Diabetes Autoimmunity Withdrawn In New Onset and In Established Patients

Diabetes Mellitus, Type 1 Clinical Trial

— SUNRISE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03895437
• Other study ID #: TOL-3021-231
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 17, 2019
• Est. completion date: September 30, 2023

Study information

• Verified date: July 2020
• Source: Tolerion, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 78
• Est. completion date: September 30, 2023
• Est. primary completion date: March 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 40 Years

Eligibility

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 10?/L; platelets <100 x 10?/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 a-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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

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

Locations

Country	Name	City	State
United States	Mountain Diabetes and Endocrine Center	Asheville	North Carolina
United States	Emory University	Atlanta	Georgia
United States	MedStar Health Research Institute	Baltimore	Maryland
United States	Joslin Diabetes Center- Adult & Pediatric	Boston	Massachusetts
United States	University of North Carolina Diabetes Care Center	Chapel Hill	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Barbara Davis Center - University of Colorado Denver	Denver	Colorado
United States	University of Florida	Gainesville	Florida
United States	MedStar Health Research Institute	Hyattsville	Maryland
United States	Rocky Mountain Clinical Research	Idaho Falls	Idaho
United States	University of Iowa	Iowa City	Iowa
United States	Baptist Health Research Institute	Jacksonville	Florida
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	University of Miami Diabetes Research Institute	Miami	Florida
United States	Yale University	New Haven	Connecticut
United States	Naomi Berrie Diabetes Center, Columbia University	New York	New York
United States	Diabetes and Glandular Disease Clinic, P.A.	San Antonio	Texas
United States	Altman Clinical and Translational Research Institute UCSD	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	Mills-Peninsula Medical Center	San Mateo	California
United States	Stanford University	Stanford	California
United States	SUNY Upstate Medical University	Syracuse	New York
United States	University of South Florida Diabetes Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Tolerion, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment effect on log-transformed MMTT C-peptide area under the curve (AUC)	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	12. 16, 24 weeks
Secondary	Treatment effect on rates of clinically important hypoglycemia	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	12, 24, 36, 52 weeks
Secondary	Treatment effect on daily Insulin requirements	Total daily insulin requirements in units per kilogram (kg) body weight	24, 52 weeks
Secondary	Treatment effect on HbA1c	Change in HbA1c from baseline at Weeks 24 and 52	baseline, 24, 52 weeks
Secondary	Treatment effect on log-transformed MMTT C-peptide area under the curve (AUC)	Repeated measures analysis of change from baseline in the log-transformed MMTT C-peptide AUC at 12, 16, 24, and 52 weeks	12, 16, 24, 52 weeks
Secondary	Treatment effect on GCM measurement of glucose levels l< 70 and <55 mg/dL	Number of times the CGM reports glucose levels of <70 and <55 mg/dL	12, 16, 24, 52 weeks
Secondary	Treatment effect on a Clinical responder analysis	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.	12, 16, 24, 52 weeks
Secondary	Treatment effect on non-fasting or fasting C-peptide single test	Fasting or non-fasting C-peptide levels at baseline and at weeks 12, 16, 24, 52	baseline, 12, 16, 24, 52 weeks
Secondary	Treatment effect on HbA1c	Proportion of subjects in each treatment arm with HbA1c levels <6.5% at Week 52	52 weeks
Secondary	Treatment effect on CGM parameters	Time in range of 70-180 mg/dL	12, 16, 24, 52
Secondary	Treatment effect on CGM parameters	Time > 180 mg/dL;	12, 16, 24, 52
Secondary	Treatment effect on CGM parameters	Time > 250 mg/dL	12, 16, 24, 52
Secondary	Treatment effect on CGM parameters	Mean Glucose Coefficient of Variation	12, 16, 24, 52
Secondary	Treatment effect on CGM parameters	Low Blood Glucose Index (LBGI)	12, 16, 24, 52
Secondary	Treatment effect on CGM parameters	Glucose <70 mg/dL	12, 16, 24, 52
Secondary	Treatment effect on CGM parameters	Area Under the Curve (AUC70)	12, 16, 24, 52
Secondary	Treatment effect on other measures of hypoglycemia	Severe hypoglycemia (SH) events (impaired or loss of consciousness requiring assistance of another).	12, 16, 24, 52 weeks
Secondary	Treatment effect on other measures of hypoglycemia	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).	12, 16, 24, 52 weeks
Secondary	Treatment effect on other measures of hypoglycemia	Total time <70 mg/dL by CGM.	12, 16, 24, 52 weeks
Secondary	Treatment effect on other measures of hypoglycemia	Nocturnal hypoglycemia, i.e. severe or documented symptomatic episodes (as defined above) occurring after the subject has retired for the primary sleeping period.	12, 16, 24, 52 weeks
Secondary	Immunologic - Quantum dot (Q-dot) responses	Quantum dot (Q-dot) responses within the qualifying subpopulation to confirm induction of specific autoantigen tolerance	at Week 52
Secondary	Immunologic - Quantum dot (Q-dot) responses	Comparison of quantum dot responses within the qualifying subpopulation to clinical outcomes to confirm correlation with specific autoantigen tolerance;	at Week 52
Secondary	Immunologic - determine effect of treatment and predictive values of antibody response	Regulatory/protective humoral immune response to proinsulin/insulin	at Week 52
Secondary	Immunologic - determine effect of treatment and predictive values of antibody response	Serum insulin autoantibody affinity for subjects	at Week 52
Secondary	Immunologic - determine effect of treatment and predictive values of antibody response	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.	at Week 52
Secondary	Immunologic - determine effect of treatment and predictive values of antibody response	Serum insulin, glutamic acid decarboxylase, IA-2, and ZnT8 antibodies by radio-binding assay (RBA) assay	at Week 52
Secondary	Immunologic - determine effect of treatment and predictive values of antibody response	Competition assays of serum insulin and proinsulin IgM and IgG antibodies.	at Week 52
Secondary	Safety Variables	Clinical laboratory tests (hematology, chemistry, urinalysis)	12, 16, 24, 52 weeks
Secondary	Safety Variables	Urine pregnancy test (UPT) for women of childbearing potential (WOCBP)c	12, 16, 24, 52 weeks
Secondary	Safety Variables	Use of concomitant medications	12, 16, 24, 52 weeks
Secondary	Safety Variables	Analysis of reported Adverse event (AEs)	12, 16, 24, 52 weeks
Secondary	Safety Variables	Number of subjects with injection site reactions	12, 16, 24, 52 weeks
Secondary	Safety Variables	Number of subjects with severe hypoglycemia or hyperglycemia events monitored by CGM	12, 16, 24, 52 weeks
Secondary	Events of Special Interest	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	12, 16, 24, 52 weeks