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Type 1 diabetes — clinical trials landscape

TL;DR — T1D trials now span stage-1/2 prevention, new-onset immune preservation, glucose automation, hypoglycemia rescue, and renewable cell replacement. A registry entry proves a protocol exists, not efficacy; status can change and must be date-stamped. Teplizumab is the sole stage-2 program here with randomized delay evidence (HR 0.41, 95% CI 0.22–0.78), while zimislecel has early uncontrolled insulin-independence evidence and has entered phase 3 (Herold 2019, PMID 31180194; Reichman 2025, PMID 40544428; NCT01030861; NCT04786262). Combination trials reflect the field’s move from single transient perturbations toward sequenced immune and β-cell-directed therapy.

Selected registry-verified portfolio

ClinicalTrials.gov records below were re-fetched live on 2026-10-29. NCT05901831 and NCT06305286 were first added on that date; the other 17 records were already in this portfolio.

NCT Program Stage Phase/status at query Evidence boundary
NCT01030861 Teplizumab TN-10 Stage 2 Phase 2; completed Published delay RCT
NCT03875729 Teplizumab PROTECT New onset Phase 3; completed Published C-peptide benefit
NCT05757713 Teplizumab pediatric stage 2 Stage 2 Phase 4; completed Completed 2026-08-28; no posted results
NCT03929601 Rituximab + abatacept New onset Phase 2; active, not recruiting Sequence vs rituximab alone
NCT06455319 Precision ATG ± verapamil New onset Phase 2; recruiting Immune + β-cell protection
NCT07216391 Teplizumab vs ATG platform Stage 2 Phase 2; recruiting Comparative prevention; no posted results
NCT01773707 Abatacept prevention Stage 1 Phase 2; completed Published negative primary endpoint
NCT00279305 Rituximab New onset Phase 2; completed Published C-peptide signal
NCT00505375 Abatacept New onset Phase 2; completed Published transient C-peptide preservation
NCT02215200 ATG-GCSF New onset Phase 2; completed Published component findings
NCT04786262 Zimislecel/VX-880 and VX-017 master protocol Established severe T1D Phase 3; recruiting Early phase 1–2 report
NCT06832410 Zimislecel after kidney transplant Established T1D Phase 3; recruiting Distinct risk-benefit population
NCT05791201 Encapsulated VX-264 Established T1D Phase 1/2; active, not recruiting No efficacy conclusion
NCT06239636 Gene-edited hypoimmune primary islets Established T1D Early phase 1; recruiting Two-participant safety study; sponsor status last verified 2024-12
NCT02940873 HARPdoc Problematic hypoglycemia Completed Published education RCT
NCT02536950 Insulin-only bionic pancreas Established T1D Completed Technology development
NCT07880769 Verapamil VIP-1 Stage 1 Phase 2/3; not yet recruiting Registered 2026-10-19; primary outcome is a 48-week beta-cell function index, not time to stage 3; no results
NCT05901831 Finerenone FINE-ONE Established T1D with CKD Phase 3; completed Results first posted 2026-10-27; published 6-month UACR endpoint, not a kidney-outcome trial
NCT06305286 Tegoprubart (anti-CD40L) islet transplant Established T1D, problematic hypoglycemia Phase 1/2; active, not recruiting Estimated 70; calcineurin-inhibitor-free regimen; no posted results and no peer-reviewed human efficacy report found in PubMed on 2026-10-29

Prevention and preservation

Teplizumab TN-10 randomized 76 relatives and delayed median diagnosis by about two years (Herold 2019, PMID 31180194). Stage-1 abatacept did not significantly reduce progression to dysglycemia/stage 3 (HR 0.702, 95% CI 0.452–1.09), despite immune and C-peptide effects (Russell 2023, PMID 36920087).

Oral insulin failed its primary prevention stratum, illustrating the difference between plausible antigen-specific tolerance and demonstrated clinical delay (TrialNet Oral Insulin Study Group 2017, PMID 29164254).

Failure pattern Example Trial-design lesson
Primary endpoint negative Oral insulin, stage-1 abatacept Do not promote subgroup/biomarker results to efficacy
Surrogate positive, clinical endpoints neutral PROTECT secondary outcomes Extend follow-up and power patient outcomes
Effect wanes Immune-cell reconstitution after rituximab Test sequence/repeat strategies
Added agent fails to add ATG + GCSF Combinations need factorial/attribution logic
Selected population Relative-based prevention Validate general-population screen-detected cohorts

Replacement pipeline

Donor-islet transplantation achieved the composite endpoint in 87.5% at one year among 48 selected adults but required immunosuppression (Hering 2016, PMID 27208344). Zimislecel generated C-peptide in all 14 early recipients and insulin independence in 10/12 full-dose recipients at one year, with neutropenia and deaths requiring careful longer follow-up (Reichman 2025, PMID 40544428).

The pivotal distinction is exposed versus protected cells. Zimislecel uses systemic immunosuppression; VX-264 tests a device intended to shield cells. Neither phase/status nor corporate nomenclature substitutes for peer-reviewed outcomes.

Technology trials

Technology studies often use TIR, HbA1c, and time below range over weeks to months. iDCL’s 11-point TIR gain is clinically interpretable, but system-specific performance, onboarding support, and rapidly changing comparators limit cross-era comparison (Brown 2019, PMID 31618560).

Pediatric meta-analysis and network meta-analysis aggregate different algorithms and comparators; heterogeneity should be preserved rather than presenting a class effect as device interchangeability (Zeng 2023, PMID 38011519; Di Molfetta 2024, PMID 39298688).

Trial endpoints by domain

Domain Preferred endpoints Required safety outcomes
Prevention Time to stage 3; stage progression Infection, cytokine effects, psychosocial burden
New onset Stimulated C-peptide AUC Severe events, immune toxicity
AID TIR, HbA1c, time <54 Severe hypoglycemia, DKA, device events
Hypoglycemia rescue Recovery time/treatment success Rebound, nausea, failure to administer
Cell replacement Severe-event freedom + HbA1c, insulin independence Death, infection, renal function, graft/procedure toxicity

Why trials succeed or fail

  • T1D is heterogeneous in age, tempo, immune phenotype, and residual function.
  • Stage-1/2 trials require long surveillance and tolerate less toxicity.
  • New-onset C-peptide decline creates a limited intervention window.
  • Background CGM/AID reduces event rates and changes comparators.
  • Small replacement cohorts can show function but not characterize rare harms.
  • Registries can be outdated; publications and regulatory data must be reconciled.
  • Commercial endpoints and mechanistic endpoints may answer different questions.

Effect sizes across trial domains

Trial/domain Sample Primary quantitative result Interpretation
TN-10 stage-2 teplizumab 76 HR 0.41 (95% CI 0.22–0.78); median 48.4 vs 24.4 months Positive progression trial
Oral insulin primary stratum 389 HR 0.87; P=0.21 Negative; secondary stratum exploratory
Stage-1 abatacept 212 HR 0.702 (0.452–1.09) Negative primary progression endpoint
New-onset low-dose ATG 89 C-peptide 0.646 vs 0.406 nmol/L at one year Positive preservation; GCSF non-additive
Pediatric verapamil 88 AUC difference 0.14 pmol/mL (0.01–0.27) Partial β-cell preservation
Tight AID at diagnosis 113 C-peptide difference −0.01 (−0.11 to 0.10) TIR improved, preservation absent
TRIMECO islets 47 treated as allocated β-score ≥6: 64% (43–82) vs 0% (0–15) Metabolic efficacy with renal/procedure harm
Young-child closed loop 102 TIR +12.4 points (9.5–15.3) Strong surrogate efficacy; rare-event uncertainty

These estimates should not be ranked as if they answer one question. Prevention trials estimate time-to-diagnosis, preservation trials estimate stimulated secretion, technology trials estimate glucose exposure, and replacement trials combine graft function with severe-event outcomes.

Registry status versus published evidence

Registry state on 2026-10-22 What can be concluded What cannot
Completed Enrollment/intervention ended per sponsor record Results are positive or peer reviewed
Recruiting Site recruitment is reported open Recruitment is global, rapid, or ultimately successful
Active, not recruiting Follow-up or analysis continues Product remains clinically available
Not yet recruiting Protocol is registered Enrollment date or feasibility is assured

The 2026-10-15 query found NCT04786262, NCT06239636, NCT06455319, NCT06832410 and NCT07216391 recruiting; NCT03929601 and NCT05791201 active but not recruiting; and the other records then in the table completed. NCT05757713 had changed to completed and NCT07216391 to recruiting relative to the August sweep. Neither has posted results. NCT06239636's sponsor verification date remains 2024-12 despite a recruiting label, illustrating why status is a dated administrative observation rather than an efficacy or operational-performance signal.

Five of those records had last-update posting dates between 2026-08-28 and 2026-10-15: NCT03929601 and NCT04786262 (September 1), NCT07216391 (September 9), and NCT05757713 (September 29), plus NCT05791201 (October 9). None of these five updated records contains a posted results section. Six other tracked records have older posted results; without a prior results snapshot, per-outcome historical changes cannot be reconstructed from this sweep alone.

The 2026-10-22 re-fetch left those 16 records unchanged in overall status, last-update post date, posted-results flag, and sponsor verification date. NCT05757713 and NCT07216391 still have no posted results. NCT06239636 remains recruiting with verification dated 2024-12, while its estimated completion date of 2025-06 has passed. A newly posted record, NCT07880769 (VIP-1; Assistance Publique – Hôpitaux de Paris), is not yet recruiting. It plans to randomize an estimated 50 people aged 7–45 years with stage 1 type 1 diabetes, weighing at least 30 kg, to extended-release verapamil or placebo for up to 48 weeks. The primary outcome is a beta-cell function index at 48 weeks. The registration shows no results and does not establish that verapamil delays stage 3. ClinicalTrials.gov lists secondary identifier 2025-524318-27-00 as an EU CT number. The CTIS page for that number returned an application shell rather than a readable trial record, so that European identifier is cited only as it appears on ClinicalTrials.gov.

The 2026-10-29 re-fetch left the 17 previously tracked records unchanged in overall status, posted-results flag and sponsor verification date. NCT07880769's last-update date moved from 2026-10-19 to 2026-10-22 with no change in status (not yet recruiting) or in its registered estimated start date of 2027-01. NCT05757713 and NCT07216391 still have no posted results. NCT06239636 remains recruiting with verification dated 2024-12. Two records were added. The first is NCT05901831 (FINE-ONE; Bayer), which completed in 2025-09 with 242 enrolled and posted results on 2026-10-27; its published primary result is summarized on the complications page (Heerspink 2026, PMID 41780000). The second is NCT06305286 (University of Chicago), which tests islet transplantation under tegoprubart-based, calcineurin-inhibitor-free immunosuppression. Its primary outcomes include insulin independence and graft failure, with estimated completion in 2029-03. A patient-organization news page retrieved on 2026-10-29 relays conference-presented reports of insulin independence in tegoprubart-treated islet recipients. It does not cite an NCT number, so those reports could not be matched to this registration (Breakthrough T1D UK — "News", https://breakthrought1d.org.uk/news/, accessed 2026-10-29). PubMed had no peer-reviewed human efficacy report for tegoprubart in islet transplantation on 2026-10-29. The only tegoprubart islet data found came from nonhuman primates (Anwar 2023, PMID 37647390). The insulin-independence reports are therefore not treated as evidence here.

Primary-endpoint discipline

Oral insulin failed its prespecified primary stratum (58/203 vs 62/186 diagnoses; HR 0.87, P=0.21), although a 55-person secondary stratum yielded HR 0.45 (Krischer 2017, PMID 29164254). Stage-1 abatacept likewise missed progression significance even though later modeling identified a high-secretor subgroup with HR 0.46 (Galderisi 2026, PMID 41237315). Both examples require prospective confirmation of subgroup hypotheses.

Low-dose ATG shows why factorial attribution matters: ATG alone preserved C-peptide at one and two years, but adding GCSF did not meet the prespecified C-peptide criterion (Haller 2018, PMID 30012675; Haller 2019, PMID 30967424). A combination arm does not prove synergy merely because both agents are biologically plausible.

Comparator drift

The comparator for severe unstable T1D has changed. TRIMECO showed islet efficacy versus intensive insulin therapy, but contemporary real-world AID synthesis estimates TIR +11.61 points (95% CI 10.47–12.76) and HbA1c −0.42% (−0.47 to −0.37) versus prior therapy (Lablanche 2018, PMID 29776895; Yang 2024, PMID 38888056). Replacement programs should therefore measure incremental severe-event freedom, burden, renal harm, and durability against optimized AID.

CGM itself has changed control arms. Across 22 trials, CGM versus SMBG reduced HbA1c −0.23% (95% CI −0.35 to −0.10), with larger benefit at baseline HbA1c >8%, while severe hypoglycemia and DKA remained too rare for firm conclusions (Teo 2022, PMID 35141761).

Trial representativeness

Selection Efficiency gained Generalizability lost
Relatives with multiple antibodies Higher stage-3 event rate Most population cases lack family history
Recent-onset residual C-peptide Detectable preservation window Excludes later presenters and rapid loss
Severe hypoglycemia despite expert care Larger replacement benefit Not routine T1D population
High baseline HbA1c Larger technology signal Smaller incremental effect in well-controlled users
Technology-capable trial sites Reliable data and support Underrepresents supply, literacy, and connectivity barriers

Response heterogeneity can be biological or operational. A routine-measure Beta2 score predicted immunotherapy response with AUC 0.765 in validation datasets, but this remains an adaptive-design tool until prospectively validated (So 2025, PMID 40424079). For AID, qualitative evidence documents meal, exercise, trust, alarm, and supply burdens that TIR alone does not capture (Garza 2025, PMID 39212346).

Minimum endpoint sets

Domain Efficacy core Patient-experienced core Long-term safety core
Stage 1/2 Stage-free survival; metabolic trajectory Anxiety, monitoring burden, days without insulin Infection, malignancy, immune sequelae
New onset Standardized stimulated C-peptide Insulin dose, TIR, severe events, burden Immune toxicity and off-treatment durability
AID TIR, HbA1c, time <54 Sleep, alarms, discontinuation, trust DKA, severe hypoglycemia, device failures
Replacement Graft function and insulin independence Severe-event freedom and treatment burden Death, renal function, infection, neoplasm, sensitization

Cell-replacement trials especially need denominators that distinguish all enrolled, transplanted, full-dose, evaluable, and insulin-independent participants. Early function in every recipient can coexist with incomplete full-dose follow-up and serious adverse events (Reichman 2025, PMID 40544428).

Open questions

  • What adaptive platform design can compare sequences while preserving interpretable safety? (NCT07216391)
  • Which biomarker should enrich stage-2 trials without excluding slow progressors who benefit? (Weiss 2022, PMID 36028774)
  • What minimum follow-up establishes durable cell-replacement net benefit? (Reichman 2025, PMID 40544428)
  • How should AID trials measure burden, discontinuation, and access alongside TIR? (Canha 2025, PMID 39726162)

References

  1. Hering BJ, et al. Phase 3 Trial of Human Islets. Diabetes Care. 2016;39:1230-1240. PMID 27208344
  2. TrialNet Oral Insulin Study Group. Oral Insulin Prevention Trial. JAMA. 2017;318:1891-1902. PMID 29164254
  3. Herold KC, et al. Teplizumab in Relatives at Risk. N Engl J Med. 2019;381:603-613. PMID 31180194
  4. Brown SA, et al. Six-Month Closed-Loop Trial. N Engl J Med. 2019;381:1707-1717. PMID 31618560
  5. Russell WE, et al. Abatacept for Stage-1 Progression. Diabetes Care. 2023;46:1005-1013. PMID 36920087
  6. Zeng B, et al. AID in Children and Adolescents. Diabetes Care. 2023. PMID 38011519
  7. Di Molfetta S, et al. Hybrid Closed Loop Network Meta-analysis. Diabetes Metab Res Rev. 2024. PMID 39298688
  8. Reichman TW, et al. Stem Cell-Derived Fully Differentiated Islets. N Engl J Med. 2025;393:858-868. PMID 40544428
  9. Weiss A, et al. Progression likelihood score. Diabetologia. 2022;65:2121-2131. PMID 36028774
  10. Canha D, et al. AID and diabetes distress. Diabet Med. 2025. PMID 39726162
  11. Haller MJ, et al. Low-Dose ATG Preserves β-Cell Function and Improves HbA1c. Diabetes Care. 2018;41:1917-1925. PMID 30012675
  12. Haller MJ, et al. Low-Dose ATG: Two-Year Clinical Trial Data. Diabetes. 2019;68:1267-1276. PMID 30967424
  13. Forlenza GP, et al. Effect of Verapamil on Pancreatic Beta Cell Function. JAMA. 2023;329:990-999. PMID 36826844
  14. McVean J, et al. Tight Glycemic Control and Pancreatic Beta Cell Function. JAMA. 2023;329:980-989. PMID 36826834
  15. Lablanche S, et al. Islet transplantation versus insulin therapy: TRIMECO. Lancet Diabetes Endocrinol. 2018;6:527-537. PMID 29776895
  16. Wadwa RP, et al. Trial of Hybrid Closed-Loop Control in Young Children. N Engl J Med. 2023;388:991-1001. PMID 36920756
  17. Galderisi A, et al. Baseline Insulin Secretion Determines Response to Abatacept. Diabetes. 2026;75:229-240. PMID 41237315
  18. Yang Q, et al. Real-world glycaemic outcomes of automated insulin delivery. Diabetes Obes Metab. 2024;26:3753-3763. PMID 38888056
  19. Teo E, et al. Effectiveness of continuous glucose monitoring in type 1 diabetes. Diabetologia. 2022;65:604-619. PMID 35141761
  20. So M, et al. β-Cell Function Derived From Routine Measures Predicts Immunotherapy Response. Diabetes Care. 2025;48:1370-1376. PMID 40424079
  21. Garza KP, et al. Adult's Lived Experience Using the Insulin-Only Bionic Pancreas. J Diabetes Sci Technol. 2025;19:11-17. PMID 39212346
  22. Barton FB, et al. Improvement in outcomes of clinical islet transplantation. Diabetes Care. 2012;35:1436-1445. PMID 22723582
  23. Vantyghem MC, et al. Ten-Year Outcome of Islet Transplantation. Diabetes Care. 2019;42:2042-2049. PMID 31615852
  24. Perdigoto AL, et al. Teplizumab follow-up after 7 years. Diabetologia. 2019;62:655-664. PMID 30569273
  25. Gubitosi-Klug RA, et al. Residual β cell function in long-term type 1 diabetes. J Clin Invest. 2021;131. PMID 33529168
  26. Heerspink HJL, et al. Finerenone in Type 1 Diabetes and Chronic Kidney Disease. N Engl J Med. 2026;394:947-957. PMID 41780000
  27. Anwar IJ, et al. The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates. Sci Transl Med. 2023;15:eadf6376. PMID 37647390