Diabetes AutoimmunitY Withdrawn in Established Patients (DAY) (DAY)
Primary Purpose
Diabetes Mellitus, Type 1
Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
TOL-3021
TOL-3021 Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring Diabetes, Type 1 Diabetes, Diabetes Mellitus
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of Type 1 Diabetes Mellitus based on American Diabetes Association (ADA) criteria and within 1.0 to 5.0 years from diagnosis, defined as the first day of insulin administration.
- Adequate glycemic control for >14 days, defined as 3 consecutive fasting glucose levels by self-administered blood glucose (SMBG) or lab testing <130 mg/dL.
- Age at randomization of 12.0 - <18.0 years (adolescent), 18.0 - <36.0 years of age (adult) .
HbA1c <8.5% based on point-of-care or local lab measurement.
• Measurement can be repeated every 5-7 days if >8.5%.
- Presence of antibodies to at least one of the following antigens: GAD-65, IA-2, ZnT8; or insulin.
- Peak C-peptide during screening 4-hour mixed meal tolerance test (MMTT) ≥ 0.2pmol/mL.
- Willingness to wear a continuous glucose monitoring (CGM) device for specified periods of time.
- Written informed consent, including authorization to release health information and assent for adolescent subjects.
- Willingness and ability of subject or adult guardian to comply with all study procedures of the study protocol, including attending all clinic visits.
Exclusion Criteria:
- Body Mass Index (BMI) >30 kg/m2 for adults; >95 percentile BMI-for-age for subjects under 18 years of age.
- Previous immunotherapy for T1D.
- Diagnosis of liver disease or hepatic enzymes, as defined by ALT and/or AST ≥ 2.5 times the upper limit of normal (ULN).
- 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.)
- Serum creatinine >1.5 times ULN.
- History of malignancy, except for cancers in remission >5 years, or basal cell or in situ squamous cell carcinoma of the skin.
- Significant cardiovascular disease (including inadequately controlled hypertension), history of myocardial infarction, 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.
- Immunosuppressive therapy (systemic corticosteroids, cyclosporine, azathioprine, or biologics) within 30 days of screening.
- Current or prior (within the last 30 days) use of metformin, sulfonylureas, glinides, thiazolidinediones, GLP1-RAs, DPP-IV inhibitors, pramlintide, or SGLT-2 inhibitors.
- Current use of verapamil or α-methyldopa.
- History of any organ transplant, including islet cell transplant.
- Active autoimmune or immune deficiency disorder other than T1D or well-controlled autoimmune thyroid disease (e.g., sarcoidosis, rheumatoid arthritis, moderate-to-severe psoriasis, inflammatory bowel disease, and other autoimmune conditions that may require treatment with TNF or other biologics), unless approved by the Medical Monitor.
- Thyroid-stimulating hormone (TSH) at screening >2.5 mIU/L.
- History of adrenal insufficiency.
- Evidence of infection with HBV (as defined by hepatitis B surface antigen, HBsAg), HCV (anti-HCV antibodies), or HIV.
- Positive urine pregnancy test: 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).
- Males of reproductive potential who are unwilling to use medically acceptable birth control, unless the female partner is postmenopausal or surgically sterile.
- 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.
- Anticipated major surgery during the duration of the trial, which could interfere with participation in the trial.
- History of drug or alcohol dependence within 12 months of screening.
- Psychiatric disorder that would prevent subjects from giving informed consent.
- Participation in other studies involving the administration of an investigational drug or device, including the administration of an experimental agent for T1D, at any time, or use of an experimental device for T1D within 30 days prior to screening, unless approved by the Medical Monitor.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
TOL-3021
TOL-3021 Placebo
Arm Description
Outcomes
Primary Outcome Measures
Treatment Effect
The primary outcome is the treatment effect on log-transformed MMTT C-peptide area under the curve (AUC) after 52 weeks of TOL-3021 treatment
Secondary Outcome Measures
Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
By glucometer, a single blood glucose level
Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
By CGM, ≥15 consecutive minutes with glucose <54 mg/dL
Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
Total daily insulin requirements in units per kilogram (kg) body weight
Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
HbA1c
Clinical responder analysis
Proportion of subjects in each treatment arm with HbA1c levels less than 6.5% at Week 52
Clinical responder analysis
Measure by GMS - Time in range 70 - 80 mg/dL
Clinical responder analysis
Measure by GMS - Time >180 mg/dL
Clinical responder analysis
Measure by GMS - Time >250 mg/dL
Clinical responder analysis
Measure by GMS - Mean Glucose Coefficient of Variation
Clinical responder analysis
Measure by GMS - Low Blood Glucose Index (LBGI)
Clinical responder analysis
Measure by GMS - Glucose below 70 mg/dL Area Over the Curve (AOC70)
Other measures of hypoglycemia
Severe hypoglycemia (SH) events (impaired or loss of consciousness requiring assistance of another)
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))
Other measures of hypoglycemia
Total time <70 mg/dL by CGM
Other measures of hypoglycemia
Nocturnal hypoglycemia, 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 within the qualifying subpopulation to confirm induction of specific autoantigen tolerance
Immunologic
Comparison of quantum dot responses within the qualifying subpopulation to clinical outcomes to confirm correlation with specific autoantigen tolerance.
Immunologic
Determine effect of treatment on and predictive value of regulatory/protective humoral immune response to proinsulin/insulin
Immunologic
Determine effect of treatment on and predictive value of serum insulin autoantibody affinity for subjects
Immunologic
Determine effect of treatment on and predictive value of Insulin autoantibody isotypes (IgA and IgM) and IgG subclasses
Immunologic
Determine effect of treatment on and predictive value of serum insulin, glutamic acid decarboxylase, IA-2, and ZnT8 antibodies by highly sensitive ECL assay
Immunologic
Determine effect of treatment on and predictive value of competition assays of serum insulin and proinsulin IgM and IgG antibodies
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03794960
Brief Title
Diabetes AutoimmunitY Withdrawn in Established Patients (DAY)
Acronym
DAY
Official Title
A Phase 2b Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of TOL-3021 in Patients With Established Type 1 Diabetes Mellitus
Study Type
Interventional
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Withdrawn
Why Stopped
Modification to Clinical Development Plan
Study Start Date
December 14, 2019 (Anticipated)
Primary Completion Date
December 14, 2021 (Anticipated)
Study Completion Date
December 14, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tolerion, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The study is a prospective, randomized, double-blind, placebo-controlled, multicenter trial in subjects with established T1D.
Detailed Description
The study will include 216 male or female subjects aged 12 to 35 years diagnosed with T1D, as defined by the American Diabetes Association (ADA) criteria and meeting enrollment criteria as follows. Initial enrollment will be restricted to subjects aged 18-35 until an analysis of data from subjects with 3 months' exposure to drug confirms safety. Upon completion of this assessment, enrollment will be open without further restrictions for subjects aged 12-35.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1
Keywords
Diabetes, Type 1 Diabetes, Diabetes Mellitus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
TOL-3021
Arm Type
Experimental
Arm Title
TOL-3021 Placebo
Arm Type
Placebo Comparator
Intervention Type
Biological
Intervention Name(s)
TOL-3021
Intervention Description
A plasmid expression vector containing the coding sequences for full-length human proinsulin.
Intervention Type
Other
Intervention Name(s)
TOL-3021 Placebo
Other Intervention Name(s)
Placebo
Intervention Description
TOL-3021 Placebo
Primary Outcome Measure Information:
Title
Treatment Effect
Description
The primary outcome is the treatment effect on log-transformed MMTT C-peptide area under the curve (AUC) after 52 weeks of TOL-3021 treatment
Time Frame
at Week 52
Secondary Outcome Measure Information:
Title
Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
Description
By glucometer, a single blood glucose level
Time Frame
at Week 52
Title
Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
Description
By CGM, ≥15 consecutive minutes with glucose <54 mg/dL
Time Frame
at Week 52
Title
Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
Description
Total daily insulin requirements in units per kilogram (kg) body weight
Time Frame
at Week 52
Title
Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
Description
HbA1c
Time Frame
at Week 52
Title
Clinical responder analysis
Description
Proportion of subjects in each treatment arm with HbA1c levels less than 6.5% at Week 52
Time Frame
at Week 52
Title
Clinical responder analysis
Description
Measure by GMS - Time in range 70 - 80 mg/dL
Time Frame
at Week 52
Title
Clinical responder analysis
Description
Measure by GMS - Time >180 mg/dL
Time Frame
at Week 52
Title
Clinical responder analysis
Description
Measure by GMS - Time >250 mg/dL
Time Frame
at Week 52
Title
Clinical responder analysis
Description
Measure by GMS - Mean Glucose Coefficient of Variation
Time Frame
at Week 52
Title
Clinical responder analysis
Description
Measure by GMS - Low Blood Glucose Index (LBGI)
Time Frame
at Week 52
Title
Clinical responder analysis
Description
Measure by GMS - Glucose below 70 mg/dL Area Over the Curve (AOC70)
Time Frame
at Week 52
Title
Other measures of hypoglycemia
Description
Severe hypoglycemia (SH) events (impaired or loss of consciousness requiring assistance of another)
Time Frame
at Week 52
Title
Other measures of hypoglycemia
Description
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))
Time Frame
at Week 52
Title
Other measures of hypoglycemia
Description
Total time <70 mg/dL by CGM
Time Frame
at Week 52
Title
Other measures of hypoglycemia
Description
Nocturnal hypoglycemia, severe or documented symptomatic episodes (as defined above) occurring after the subject has retired for the primary sleeping period
Time Frame
at Week 52
Title
Immunologic
Description
Quantum dot (Q-dot) responses within the qualifying subpopulation to confirm induction of specific autoantigen tolerance
Time Frame
at Week 52
Title
Immunologic
Description
Comparison of quantum dot responses within the qualifying subpopulation to clinical outcomes to confirm correlation with specific autoantigen tolerance.
Time Frame
at Week 52
Title
Immunologic
Description
Determine effect of treatment on and predictive value of regulatory/protective humoral immune response to proinsulin/insulin
Time Frame
at Week 52
Title
Immunologic
Description
Determine effect of treatment on and predictive value of serum insulin autoantibody affinity for subjects
Time Frame
at Week 52
Title
Immunologic
Description
Determine effect of treatment on and predictive value of Insulin autoantibody isotypes (IgA and IgM) and IgG subclasses
Time Frame
at Week 52
Title
Immunologic
Description
Determine effect of treatment on and predictive value of serum insulin, glutamic acid decarboxylase, IA-2, and ZnT8 antibodies by highly sensitive ECL assay
Time Frame
at Week 52
Title
Immunologic
Description
Determine effect of treatment on and predictive value of competition assays of serum insulin and proinsulin IgM and IgG antibodies
Time Frame
at Week 52
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
36 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of Type 1 Diabetes Mellitus based on American Diabetes Association (ADA) criteria and within 1.0 to 5.0 years from diagnosis, defined as the first day of insulin administration.
Adequate glycemic control for >14 days, defined as 3 consecutive fasting glucose levels by self-administered blood glucose (SMBG) or lab testing <130 mg/dL.
Age at randomization of 12.0 - <18.0 years (adolescent), 18.0 - <36.0 years of age (adult) .
HbA1c <8.5% based on point-of-care or local lab measurement.
• Measurement can be repeated every 5-7 days if >8.5%.
Presence of antibodies to at least one of the following antigens: GAD-65, IA-2, ZnT8; or insulin.
Peak C-peptide during screening 4-hour mixed meal tolerance test (MMTT) ≥ 0.2pmol/mL.
Willingness to wear a continuous glucose monitoring (CGM) device for specified periods of time.
Written informed consent, including authorization to release health information and assent for adolescent subjects.
Willingness and ability of subject or adult guardian to comply with all study procedures of the study protocol, including attending all clinic visits.
Exclusion Criteria:
Body Mass Index (BMI) >30 kg/m2 for adults; >95 percentile BMI-for-age for subjects under 18 years of age.
Previous immunotherapy for T1D.
Diagnosis of liver disease or hepatic enzymes, as defined by ALT and/or AST ≥ 2.5 times the upper limit of normal (ULN).
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.)
Serum creatinine >1.5 times ULN.
History of malignancy, except for cancers in remission >5 years, or basal cell or in situ squamous cell carcinoma of the skin.
Significant cardiovascular disease (including inadequately controlled hypertension), history of myocardial infarction, 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.
Immunosuppressive therapy (systemic corticosteroids, cyclosporine, azathioprine, or biologics) within 30 days of screening.
Current or prior (within the last 30 days) use of metformin, sulfonylureas, glinides, thiazolidinediones, GLP1-RAs, DPP-IV inhibitors, pramlintide, or SGLT-2 inhibitors.
Current use of verapamil or α-methyldopa.
History of any organ transplant, including islet cell transplant.
Active autoimmune or immune deficiency disorder other than T1D or well-controlled autoimmune thyroid disease (e.g., sarcoidosis, rheumatoid arthritis, moderate-to-severe psoriasis, inflammatory bowel disease, and other autoimmune conditions that may require treatment with TNF or other biologics), unless approved by the Medical Monitor.
Thyroid-stimulating hormone (TSH) at screening >2.5 mIU/L.
History of adrenal insufficiency.
Evidence of infection with HBV (as defined by hepatitis B surface antigen, HBsAg), HCV (anti-HCV antibodies), or HIV.
Positive urine pregnancy test: 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).
Males of reproductive potential who are unwilling to use medically acceptable birth control, unless the female partner is postmenopausal or surgically sterile.
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.
Anticipated major surgery during the duration of the trial, which could interfere with participation in the trial.
History of drug or alcohol dependence within 12 months of screening.
Psychiatric disorder that would prevent subjects from giving informed consent.
Participation in other studies involving the administration of an investigational drug or device, including the administration of an experimental agent for T1D, at any time, or use of an experimental device for T1D within 30 days prior to screening, unless approved by the Medical Monitor.
12. IPD Sharing Statement
Plan to Share IPD
Undecided
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