A Multiple Ascending Dose Trial Investigating Safety, Tolerability and Pharmacokinetics of NNC0361-0041 (TOPPLE T1D)

A Multiple Ascending Dose Trial Investigating Safety, Tolerability and Pharmacokinetics of NNC0361-0041 Administered Subcutaneously to Patients With Type 1 Diabetes Mellitus

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Type I Diabetes
• Intervention / Treatment: Other: Placebo; Drug: NNC0361-0041

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.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Lisa Rafkin, MS; Phone Number: 305-243-6146; Email: LRafkin@med.miami.edu
• Study Contact Backup: Name: Ryan O'Donnell, MS; Email: Ryan.O'Donnell@epi.usf.edu

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94143
      • University of California - San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Barbara Davis Center at University of Colorado Anschutz Medical Campus
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University School of Medicine
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory Children's Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University - Riley Hospital for Children
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55466
      • Regents of the University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Children's Mercy Hospital
  • New York
    • New York, New York, United States, 10032
      • The Naomi Berrie Diabetes Center at Columbia University Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Eskind Diabetes Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Washington
    • Seattle, Washington, United States, 98101
      • Benaroya Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

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 exclusion criteria:

1. One or more screening laboratory values as stated

   1. Leukocytes < 3,000/μL
   2. Neutrophils <1,500 /μL
   3. Lymphocytes <800 /μL
   4. Platelets <100,000 /μL
   5. Haemoglobin <6.2 mmol/L (10.0 g/dL)
   6. Potassium >5.5 mmol/L or <3.0 mmol/L
   7. Sodium >150mmol/L or < 130mmol/L
   8. AST or ALT ≥2.5 times the upper limits of normal
   9. Bilirubin ≥ 1.5 times upper limit of normal
   10. Glomerular Filtration Rate (eGFR) value of eGFR < 60 ml/min/1.73 m2 as defined by KDIGO 2012 (43)
   11. Any other laboratory abnormality that might, in the judgment of the investigator, place the subject at unacceptable risk for participation in this trial
2. Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within prior 7 days of screening
3. Use of other immunosuppressive agents including chronic use of systemic steroids. Topical products are acceptable (nasal, conjunctival, skin)
4. Have active signs or symptoms of acute infection at the time of randomization
5. Have current, confirmed COVID-19 infection
6. Chronic active infection other than localized skin infections
7. Have evidence of prior or current tuberculosis infection as assessed by PPD, interferon gamma release assay or by history
8. Have evidence of current or past HIV, Hepatitis B infection
9. Have evidence of active Hepatitis C infection
10. Vaccination with a live virus within the last 6 weeks and killed vaccine within 4 weeks (except 2 weeks for flu vaccine)
11. Be currently pregnant or lactating, or anticipate getting pregnant within the one-year study period.
12. Have severe obesity: adults BMI ≥ 40
13. Have a history of malignancies
14. Untreated hypothyroidism or active Graves' disease
15. History of severe reaction to prior vaccination
16. Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days after last blood draw (or 5 half-lives of investigational drug, whichever is greater) before screening, or currently enrolled in any other clinical trial
17. Subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the trial
18. Supine blood pressure at screening outside the range of 90-139 mmHg for systolic or 50-89 mmHg for diastolic. To exclude white-coat nervousness a single repeat measurement is allowed
19. Have any complicating medical issues or abnormal clinical laboratory results that may interfere with study conduct, or cause increased risk
20. Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NNC0361-0041; Dosage form: 9 mg/ml Solution for injection Route of administration: Subcutaneous Initial dose/Unit dose strength(s)/Dosage level(s) in cohort 1: 1mg Additional doses in cohorts 2, 3, and 4: 5mg, 12.5mg and 25mg Dosing instructions: Once weekly on site	Drug: 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) is administered s.c. via syringe and needle.
Placebo Comparator: Placebo; Dosage form: Solution for injection Route of administration: Subcutaneous Dosing instructions: Once weekly on site	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Number of adverse events recorded from the time of first dosing (Day 1) and until completion of the follow-up visit #17	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the area under the plasma C-peptide concentration-time curve	Relative change in the area under the plasma C-peptide concentration-time curve from time 0 to 2 hours during MMTT from baseline to 3 months between groups	3 months

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: Novo Nordisk A/S
• Investigators: Study Chair: Robin Goland, MD, Type 1 Diabetes TrialNet; Study Director: Carla Greenbaum, MD, Type 1 Diabetes TrialNet

Publications and helpful links

General Publications

• Pagni PP, Chaplin J, Wijaranakula M, Wesley JD, Granger J, Cracraft J, O'Brien C, Perdue N, Kumar V, Li S, Ratliff SS, Roach A, Misquith A, Chan CL, Coppieters K, von Herrath M. Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes. Diabetes. 2021 Aug 13:db210327. doi: 10.2337/db21-0327. Online ahead of print.
• Pagni PP, Chaplin J, Wijaranakula M, Wesley JD, Granger J, Cracraft J, O'Brien C, Perdue N, Kumar V, Li S, Ratliff SS, Roach A, Misquith A, Chan CL, Coppieters K, von Herrath M. Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes. Diabetes. 2021 Aug 13:db210327. doi: 10.2337/db21-0327. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2020
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: February 19, 2020
• First Submitted That Met QC Criteria: February 19, 2020
• First Posted (Actual): February 21, 2020

Study Record Updates

• Last Update Posted (Actual): October 30, 2023
• Last Update Submitted That Met QC Criteria: October 27, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: TN27 Immunoplasmid Therapy; UC4DK117009 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be available at the National Institute of Diabetes Digestive and Kidney Diseases (NIDDK) Central Repository

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No