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

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ClinicalTrials.gov Identifier: NCT04279613
Recruitment Status : Recruiting
First Posted : February 21, 2020
Last Update Posted : November 3, 2022
Novo Nordisk A/S
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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.

Condition or disease Intervention/treatment Phase
Type I Diabetes Drug: NNC0361-0041 Other: Placebo Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
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).
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Multiple Ascending Dose Trial Investigating Safety, Tolerability and Pharmacokinetics of NNC0361-0041 Administered Subcutaneously to Patients With Type 1 Diabetes Mellitus
Actual Study Start Date : November 23, 2020
Estimated Primary Completion Date : January 31, 2024
Estimated Study Completion Date : January 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

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

Primary Outcome Measures :
  1. Adverse Events [ Time Frame: 1 year ]
    Number of adverse events recorded from the time of first dosing (Day 1) and until completion of the follow-up visit #17

Secondary Outcome Measures :
  1. Change in the area under the plasma C-peptide concentration-time curve [ Time Frame: 3 months ]
    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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04279613

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Contact: Lisa Rafkin, MS 305-243-6146 LRafkin@med.miami.edu
Contact: Ryan O'Donnell, MS Ryan.O'Donnell@epi.usf.edu

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United States, California
Children's Hospital of Orange County Recruiting
Orange, California, United States, 92868
Contact: Heather Speer    714-509-8613    HSpeer@choc.org   
Principal Investigator: Mark Daniels, MD         
University of California - San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Rebecca Wesch    415-476-5984    rebecca.wesch@ucsf.edu   
Contact: Karen Ko    415-514-3730    karen.ko@ucsf.edu   
Principal Investigator: Stephen Gitelman, MD         
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Trudy Esrey    650-498-4450    tesrey@stanford.edu   
Principal Investigator: Darrell Wilson, MD         
United States, Colorado
Barbara Davis Center at University of Colorado Anschutz Medical Campus Recruiting
Aurora, Colorado, United States, 80045
Contact: Morgan Sooy    303-724-5686    MORGAN.QUIST@CUANSCHUTZ.EDU   
Principal Investigator: Andrea Steck, MD         
United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06519
Contact: Laurie Feldman    203-737-2760    laurie.feldman@yale.edu   
Principal Investigator: Kevan Herold, MD, Ph.D.         
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Jennifer Hosford    352-294-5759    jennifer.hosford@peds.ufl.edu   
Principal Investigator: Michael Haller, MD         
United States, Georgia
Emory Children's Center Recruiting
Atlanta, Georgia, United States, 30329
Contact: Xiaomiao Lan-Pidhainy    404-712-0051    xlanpid@emory.edu   
Principal Investigator: Andrew Muir, MD         
United States, Indiana
Indiana University - Riley Hospital for Children Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Maria Spall    317-278-8879    malnicho@iu.edu   
Principal Investigator: Linda DiMeglio, MD         
United States, Massachusetts
Joslin Diabetes Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Jason Gaglia, MD    888-813-8669    TrialNet@joslin.harvard.edu   
Principal Investigator: Jason Gaglia, MD         
United States, Minnesota
Regents of the University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55466
Contact: Janice Leschyshyn    612-626-8467    lesch004@umn.edu   
Principal Investigator: Antoinette Moran, MD         
United States, Missouri
The Children's Mercy Hospital Recruiting
Kansas City, Missouri, United States, 64108
Contact: Jennifer James    913-696-5059    jljames@cmh.edu   
Principal Investigator: Wayne Moore, MD         
United States, New York
The Naomi Berrie Diabetes Center at Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Sarah Pollak    212-851-5425    sjp2174@columbia.edu   
Principal Investigator: Robin Goland, MD         
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Kelli DeLallo    412-692-5210    kelli.delallo@chp.edu   
Principal Investigator: Dorothy Becker, MD         
United States, Tennessee
Vanderbilt Eskind Diabetes Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Faith Brendle    615-936-8638    faith.brendle@vumc.org   
Principal Investigator: William Russell, MD         
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Serey Sao    214-648-3061    serey.sao@utsouthwestern.edu   
Contact: Lindsay Harter       Lindsay.Harter@UTSouthwestern.edu   
Principal Investigator: Perrin White, MD         
United States, Washington
Benaroya Research Institute Recruiting
Seattle, Washington, United States, 98101
Contact: Corinna Tordillos    206-341-8937    ctordillos@benaroyaresearch.org   
Principal Investigator: Carla Greenbaum, MD         
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Novo Nordisk A/S
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Study Chair: Robin Goland, MD Type 1 Diabetes TrialNet
Study Director: Carla Greenbaum, MD Type 1 Diabetes TrialNet
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT04279613    
Other Study ID Numbers: TN27 Immunoplasmid Therapy
UC4DK117009 ( U.S. NIH Grant/Contract )
First Posted: February 21, 2020    Key Record Dates
Last Update Posted: November 3, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be available at the National Institute of Diabetes Digestive and Kidney Diseases (NIDDK) Central Repository
URL: https://repository.niddk.nih.gov/home/

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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
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases