Type I Diabetes
Conditions
Brief summary
The trial is a placebo-controlled, double-blinded within cohorts, randomized, multiple ascending dose trial with a sequential trial design. The primary outcome is to investigate the safety and tolerability of ascending subcutaneous weekly doses of NNC0361-0041 plasmid in patients with T1D.
Detailed description
A total of 48 patients with T1D are planned to be studied in 4 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 data safety review (as described in section 4.9.2). An MMTT to assess insulin secretion will be done at baseline, 1, 3, 6, and 12 months. The follow-up (FU) period will be 1 week after the last dose, as well as 4, 6 and 12 months after the first dose.
Interventions
DRUGNNC0361-0041
Recombinant supercoiled plasmid encoding four human proteins: (pre-proinsulin (PPI), transforming growth factor β1 (TGF-β1), interleukin-10 (IL-10), and interleukin-2 (IL-2) is administered s.c. via syringe and needle.
OTHERPlacebo
Placebo
Sponsors
Novo Nordisk A/S
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
The trial is a placebo-controlled, double-blinded within cohorts, randomized, multiple ascending dose trial with a sequential trial design. A total of 48 patients with T1D are planned to be studied in 4 cohorts of 12 patients (9 on active and 3 on placebo treatment).
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Willing to provide Informed Consent 2. Participants must live in a location with rapid access to emergency medical services 3. Age 18-45 years (both inclusive) at the time of signing informed consent 4. Must have a diagnosis of T1D for less than 48 months at randomization 5. Must have 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) 6. Must have 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 (37 days) of randomization 7. Be willing to comply with intensive diabetes management 8. HbA1c ≤8.5% at screening 9. Subjects who are CMV and/or EBV seronegative at screening must be CMV and/or EBV PCR negative within 37 days of randomization and may not have had signs or symptoms of a CMV and/or EBV compatible illness lasting longer than 7 days within 37 days of randomization 10. Be up to date on recommended immunizations 11. Be at least 6 weeks from last live immunization 12. Be at least 4 weeks from killed vaccine other than flu vaccine 13. Participants are required to receive killed influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available 14. Be willing and medically acceptable to postpone live vaccines during the treatment period and for 3 months following last dose of study drug 15. If participant is female with reproductive potential, she must have a negative pregnancy test at screening and be willing to avoid pregnancy using a highly effective contraceptive method for the 12 months of the study 16. Males of reproductive age must use adequate contraceptive method during the treatment phase and for 3 months following last dose of study drug 17. Participants are required to receive an authorized non-live COVID-19 vaccination and be fully vaccinated, including eligible boosters as indicated, at least two weeks prior to randomization.
Exclusion criteria
Potential participants must not meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 16 Weeks | Number of adverse events recorded during the on-treatment period, which is defined as from first treatment through visit 15 (or 5 weeks after last treatment for subjects not receiving all injections) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 4-, 12-, 24- and 52-weeks from baseline | Proportional change from baseline c-peptide AUC mean from a 2-hour mixed meal tolerance test by assessment schedule. The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes. The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the AUC mean and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1 mg/0.11 mL NNC0361-0041 Plasmid Dosage form: 9 mg/ml plasmid in isotonic solution for injection Route of administration: Subcutaneous injection (into the abdomen) Dosing instructions: Once weekly on site for 12 injections Dose/Unit strength in cohort 1: 1mg/0.11 mL
NNC0361-0041: Recombinant supercoiled plasmid encoding four human proteins: (pre-proinsulin (PPI), transforming growth factor β1 (TGF-β1), interleukin-10 (IL-10), and interleukin-2 (IL-2). | 9 |
| 5 mg/0.56 mL NNC0361-0041 Plasmid Dosage form: 9 mg/ml plasmid in isotonic solution for injection Route of administration: Subcutaneous injection (into the abdomen) Dosing instructions: Once weekly on site for 12 injections Dose/Unit strength in cohort 2: 5mg/0.56 mL
NNC0361-0041: Recombinant supercoiled plasmid encoding four human proteins: (pre-proinsulin (PPI), transforming growth factor β1 (TGF-β1), interleukin-10 (IL-10), and interleukin-2 (IL-2). | 9 |
| 12.5 mg/1.4 mL NNC0361-0041 Plasmid Dosage form: 9 mg/ml plasmid in isotonic solution for injection Route of administration: Subcutaneous injection (into the abdomen) Dosing instructions: Once weekly on site for 12 injections Dose/Unit strength in cohort 3: 12.5mg/ 1.4 mL
NNC0361-0041: Recombinant supercoiled plasmid encoding four human proteins: (pre-proinsulin (PPI), transforming growth factor β1 (TGF-β1), interleukin-10 (IL-10), and interleukin-2 (IL-2). | 9 |
| 25 mg/2.8 mL NNC0361-0041 Plasmid Dosage form: 9 mg/ml plasmid in isotonic solution for injection Route of administration: Subcutaneous injection (into the abdomen) Dosing instructions: Once weekly on site for 12 injections Dose/Unit strength in cohort 4: 25mg/2.8 mL
NNC0361-0041: Recombinant supercoiled plasmid encoding four human proteins: (pre-proinsulin (PPI), transforming growth factor β1 (TGF-β1), interleukin-10 (IL-10), and interleukin-2 (IL-2). | 8 |
| Placebo Dosage form: 0 mg/mL Isotonic solution for injection Route of administration: Subcutaneous injection (into the abdomen) Dosing instructions: Once weekly on site for 12 total injections, equivalent volume as prepared IMP
Placebo: Placebo | 12 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Cohort 1: Dose Level 1 mg | Protocol Violation | 0 | 0 | 0 | 0 | 1 |
| Cohort 2: Dose Level 5 mg | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| Cohort 3: Dose Level 12.5 mg | Protocol Violation | 0 | 0 | 1 | 0 | 0 |
| Cohort 4: Dose Level 25 mg | Adverse Event | 0 | 0 | 0 | 0 | 1 |
| Cohort 4: Dose Level 25 mg | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | 5 mg/0.56 mL NNC0361-0041 Plasmid | Total | Placebo | 1 mg/0.11 mL NNC0361-0041 Plasmid | 25 mg/2.8 mL NNC0361-0041 Plasmid | 12.5 mg/1.4 mL NNC0361-0041 Plasmid |
|---|---|---|---|---|---|---|
| Age, Continuous | 30.9 years STANDARD_DEVIATION 6 | 30.2 years STANDARD_DEVIATION 7.52 | 29.1 years STANDARD_DEVIATION 7.85 | 36.7 years STANDARD_DEVIATION 7.62 | 29.5 years STANDARD_DEVIATION 7.43 | 25.3 years STANDARD_DEVIATION 4.57 |
| Autoantibodies positive GAD | 9 Participants | 45 Participants | 12 Participants | 9 Participants | 7 Participants | 8 Participants |
| Autoantibodies positive IA-2 | 4 Participants | 27 Participants | 10 Participants | 2 Participants | 7 Participants | 4 Participants |
| Autoantibodies positive ICA | 5 Participants | 24 Participants | 6 Participants | 6 Participants | 3 Participants | 4 Participants |
| Autoantibodies positive Micro-IAA | 9 Participants | 36 Participants | 10 Participants | 5 Participants | 7 Participants | 5 Participants |
| Autoantibodies positive ZnT8 | 5 Participants | 27 Participants | 7 Participants | 5 Participants | 6 Participants | 4 Participants |
| Average total daily dose of Insulin | 31.3 Units of Insulin STANDARD_DEVIATION 22.5 | 27.9 Units of Insulin STANDARD_DEVIATION 17.9 | 31.2 Units of Insulin STANDARD_DEVIATION 20.7 | 22.5 Units of Insulin STANDARD_DEVIATION 16.6 | 26.4 Units of Insulin STANDARD_DEVIATION 12.3 | 25.8 Units of Insulin STANDARD_DEVIATION 14.9 |
| BMI | 25.6 kg/m^2 STANDARD_DEVIATION 3.36 | 25.1 kg/m^2 STANDARD_DEVIATION 3.76 | 25.1 kg/m^2 STANDARD_DEVIATION 3.73 | 24.1 kg/m^2 STANDARD_DEVIATION 4.43 | 26 kg/m^2 STANDARD_DEVIATION 4.24 | 24.8 kg/m^2 STANDARD_DEVIATION 3.63 |
| Count of autoantibodies positive 1 | 0 Participants | 5 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants |
| Count of autoantibodies positive 2 | 3 Participants | 7 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Count of autoantibodies positive 3 | 1 Participants | 11 Participants | 2 Participants | 4 Participants | 0 Participants | 4 Participants |
| Count of autoantibodies positive 4 | 2 Participants | 13 Participants | 4 Participants | 2 Participants | 3 Participants | 2 Participants |
| Count of autoantibodies positive 5 | 3 Participants | 11 Participants | 4 Participants | 1 Participants | 3 Participants | 0 Participants |
| C-peptide AUC Mean | 0.645 pmol/mL STANDARD_DEVIATION 0.417 | 0.774 pmol/mL STANDARD_DEVIATION 0.505 | 0.753 pmol/mL STANDARD_DEVIATION 0.314 | 0.838 pmol/mL STANDARD_DEVIATION 0.385 | 0.691 pmol/mL STANDARD_DEVIATION 0.623 | 0.943 pmol/mL STANDARD_DEVIATION 0.78 |
| Diagnosis to Randomization | 20.2 months STANDARD_DEVIATION 12.8 | 16.6 months STANDARD_DEVIATION 12.6 | 15.7 months STANDARD_DEVIATION 12.6 | 17.8 months STANDARD_DEVIATION 15.3 | 19 months STANDARD_DEVIATION 14.1 | 10.8 months STANDARD_DEVIATION 7.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 45 Participants | 12 Participants | 9 Participants | 8 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Glycated hemoglobin level | 6.36 % STANDARD_DEVIATION 0.922 | 6.21 % STANDARD_DEVIATION 0.779 | 6.36 % STANDARD_DEVIATION 0.817 | 6.08 % STANDARD_DEVIATION 0.565 | 6.15 % STANDARD_DEVIATION 0.949 | 6.01 % STANDARD_DEVIATION 0.692 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 42 Participants | 11 Participants | 9 Participants | 8 Participants | 8 Participants |
| Sex: Female, Male Female | 5 Participants | 25 Participants | 4 Participants | 6 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 22 Participants | 8 Participants | 3 Participants | 4 Participants | 3 Participants |
| Weight | 72 kg STANDARD_DEVIATION 11.5 | 75.2 kg STANDARD_DEVIATION 13.5 | 79.9 kg STANDARD_DEVIATION 17.3 | 72.2 kg STANDARD_DEVIATION 14.4 | 75.9 kg STANDARD_DEVIATION 13.3 | 71.9 kg STANDARD_DEVIATION 11 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 8 | 0 / 12 |
| other Total, other adverse events | 9 / 9 | 9 / 9 | 9 / 9 | 8 / 8 | 12 / 12 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 1 / 9 | 0 / 8 | 0 / 12 |
Outcome results
Primary
Adverse Events
Number of adverse events recorded during the on-treatment period, which is defined as from first treatment through visit 15 (or 5 weeks after last treatment for subjects not receiving all injections)
Time frame: 16 Weeks
Population: The safety analysis set contained all participants who recieved at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 mg/0.11 mL NNC0361-0041 Plasmid | Adverse Events | 230 adverse events |
| 5 mg/0.56 mL NNC0361-0041 Plasmid | Adverse Events | 217 adverse events |
| 12.5 mg/1.4 mL NNC0361-0041 Plasmid | Adverse Events | 215 adverse events |
| 25 mg/2.8 mL NNC0361-0041 Plasmid | Adverse Events | 169 adverse events |
| Placebo | Adverse Events | 240 adverse events |
Secondary
Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period.
Proportional change from baseline c-peptide AUC mean from a 2-hour mixed meal tolerance test by assessment schedule. The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes. The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the AUC mean and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis.
Time frame: 4-, 12-, 24- and 52-weeks from baseline
Population: number of participants analyzed differs in one or more of the rows due to a participant not completing the assessment (MMTT) required to include in computing the geometric mean of the C-peptide change from baseline.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| 1 mg/0.11 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 4 weeks | 0.861 pmol/mL |
| 1 mg/0.11 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 12 weeks | 0.83 pmol/mL |
| 1 mg/0.11 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 24 weeks | 0.761 pmol/mL |
| 1 mg/0.11 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 52 weeks | 0.742 pmol/mL |
| 5 mg/0.56 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 4 weeks | 0.955 pmol/mL |
| 5 mg/0.56 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 52 weeks | 0.626 pmol/mL |
| 5 mg/0.56 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 12 weeks | 0.807 pmol/mL |
| 5 mg/0.56 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 24 weeks | 0.655 pmol/mL |
| 12.5 mg/1.4 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 52 weeks | 1.01 pmol/mL |
| 12.5 mg/1.4 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 12 weeks | 0.914 pmol/mL |
| 12.5 mg/1.4 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 24 weeks | 0.93 pmol/mL |
| 12.5 mg/1.4 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 4 weeks | 1.15 pmol/mL |
| 25 mg/2.8 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 4 weeks | 0.823 pmol/mL |
| 25 mg/2.8 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 12 weeks | 0.775 pmol/mL |
| 25 mg/2.8 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 52 weeks | 0.65 pmol/mL |
| 25 mg/2.8 mL NNC0361-0041 Plasmid | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 24 weeks | 0.809 pmol/mL |
| Placebo | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 52 weeks | 0.585 pmol/mL |
| Placebo | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 24 weeks | 0.764 pmol/mL |
| Placebo | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 12 weeks | 0.794 pmol/mL |
| Placebo | Change in the Area Under the Plasma C-peptide Concentration-time Curve Across the 2-hour Test Period. | 4 weeks | 0.8 pmol/mL |