Metabolic Efficiency of Combined Pancreatic Islet and Lung Transplant for the Treatment of End-Stage Cystic Fibrosis

Study Overview
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Brief Summary
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Patients with end-stage cystic fibrosis (CF) and severe CF-related diabetes (CFRD) may benefit from combined lung-pancreatic islet transplantation. A recent case series showed that combined bilateral lung and pancreatic islet transplantation is a viable therapeutic option for patients with end-stage CF and CFRD. The use of different organs from a single donor may lead to reduced immunogenicity. As the prevalence of CFRD has increased dramatically with the improved life expectancy of patients with CF, islet transplantation should be considered at the end-stage CF. By restoring metabolic control, the investigators hypothesize that islet transplantation may improve the management of CF patients undergoing lung transplant and decrease the complication rate in the early postoperative period.

Official Title
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Metabolic Efficiency of Combined Pancreatic Islet and Lung Transplant for the Treatment of End-Stage Cystic Fibrosis : a Pilot Study

Conditions
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Cystic Fibrosis, Diabetes Related Cystic Fibrosis, Insulin-dependent Diabetes

Intervention / Treatment
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* Procedure: Combined pancreatic islet and lung transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patient with cystic fibrosis Patient able to respect the protocol procedures Patient with end-stage respiratory insufficiency indicating a lung transplant Clinical history of cystic fibrosis related diabetes and/or insulin-dependent diabetes, with no residual insulin secretion (C-peptide < 0,5 ng/mL) and/or no response to IV glucagon stimulation: [peak stimulated C-peptide (T6min)/basal plasma C-peptide(T0)] < 2. The absence of insulin secretion will be verified 2 times before inclusion Evolution of diabetes for over 3 years Patient whose glycaemic control obtained with insulin therapy is not satisfactory and could significantly alter quality of life (HbA1c > 7% and/or MAGE index > 1,25). This situation is assessed by a diabetologist. Social Security membership or benefit from Social Welfare Patient who received the results of the medical evaluation required Non-inclusion criteria: Patient with contra-indication for undergo a lung transplant Patient with an indication of heart, liver or kidney transplantation Patient for which poor therapeutic compliance is expected Patient under oral antidiabetic drug In women of childbearing potential: pregnancy test (urine and / or blood) positive, lactation, or unwilling to use effective contraception for the duration of the study until 3 months after the end . Men: procreation project during the study period up to 3 months after its end, or unwilling to use effective contraception patient. Active infection, including hepatitis B, hepatitis C, HIV Any history of malignancy within the past 5 years, with the exception of cutaneous basal cell carcinomas completely resected. The history of breast or melanoma cancers are an absolute contraindication Alcoholic intoxication or drug addiction Anemia (hemoglobin Hb <10g / dL in women and Hb <11 g / dL in men), lymphopenia (<1000 / uL), neutropenia (<1500 / uL) or thrombocytopenia (<100,000 / uL). Persistent elevated liver enzymes at baseline Portal hypertension identified by oesophageal varice and/or hypersplenism (platelets < 120 000 /mm3) or Child-Pugh score > 6. Use of a medical treatment under investigation within 4 weeks before inclusion All medical situation assessed by an investigator which could interfere with the good management of the project Patient restricted of freedom or unable to give his consent Patient has been included in another study that could interfere with the results of the study Contraindications to the use of experimental drugs (Cellcept®, prednisone, Prograf, prednisolone, methylprednisolone, and pancreatic islets)

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient with cystic fibrosis<br>Patients with end-stage cystic fibrosis | Procedure: Combined pancreatic islet and lung transplantation<br>* Combined pancreatic islet and lung transplant from the same donor for the treatment of patients with end-stage cystic fibrosis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic efficiency at 1 year | Combined criteria based on the 4 following criteria: weight increase > 5% compared to inclusion, fasting blood glucose < 1.1 g/l at 12 months post-transplant (beta score criterion), Reducing insulin requirements (expressed in UI/day) compared to inclusion & decreased in HbA1c >= 0.5% (in absolute value) compared to inclusion Success is defined by achieving at least three of these criteria | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio [C-peptide stimulated T6min/ C-peptide basal T0] | Δ C peptide = [ C-peptide stimulated T6min/ C-peptide basal T0] Success if Δ C peptide > 2 | 1 year after transplant | 
| Ratio [C-peptide/Glucose-Creatinine] & ratio [C-peptide/Glucose] |  | Every week during the first month, and every month during 1 year | 
| HbA1c |  | Every 3 months during 1 year after transplant | 
| C-peptide stimulated by glucagon |  | Every 3 months during 1 year after transplant | 
| Ratio [C-peptide stimulated T6min/ C-peptide basal T0] |  | Every 3 months during 1 year after transplant | 
| Microalbuminuria & proteinuria |  | Every 3 months during 1 year after transplant | 
| Insulin requirements | Unit/day | Every month during 1 year after transplant | 
| Number of minor hypoglycemia | defined by a blood glucose level < 0.6g/L at which the patient is capable of self-sugaring | Every month during 1 year after transplant | 
| Number of major hypoglycemia |  | Every month during 1 year after transplant | 
| Glycemic variability (MAGE) | by continuous glycemic measurement Holter (CGMS) & glycemic reader memory analysis | Every 6 months during 1 year after transplant | 
| duration of hypoglycemia | by continuous glycemic measurement Holter (CGMS) & glycemic reader memory analysis | Every 6 months during 1 year after transplant | 
| Forced Expiratory Volume (FEV1) |  | Every month during 1 year after transplant | 
| Forced Vital Capacity (FVC) |  | Every month during 1 year after transplant | 
| Tiffeneau-Pinelli index | FEV1/FVC | Every month during 1 year after transplant | 
| Nature of pulmonary infection episodes and nature of acute lung rejection if need be |  | Every month during 1 year after transplant | 
| Dyspnea score according to the mMRC scale |  | Every month during 1 year after transplant | 
| Oxygen saturation SaO2 room air |  | Every month during 1 year after transplant | 
| Median maximum expiration flow |  | Every month during 1 year after transplant | 
| Number of episodes of pulmonary rejection | requiring a corticosteroid bolus | Every visit during 1 year after transplant | 
| Number of days of post-transplant hospitalization and during the follow-up |  | Every visit during 1 year after transplant | 
| Mortality |  | Every visit during 1 year after transplant | 
| Adverse events |  | Every visit during 1 year after transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, Diabetes Related Cystic Fibrosis, Lung transplantation, Pancreatic islets, Insulin-dependent diabetes