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

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

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; Insulin-dependent Diabetes; Diabetes Related Cystic Fibrosis
• Intervention / Treatment: Procedure: Combined pancreatic islet and lung transplantation

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Grenoble, France, 38 043
    • CRCM AdulteCHU de Grenoble, Hôpital A. Michallon
  • Grenoble, France, 38043
    • Nephrologie, CHU Grenoble
  • Grenoble, France, 38043
    • Réanimation Cardiovasculaire et Thoracique, Hôpital Michallon
  • Grenoble, France, 38043
    • Service d'Endocrinologie, CHU de Grenoble
  • Grenoble, France, 38043
    • Service de Chirurgie Cardiaque, CHU Grenoble
  • Grenoble, France, 38043
    • Service de Radiologie Interventionnelle, CHU de Grenoble
  • Grenoble, France, 38700
    • Service de Pneumologie, Hôpital A. MICHALLON , CHU de Grenoble
  • Lyon, France, 69 437
    • Service d'Urologie et chirurgie de la Transplantation, Groupement Hospitalier Edouard Herriot
  • Lyon, France, 69437
    • Service de médecine de la transplantation et immunologie clinique, Hôpital Edouard Herriot
  • Lyon, France, 69495
    • CRCM adulte, Centre Hospitalier Lyon-Sud
  • Lyon, France, 69495
    • Service d'Endocrinologie, Pavillon médical
  • Lyon, France, 69495
    • Service d'imagerie radiologique et de médecine nucléaire, Centre Hospitalier Lyon-Sud
  • Lyon, France, 69677
    • Service de Chirurgie Thoracique, HOPITAL LOUIS PRADEL
  • Lyon, France, 69677
    • Service de pneumologie, Hôpital Louis Pradel
  • Nantes, France, 44093
    • Service de Pneumologie
  • Nantes, France, 44093
    • Service de la Clinique d'Endocrinologie, maladies métaboliques et Nutrition
  • Nantes, France, 44093
    • Service de Néphrologie et Immuno-transplantation
  • Nantes, France, 44093
    • Service de Radiologie
  • Strasbourg, France, 67 091
    • Service d'endocrinologie, diabète et maladies métaboliques
  • Strasbourg, France, 67091
    • Service d'Anesthésie-Réanimations chirurgicales, Nouvel Hôpital Civil
  • Strasbourg, France, 67091
    • Service d'Anesthésie-Réanimations Chirurgicales
  • Strasbourg, France, 67091
    • Service de chirurgie, Nouvel Hôpital Civil
  • Strasbourg, France, 67091
    • Service de pneumologie, Nouvel Hôpital Civil
  • Strasbourg, France, 67098
    • Service de Radiologie, Hôpital de Hautepierre
  • Suresnes, France, 92150
    • Unité d'Endocrinologie, Diabétologie et Médecine Métabolique - Hôpital Foch
  • Suresnes, France, 92151
    • Service d'Imagerie - Hôpital Foch
  • Suresnes, France, 92151
    • Service de Chirurgie Thoracique et Transplantation Pulmonaire - Hôpital Foch
  • Suresnes, France, 92151
    • Service de Pneumologie - Hôpital Foch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France
• Investigators: Principal Investigator: Laurence KESSLER, MD, PhD, Hopitaux Universitaires de Strasbourg; Principal Investigator: Pierre Yves BENHAMOU, MD, phD, University Hospital, Grenoble; Principal Investigator: Dominique Grenet, MD, HOPITAL FOCH DE SURESNES; Principal Investigator: Charles THIVOLET, MD, Hospices Civils de Lyon; Principal Investigator: Thierry BERNEY, MD PhD, CENTRE ROMAND DE TRANSPLANTATION - SUISSE

Publications and helpful links

General Publications

• Rakotoarisoa L, Wagner C, Munch M, Renaud Picard B, Grenet D, Olland A, Greget M, Enescu I, Bouilloud F, Bonnette P, Guth A, Bosco D, Mercier C, Rabilloud M, Berney T, Yves Benhamou P, Massard G, Camilo C, Colin C, Arnold C, Kessler R, Kessler L; GRAGIL-TREPID Group. Feasibility and efficacy of combined pancreatic islet-lung transplantation in cystic fibrosis-related diabetes-PIM study: A multicenter phase 1-2 trial. Am J Transplant. 2022 Jul;22(7):1861-1872. doi: 10.1111/ajt.17058. Epub 2022 Apr 26.

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2012
• Primary Completion (Actual): December 20, 2019
• Study Completion (Actual): December 20, 2019

Study Registration Dates

• First Submitted: February 10, 2012
• First Submitted That Met QC Criteria: March 5, 2012
• First Posted (Estimate): March 8, 2012

Study Record Updates

• Last Update Posted (Actual): March 30, 2021
• Last Update Submitted That Met QC Criteria: March 29, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; Lung transplantation; Pancreatic islets; Diabetes Related Cystic Fibrosis; Insulin-dependent diabetes
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Lung Diseases; Endocrine System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Diabetes Mellitus; Diabetes Mellitus, Type 1; Cystic Fibrosis
• Other Study ID Numbers: 4790