Switching From Insulin to Sulfonylurea in Diabetes Associated With Variants in MODY Genes (SUtoChildT1D)

January 21, 2020 updated by: Haukeland University Hospital

Switching From Insulin to Sulfonylurea in Childhood and Adult Diabetes Due to Variants in the HNF1A, HNF4A, or HNF1B Genes

The purpose of this study is to switch from insulin to oral sulfonylurea in patients with apparent type 1 diabetes or maturity onset diabetes in the young that are insulin treated. The molecular cause will be DNA variants in the HNF1A, HNF4A, or HNF1B genes that are of unknown significance (VUS, class 3) or known to be pathogenic (class 4 and 5).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Maturity onset diabetes in the young (MODY) is characterised by monogenic diabetes due to beta-cell dysfunction, with typical onset of diabetes before age of 25 years. There are 14 known forms of MODY, ranging from rather common to extremely rare.

About 1% of patients in the Norwegian Childhood Diabetes registry may have disease causing MODY mutations, according to a study recently published by the investigator's group and others.

MODY associated mutations in the transcription factors HNF1A, HNF4A, and HNF1B leads to activation of the potassium channel causing depolarisation of the beta-cell membrane, which is crucial for excretion of insulin. By treating patients with HNF1A-MODY, HNF4A-MODY, and HNF1B-MODY with sulfonylurea class of drugs, these channels will close, causing depolarisation of the beta-cell membrane, and release of insulin. Hence, these patients can often stop insulin treatment when they are treated with sulfonylurea class drugs.

Due to high throughput sequencing, a number of rare variants in these genes have been discovered. In many cases, bioinformatic tools are not sufficient to correctly classify these variants. In the present study, we intend to identify rare variants in the HNF1A, HNF4A, and HNF1B genes in patients with insulin dependent diabetes identified through the Norwegian Childhood Diabetes registry or the Norwegian MODY Registry with possibly disease causing HNF1A, HNF4A, or HNF1B mutations with sulfonylurea to see if they can reduce or even stop insulin treatment, and regulate their diabetes with sulfonylurea only. All variants will be investigated by bioinformatics tools as well as functional assays (tests for DNA-binding, transcriptional activation, nuclear localisation, protein expression). Primary endpoints are efficacy of sulfonylurea treatment measured by insulin requirement or not and level of HbA1c. Secondary endpoints are tolerance of sulfonylurea and effect on insulin secretion by oral and intravenous glucose tolerance tests. Bioinformatics and functional characterisation will be compared with success to reach primary endpoints.

Study Type

Interventional

Enrollment (Anticipated)

30

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Norway
      • Bergen, Norway, NO-5021
        • Department of Pediatrics and Adolescents, Haukeland University Hospital, and Department of Clinical Science, Faculty of Medicine, University of Bergen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

8 months to 93 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Diabetes and DNA sequence variant of unknown significance (VUS, class 3) or pathogenic (class 4, and 5) in the HNF1A, HNF4A, or HNF1B genes
  • On insulin treatment
  • Willing and able to provide informed consent (parents if younger than 16 years of age)

Exclusion Criteria:

  • Known anaphylactic response to sulfonylurea
  • Diabetes and DNA sequence variant in the HNF1A, HNF4A, or HNF1B genes that are known to be non-pathogenic (class 1-2)
  • Not willing or able to provide informed consent (parents if younger than 16 years of age)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Sulfonylurea treatment group
Increasing doses of sulfonylurea class of drug to see whether insulin treatment can be reduced in dose or stopped.
Drug: Sulfonylurea
Starting treatment with sulfonylurea class of drug
Other Names:
  • Glibenclamide
  • Glipizide
  • Glimerepiride

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect of sulfonylurea treatment on insulin requirement measured in units insulin per kg per day
Time Frame: 5 years
Effect of sulfonylurea treatment on insulin requirement measured in units insulin per kg bodyweight per day, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea
5 years
Metabolic control of diabetes measured by HbA1c in mmol/mol
Time Frame: 5 years
Metabolic control of diabetes measured by HbA1c in mmol/mol, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Level of sulfonylurea dose in mg per kg per day
Time Frame: 5 years
Level of sulfonylurea dose in mg per kg body weight per day, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea
5 years
Prevalence of side effects of sulfonylurea
Time Frame: 5 years
Recording potential side effects of sulfonylurea, such as nausea, change in body weight, episodes of severe hypoglycemia, discolouration of teeth, diarrhoea, cardiovascular events, recorded at intervals of 3-6 months after exposure to sulfonylurea compared to before initiation of sulfonylurea
5 years
Effect on endogenous insulin secretion assessed by intravenous glucose tolerance tests
Time Frame: 5 years
Maximum increment of serum insulin in nmol/L and serum c-peptide in pmol/L at intravenous glucose tolerance tests, recorded at intervals of 6-12 months after exposure to sulfonylurea compared to before initiation of sulfonylurea
5 years
Effect on secretion of incretin hormones, assessed by oral glucose tolerance tests
Time Frame: 5 years
Maximum increment of serum insulin in nmol/L, serum c-peptide in pmol/L and incretins (GIP in pmol/L and GLP-1 in pmol/L) at oral glucose tolerance tests and in comparison with intravenous gluclose tolerance tests, recorded at intervals of 6-12 months after exposure to sulfonylurea compared to before initiation of sulfonylurea
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Haukeland University Hospital

Investigators

  • Principal Investigator: Pål R. Njølstad, MD, PhD, Haukeland University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 18, 2017

Primary Completion (Anticipated)

April 1, 2022

Study Completion (Anticipated)

April 1, 2022

Study Registration Dates

First Submitted

January 2, 2020

First Submitted That Met QC Criteria

January 21, 2020

First Posted (Actual)

January 27, 2020

Study Record Updates

Last Update Posted (Actual)

January 27, 2020

Last Update Submitted That Met QC Criteria

January 21, 2020

Last Verified

January 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2018/2388

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

IPD that underlie the results in the planned publications. The IPD will be summary data, and with no personal identifiers.

IPD Sharing Time Frame

6 months after the planned publications are finally accepted for publication.

IPD Sharing Access Criteria

IPD will be shared after written request and consideration to the corresponding author of the respective publication. Data will be shared with researchers in the same or similar field only. IPD will include summary data without personal identity and Describe by what access criteria IPD and any additional supporting information will be shared, including with whom, for what types of analyses, and by what mechanism. The corresponding and first authors will review requests and criteria for reviewing requests may also be provided.

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)
  • Clinical Study Report (CSR)
  • Analytic Code

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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