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Pilot / feasibilityCompletedNCT02352974

DIAGNODE-1: First intralymphatic GAD-alum dosing study

An open-label pilot study in 12 people with recent-onset type 1 diabetes that tested injecting the GAD65 autoantigen vaccine (Diamyd / GAD-alum) directly into a lymph node, alongside oral vitamin D. It showed the approach was safe and produced a strong, Th2-skewed immune response with apparent preservation of insulin production, paving the way for the larger randomized DIAGNODE-2 trial.

Primary endpoints

  • Safety: injection-site reactions (erythema, edema, hematoma, tenderness, pain, itching) at months 1, 2, 3 and 32

Results so far

No serious adverse events occurred; injection-site reactions were minimal (only mild tenderness in 1-2 participants). The lymph-node route induced a strong antigen-specific immune response (GAD antibodies far higher than older subcutaneous dosing, a Th2-skewed cytokine profile dominated by IL-13, a shift in IgG subclasses, and reduced T-cell proliferation). Insulin-producing capacity (C-peptide) appeared preserved at 6 and 15 months, with 11 of 12 reaching partial remission at 15 months; in longer follow-up, 8 of 12 were classified as "good responders."

The full picture

What was tested, and why it matters

Type 1 diabetes happens because the immune system mistakenly attacks the insulin-producing beta cells in the pancreas. One protein the immune system targets is GAD65. For years, researchers have tried to "retrain" the immune system by giving GAD65 as a kind of therapeutic vaccine (called GAD-alum, or Diamyd), but injecting it under the skin produced only modest effects.1

DIAGNODE-1 tested a smarter delivery route: injecting a tiny dose of GAD-alum directly into a lymph node — the place where immune responses are actually coordinated — guided by ultrasound.2 The hope was that this would generate a stronger, more protective (tolerance-promoting) immune response using far less drug.

Who it was for, and how it was designed

This was a small open-label pilot trial (no placebo group) run in Linköping, Sweden, enrolling 12 people with recently diagnosed type 1 diabetes (within 6 months) who still made some of their own insulin.3 Participants were diagnosed between ages 12 and 30 and carried GAD autoantibodies.3 Each received 4 µg of GAD-alum injected into a groin lymph node on three occasions, one month apart, plus daily oral vitamin D as an immune-supporting add-on.3 The main goal was simply to check safety; the team also tracked immune markers and insulin production for years afterward.3

Key results

The approach was safe and well tolerated. There were no serious adverse events, and injection-site reactions were minimal — only mild tenderness in one or two participants.4

Despite using a much smaller dose, the lymph-node route triggered a stronger and qualitatively different immune response than older under-the-skin dosing: GAD antibody levels rose far higher, the cytokine profile shifted toward a calmer, Th2-type pattern dominated by IL-13, antibody subclasses shifted (less IgG1, more IgG2/IgG3/IgG4), and GAD-specific T-cell proliferation went down — all consistent with steering the immune system away from attack.5

Encouragingly, insulin-producing capacity (C-peptide) appeared preserved at 6 and 15 months, and 11 of 12 participants reached partial remission by 15 months.6 In longer follow-up, 8 of 12 were classified as "good responders," and a genetic subgroup (carrying the HLA DR3-DQ2 type) seemed to respond best.7

What it means and what's next

DIAGNODE-1 was the proof-of-concept that made lymph-node GAD-alum worth pursuing. Because there was no placebo group, it could not prove the treatment slows diabetes on its own — but its safety and immune signals directly justified the larger, randomized, placebo-controlled DIAGNODE-2 trial.7

References

  1. Tavira B, Barcenilla H, Wahlberg J, Achenbach P, Ludvigsson J, Casas R. Intralymphatic Glutamic Acid Decarboxylase-Alum Administration Induced Th2-Like-Specific Immunomodulation in Responder Patients: A Pilot Clinical Trial in Type 1 Diabetes. Journal of Diabetes Research (2018). https://doi.org/10.1155/2018/9391845 ↩

  2. ClinicalTrials.gov. Open Label Pilot Trial in Adults With Recent-onset T1D to Evaluate the Safety, Diabetes Status and Immune Response of GAD-antigen (Diamyd) Therapy Administered Into Lymph Nodes (DIAGNODE), NCT02352974. ClinicalTrials.gov (2020). https://clinicaltrials.gov/study/NCT02352974 ↩

  3. ClinicalTrials.gov. NCT02352974 — study design, eligibility, intervention and dosing schedule. ClinicalTrials.gov (2020). https://clinicaltrials.gov/study/NCT02352974 ↩ ↩2 ↩3 ↩4

  4. ClinicalTrials.gov. NCT02352974 — posted results: adverse events (0 serious events in 12 participants) and injection-site reaction outcomes. ClinicalTrials.gov (2020). https://clinicaltrials.gov/study/NCT02352974 ↩

  5. Tavira B, et al. Intralymphatic GAD-Alum Administration Induced Th2-Like-Specific Immunomodulation in Responder Patients. Journal of Diabetes Research (2018). https://doi.org/10.1155/2018/9391845 ↩

  6. Ludvigsson J, et al. Intra-lymphatic administration of GAD-alum in type 1 diabetes: long-term follow-up and effect of a late booster dose (the DIAGNODE Extension trial). Diabetologia / PMC (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8995247/ ↩

  7. Ludvigsson J, et al. DIAGNODE Extension trial — responder analysis, HLA DR3-DQ2 subgroup, and late booster dose. PMC (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8995247/ ↩ ↩2