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Phase 2CompletedNCT03345004

DIAGNODE-2: Intralymphatic GAD-alum (Diamyd) in recent-onset type 1 diabetes

What this study tests

A Phase 2b trial that injected the diabetes autoantigen GAD65 (Diamyd) directly into lymph nodes to try to halt the immune attack on insulin-producing cells. It missed its overall goal but preserved insulin production in a pre-specified HLA DR3-DQ2 subgroup — a finding that motivated DIAGNODE-3, which was later stopped for futility.

Editorial review: .

Registry checked: 2026-09-17. Registry’s own update: 2023-01-09.

Most recent recorded citation date: 2022-08-01. Only explicit date metadata is included; an undated citation may be newer. This does not mean every claim was reviewed on that date.

Trial status, labels and access can change between reviews. How we review the evidence · How to read the evidence

Full sources ↓Full discussion ↓Report an issue →

Evidence at a glance

Who can enter the study?
For people aged 12–24 recently diagnosed with type 1 diabetes (within 6 months) who still make some of their own insulin (fasting C-peptide >= 0.12 nmol/L) and test positive for GAD65 autoantibodies. People who had taken immune-suppressing or continuous anti-inflammatory drugs, or had a recent vaccination, were excluded. Registered eligibility ↗Enrollment criteria describe who may enter. They do not establish who was analyzed or the denominator for a reported result.
Reported benefit and results
The trial missed its main goal: across all participants, GAD-alum did not preserve C-peptide significantly better than placebo at 15 months (treatment effect ratio 1.091; 95% CI 0.845-1.408; p=0.50). But in a pre-defined subgroup carrying the HLA DR3-DQ2 gene type, GAD-alum preserved more than 50% greater insulin-producing capacity than placebo at 15 months (effect ratio ~1.56; 95% CI 1.13-2.15; p~0.008), and a continuous-glucose-monitoring analysis found better preserved time-in-range in that same subgroup (decline of -5.1% vs -16.7% over 15 months; p=0.0075). The published report described the treatment as well tolerated. These genotype-specific findings motivated DIAGNODE-3, which enrolled only DR3-DQ2-positive patients and was terminated for futility (NCT05018585; actual n=321; completed 24 June 2026, per the registry listing).Read the result sources and their limitations →
Important harms
Read the reported results, safety discussion and original sources. A separate harms summary is not available; this does not establish safety.
Research access and approval
Study regions: European Union. A trial listing does not establish product approval or current recruitment at a particular site. Check the study’s current entry requirements.
What remains uncertain?
Read the full discussion and original sources for study limitations. Planned endpoints and completion dates are not results.

Research status alone does not establish approval, clinical benefit or local availability.

Primary endpoints

  • Change in stimulated C-peptide (mixed-meal tolerance test, AUC) from baseline to 15 months

The full picture

What was tested, and why it matters

Type 1 diabetes happens when the immune system mistakenly destroys the insulin-producing beta cells in the pancreas. DIAGNODE-2 tested GAD-alum (Diamyd) — a piece of one of the proteins the immune system attacks (GAD65), combined with an alum carrier — given as an antigen-specific immunotherapy. The idea is to re-train the immune system to tolerate beta cells instead of attacking them, without broadly suppressing immunity.1 Crucially, the injections went directly into a lymph node in the groin, where immune education happens, rather than under the skin, allowing a small (4 µg) dose.2

Preserving even a little of a person's own insulin production matters: residual beta-cell function has been observationally associated with steadier glucose, fewer dangerous lows, and a lower risk of long-term complications.2

Who it was for

Young people aged 12 to 24 who had been diagnosed with type 1 diabetes within the previous 6 months, who still made some of their own insulin (fasting C-peptide >= 0.12 nmol/L), and who tested positive for GAD65 autoantibodies.1

How it was designed

DIAGNODE-2 was a Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial that enrolled 109 participants across Sweden, Spain, the Czech Republic, and the Netherlands.13 Participants received either three intralymphatic injections of 4 µg GAD-alum plus oral vitamin D, or matching placebo, and were followed for 15 months, with the primary measure being change in stimulated C-peptide (a marker of insulin production).13 Per the registry, the study started in December 2017 and completed in 2021.1

Key results

In the full group, the trial missed its primary endpoint — GAD-alum did not preserve C-peptide significantly better than placebo at 15 months (treatment effect ratio 1.091; 95% CI 0.845-1.408; p=0.50).34 However, in a pre-specified subgroup carrying the HLA DR3-DQ2 gene type, the active treatment preserved more than 50% greater insulin-producing capacity than placebo (effect ratio 1.56; 95% CI 1.13-2.15; p0.008).34 A separate continuous-glucose-monitoring analysis found these same DR3-DQ2 patients held their time-in-range far better (a decline of just -5.1% versus -16.7% on placebo over 15 months; p=0.0075).3 The published trial report described the therapy as well tolerated.4

What it means and what's next

DIAGNODE-2 is a landmark example of how a missed overall endpoint plus a pre-specified genetic subgroup can look like precision medicine — and why that bet has to be tested, not assumed.3 Those DR3-DQ2 findings motivated DIAGNODE-3 (NCT05018585), which enrolled only DR3-DQ2-positive patients aged 12–28. That Phase 3 was stopped for futility in April 2026; ClinicalTrials.gov now lists it TERMINATED (actual n=321, completed 24 June 2026, last update 24 August 2026) with no posted results.5 No replication of the subgroup signal has been posted; the futility stop ended that test. See DIAGNODE-3.

Sources

  1. [1]
    Diamyd Medical AB. DIAGNODE-2: Diamyd Administered Into Lymph Nodes in Combination With Vitamin D in Type 1 Diabetes. *ClinicalTrials.gov*, NCT03345004 (accessed 2026) · Trial registry

    Diamyd Medical AB. DIAGNODE-2: Diamyd Administered Into Lymph Nodes in Combination With Vitamin D in Type 1 Diabetes. ClinicalTrials.gov, NCT03345004 (accessed 2026).

  2. [2]
    Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2. · Peer-reviewed study · 2022-08-01

    Nowak C, Ludvigsson J, et al. Intralymphatic GAD-Alum (Diamyd) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2. J Clin Endocrinol Metab 107(9):2644-2651 (2022).

    Nowak C, Ludvigsson J, et al. Intralymphatic GAD-Alum (Diamyd) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2 (introduction: residual beta-cell function and complication risk). J Clin Endocrinol Metab 107(9):2644-2651 (2022).

  3. [3]
    Nowak C, Ludvigsson J, et al. Intralymphatic GAD-Alum (Diamyd) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2 (DIAGNODE-2 design and DR3-DQ2 CGM/C-peptide results). *J Clin Endocrinol Metab* 107(9):2644-2651 (2022) · Peer-reviewed study

    Nowak C, Ludvigsson J, et al. Intralymphatic GAD-Alum (Diamyd) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2 (DIAGNODE-2 design and DR3-DQ2 CGM/C-peptide results). J Clin Endocrinol Metab 107(9):2644-2651 (2022).

  4. [4]
    Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial. · Peer-reviewed study · 2021-05-21

    Ludvigsson J, et al. Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial. Diabetes Care 44(7):1604-1612 (2021).

  5. [5]
    Diamyd Medical AB. A Phase III Study to Investigate if Diamyd Can Preserve Insulin Production in Patients Newly Diagnosed With Type 1 Diabetes (DIAGNODE-3). *ClinicalTrials.gov*, NCT05018585 (accessed 2026) · Trial registry

    Diamyd Medical AB. A Phase III Study to Investigate if Diamyd Can Preserve Insulin Production in Patients Newly Diagnosed With Type 1 Diabetes (DIAGNODE-3). ClinicalTrials.gov, NCT05018585 (accessed 2026).