LEARNING OBJECTIVES
After completing Module 10, the learner should be able to:
1. Recognize the pivotal role of clinical trials in contributing data to inform current and future approaches to intervene
in the early stages of T1D.
2. Name a resource for learning about ongoing clinical trials in the US.
Clinical Trials
10 |
Module Authors: Andrea Steck, Hali Broncucia, Kimberly Bautista, Kimber Simmons
Clinical trials are fundamental in developing strategies for prevention of T1D. By actively engaging in clinical trials, researchers and participants contribute invaluable data that can shape future preventive measures and enhance the ability to intervene in the early stages of diabetes. Clinical trials can explore innovative interventions, determine which patients are most likely to benefit, assess potential risk factors and serve as critical pathways toward the development of effective strategies to halt or delay the onset
of this autoimmune condition. Future clinical trials may also be important to discover whether various interventions are beneficial in combination or in sequence in both early-stage T1D and newly-diagnosed stage 3 T1D.
FIGURE 1 Prevention Therapies in Individuals at Risk for T1D. Adapted from Felton JL et al. Communications Medicine (1)
Previous Clinical Trials
Several immunotherapies have shown benefit in preserving beta cell function (insulin production) in patients with newly diagnosed Stage 3 T1D.(2) These promising research trials include the Janssen-sponsored golimumab (T1GER study)(3), the Sanofi-sponsored teplizumab (PROTECT) study(4), the T1D TrialNet-sponsored rituximab (5), abatacept (6) and low-dose antithymocyte globulin (ATG) (7)trials, the Immune Tolerance Network (ITN)-sponsored teplizumab (8-9) and alefacept trials (10-11), and the JDRF-funded verapamil (CLVer) (12) and baricitinib (BANDIT)(13) studies.
In addition to trials in Stage 3 T1D, there have been several primary and secondary prevention studies in individuals at risk for developing clinical T1D (See Figure 1).(1) A TrialNet-sponsored randomized double-blinded placebo-controlled phase 2 efficacy trial in subjects at Stage 2 T1D demonstrated teplizumab delayed the onset of clinical T1D by nearly 3 years compared to placebo.(14-15) These results led to the first FDA-approved immunotherapy, teplizumab-mzwv (an anti-CD3 monoclonal antibody), in November 2022 to delay the onset of clinical T1D causing a paradigm shift for preventing and treating T1D (see Module 9).
The Diabetes Prevention Trial (DPT-1) trials testing parenteral insulin in relatives with >50% projected 5-year risk of T1D and oral insulin in relatives with a projected 5-year risk of T1D of 26–50% did not delay or prevent Stage 3 T1D.(16-17) Furthermore, the TrialNet led prevention trials at Stage 1 T1D (oral insulin, abatacept and hydroxychloroquine) did not have a positive impact on time to either Stage 2 or Stage 3 T1D.(18-20)
Current data does not support the use of any supplements to prevent or delay the onset of clinical T1D. Primary dietary modifications trials to delay or prevent clinical T1D have failed to show efficacy so far, including the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) evaluating the role of a hydrolyzed casein-based formula compared to cow’s milk-based formula and the BABYDIET intervention study looking at a gluten-free diet in the first year of life.(21-22) Randomized controlled trials (RCTs) to prevent or delay the onset of Stage 3 T1D include the TrialNet Nutritional Intervention (NIP) to Prevent T1D study with docosahexaenoic acid (DHA)(23) and the Immune-tolerance with Alum-GAD (Diamyd) and Vitamin D3 to Children with multiple IA (DiAPREV-IT2) trial (www.clinicaltrials.gov), which did not show efficacy.
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Current Trials
Many prevention trials to prevent or delay the onset of Stage 3 T1D are led in the US by the TrialNet Clinical Research Network (see https://www.trialnet.org/ and www.clinicaltrials.gov) and in Europe
by INNODIA. (For details on one current trial enrolling individuals at Stage 2 T1D, see Figure 2).
TrialNet ATG Prevention Study
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TrialNet is testing a low dose of the immunotherapy drug anti-thymocyte globulin (ATG) in people with high risk of developing stage 3 T1D within the next two years to see if the treatment can delay or prevent progression to clinical diabetes.
Inclusion Criteria:
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Ages 12 to 35 years
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50% risk of developing stage 3 T1D within 2 years:
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2 or more islet autoantibodies
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Blood glucose meeting Stage 2 T1D criteria
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Additional high-risk marker​
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Locations:
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US and International TrialNet centers
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Travel assistance may be available
FIGURE 2 Enrollment Criteria for a Current TrialNet Study
There are several ongoing randomized controlled trials (RCTs) with probiotics in participants at risk for developing T1D, such as the Prevention of Autoimmunity with Lactobacilli (PAL) and the Supplementation with B. Infantis for Mitigation of T1D Autoimmunity (SINT1A) trials (www.clinicaltrials.gov).
In summary, individuals who test positive for islet autoantibodies should be provided with information on clinical preventative therapies. This includes being referred to the TrialNet Clinical Research Network, where they can explore opportunities to participate in clinical trials focused on preventing the development of clinical (Stage 3) T1D.
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Links
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REFERENCES
1. Felton JL, Griffin KJ, Oram RA, et al. Disease-modifying therapies and features
linked to treatment response in type 1 diabetes prevention: a systematic
review. Commun Med (Lond). 2023;3(1):130.
2. Jacobsen LM, Bundy BN, Greco MN, et al. Comparing Beta Cell
Preservation Across Clinical Trials in Recent-Onset Type 1 Diabetes.
Diabetes Technol Ther 2020;22(12):948–53.
3. Quattrin T, Haller MJ, Steck AK, et al. Golimumab and beta-cell function in
youth with new-onset type 1 diabetes. N Engl J Med 2020;383(21):2007–17.
4. Ramos EL, Dayan CM, Chatenoud L, et al. Teplizumab and β-Cell Function in
Newly Diagnosed Type 1 Diabetes. N Engl J Med 2023;389:2151-2161.
5. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Rituximab, B-
lymphocyte depletion, and preservation of beta-cell function. N Engl J Med
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6. Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with
abatacept in patients with recent-onset type 1 diabetes: a randomised,
double-blind, placebo-controlled trial. Lancet Lond Engl
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7. Haller MJ, Schatz DA, Skyler JS, et al. Low-Dose Anti-Thymocyte Globulin
(ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1
Diabetes. Diabetes Care 2018;41(9):1917–25.
8. Perdigoto AL, Preston-Hurlburt P, Clark P, et al. Treatment of type 1 diabetes
with teplizumab: clinical and immunological follow-up after 7 years from
diagnosis. Diabetologia 2019;62(4):655–64.
9. Herold KC, Gitelman SE, Willi SM, et al. Teplizumab treatment may improve
C-peptide responses in participants with type 1 diabetes after the new-
onset period: a randomised controlled trial. Diabetologia 2013;56(2):391–400.
10.Rigby MR, Harris KM, Pinckney A, et al. Alefacept provides sustained clinical
and immunological effects in new-onset type 1 diabetes patients. J Clin
Invest 2015;125(8):3285–96.
11.Rigby MR, DiMeglio LA, Rendell MS, et al. Targeting of memory T cells with
alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a
randomised, double-blind, placebo-controlled phase 2 trial. Lancet
Diabetes Endocrinol 2013;1(4):284–94.
12.Forlenza GP, McVean J, Beck RW, et al. Effect of Verapamil on Pancreatic Beta
Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized
Clinical Trial. JAMA. 2023;329(12):990-999.
13.Waibel M, Wentworth JM, So M, et al. Baricitinib and β-Cell Function in Patients
with New-Onset Type 1 Diabetes. N Engl J Med. 2023;389(23):2140-2150.
14.Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in
Relatives at Risk for Type 1 Diabetes. N Engl J Med 2019;381:603-613.
15.Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta
cell function in antibody-positive high-risk individuals. Sci Transl Med
2021;13(583).
16.Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of
patients with type 1 diabetes: The Diabetes Prevention Trial—Type 1. Diabetes
Care 2005;28:1068–76.
17.Diabetes Prevention Trial—Type 1 Diabetes Study Group. Effects of insulinin
relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;
346(22):1685–91.
18.Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group,
Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ. Effect of Oral
Insulin on Prevention of Diabetes in Relatives of Patients With Type 1
Diabetes: A Randomized Clinical Trial. JAMA 2017;318(19):1891–902.
19.Russell WE, Bundy BN, Anderson MS, et al. Abatacept for Delay of Type 1
Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-
Masked, Controlled Trial. Diabetes Care 2023;dc222200.
20.Libman I, Bingley PJ, Becker D, et al. Hydroxychloroquine in Stage 1 Type 1
Diabetes. Diabetes Care 2023;46(11):2035–43.
21.Writing Group for the TRIGR Study Group, Knip M, Åkerblom HK, et al. Effect
of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1
Diabetes: The TRIGR Randomized Clinical Trial. JAMA 2018;319(1):38–48.
22.Hummel S, Pfluger M, Hummel M, Bonifacio E, Ziegler AG. Primary dietary
intervention study to reduce the risk of islet autoimmunity in children at
increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care
2011;34(6):1301–5.
23.Chase HP, Boulware D, Rodriguez H, et al. Effect of docosahexaenoic acid
supplementation on inflammatory cytokine levels in infants at high genetic
risk for type 1 diabetes. Pediatr Diabetes 2015;16(4):271–9.
This program was developed independently
by the Barbara Davis Center for Diabetes and supported in part by a grant from Sanofi US.
Version 2.0_6.2024