Clinical trial NCT04379726: β-cell Function and Insulin Sensitivity in Patients With Cystic Fibrosis
Official title: Characterization of β-cell Function and Insulin Sensitivity in Pre-transplant Patients With Cystic Fibrosis
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Cystic Fibrosis-related Diabetes
Keywords: insulin
beta cell function
insulin resistance
Lead sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Sponsor class: OTHER
First posted: 2020-05-07
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: patients will be followed for three years as described in the protocol

Brief summary: Cystic fibrosis is a genetic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, leading to pulmonary infections, sinus disease, pancreatic insufficiency, hepatobiliary disease and male infertility, with respiratory failure being the primary cause of death. Cystic Fibrosis Related Diabetes (CFRD) in one of the most common complication of cystic fibrosis (CF) and it's associated with a worse respiratory and nutritional state, with a negative impact on life expectancy. It differs from type 1 diabetes and type 2 diabetes for particular characteristics making this disease a separated clinical entity.

To date, there is a lack of evidence on many aspects concerning this disease:

* the pathophysiology of the disease: decreased insulin secretion has historically been seen has the major trigger for CFRD, but data about this mechanism are scarce and conflicting. Moreover, the role of insulin-resistance seems to be not consistent, but pulmonary exacerbations are very common and, in this setting, insulin sensitivity can worsen significantly.
* the relationship between its development and particular genetic settings: certain CFTR genotypes are known to be most related to the risk of diabetes, and only few susceptibility genes for type 2 diabetes have been evaluated as potential predisposing factors for CFRD.
* the relationship between the therapeutic optimization and its impact on metabolic status and lung function: CFRD is known to be associated with worse clinical outcomes, reflected in more frequent clinical exacerbations, greater reduction in lung function, poorer nutritional status and decreased survival. It has also been demonstrated that insulin therapy can improve pulmonary function, increase body weight and reduce lung exacerbations. However, no study on the clinical impact of the optimization of insulin therapy on pulmonary outcomes and life expectancy are available in this population.
* finally, no data about potential predisposing pre-transplant risk factors for development of post-transplant DM are available

For this reason, the investigators have structured a study with the aim to:

* characterize the pathophysiological process leading to CFRD, with assessment of the relative contribution of the insulin resistance and the β-cellular secretion impairment
* define the prevalence of CFRD in relation to the mutations of the CFTR gene and to the presence of candidate genes for the development of type 2 diabetes
* perform a proteomic analysis to identify potential proteomic biomarkers among CFRD patients
* evaluate the body composition, muscle performance and respiratory outcomes in patients on insulin therapy, before and after therapeutic optimization, in a follow-up period of 24 months.
* identify eventual predisposing factors for the development of post-transplant diabetes in subjects without pre-transplant CFRD.

Detailed description: The study aims are:

* Task 1: pathophysiological characterization of CFRD with assessment of the relative contribution of the insulin resistance and the β-cellular secretion impairment through the use of a Minimum Model applied to OGTT for the evaluation of insulin sensitivity and secretion
* Task 2:

  2a) determination of the prevalence of CFRD in relation to the mutations of the CFTR gene (presence of mutations with residual function of the CFTR protein) 2b) determination of the prevalence of CFRD in relation to the presence of candidate genes for the devel-opment of type 2 diabetes (NOTCH2, BCL11A, THADA, IGFBP-2, PPARG, ADAMTS9, CDKAL1, VEFGA, JAZF1, CDKN2A / 2B, HHEX, CDC123 / CAMK1D, TCF7L2, KCNJ11, DCD, TSPAN8 / LGR5, FTO, WFS1, SLC30A8 and INS).

  2c) determination of variations in the proteomic analysis of CFRD patients compared to CF without DM and a control group of healthy individuals.
* Task 3: evaluation of the effect of the therapeutic optimization of glycometabolic control on body composition and respiratory outcomes in patients on insulin therapy, in a follow-up period of 24 months.
* Task 4: identification of predisposing factors for the development of post-transplant diabetes in subjects without CFRD.

METHODS:

All CF patients currently followed at the Unit of Pulmonology of our Center (250 subjects) will be considered eligible for the study.

Total duration of the study: 156 weeks (3 years).

The enrolled patients will be divided into two groups:

GROUP 1: subjects with a negative history for CFRD or with a CFRD diagnosis that does not require insulin therapy GROUP 2: subjects suffering from CFRD in insulin therapy

Protocol 1: Group 1; metabolic and anthropometric evaluation and assessment of insulin sensitivity / secretion.

Protocol 2: Group 1 and Group 2; genetic evaluation / proteomic evaluation Protocol 3: Group 2; pre- and post-intervention metabolic, anthropometric and nutritional assessment.

Protocol 4: Group 1 patients without CFRD undergoing lung transplantation (10); genetic, metabolic, an-thropometric and pre-and post-transplant assessment of insulin sensitivity / secretion.

Patients will undergo a:

1. METABOLIC EVALUATION: a venous sampling will be performed for blood glucose, HbA1c, total cholesterol, HDL, triglycerides, blood count, albumin, total proteins, pseudocholinesterase, AST, ALT, GGT, ALP, 25OHvitD
2. GENETIC EVALUATION: the investigators will evaluate the specific genetic mutation of the CFTR gene and the presence of gene variants related to the development of DM2 (NOTCH2, BCL11A, THADA, IGFBP-2, PPARG, ADAMTS9, CDKAL1, VEFGA, JAZF1, CDKN2A / 2B, HHEX, CDC123 / CAMK1D, TCF7L2, KCNJ11, DCD, TSPAN8 / LGR5, FTO, WFS1, SLC30A8 and INS)
3. PROTEOMIC EVALUATION: the investigators will perform a Mass Spectrometry to identify variations in the protein pattern expression in CFRD patients if compared to CF patients without DM and healthy control individuals. The list of analyzed protein is available in supplemental data 2.
4. ANTROPOMETRIC EVALUATION. the anthropometric evaluation will be performed with objective exami-nation (Body Mass Index - BMI, waist circumference - CV and hip circumference - CF) , DEXA total body and bioimpedentiometry
5. DYNAMIC EVALUATION OF INSULIN SENSITIVITY AND β CELL SECRETION. Patients will undergo a 5-hours OGTT with serial blood samples and with the application of a Mathematical Model adapted ad hoc (Appendix 1 for a detailed description of the model), in order to quantify the contribution of insulin resistance and β-cell secretion to the development of CFRD
6. PULMONARY EVALUATION. According to clinical practice, patients will be subjected to respiratory function tests with the calculation of FEV1 (absolute and percentage), exacerbation rate, rate of severe exacerbation (need of hospitalization), patient-reported outcomes (PROs) obtained from the sCF-quality of life questionnaire, which will be provided to patients in paper form.

SAMPLE SIZE AND STATISTICAL ANALYSIS:

Referring to the primary objective of the project, the observational nature of the study and the absence of evidence about the topic make a precise evaluation of the power of the study a difficult issue. However, considering the number of patients available and followed by our Center (n = 136), it has been calculated that the present study will have the power of 80% and an alpha level equal to 5% to show a significant reduction of at least 25% in the 1st phase secretion in the group of diabetics if compared to the non-diabetic group (assuming a mean value in non-diabetics of 1500 (aggiungere udm) and a SD of 500 (udm) (Pass v. 11 NCSS software, LCC, Kaysville, Utah, USA).

A series of descriptive analyzes will be performed: the continuous variables will be presented as averages and standard deviations or median with interquartile ranges, depending on the distribution. Frequency distributions will be presented as numbers and percentages. Data will also be presented graphically with histograms and "Box-and-Whisker" plots in order to evaluate potential anomalous values, allowing a further data-check phase in order to have reliable data for subsequent analyzes. Differences between the groups will be analyzed using parametric tests (t-test or ANOVA) without repeated tests or repeated tests, depending on the task of the project. If the normality of the distributions were violated (normal test based on the Shapiro-Wilk statistics), non-parametric technical correspondents will be used. Categorical data will be compared using contingency tables through the Chi-square test or Fisher's exact test, where appropriate. All tests will be two-tailed and p-values less than 5% will be considered statistically significant.

A series of descriptive analyzes will be performed: the continuous variables will be presented as averages and standard or median deviations with interquartile ranges, depending on the distribution. Frequency distributions will be presented as numbers and percentages. The data will also be presented graphically through histograms and "Box-and-Whisker" plots in order to evaluate potential anomalous values that will allow a further data-check phase in order to have valid data for subsequent analyzes. The differences between the groups will be analyzed using parametric techniques (t-test or ANOVA) without repeated tests or with repeated tests, depending on the task of the project. If the normality of the distributions was violated (normality test based on the Shapiro-Wilk statistics), corresponding non-parametric techniques will be used. Categorical data will be compared using contingency tables through the Chi-square test or Fisher's exact test, where appropriate. All tests will be two-tailed and a p-values less than 5% will be considered statistically significant.

Eligibility criteria: Inclusion Criteria:

* written informed
* diagnosis of cystic fibrosis

Exclusion Criteria:

* celiac disease
* pregnancy
* diagnosis of T1DM

Primary outcomes:
measure: TASK 1: derivative control (DC)
timeFrame: 2 YEARS
measure: TASK 1: proportional control (PC)
timeFrame: 2 YEARS
measure: TASK 1: OGIS-2H
timeFrame: 2 YEARS
measure: TASK 2: prevalence of CFRD in relation to the classes of mutations in the CFTR gene
timeFrame: 2 YEARS
measure: TASK 3: variation of FEV1
timeFrame: 2 YEARS
measure: TASK 4: incidence of post-transplant diabetes in subjects without CFRD
timeFrame: 2 YEARS
Secondary outcomes:
measure: TASK 2: prevalence of candidate genes for DM2 in the population with CF
timeFrame: 2 YEARS
measure: TASK2: variations in the protein pattern expression in CFRD population
timeFrame: 2 YEARS
measure: TASK 3: variations of other respiratory and muscle-performance parameters
timeFrame: 2 YEARS
Other outcomes:
Locations:
Study officials:
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