This trial is a phase-1, placebo-controlled, double-blinded within cohorts, randomized, multiple ascending dose trial with a sequential trial design to investigate the safety and tolerability of ascending subcutaneous weekly doses of NNC0361-0041 plasmid in patients with type 1 diabetes (T1D). This treatment delivers DNA into cells, where it can communicate with the immune system. Earlier lab studies suggest this treatment might retrain the immune system to stop its attack on insulin-producing beta cells. This study will determine whether NNC0361-0041 therapy is safe, and if it has an effect on the immune cells involved in T1D.

A total of 48 patients with T1D are planned to be studied in four cohorts of 12 patients (9 on active and 3 on placebo treatment). Within each cohort, sentinel enrollment will occur and safety assessment will occur before remaining participants are enrolled. The treatment period will be 12 weeks with once weekly dosing leading to 12 doses in total. Dose escalation will occur after a data safety review. An MMTT to assess insulin secretion will be completed at baseline, 1, 3, 6, and 12 months. The follow-up period will be 1 week after the last dose, as well as 4, 6, and 12 months after the first dose.

The main objective of this study is to evaluate the safety and tolerability of ascending subcutaneous weekly doses of NNC0361-0041 plasmid, a novel treatment that transfers DNA into cells to communicate with the immune system to stop its attack on insulin-producing beta cells, in patients with T1D. Participants will be monitored for adverse events and to test for safety and dosing.

The primary outcome is the number of adverse events recorded from the time of first dosing and until completion of follow-up. The secondary outcome is the change in the area under the plasma C-peptide concentration-time curve from baseline to 3 months.

Inclusion Criteria:

• Willing to provide informed consent
• Live in a location with rapid access to emergency medical services
• Age 18-45 years (inclusive) at time of informed consent
• Diagnosis of T1D for less than 48 months at randomization
• At least one diabetes-related autoantibody present (GAD65A; mIAA, if obtained within 10 days of the onset of insulin therapy; IA-2A; ICA; or ZnT8A)
• Stimulated C-peptide levels greater than or equal to 0.2 pmol/ml measured during an MMTT conducted at least 21 days from diagnosis of diabetes and within one month of randomization
• Willing to comply with intensive diabetes management
• HbA1c ≤ 8.5% at screening
• No CMV and/or EBV at randomization
• Up-to-date on recommended immunizations
• At least 6 weeks from last live immunization, and at least 4 weeks from killed vaccine other than flu vaccine
• Received killed influenza vaccination at least 2 weeks prior to randomization
• Willing and medically acceptable to postpone live vaccines during the treatment period and for 3 months following last dose of study drug
• If a female participant with reproductive potential, must have a negative pregnancy test at screening and be willing to avoid pregnancy for the 12 months of the study
• Male participants must use adequate contraceptive methods during the treatment phase and for 3 months following the last dose of study drug
• At least 2 weeks from receiving a COVID-19 vaccine at time of receiving study drug

Exclusion Criteria:

• One or more screening laboratory values as stated:
  • Leukocytes < 3,000 /μL
  • Neutrophils < 1,500 /μL
  • Lymphocytes <800 /μL
  • Platelets < 100,000 /μL
  • Haemoglobin < 6.2 mmol/L (10.0 g/dL)
  • Potassium > 5.5 mmol/L or < 3.0 mmol/L
  • Sodium > 150 mmol/L or < 130 mmol/L
  • AST or ALT ≥ 2.5 times the upper limits of normal
  • Bilirubin ≥ 1.5 times the upper limit of normal
  • Glomerular Filtration Rate (eGFR) value of eGFR < 60 ml/min/1.73 m2
• Use of non-insulin pharmaceuticals that affect glycemic control or use of immunosuppressive agents
• Acute infection at time of randomization or chronic active infection
• Current and confirmed COVID-19 infection
• Prior or current tuberculosis infection, HIV, or Hepatitis B infection
• Active Hepatitis C infection
• Vaccination with a live virus within the last 6 weeks and killed vaccine within 4 weeks (except 2 weeks for flu vaccine)
• Currently pregnant or lactating, or anticipate getting pregnant within the one-year study period
• Severe obesity
• History of malignancies
• Untreated hypothyroidism or active Graves' disease
• History of severe reaction to prior vaccination
• Enrolled in any other clinical trial; or the participant (or relative) is involved directly or indirectly in the conduct of the trial
• Supine blood pressure at screening outside the range of 90-139 mmHg for systolic or 50-89 mmHg for diastolic
• Any complicating medical issues or abnormal clinical laboratory results or any condition that in the investigators’ opinion may adversely affect participation or may compromise the results

This study is ongoing.