Introduction: From a risk-benefit perspective, patients with type 1 diabetes (T1D) who are already obligated to long-term immunosuppression to support a kidney transplant and who suffer labile glycemia despite optimal diabetes management may be ideal candidates for purified human pancreatic islets (PHPI). We report results from the Clinical Islet Transplant Consortium (CIT) 06 protocol, a prospective, open label, single arm phase 3 trial to determine the effectiveness and safety of PHPI in the treatment of patients with T1D after renal transplant.

Methods: Eight sites enrolled 24 adults with T1D, absent stimulated C-peptide, and either reduced awareness of hypoglycemia and ≥1 episode of severe hypoglycemia (SHE) in the prior year, or an HbA1c of >7.5% despite expert diabetes care. PHPI were isolated from deceased donor pancreases using a standardized manufacturing process and delivered intraportally. Immunosuppression included antithymocyte globulin and etanercept induction and maintenance sirolimus and tacrolimus.

Results: At 1 year after the initial islet infusion, 9/24 (37.5%) subjects were insulin-independent. Insulin requirements decreased from a baseline mean of 34.9±SD to 2.3±SD U/d 1 year post transplant. Improvements in measures of glycemic control and hypoglycemic unawareness from baseline to day 365 included: MAGE (179 to 58; p=0.002), LI (400 to 21; p=0.008), HYPO score (576 to 0.0; p=0.008), and Clarke score (6 to 0; p<0.0001). Transplanted patients exhibited a robust response to a mixed meal tolerance test with C-peptide levels of 6.1 ng/ml at 1 hour and glucose levels of 169 at 90 minutes. The eGFR remained stable at 1 year at 77.1 vs 76.0 ml/min at baseline. De novo low-level cPRA developed in 3 patients, with donor specific antibodies in one.

Conclusion: PHPI transplanted after renal transplant safely restored glycemic stability and protection from SHE with recovery of hypoglycemia awareness in kidney transplant patients with long-standing T1D and problematic hypoglycemia or uncontrolled hyperglycemia. These results add to the recently published phase 3 CIT07 trial in patients with normal renal function, demonstrating the efficacy of PHPI in controlling labile diabetes. Based on these results, islet transplantation should be considered in this subgroup of patients when other treatments have failed.

CITATION INFORMATION: Markmann J, Alejandro R, Bellin M, Bridges N, Clarke W, Eggerman T, Foster E, Hering B, Kaufman D, Korsgren O, Luo X, Naji A, Oberholzer J, Posselt A, Rickels M, Ricordi C, Robien M, Senior P, Shapiro A, Turgeon N. Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes (T1D) Post Renal Transplantation. Am J Transplant. 2017;17 (suppl 3).

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