Clinical trial NCT01548729: Metabolic Efficiency of Combined Pancreatic Islet and Lung Transplant for the Treatment of End-Stage Cystic Fibrosis
Official title: Metabolic Efficiency of Combined Pancreatic Islet and Lung Transplant for the Treatment of End-Stage Cystic Fibrosis : a Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cystic Fibrosis
Diabetes Related Cystic Fibrosis
Insulin-dependent Diabetes
Keywords: Cystic Fibrosis
Diabetes Related Cystic Fibrosis
Lung transplantation
Pancreatic islets
Insulin-dependent diabetes
Lead sponsor: University Hospital, Strasbourg, France
Sponsor class: OTHER
First posted: 2012-03-08
Enrollment: 14
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Metabolic efficiency at 1 year
timeFrame: 1 year
Secondary outcomes:
measure: Ratio [C-peptide stimulated T6min/ C-peptide basal T0]
timeFrame: 1 year after transplant
measure: Ratio [C-peptide/Glucose-Creatinine] & ratio [C-peptide/Glucose]
timeFrame: Every week during the first month, and every month during 1 year
measure: HbA1c
timeFrame: Every 3 months during 1 year after transplant
measure: C-peptide stimulated by glucagon
timeFrame: Every 3 months during 1 year after transplant
measure: Ratio [C-peptide stimulated T6min/ C-peptide basal T0]
timeFrame: Every 3 months during 1 year after transplant
measure: Microalbuminuria & proteinuria
timeFrame: Every 3 months during 1 year after transplant
measure: Insulin requirements
timeFrame: Every month during 1 year after transplant
measure: Number of minor hypoglycemia
timeFrame: Every month during 1 year after transplant
measure: Number of major hypoglycemia
timeFrame: Every month during 1 year after transplant
measure: Glycemic variability (MAGE)
timeFrame: Every 6 months during 1 year after transplant
measure: duration of hypoglycemia
timeFrame: Every 6 months during 1 year after transplant
measure: Forced Expiratory Volume (FEV1)
timeFrame: Every month during 1 year after transplant
measure: Forced Vital Capacity (FVC)
timeFrame: Every month during 1 year after transplant
measure: Tiffeneau-Pinelli index
timeFrame: Every month during 1 year after transplant
measure: Nature of pulmonary infection episodes and nature of acute lung rejection if need be
timeFrame: Every month during 1 year after transplant
measure: Dyspnea score according to the mMRC scale
timeFrame: Every month during 1 year after transplant
measure: Oxygen saturation SaO2 room air
timeFrame: Every month during 1 year after transplant
measure: Median maximum expiration flow
timeFrame: Every month during 1 year after transplant
measure: Number of episodes of pulmonary rejection
timeFrame: Every visit during 1 year after transplant
measure: Number of days of post-transplant hospitalization and during the follow-up
timeFrame: Every visit during 1 year after transplant
measure: Mortality
timeFrame: Every visit during 1 year after transplant
measure: Adverse events
timeFrame: Every visit during 1 year after transplant
Other outcomes:
Locations:
city: Grenoble
country: France
facility: CRCM AdulteCHU de Grenoble, Hôpital A. Michallon
city: Grenoble
country: France
facility: Nephrologie, CHU Grenoble
city: Grenoble
country: France
facility: Réanimation Cardiovasculaire et Thoracique, Hôpital Michallon
city: Grenoble
country: France
facility: Service d'Endocrinologie, CHU de Grenoble
city: Grenoble
country: France
facility: Service de Chirurgie Cardiaque, CHU Grenoble
city: Grenoble
country: France
facility: Service de Radiologie Interventionnelle, CHU de Grenoble
city: Grenoble
country: France
facility: Service de Pneumologie, Hôpital A. MICHALLON , CHU de Grenoble
city: Lyon
country: France
facility: Service d'Urologie et chirurgie de la Transplantation, Groupement Hospitalier Edouard Herriot
city: Lyon
country: France
facility: Service de médecine de la transplantation et immunologie clinique, Hôpital Edouard Herriot
city: Lyon
country: France
facility: CRCM adulte, Centre Hospitalier Lyon-Sud
city: Lyon
country: France
facility: Service d'Endocrinologie, Pavillon médical
city: Lyon
country: France
facility: Service d'imagerie radiologique et de médecine nucléaire, Centre Hospitalier Lyon-Sud
city: Lyon
country: France
facility: Service de Chirurgie Thoracique, HOPITAL LOUIS PRADEL
city: Lyon
country: France
facility: Service de pneumologie, Hôpital Louis Pradel
city: Nantes
country: France
facility: Service de la Clinique d'Endocrinologie, maladies métaboliques et Nutrition
city: Nantes
country: France
facility: Service de Néphrologie et Immuno-transplantation
city: Nantes
country: France
facility: Service de Pneumologie
city: Nantes
country: France
facility: Service de Radiologie
city: Strasbourg
country: France
facility: Service d'endocrinologie, diabète et maladies métaboliques
city: Strasbourg
country: France
facility: Service d'Anesthésie-Réanimations chirurgicales, Nouvel Hôpital Civil
city: Strasbourg
country: France
facility: Service d'Anesthésie-Réanimations Chirurgicales
city: Strasbourg
country: France
facility: Service de chirurgie, Nouvel Hôpital Civil
city: Strasbourg
country: France
facility: Service de pneumologie, Nouvel Hôpital Civil
city: Strasbourg
country: France
facility: Service de Radiologie, Hôpital de Hautepierre
city: Suresnes
country: France
facility: Unité d'Endocrinologie, Diabétologie et Médecine Métabolique - Hôpital Foch
city: Suresnes
country: France
facility: Service d'Imagerie - Hôpital Foch
city: Suresnes
country: France
facility: Service de Chirurgie Thoracique et Transplantation Pulmonaire - Hôpital Foch
city: Suresnes
country: France
facility: Service de Pneumologie - Hôpital Foch
Study officials:
affiliation: Hôpitaux Universitaires de Strasbourg
name: Laurence KESSLER, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Grenoble
name: Pierre Yves BENHAMOU, MD, phD
role: PRINCIPAL_INVESTIGATOR
affiliation: HOPITAL FOCH DE SURESNES
name: Dominique Grenet, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospices Civils de Lyon
name: Charles THIVOLET, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CENTRE ROMAND DE TRANSPLANTATION - SUISSE
name: Thierry BERNEY, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.