Diabetes/ Endocrine Surveillance in SDS

Terminated

• Conditions: Shwachman-Diamond Syndrome
• Interventions: Diagnostic Test: Oral Glucose Tolerance Test; Other: Modified Oral Glucose Tolerance Test; Other: Modified Mixed Meal Tolerance Test; Other: Food Diary; Other: Medical History Questionnaires; Device: Continuous Glucose Monitor

• Registration Number: NCT04275479
• Lead Sponsor: Washington University School of Medicine

Brief Summary

Shwachman-Diamond syndrome(SDS) is a rare autosomal recessive disorder involving primarily the Shwachman-Bodian-Diamond syndrome gene located on chromosome 7q11. The gene effects function of the 60S ribosome by interfering with the function of the Guanasine triphosphatase elongation factor 1 in the release of eukaryotic initiation factor 6 from the 60 S ribosomal subunit for translation initiation. Seventy five percent of the individual affected by the syndrome have a biallelic mutation (258+2T\>C and 183-184T \> CT). The syndrome results in defects primarily in the pancreas and bone marrow resulting in pancreatic insufficiency, leukopenia with an increased risk of infection and an increased risk for acute myelocytic leukemia. Animal models that have knocked out the function of the SBDS gene in the pancreas reveals at the pancreas at birth as well as the insulin producing cells in the pancreas are normal but subsequently developed fatty infiltration and apoptosis without inflammation resulting in pancreatic exocrine insufficiency with initially normal endocrine pancreatic function. The endocrine pancreatic function declines over time such that by 12 months of age these mice show a phenotype of impaired glucose tolerance. The finding of early onset diabetes is not yet considered a manifestation of this genetic defect but likely is occurring. This study is designed to assist in understanding the prevalence of glucose abnormalities in this syndrome.

Exocrine pancreatic insufficiency leading to diabetes is a common hallmark of cystic fibrosis and cystic fibrosis related diabetes. Prevalence of glucose abnormalities in diabetes is a approaching 50% by the 2nd and 3rd decade of life in this disorder. The cystic fibrosis Foundation recommend screening for diabetes utilizing an oral glucose tolerance by the age of 10. Early diagnosis of diabetes in the syndrome as resulted in improved outcomes for patients with cystic fibrosis. It is my expectation that the prevalence of diabetes will be similar in SBDS patients. A small study performed I had the University of Cincinnati showed glucose abnormalities to occur in 5/20 individuals with the classic mutation.

Investigators propose to screen patients with the classic mutation for diabetes and endocrine disease utilizing continuous glucose monitoring over a 14 day period in addition to baseline fasting blood tests for insulin, GAD 65 antibody, Fructosamine, A1c and C peptide.

Detailed Description

The purpose of the study is to learn about how common early onset diabetes and other endocrine issues occur in people who have been diagnosed with SDS.

Study procedures include:

For participants with SDS:

obtaining informed consent/assent; obtaining medical \& medication history, including history of diabetes, review of medical records and lab results for confirmation of diagnosis and inclusion/exclusion assessment; performance of a standard oral glucose tolerance test (OGTT) to be performed at a center close to the participants home, a modified oral glucose tolerance test and a modified mixed meal tolerance test to be performed by participant at home with phone access to study staff for directions, blood draws performed at a local lab or local physician office or other medical center in close proximity to the participants home. Completion of on-line, or in the case of no computer access - paper, questionnaires completed by the participant/parent to collect medical and health history, parents/siblings will be asked to complete a health history, 3 day food diary completed by participant/parent; phone calls; wearing of blinded continuous glucose monitoring device for 14 days; medical records release, 3-day diet diary; Additional optional biological specimens to look at cell free DNA and future biomarkers of endoplasmic reticulum stress in the beta cells of the pancreas will be obtained and stored for future study Parent(s) and/or siblings if willing and consented, will complete on-line medical history questionnaire and provide medical record release.

Data to be obtained from on-going study for subjects with Cystic Fibrosis

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2020-01-10
• Study First Submitted: 2020-02-10
• Study First Submitted QC: 2020-02-14
• Study First Posted: 2020-02-19
• Primary Completion: 2022-12-30
• Study Completion: 2022-12-30
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-15
• Last Update Posted: 2024-08-19

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 11

Inclusion Criteria

Population 1: SDS and non-diabetic

• Age: 3 years of age and older to allow for baseline blood to be drawn. The Cystic Fibrosis group has seen glucose abnormalities well before age 10 but recommends screening after age 10. Investigators are attempting to define the population and will screen starting at age 3 to get a baseline data set.
• Willing to provide consent/ assent
• Stable health in the last month- i.e. not hospitalized/ ill in the last 6 weeks
• Patients should have been on stable medications for at least 4 weeks prior to testing - This includes neupogen and other white cell stimulators.
• Classic SBDS mutation with pancreatic insufficiency as determined by medical history.
• Able/willing to have a standard OGTT and modified OGTT
• Able/ willing to wear a Libre- Pro sensor and have sensor returned. If not willing to wear CGM- willing to do a standard OGTT as described.
• Not currently on diabetic therapy or labeled as diabetic.
• Willing to complete a health survey in regard to the SBDS and endocrine History

Population 2: SDS and Labeled as diabetic

• Age greater than 3
• If labeled as diabetic - obtain data for age of onset and treatment utilized for the diabetes
• Willing to provide consent/ assent and complete health survey for SBDS and endocrine history
• Willing/able to wear 14 day blinded Libre-Pro to assess the response to current therapy and food diary.
• Willing to provide Fasting labs as outlined above for the group- no OGT, just the mixed meal tolerance test

Population 1 and 2 Future Sub-study: Assess alpha cell and insulin dynamic response

• Participant in primary study who agree to the sub-study
• Willing to travel to St. Louis for clamp procedure.
• Budget will determine the actual number to be screened.
• Travel will be included.

Population 3: Control groups

• Other control groups for the study will be age matched population norms, Cystic Fibrosis patients associated pancreatic insufficiency known or treated diabetes.

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
SDS with Diabetes Diagnosis	Medical History Questionnaires	SDS with Diabetes Diagnosis
SDS - without Diabetes diagnosis	Modified Oral Glucose Tolerance Test	SDS - without Diabetes diagnosis
SDS - without Diabetes diagnosis	Modified Mixed Meal Tolerance Test	SDS - without Diabetes diagnosis
SDS - without Diabetes diagnosis	Oral Glucose Tolerance Test	SDS - without Diabetes diagnosis
SDS - without Diabetes diagnosis	Continuous Glucose Monitor	SDS - without Diabetes diagnosis
SDS with Diabetes Diagnosis	Modified Mixed Meal Tolerance Test	SDS with Diabetes Diagnosis
SDS with Diabetes Diagnosis	Food Diary	SDS with Diabetes Diagnosis
SDS - without Diabetes diagnosis	Food Diary	SDS - without Diabetes diagnosis
SDS - without Diabetes diagnosis	Medical History Questionnaires	SDS - without Diabetes diagnosis
SDS with Diabetes Diagnosis	Continuous Glucose Monitor	SDS with Diabetes Diagnosis

Primary Outcome Measures

Name	Time	Method
Systematically assess the prevalence of diabetes or glucose intolerance in participants with the classic biallelic mutation	1 Year	Aim 1
Share data with the current SBDS Registry	Through study completion, and average of 3 years	Aim 5
Longitudinal screening of the enrolled population to assess the prevalence of diabetes or glucose intolerance	Through study completion, an average of 3 years	Aim 2
Assess individuals who have previously been diagnosed with diabetes in regard to age of onset, complications and the treatments utilized.	1 year	Aim 3
Assist families and patients in understanding their diet and fine tuning their approach to carbohydrates and fat in the diet	1 year	Aim 4

Trial Locations

Locations (1)

Washington University; 🇺🇸 Saint Louis, Missouri, United States