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The use of intermediate endpoints in the design of type 1 diabetes prevention trials

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This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials.


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.


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.


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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Jeffrey P. Krischer is the guarantor of this work, had full access to all the data and takes full responsibility for the integrity of data and the accuracy of data analysis.


The sponsor of the Natural History Study is the Type 1 Diabetes TrialNet Study Group. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded: (1) by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases; and (2) by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The above funding was through the cooperative agreements U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505 and U01 DK085509, and through contract HHSN267200800019C. The National Center for Advancing Translational Sciences also provided funding through Clinical Translational Science Awards UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890 and UL1 RR031986, and through the General Clinical Research Center Award M01 RR00400. Other funding came from JDRF and the ADA. The contents of this Article are solely the responsibility of the author and do not necessarily represent the official views of the NIH, JDRF or ADA.

Duality of interest

JPK is Director of the TrialNet Coordinating Center, which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. Otherwise, the authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

JPK researched the data, contributed to the discussion, and wrote, reviewed and edited the manuscript.

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Correspondence to Jeffrey P. Krischer.

Additional information

Details of the Type 1 Diabetes TrialNet Study Group (co-authors) are provided in the electronic supplementary material (ESM) Appendix.

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Krischer, J.P., the Type 1 Diabetes TrialNet Study Group. The use of intermediate endpoints in the design of type 1 diabetes prevention trials. Diabetologia 56, 1919–1924 (2013).

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