Diabetes/ Endocrine Surveillance in SDS

NCT04275479 | Terminated FDA Device

• 1 other identifier: 201909102
• Study Type: observational
• Target: 11
• Locations: 1 country
• Sites: 1

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.

Conditions

Shwachman-Diamond Syndrome

Keywords

Shwachman-Diamond Syndrome; Atypical Diabetes; Exocrine Pancreatic Insufficiency

Outcome Measures

Primary Outcomes (5)

• Systematically assess the prevalence of diabetes or glucose intolerance in participants with the classic biallelic mutation

  Aim 1

  1 Year

• Longitudinal screening of the enrolled population to assess the prevalence of diabetes or glucose intolerance

  Aim 2

  Through study completion, an average of 3 years

• Assess individuals who have previously been diagnosed with diabetes in regard to age of onset, complications and the treatments utilized.

  Aim 3

  1 year

• Assist families and patients in understanding their diet and fine tuning their approach to carbohydrates and fat in the diet

  Aim 4

  1 year

• Share data with the current SBDS Registry

  Aim 5

  Through study completion, and average of 3 years

Study Arms (3)

SDS - without Diabetes diagnosis

SDS - without Diabetes diagnosis

Diagnostic Test: Oral Glucose Tolerance Test; Other: Modified Oral Glucose Tolerance Test; Other: Modified Mixed Meal Tolerance Test; Device: Continuous Glucose Monitor; Other: Food Diary; Other: Medical History Questionnaires

SDS with Diabetes Diagnosis

SDS with Diabetes Diagnosis

Other: Modified Mixed Meal Tolerance Test; Device: Continuous Glucose Monitor; Other: Food Diary; Other: Medical History Questionnaires

Cystic Fibrosis (CF) patients data & lab results

De-identified data from age matched population norms, CF patients associated pancreatic insufficiency known or treated diabetes

Interventions

Oral Glucose Tolerance Test DIAGNOSTIC_TEST

This is a two step process. Subjects will be asked to fast overnight,(no food and only water to drink for at least 8 hours). Then when subjects arrive for the visit,participants will have blood drawn and be asked to drink a sugary liquid. One hour later, another blood sample will be drawn and after two hours a final blood sample will be drawn.

Also known as: OGTT

SDS - without Diabetes diagnosis

Modified Oral Glucose Tolerance Test OTHER

The participant will be asked to fast overnight (no food and only water to drink for at least 8 hours). There will be no blood drawn during this test, participant will be asked to drink a sugary liquid and to remaining fasting (water only) for the two hour after finishing the drink.

Also known as: Modified OGTT

SDS - without Diabetes diagnosis

Modified Mixed Meal Tolerance Test OTHER

The participant will be asked to fast overnight (no food and only water to drink for at least 8 hours). The participant will be given a meal supplement to drink in place of breakfast, for example Boost Plus. The participant will be asked to drink the meal supplement and to remaining fasting (water only) for the next two hours.

Also known as: MMTT

SDS - without Diabetes diagnosis; SDS with Diabetes Diagnosis

Continuous Glucose Monitor DEVICE

The participant will be provided a CGM device to wear for 10 days during the study period. The CGM will be blinded (meaning that the participant will not be able to see the results).

Also known as: CGM

SDS - without Diabetes diagnosis; SDS with Diabetes Diagnosis

Food Diary OTHER

The participant will be asked to maintain a detailed food diary for 3 days during the 10 day study period.

SDS - without Diabetes diagnosis; SDS with Diabetes Diagnosis

Medical History Questionnaires OTHER

The participant will be asked to provide detailed medical history

SDS - without Diabetes diagnosis; SDS with Diabetes Diagnosis

Eligibility Criteria

• Age: 3 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Community Sample, SDS Registry

You may qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Shwachman Diamond Syndrome Foundation: collaborator
• Barnes-Jewish Hospital: collaborator

Study Sites (1)

Washington University

St Louis, Missouri, 63110, United States

Location

Related Publications (21)

• Finch AJ, Hilcenko C, Basse N, Drynan LF, Goyenechea B, Menne TF, Gonzalez Fernandez A, Simpson P, D'Santos CS, Arends MJ, Donadieu J, Bellanne-Chantelot C, Costanzo M, Boone C, McKenzie AN, Freund SM, Warren AJ. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011 May 1;25(9):917-29. doi: 10.1101/gad.623011.

  PMID: 21536732 BACKGROUND

• Menne TF, Goyenechea B, Sanchez-Puig N, Wong CC, Tonkin LM, Ancliff PJ, Brost RL, Costanzo M, Boone C, Warren AJ. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nat Genet. 2007 Apr;39(4):486-95. doi: 10.1038/ng1994. Epub 2007 Mar 11.

  PMID: 17353896 BACKGROUND

• Tourlakis ME, Zhong J, Gandhi R, Zhang S, Chen L, Durie PR, Rommens JM. Deficiency of Sbds in the mouse pancreas leads to features of Shwachman-Diamond syndrome, with loss of zymogen granules. Gastroenterology. 2012 Aug;143(2):481-92. doi: 10.1053/j.gastro.2012.04.012. Epub 2012 Apr 14.

  PMID: 22510201 BACKGROUND

• Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B; CFRD Guidelines Committee. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010 Dec;33(12):2697-708. doi: 10.2337/dc10-1768. No abstract available.

  PMID: 21115772 BACKGROUND

• Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O, Kerr E, Zeidler C, Shimamura A, Shah N, Cipolli M, Kuijpers T, Durie P, Rommens J, Siderius L, Liu JM. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci. 2011 Dec;1242:40-55. doi: 10.1111/j.1749-6632.2011.06349.x.

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• Myers KC, Rose SR, Rutter MM, Mehta PA, Khoury JC, Cole T, Harris RE. Endocrine evaluation of children with and without Shwachman-Bodian-Diamond syndrome gene mutations and Shwachman-Diamond syndrome. J Pediatr. 2013 Jun;162(6):1235-40, 1240.e1. doi: 10.1016/j.jpeds.2012.11.062. Epub 2013 Jan 8.

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• Diabetes Care. Introduction. Diabetes Care. 2010 Jan;33 Suppl 1(Suppl 1):S1-2. doi: 10.2337/dc10-S001. No abstract available.

  PMID: 20042770 BACKGROUND

• Jivani N, Torrado-Jule C, Vaiselbuh S, Romanos-Sirakis E. A unique case of Shwachman-Diamond syndrome presenting with congenital hypopituitarism. J Pediatr Endocrinol Metab. 2016 Nov 1;29(11):1325-1327. doi: 10.1515/jpem-2016-0299.

  PMID: 27754968 BACKGROUND

• Gana S, Sainati L, Frau MR, Monciotti C, Poli F, Cannioto Z, Comelli M, Danesino C, Minelli A. Shwachman-Diamond syndrome and type 1 diabetes mellitus: more than a chance association? Exp Clin Endocrinol Diabetes. 2011 Nov;119(10):610-2. doi: 10.1055/s-0031-1275699. Epub 2011 May 6.

  PMID: 21553366 BACKGROUND

• Akdogan MF, Altay M, Denizli N, Gucun M, Tanrikulu S, Duranay M. A rare case: Shwachman-Diamond syndrome presenting with diabetic ketoacidosis. Endocrine. 2011 Aug;40(1):146-7. doi: 10.1007/s12020-011-9460-7. No abstract available.

  PMID: 21448781 BACKGROUND

• Besser RE, Shields BM, Casas R, Hattersley AT, Ludvigsson J. Lessons from the mixed-meal tolerance test: use of 90-minute and fasting C-peptide in pediatric diabetes. Diabetes Care. 2013 Feb;36(2):195-201. doi: 10.2337/dc12-0836. Epub 2012 Oct 30.

  PMID: 23111058 BACKGROUND

• Al Hayek AA, Robert AA, Al Dawish MA. Evaluation of FreeStyle Libre Flash Glucose Monitoring System on Glycemic Control, Health-Related Quality of Life, and Fear of Hypoglycemia in Patients with Type 1 Diabetes. Clin Med Insights Endocrinol Diabetes. 2017 Dec 10;10:1179551417746957. doi: 10.1177/1179551417746957. eCollection 2017.

  PMID: 29270042 BACKGROUND

• Boudreau V, Lehoux Dubois C, Desjardins K, Mailhot M, Tremblay F, Rabasa-Lhoret R. Sensitivity and specificity of cystic fibrosis-related diabetes screening methods: which test should be the reference method? J Pediatr Endocrinol Metab. 2017 Aug 28;30(8):885-887. doi: 10.1515/jpem-2017-0122. No abstract available.

  PMID: 28742521 BACKGROUND

• Brugha R, Wright M, Nolan S, Bridges N, Carr SB. Quantifying fluctuation in glucose levels to identify early changes in glucose homeostasis in cystic fibrosis. J Cyst Fibros. 2018 Nov;17(6):791-797. doi: 10.1016/j.jcf.2017.12.004. Epub 2018 Jan 10.

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• Clemente Leon M, Bilbao Gasso L, Moreno-Galdo A, Campos Martorrell A, Gartner Tizzano S, Yeste Fernandez D, Carrascosa Lezcano A. Oral glucose tolerance test and continuous glucose monitoring to assess diabetes development in cystic fibrosis patients. Endocrinol Diabetes Nutr (Engl Ed). 2018 Jan;65(1):45-51. doi: 10.1016/j.endinu.2017.08.008. Epub 2017 Nov 12. English, Spanish.

  PMID: 29137964 BACKGROUND

• Deja G, Kleczek M, Chumiecki M, Strzala-Kleczek A, Deja R, Jarosz-Chobot P. The usefulness of the FlashStyle Libre system in glycemic control in children with type 1 diabetes during summer camp. Pediatr Endocrinol Diabetes Metab. 2018;24(1):11-19. doi: 10.18544/PEDM-24.01.0098.

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• Giani E, Macedoni M, Barilli A, Petitti A, Mameli C, Bosetti A, Cristiano A, Radovanovic D, Santus P, Zuccotti GV. Performance of the Flash Glucose Monitoring System during exercise in youth with Type 1 diabetes. Diabetes Res Clin Pract. 2018 Dec;146:321-329. doi: 10.1016/j.diabres.2018.10.001. Epub 2018 Oct 9.

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Related Links

• Shwachman-Diamond Syndrome Foundation
• Washington University Research Participant Registry
• Washington University- Understanding Clinical Trials

Biospecimen

Retention: SAMPLES WITH DNA

Optional whole blood, serum

MeSH Terms

Conditions

Shwachman-Diamond Syndrome; Exocrine Pancreatic Insufficiency

Interventions

Glucose Tolerance Test; Diet Records

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipomatosis

Intervention Hierarchy (Ancestors)

Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Endocrine; Investigative Techniques; Records; Organization and Administration; Health Services Administration

Study Officials

• Garry Tobin, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2020
• First Posted: February 19, 2020
• Study Start: January 10, 2020
• Primary Completion: December 30, 2022
• Study Completion: December 30, 2022
• Last Updated: August 19, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)