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Diabetes Autoimmunity Withdrawn In New Onset and In Established Patients (SUNRISE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03895437
Recruitment Status : Active, not recruiting
First Posted : March 29, 2019
Last Update Posted : November 9, 2020
Sponsor:
Information provided by (Responsible Party):
Tolerion, Inc.

Tracking Information
First Submitted Date  ICMJE March 26, 2019
First Posted Date  ICMJE March 29, 2019
Last Update Posted Date November 9, 2020
Actual Study Start Date  ICMJE June 17, 2019
Estimated Primary Completion Date March 15, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 26, 2020)
Treatment effect on log-transformed MMTT C-peptide area under the curve (AUC) [ Time Frame: 12. 16, 24 weeks ]
The primary outcome is the TOL-3021 treatment effect as determined by a repeated measures analysis of change from baseline in the log-transformed MMTT C-peptide AUC at 12, 16, and 24 weeks
Original Primary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
Treatment effect on log-transformed MMTT C-peptide area under the curve (AUC) [ Time Frame: 52 weeks ]
The primary outcome is the treatment effect on log-transformed MMTT C-peptide area under the curve (AUC)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 26, 2020)
  • Treatment effect on rates of clinically important hypoglycemia [ Time Frame: 12, 24, 36, 52 weeks ]
    Rates of clinically important hypoglycemia events as defined by total measured glucose value of <54 mg/dL (3.0 mM/L) over each approximately 12-week period ending at Weeks 12, 24, 36, and 52 by a single blood glucose level, and by CGM, ≥10 consecutive minutes with glucose <54 mg/dL
  • Treatment effect on daily Insulin requirements [ Time Frame: 24, 52 weeks ]
    Total daily insulin requirements in units per kilogram (kg) body weight
  • Treatment effect on HbA1c [ Time Frame: baseline, 24, 52 weeks ]
    Change in HbA1c from baseline at Weeks 24 and 52
  • Treatment effect on log-transformed MMTT C-peptide area under the curve (AUC) [ Time Frame: 12, 16, 24, 52 weeks ]
    Repeated measures analysis of change from baseline in the log-transformed MMTT C-peptide AUC at 12, 16, 24, and 52 weeks
  • Treatment effect on GCM measurement of glucose levels l< 70 and <55 mg/dL [ Time Frame: 12, 16, 24, 52 weeks ]
    Number of times the CGM reports glucose levels of <70 and <55 mg/dL
  • Treatment effect on a Clinical responder analysis [ Time Frame: 12, 16, 24, 52 weeks ]
    A clinical responder analysis defined as no change or an increase in C-peptide AUC from baseline between treatment and placebo at Weeks 12, 16, and 24 weeks. Upon completion of 52 week data, a similar analysis will include the 52 week data.
  • Treatment effect on non-fasting or fasting C-peptide single test [ Time Frame: baseline, 12, 16, 24, 52 weeks ]
    Fasting or non-fasting C-peptide levels at baseline and at weeks 12, 16, 24, 52
  • Treatment effect on HbA1c [ Time Frame: 52 weeks ]
    Proportion of subjects in each treatment arm with HbA1c levels <6.5% at Week 52
  • Treatment effect on CGM parameters [ Time Frame: 12, 16, 24, 52 ]
    Time in range of 70-180 mg/dL
  • Treatment effect on CGM parameters [ Time Frame: 12, 16, 24, 52 ]
    Time > 180 mg/dL;
  • Treatment effect on CGM parameters [ Time Frame: 12, 16, 24, 52 ]
    Time > 250 mg/dL
  • Treatment effect on CGM parameters [ Time Frame: 12, 16, 24, 52 ]
    Mean Glucose Coefficient of Variation
  • Treatment effect on CGM parameters [ Time Frame: 12, 16, 24, 52 ]
    Low Blood Glucose Index (LBGI)
  • Treatment effect on CGM parameters [ Time Frame: 12, 16, 24, 52 ]
    Glucose <70 mg/dL
  • Treatment effect on CGM parameters [ Time Frame: 12, 16, 24, 52 ]
    Area Under the Curve (AUC70)
  • Treatment effect on other measures of hypoglycemia [ Time Frame: 12, 16, 24, 52 weeks ]
    Severe hypoglycemia (SH) events (impaired or loss of consciousness requiring assistance of another).
  • Treatment effect on other measures of hypoglycemia [ Time Frame: 12, 16, 24, 52 weeks ]
    Documented symptomatic hypoglycemia (an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <70 mg/dl (3.9 mmol/L).
  • Treatment effect on other measures of hypoglycemia [ Time Frame: 12, 16, 24, 52 weeks ]
    Total time <70 mg/dL by CGM.
  • Treatment effect on other measures of hypoglycemia [ Time Frame: 12, 16, 24, 52 weeks ]
    Nocturnal hypoglycemia, i.e. severe or documented symptomatic episodes (as defined above) occurring after the subject has retired for the primary sleeping period.
  • Immunologic - Quantum dot (Q-dot) responses [ Time Frame: at Week 52 ]
    Quantum dot (Q-dot) responses within the qualifying subpopulation to confirm induction of specific autoantigen tolerance
  • Immunologic - Quantum dot (Q-dot) responses [ Time Frame: at Week 52 ]
    Comparison of quantum dot responses within the qualifying subpopulation to clinical outcomes to confirm correlation with specific autoantigen tolerance;
  • Immunologic - determine effect of treatment and predictive values of antibody response [ Time Frame: at Week 52 ]
    Regulatory/protective humoral immune response to proinsulin/insulin
  • Immunologic - determine effect of treatment and predictive values of antibody response [ Time Frame: at Week 52 ]
    Serum insulin autoantibody affinity for subjects
  • Immunologic - determine effect of treatment and predictive values of antibody response [ Time Frame: at Week 52 ]
    Insulin autoantibody isotypes (IgA and IgM) and IgG subclasses;;serum insulin, glutamic acid decarboxylase, IA-2, and ZnT8 antibodies by radio-binding assay (RBA) assay; competition assays of serum insulin and proinsulin IgM and IgG antibodies.
  • Immunologic - determine effect of treatment and predictive values of antibody response [ Time Frame: at Week 52 ]
    Serum insulin, glutamic acid decarboxylase, IA-2, and ZnT8 antibodies by radio-binding assay (RBA) assay
  • Immunologic - determine effect of treatment and predictive values of antibody response [ Time Frame: at Week 52 ]
    Competition assays of serum insulin and proinsulin IgM and IgG antibodies.
  • Safety Variables [ Time Frame: 12, 16, 24, 52 weeks ]
    Clinical laboratory tests (hematology, chemistry, urinalysis)
  • Safety Variables [ Time Frame: 12, 16, 24, 52 weeks ]
    Urine pregnancy test (UPT) for women of childbearing potential (WOCBP)c
  • Safety Variables [ Time Frame: 12, 16, 24, 52 weeks ]
    Use of concomitant medications
  • Safety Variables [ Time Frame: 12, 16, 24, 52 weeks ]
    Analysis of reported Adverse event (AEs)
  • Safety Variables [ Time Frame: 12, 16, 24, 52 weeks ]
    Number of subjects with injection site reactions
  • Safety Variables [ Time Frame: 12, 16, 24, 52 weeks ]
    Number of subjects with severe hypoglycemia or hyperglycemia events monitored by CGM
  • Events of Special Interest [ Time Frame: 12, 16, 24, 52 weeks ]
    Number of subjects with systemic or hypersensitivity reactions associated with injection, which consist of fever, chills, headache, nausea, vomiting, and/or other signs and symptoms, such as anaphylaxis, wheezing dyspnea, urticaria, and hypotension
Original Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
  • Rate of clinically important hypoglycemia [ Time Frame: 52 weeks ]
    glucometer, a single blood glucose level
  • Rate of clinically important hypoglycemia [ Time Frame: 52 weeks ]
    CGM, ≥15 consecutive minutes with glucose <54 mg/dL
  • Daily Insulin requirements [ Time Frame: 52 weeks ]
    Total daily insulin requirements in units per kilogram (kg) body weight
  • Clinical Responder [ Time Frame: 52 weeks ]
    A clinical responder analysis will be undertaken as a secondary endpoint to further characterize the treatment effect on a clinical level. A positive responder outcome will be defined as no change or increase in C-peptide AUC from baseline vs. Week 52
  • Proportion of subjects in each treatment arm who are exogenous insulin-free for at least 3 months with HbA1c levels less than 6.5% [ Time Frame: at Week 52 ]
    Proportion of subjects in each treatment arm who are exogenous insulin-free for at least 3 months with HbA1c levels less than 6.5%
  • GCM Measurement [ Time Frame: at Week 52 ]
    Time in range 70-80 mg/dL
  • GCM Measurement [ Time Frame: at Week 52 ]
    Time in range 70-180 mg/dL
  • GCM Measurement [ Time Frame: at Week 52 ]
    Time >180 mg/dL
  • GCM Measurement [ Time Frame: at Week 52 ]
    Time >250 mg/dL
  • GCM Measurement [ Time Frame: at Week 52 ]
    Mean Glucose Coefficient of Variation
  • GCM Measurement [ Time Frame: at Week 52 ]
    Low Blood Glucose Index (LBGI)
  • GCM Measurement [ Time Frame: at Week 52 ]
    Glucose below 70 mg/dL Area Over the Curve (AOC70)
  • Other measures of hypoglycemia [ Time Frame: at Week 52 ]
    Severe hypoglycemia (SH) events (impaired or loss of consciousness requiring assistance of another)
  • Other measures of hypoglycemia [ Time Frame: at Week 52 ]
    Documented symptomatic hypoglycemia (an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <70 mg/dl (3.9 mmol/L))
  • Other measures of hypoglycemia [ Time Frame: at Week 52 ]
    Total time <70 mg/dL by CGM
  • Other measures of hypoglycemia [ Time Frame: at Week 52 ]
    Nocturnal hypoglycemia, severe or documented symptomatic episodes (as defined above) occurring after the subject has retired for the primary sleeping period
  • Immunologic - specific autoantigen tolerance [ Time Frame: at Week 52 ]
    Quantum dot (Q-dot) responses within the qualifying subpopulation to confirm induction of specific autoantigen tolerance
  • Immunologic - specific autoantigen tolerance [ Time Frame: at Week 52 ]
    Comparison of quantum dot responses within the qualifying subpopulation to clinical outcomes to confirm correlation with specific autoantigen tolerance
  • Immunologic - immune response to proinsulin/insulin [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of regulatory/protective humoral immune response to proinsulin/insulin
  • Immunologic - serum insulin autoantibody affinity [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of serum insulin autoantibody affinity for subjects
  • Immunologic - insulin autoantibody isotypes [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of insulin autoantibody isotypes (IgA and IgM) and IgG subclasses
  • Immunologic - ECL assay for serum insulin antibodies [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of serum insulin by highly sensitive ECL assay
  • Immunologic - ECL assay for glutamic acid decarboxylase antibodies [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of glutamic acid decarboxylase by highly sensitive ECL assay
  • Immunologic - ECL assay for IA-2 antibodies [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of IA-2 by highly sensitive ECL assay
  • Immunologic - ECL assay for ZnT8 antibodies [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of ZnT8 antibodies by highly sensitive ECL assay
  • Immunologic - serum insulin antibodies [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of competition assays of serum insulin
  • Immunologic - proinsulin IgM antibodies [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of competition assays of proinsulin IgM
  • Immunologic - proinsulin IgG antibodies [ Time Frame: at Week 52 ]
    Determine the effect of treatment on and predictive value of competition assays of proinsulin IgG antibodies
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Diabetes Autoimmunity Withdrawn In New Onset and In Established Patients
Official Title  ICMJE A Phase 2 Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of TOL-3021 in Patients With New Onset or Established Type 1 Diabetes Mellitus
Brief Summary The study is a prospective, randomized, 52-week double-blind, placebo-controlled, multicenter trial in subjects with T1D followed by a 2-year safety follow-up.
Detailed Description The SUNRISE study is a prospective, multi-center, double-blind, randomized, placebo-controlled trial in subjects aged 12.0 to <41.0 years diagnosed with T1D, as defined by American Diabetes Association (ADA) criteria, and within 5 years of diagnosis. Time of diagnosis is defined as the first day of insulin administration. Subjects will be stratified by duration (zero up to 1 year and 1 year up to five years) to ensure balance of disease duration across treatment and placebo groups in each strata. For analytical purposes, all subjects12-<41 will be considered cohort A, subjects aged 12-<18 will considered cohort B and subjects aged 18-<41 will be considered cohort C. For subjects aged 12-<18 (Cohort B), dosing will be staggered with an initial 6 subjects aged 14-<18 being enrolled with the last subject a having a minimum of 2 injections with at least 1 week follow-up after the 2nd injection. Safety data from this cohort will be evaluated before opening the study to subjects 12 and older. Subjects should be randomized no sooner than 6 weeks after diagnosis, unless glycemic range is adequately controlled as confirmed by time in glycemic range (70-180 mg/dL) >55% by CGM recording over 3 or more consecutive or non-consecutive days. Screening assessments will include a physical examination, a fundoscopic photograph, chemistry and hematology safety labs, urinalysis, 24-hour urine protein and creatinine, HbA1c, presence of T1D antibodies, and a 4-hour MMTT. Approximately 99 qualified subjects who meet all selection criteria will be randomized in a 2:1 ratio to treatment with TOL-3021 or placebo and treated for 52 weeks. Study drug treatments will be administered via an IM injection into a large muscle every week for 52 weeks. Continuous glucose monitoring (CGM) will be initiated within 5 days prior to the screening MMTT visit and continued through Week 52. Subjects will agree to diabetes management during the study with the goal of maintaining HbA1c levels of approximately 7.0% without frequent episodes of hypoglycemia.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Subjects will be randomly assigned to treatment with TOL-3021 or placebo in a 2:1 fashion
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus, Type 1
Intervention  ICMJE
  • Biological: TOL-3021
    TOL-3021 1 mg is a bacterial plasmid expression vector containing the coding sequences for the human proinsulin (hINS) gene.
  • Other: TOL-3021 Placebo
    TOL-3021 Placebo
    Other Name: Placebo
Study Arms  ICMJE
  • Experimental: TOL-3021
    TOL-3021 2 mg/mL
    Intervention: Biological: TOL-3021
  • Placebo Comparator: TOL-3021 Placebo
    TOL-3021 Placebo
    Intervention: Other: TOL-3021 Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 5, 2020)
78
Original Estimated Enrollment  ICMJE
 (submitted: March 28, 2019)
51
Estimated Study Completion Date  ICMJE September 30, 2023
Estimated Primary Completion Date March 15, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Diagnosis of Type 1 Diabetes Mellitus based on American Diabetes Association (ADA) criteria and within 5.0 years from diagnosis, defined as the first day of insulin administration.
  2. Age at randomization of 12.0 - <41.0 years of age .
  3. Adequate glycemic control as defined by HbA1c ≤7.9% based on point-of-care or local lab measurement and time in glycemic range (70-180 mg/dL) >55% by CGM recording over 3 or more consecutive or non-consecutive days within 5 days prior to baseline mixed meal tolerance test (MMTT).
  4. On insulin therapy (total insulin dose >0.125 U/kg BW)
  5. Presence of antibodies to at least one of the following antigens: GAD65, IA-2, ZnT8, or insulin if obtained within 10 days of the onset of exogenous insulin therapy, or documentation of positive antibodies. In the absence of a positive result for one of the specified antibodies, diagnosis of T1D as per the ADA guidelines..
  6. Peak C-peptide during screening 4-hour mixed meal tolerance test (MMTT) ≥ 0.150 nmol/L.
  7. Willingness to wear the Dexcom G6 continuous glucose monitoring (CGM) device and use according to instructions including recording of total daily insulin dose taken most of each day from screening to end of treatment period.
  8. Written informed consent and, for subjects aged 12-<18 years of age, patient assent and parental or guardian consent, including authorization to release health information.
  9. Willingness and ability of subject to comply with all study procedures of the study protocol, including attending all clinic visits.

Exclusion Criteria

  1. Receiving a dose of acetaminophen >4,000 mg per day.
  2. Body Mass Index (BMI) >32 kg/m² for patients 18 and older (>85th percentile for ages 12-17)
  3. Previous immunotherapy for T1D within 2 years of enrollment.
  4. Diagnosis of liver disease or hepatic enzymes, as defined by ALT and/or AST ≥ 2.5 times the upper limit of normal (ULN).
  5. Hematology: white blood cells (WBC) <3 x 10⁹/L; platelets <100 x 10⁹/L; hemoglobin <10.0 g/dL. (Low WBC values may be repeated every 3-7 days, and results to be discussed with the Medical Monitor.) Any underlying conditions likely to impact red blood cell turnover.
  6. Latent autoimmune diabetes of adults (LADA), which is generally associated with preceding history and treatment of T2D with medications typically used for treatment of T2D for more than 30 days.
  7. Monogenic diabetes (MODY).
  8. Estimated glomerular filtration rate (eGFR) <60 ml/min for ages 18-<41, and <75 ml/min per 1.73 m² for ages 12-<18.
  9. History of malignancy, except for cancers in remission >5 years, or basal cell or in situ squamous cell carcinoma of the skin.
  10. Significant cardiovascular disease (including inadequately controlled hypertension), history of myocardial infarction, unstable angina, use of anti-anginal medicines (e.g., nitroglycerin), or abnormal stress test, which, in the opinion of the Principal Investigator (PI), would interfere with participation in the trial.
  11. Immunosuppressive therapy (systemic corticosteroids, cyclosporine, azathioprine, or biologics) within 30 days of screening.
  12. Current or prior (within the last 30 days) use of metformin, sulfonylureas, glinides, thiazolidinediones, GLP1-RAs, DPP-IV inhibitors, pramlintide, or SGLT-2 inhibitors.
  13. Current use of verapamil or α-methyldopa.
  14. History of any organ transplant, including islet cell transplant.
  15. Asthma that requires oral glucocorticoid therapy. Inhaled glucocorticoid therapy is permitted.
  16. Active autoimmune or immune deficiency disorder including rheumatoid arthritis, moderate-to-severe psoriasis, inflammatory bowel disease, and other autoimmune conditions that may require treatment with TNF or other biologics. Permitted autoimmune disorders include T1D or well-controlled autoimmune conditions (e.g., thyroid disease, celiac disease, and sarcoidosis, all with stable non-immunosuppressive medications for the past 30 days).
  17. Thyroid-stimulating hormone (TSH) at screening >7.5 mIU/L for ages 18-<41 years old and > 3.6mIU/L for ages 12-<18 years old. .
  18. Adrenal insufficiency not adequately controlled with stable replacement glucocorticoid therapy.
  19. Moderate non-proliferative retinopathy (NPDR) or proliferative retinopathy
  20. Evidence of infection with HBV (as defined by hepatitis B surface antigen, HBsAg), HCV (anti-HCV antibodies), or HIV.
  21. Subject is breastfeeding.
  22. Positive urine pregnancy test at screening or at any time during the study (pregnancy tests must be performed as per the visit schedule). Females of childbearing potential must be excluded if they have a positive urine pregnancy test at screening or randomization or if they are not using medically acceptable methods of birth control. Acceptable methods of birth control include oral or transdermal contraceptives, condom, spermicidal foam, IUD, progestin implant or injection, abstinence, vaginal ring, or sterilization of partner. The reason for non-childbearing potential, such as bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or 1 year or more postmenopausal must be specified in the subject's Case Report Form (CRF).
  23. Males of reproductive potential who are unwilling to use medically acceptable birth control, unless the female partner is postmenopausal or surgically sterile.
  24. Any social condition or medical condition that would, in the opinion of the PI, prevent complete participation in the study or would pose a significant hazard to the subject's participation.
  25. Anticipated major surgery during the duration of the trial, which could interfere with participation in the trial.
  26. History of drug or alcohol dependence within 12 months of screening.
  27. Psychiatric disorder that would prevent subjects from giving informed consent.
  28. Household members of current participants in this protocol.
  29. Subjects who are not fluent in the English language.
  30. Participation in other studies involving the administration of an investigational drug or experimental device, including the administration of an experimental agent for T1D within 30 days of screening, or use of an experimental therapeutic device for T1D within 30 days prior to screening. Subjects previously treated with diagnostic devices are not excluded.
  31. Any current use of biotin or biotin containing supplements
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03895437
Other Study ID Numbers  ICMJE TOL-3021-231
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: We recognize that sharing anonymized data and other information from clinical trials can increase the speed and success of biomedical research in addressing unmet clinical need. We are following ongoing discussions among industry, the academic community, and other stakeholders regarding data sharing. Industry and its academic partners have not yet formulated a consensus on the amount, types, and forms of data that will be useful and beneficial to the public, or the process for sharing data. As a small, young company, we await the development of guidances and best practices for industry before issuing a comprehensive data sharing plan. For now, we defer a description of what data will be shared and the process for doing so. The protocol will be shared as part of study publication in a peer reviewed medical journal. The protocol will be available as a supplement to the publication and/or on the website of the publishing journal and upon request to the Sponsor (www.tolerion.bio)
Responsible Party Tolerion, Inc.
Study Sponsor  ICMJE Tolerion, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Alexander Fleming, M.D. Tolerion, Inc.
PRS Account Tolerion, Inc.
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP