used alone are not acceptable)
• Positive pregnancy test or intent for future pregnancy, or male subject's intent to procreate
• Any condition or any circumstances that make it unsafe to undergo an islet cell transplant
• Psychogenically unable to comply
• Failed psychological evaluation
• Persistent leukopenia (white blood cell count < 3,000/uL on more than 3 occasions)