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Phase 2CompletedNCT03345004

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

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 patients with a specific gene type (HLA DR3-DQ2) — a finding now being tested in the precision Phase 3 trial DIAGNODE-3.

Primary endpoints

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

Results so far

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 treatment was well tolerated. These genotype-specific findings led to the precision Phase 3 trial DIAGNODE-3, which enrolls only DR3-DQ2-positive patients.

The full picture

Note on the registry ID: This record uses NCT03345004, which is the verified ClinicalTrials.gov identifier for DIAGNODE-2. The number "NCT02814838" given in the original request does not correspond to DIAGNODE-2 and appears to be an error.

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 very small dose.2

Preserving even a little of a person's own insulin production matters: residual beta-cell function is linked to steadier glucose, fewer dangerous lows, and a lower risk of long-term complications.3

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.14 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).14 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).45 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).45 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).4 The therapy was well tolerated.5

What it means and what's next

DIAGNODE-2 is a landmark example of precision medicine in type 1 diabetes: a therapy that fails "on average" can still work powerfully in a genetically defined group.4 These findings directly motivated DIAGNODE-3, a Phase 3 trial (NCT05018585) that enrolls only DR3-DQ2-positive patients (aged 12-28) across the US and eight European countries; it is now active and not recruiting after fully enrolling, with a positive interim analysis reported.6

References

  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). https://clinicaltrials.gov/study/NCT03345004 ↩ ↩2 ↩3 ↩4 ↩5

  2. 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). https://doi.org/10.1210/clinem/dgac343 ↩

  3. 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). https://doi.org/10.1210/clinem/dgac343 ↩

  4. 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). https://pubmed.ncbi.nlm.nih.gov/35665810/ ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  5. 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). https://doi.org/10.2337/dc21-0318 ↩ ↩2 ↩3

  6. 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). https://clinicaltrials.gov/study/NCT05018585 ↩