Clinical trial NCT04239586: Switching From Insulin to Sulfonylurea in Diabetes Associated With Variants in MODY Genes
Official title: Switching From Insulin to Sulfonylurea in Childhood and Adult Diabetes Due to Variants in the HNF1A, HNF4A, or HNF1B Genes
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Maturity-Onset Diabetes of the Young, Type 3
Maturity Onset Diabetes of the Young, Type 1
Childhood Diabetes Mellitus
Insulin-dependent Diabetes Mellitus
Keywords: Maturity onset diabetes in the young
Childhood diabetes
Type 1 diabetes
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
First posted: 2020-01-27
Enrollment: 30
Sex: ALL
Minimum age (years): 2
Maximum age (years): 95
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Switching insulin-treated diabetes patients with possibly disease causing mutations in HNF1A, HNF4A, or HNF1B to treatment with sulfonylurea.
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Effect of sulfonylurea treatment on insulin requirement measured in units insulin per kg per day
timeFrame: 5 years
measure: Metabolic control of diabetes measured by HbA1c in mmol/mol
timeFrame: 5 years
Secondary outcomes:
measure: Level of sulfonylurea dose in mg per kg per day
timeFrame: 5 years
measure: Prevalence of side effects of sulfonylurea
timeFrame: 5 years
measure: Effect on endogenous insulin secretion assessed by intravenous glucose tolerance tests
timeFrame: 5 years
measure: Effect on secretion of incretin hormones, assessed by oral glucose tolerance tests
timeFrame: 5 years
Other outcomes:
Locations:
city: Bergen
country: Norway
facility: Department of Pediatrics and Adolescents, Haukeland University Hospital, and Department of Clinical Science, Faculty of Medicine, University of Bergen
Study officials:
affiliation: Haukeland University Hospital
name: Pål R. Njølstad, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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