Cystic Fibrosis-related Diabetes Clinical Trial
Official title:
Characterization of β-cell Function and Insulin Sensitivity in Pre-transplant Patients With Cystic Fibrosis
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.
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.
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT02723968 -
Cystic Fibrosis Related Diabetes Screening.
|
N/A | |
Completed |
NCT04503408 -
A Comparison of Clinical Parameters in With and Without Abnormal Glucose Tolerance.
|
||
Recruiting |
NCT05723445 -
The Effects of a Low Glycemic Load Diet on Dysglycemia and Body Composition in Adults With Cystic Fibrosis-Related Diabetes
|
N/A | |
Completed |
NCT04519853 -
A Pilot Study of a Low Glycemic Load Diet in Adults With Cystic Fibrosis
|
N/A | |
Terminated |
NCT03234387 -
A CFit Study - Baseline
|
||
Completed |
NCT03227094 -
Simplification of CF-related Diabetes Screening at Home
|
N/A | |
Completed |
NCT03961516 -
Glycemic Characterization and Pancreatic Imaging Correlates in Cystic Fibrosis
|
||
Terminated |
NCT03237767 -
A CFit Study - Acute Exercise
|
N/A | |
Withdrawn |
NCT05229640 -
Relationship Between the Development of Impaired Glucose Tolerance, the Phenotype of CFLD, and the Risk of Liver Fibrosis
|
N/A | |
Active, not recruiting |
NCT04533646 -
Comparison of Meal-Time Dosing of Insulin in Cystic Fibrosis Related Diabetes
|
Phase 4 | |
Recruiting |
NCT05766774 -
FEED-Cystic Fibrosis (FEED-CF)
|
N/A | |
Not yet recruiting |
NCT06449677 -
Bionic Pancreas in CFRD
|
Phase 3 | |
Terminated |
NCT03939065 -
Sensor Augmented Pump (SAP) Therapy for Inpatient CFRD Management
|
N/A | |
Completed |
NCT02810691 -
The Effect of Soluble Fiber to Reduce Post-prandial Glycemic Excursion in Adults With Cystic Fibrosis
|
N/A | |
Recruiting |
NCT05568134 -
Alternate Measures of Glucose During OGTT Testing for CFRD
|
||
Recruiting |
NCT05463289 -
ACCESS 2: AI for pediatriC diabetiC Eye examS Study 2
|
N/A | |
Completed |
NCT03650712 -
EnVision CF Multicenter Study of Glucose Tolerance in Cystic Fibrosis
|
N/A | |
Active, not recruiting |
NCT06084468 -
Cardiac Structure and Function in Patients With Cystic Fibrosis
|
||
Recruiting |
NCT04530383 -
Effects of Metformin on Airway Ion Channel Dysfunction in Cystic Fibrosis-related Diabetes
|
Phase 2 | |
Recruiting |
NCT06149793 -
SGLT2 Inhibitor Therapy in Cystic Fibrosis-related Diabetes
|
Phase 2/Phase 3 |