Abstract and Introduction
Context: Participants with stage 1 or 2 type 1 diabetes (T1D) qualify for prevention trials, but factors involved in screening for such trials are largely unknown.
Objective: To identify factors associated with screening for T1D prevention trials.
Methods: This study included TrialNet Pathway to Prevention participants who were eligible for a prevention trial: oral insulin (TN-07, TN-20), teplizumab (TN-10), abatacept (TN-18), and oral hydroxychloroquine (TN-22). Univariate and multivariate logistic regression models were used to examine participant, site, and study factors at the time of prevention trial accrual.
Results: Screening rates for trials were: 50% for TN-07 (584 screened/1172 eligible), 9% for TN-10 (106/1249), 24% for TN-18 (313/1285), 17% for TN-20 (113/667), and 28% for TN-22 (371/1336). Younger age and male sex were associated with higher screening rates for prevention trials overall and for oral therapies. Participants with an offspring with T1D showed lower rates of screening for all trials and oral drug trials compared with participants with other first-degree relatives as probands. Site factors, including larger monitoring volume and US site vs international site, were associated with higher prevention trial screening rates.
Conclusions: Clear differences exist between participants who screen for prevention trials and those who do not screen and between the research sites involved in prevention trial screening. Participant age, sex, and relationship to proband are significantly associated with prevention trial screening in addition to key site factors. Identifying these factors can facilitate strategic recruitment planning to support rapid and successful enrollment into prevention trials.
The global incidence of type 1 diabetes is about 15 per 100 000 persons, with incidence increasing by 2% to 5% annually and prevalence trending upwards.[1–3] With prevalence in youth of 1.93 per 1000 in the United States, type 1 diabetes represents 1 of the most common chronic childhood diseases and generates profound medical costs.[2,4,5] The rise in disease incidence and prevalence brings concerns of future insulin availability, especially in underdeveloped and developing countries.[1–3] As such, there is a great need for research investigating the natural history of disease and potential therapies for treatment and prevention. Clinical research has reframed the disease as one that progresses sequentially through distinct stages and natural history studies have identified genetic predisposition, age at islet autoimmunity, and type of first islet autoantibody (Ab) as significant risk factors for development of type 1 diabetes.[1–3,6,7]
Evidence of disease can first be seen in stage 1, in which β-cell autoimmunity is characterized by presence of 2 or more islet Abs and normal glucose tolerance. Stage 2 occurs when a person with multiple Abs begins to have metabolic abnormalities (dysglycemia) but remains clinically asymptomatic. Stage 3 is considered the start of symptomatic disease, when a patient is diagnosed with clinical diabetes and insulin replacement therapy is usually initiated.[6,8] Identification of disease in the presymptomatic stages can reduce the rate of diabetic ketoacidosis at diagnosis and facilitate better long-term glycemic control.[9–11] Subsequently, early diagnosis of disease significantly improves long-term health outcomes, including better diabetes control (measured through hemoglobin A1c [HbA1c]), which is associated with decreased diabetes-related complications.[11,12]
Type 1 Diabetes TrialNet (TrialNet) is an international network whose mission is to prevent type 1 diabetes and stop disease progression. The TrialNet Pathway to Prevention study (PTP; ClinicalTrials.gov reg. no. NCT00097292) offers serial Ab testing for the development of islet autoimmunity and monitors disease progression with an oral glucose tolerance test (OGTT) and HbA1c.[13–16] Participants found to be in the presymptomatic stages of disease, and therefore at a higher risk of developing type 1 diabetes, are monitored for disease progression through the PTP study and offered clinical trial opportunities to prevent or delay the onset of type 1 diabetes.
Through TrialNet, the first positive clinical trial has been shown to delay the onset of type 1 diabetes. In this pivotal trial investigating anti-CD3 monoclonal antibody (teplizumab) treatment in the stage 2 population (TN-10 trial), the onset of disease was delayed by almost 3 years in those receiving active treatment.[17,18] Teplizumab was recently approved by the US Food and Drug Administration as the first drug to delay the onset of type 1 diabetes, and most of the supporting data came from this TN-10 trial. However, enrollment for the TN-10 trial spanned more than 6 years and less than 10% of those eligible screened for trial inclusion. Despite evidence supporting the benefits of delaying or preventing type 1 diabetes, studies investigating preventive therapies such as teplizumab face similar barriers to other clinical trials, with a small percent of eligible participants enrolling into trials.[11,12,19] By understanding the factors impeding prevention trial screening and enrollment, improvements can be made in study design, recruitment strategy, and research site support, which ultimately may expedite prevention trial advancement. The aim of the current study was to identify and define the potential factors influencing screening into 5 recent TrialNet prevention trials by analyzing participant and site-specific characteristics.
J Endo Soc. 2023;7(3) © 2023 Endocrine Society