The use of intermediate endpoints in the design of type 1 diabetes prevention trials
Open accessAbstract
Aims/hypothesis This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials.Methods Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression.Results Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint.Conclusions/interpretation The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.
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At stage 2 of type 1 diabetes, there is ~60% risk by 2 years and ~75% risk within 5 years of developing symptomatic type 1 diabetes.
“At stage 2 of the disease, there is 60% risk by 2 years and 75% risk within 5 years of developing symptomatic type 1 diabetes (57,58).”
From 2. Diagnosis and Classification of Diabetes: <i>Standards of Care in Diabetes—2024</i> (2024) · cites this paper as [58]
The Results (page unavailable) report a 74% risk of type 1 diabetes four years after confirmed dysglycaemia, supporting the general point that risk is high after this intermediate stage. They do not report a 60% risk of symptomatic diabetes at two years or a 75% risk at five years; for participants who reached confirmed dysglycaemia within two years, the reported proportion diagnosed by year five is 96%. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAt stage 2 of type 1 diabetes, there is 60% risk by 2 years and 75% risk within 5 years of developing a clinical diagnosis of type 1 diabetes.
“At stage 2 of the disease, there is 60% risk by 2 years and 75% risk within 5 years of developing a clinical diagnosis of type 1 diabetes (55,56).”
From 2. Diagnosis and classification of diabetes: standards of care in diabetes-2025 (2025) · cites this paper as [56]
The Results report a 74% risk of type 1 diabetes four years after confirmed dysglycaemia, close to the claimed 75% but at a different time point. They do not report a 60% risk of clinical diagnosis at two years; the two-year figure for this group is a 41% risk of progressing from normal glucose tolerance to dysglycaemia. No page number is available in our copy. (LLM, conf=0.83)
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- Authors
- the Type 1 Diabetes TrialNet Study Group, & Krischer, J. P.
- Affiliations
- University of South Florida (US)
- Corresponding author
- Krischer, Jeffrey P.
- Venue
- Diabetologia
- Published
- 2013-06-07
- Volume
- 56
- Issue
- 9
- Pages
- 1919-1924
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC3743228
- OpenAlex
- W2151627127
- Cited by
- 64
- References
- 12
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 3 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 2 · 2013: 1
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000093, 5ul1rr031986-02, UL1TR001108, UL1TR001085, UL1TR000005)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK-084565, U01DK061040, U01DK085461, U01DK085505, U01DK085499, U01DK061055, U01DK061036, U01DK061010, U01DK061058, U01DK061034, U01DK061042, HHSN267200800019C, U01DK085463, U01DK085453, UC4DK117009, U01DK061041, U01DK085466, UC4DK097835, U01DK085509, U01 DK-061016)
- U.S. National Library of Medicine (HHSN267200800019C)
- National Center for Research Resources (UL1RR029890, UL1RR024131, M01RR000400, UL1-RR031986, UL1RR025744, UL1RR024153, UL1RR024982, UL1RR025761, M01-RR00400, UL1RR024975, UL1RR024139, UL1RR025780)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- type 1 diabetes prevention, intermediate endpoints, disease progression, autoantibodies, HbA1c, C-peptide, oral glucose tolerance test, sample size determination
- MeSH terms
- Adolescent, Adult, Autoantibodies, Blood Glucose, C-Peptide, Child, Child, Preschool, Diabetes Mellitus, Type 1, Female, Glucose Tolerance Test, Glycated Hemoglobin, Humans, Infant, Male, Middle Aged, Young Adult
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