Diabetes Autoimmunity Withdrawn In New Onset and In Established Patients

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

The study is a prospective, randomized, 52-week double-blind, placebo-controlled, multicenter trial in subjects with Type 1 diabetes (T1D) followed by a 2-year safety follow-up.

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 type 1 diabetes (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 continuous glucose monitoring (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, hemoglobin A1c (HbA1c), presence of T1D antibodies, and a 4-hour mixed meal tolerance test (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 intramuscular (IM) injection into a large muscle every week for 52 weeks. 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.

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 body weight)
5. Presence of antibodies to at least one of the following antigens: glutamic acid decarboxylase (GAD65), islet antigen 2 (IA-2), zinc transporter 8 (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 alanine aminotransferase (ALT) and/or aspartate aminotransferase (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 type 2 diabetes (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 tissue necrosis factor (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 hepatitis B virus (HBV), as defined by hepatitis B surface antigen( HBsAg), HCV (anti-HCV antibodies), or human immunodeficiency virus (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 principal investigator (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