Diabetes Mellitus, Insulin-Dependent, 1, Diabetes Mellitus, Type I, IDDM, Insulin-Dependent Diabetes Mellitus 1, Type 1 Diabetes Mellitus
Conditions
Brief summary
Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of insulin-producing ß cells. Although exogenous insulin is widely available, it is not possible for affected individuals to consistently achieve euglycemia with current technology, and thus they are at risk for devastating long-term complications. This phase II study is designed to evaluate the safety and efficacy of imatinib mesylate as a novel therapy for new-onset T1DM. Imatinib is a first-in-class tyrosine kinase inhibitor. This study will explore the potential role of short-term therapy with imatinib to induce tolerance and possibly lead to a durable long-term remission of T1DM.
Detailed description
Eligible participants will be randomized to receive either imatinib mesylate or placebo daily. All participants randomized into this study will be seen at a study site for a follow-up evaluation, 2 weeks and 4 weeks after randomization, and every month month thereafter for the first year. Participants will come in for a visit ever 6 months for the second year. At the study visits, participants will undergo assessments of their insulin production, immunologic status, and overall health. Subjects will be followed until the conclusion of the study. The trial is expected to last approximately 2-4 years or until the required amount of information is gathered.
Interventions
DRUGImatinib Mesylate
DRUGPlacebo (For imatinib mesylate)
Sponsors
Juvenile Diabetes Research Foundation
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Males and females age 12-45 years of age who meet the ADA standard T1DM criteria1. Positive for at least one islet cell autoantibody. Initial enrollment will be for subjects ages 18-45, with the goal to lower the age down to 12 upon acceptable safety review and prospect of benefit for this initial older cohort. * Diagnosis of T1DM within 100 days of Visit 0. * Peak stimulated C-peptide level \>0.2 pmol/mL following an MMTT. * Participants of childbearing age who are sexually active must agree to use an effective form of birth control (e.g., barrier method, oral contraception, or surgery). For females, these contraceptive measures must be maintained throughout the study; for males these measures must be followed for a minimum of 3 months after discontinuation of imatinib therapy.
Exclusion criteria
* Prior history of any significant cardiac disease such as congestive heart failure, myocardial infarction, arrhythmia, or structural defects or suspicion thereof. * Leukopenia (\<3,000 leukocytes/μL), neutropenia (\<1,500 neutrophils/μL), or thrombocytopenia (\<125,000 platelets/μL). * Low Hemoglobin (baseline hemoglobin below lower limit of normal) * Prior history of anaphylaxis, angioedema or serious cutaneous drug reactions * Any sign of significant chronic active infection (e.g., hepatitis, tuberculosis, EBV, CMV, or toxoplasmosis), or screening laboratory evidence consistent with a significant chronic active infection (such as positive for HIV, PPD, or HBSAg). Significant acute infections must be resolved before treatment may commence, e.g., acute respiratory tract, urinary tract, or gastrointestinal tract infections. * Anticipated ongoing use of diabetes medications other than insulin that affect glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, glucagon-like peptide 1 (GLP-1) mimetics, dipeptidyl peptidase IV (DPP-IV) inhibitors, or amylin. * Prior or current treatment that is known to cause a significant, ongoing change in the course of T1DM or immunologic status, including high-dose inhaled, extensive topical or systemic glucocorticoids. * Evidence of liver dysfunction, with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.0 times the upper limit of normal persistent for 1 week or greater. * Evidence of renal insufficiency as indicated by serum creatinine \> 1.2 times the upper limit of normal and confirmed in a repeat test at least one week apart. Evidence of clinically significant metabolic bone disease (except adequately treated rickets). * Females who are pregnant at the time of screening or unwilling to defer pregnancy during the 24-month study period. * Prior treatment with imatinib or related tyrosine kinase inhibitor. * Unable to avoid medications that affect CYP3A4: either inducers that may decrease imatinib levels, or inhibitors that may increase drug concentrations. (Refer to section 1.5.1.12 for a complete list of inducers and inhibitors.) * Height standard deviation score ≥2 standard deviations below mean * Any sign of QT prolongation on Visit -1 noted on ECG (\> 450 ms in males and \> 470 ms in females) * Known coagulation disorders or use of anticoagulants * Current and anticipated on-going treatment with drugs that may increase or decrease imatinib plasma concentrations (CYP3A4 family inhibitors or inducers) or drugs that may have their plasma concentration altered by imatinib (drugs metabolized by CYP3A4/5 and CYP2D6). * Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Stimulated C-peptide Curve (AUC) Mean Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 1 Year Visit | Visit 9 (Week 52) at 0, 15, 30, 60, 90, 120 minutes post-dose | The primary outcome of each participant is the area under the stimulated c-peptide curve (AUC) mean based on data collected at time 0 to 2 hours of a 4-hour mixed meal tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30, 60, 90, and 120 minutes. The term AUC mean comes from the mean value theorem in calculus. It is the value on the scale of the y-axis that is equal to the AUC divided by the range on the x-axis (in this case 120 minutes). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Stimulated C-peptide Curve (AUC) Mean Over 4 Hours at 24 Months | Visit 13 (Week 104) | Area under the MMTT-stimulated peak, 4 hour C-peptide AUC mean at week 104. The units are reported as nano-moles/Liter because this is AUC mean (the AUC is divided by the time internal so that the units return to the c-peptide units of measure). |
| Change in HbA1c Levels Over Time | Visit 9 (Week 52) and Visit 13 (Week 104) | Change in HbA1c levels from Week 52 to Week 104 |
| Change in Insulin Dose (Units/kg) Over Time | Visit 9 (Week 52) and Visit 13 (Week 104) | Assess insulin use in units per kilogram body weight per day at weeks 52 and 104. |
| Number of Severe Hypoglycemic Events | Visit 0 (Week 0), Visit 9 (Week 52), and Visit 13 (Week 104) | Major hypoglycemic events occurring from randomization at weeks 0, 52 and 104. |
| Number of Adverse Events | Adverse Events will be assessed at Visit 0 (week 0), Visit 1 (Week 2), Visit 2 (Week 4), and every month thereafter. | Number of adverse events that were reported throughout the study. |
Countries
Australia, United States
Participant flow
Recruitment details
Recruitment Period: March 2013 to May 2016 at 9 clinical sites (8 US, 1 Australia)
Participants by arm
| Arm | Count |
|---|---|
| Imatinib Mesylate 400 mg imatinib given once daily basis.
Imatinib Mesylate | 45 |
| Placebo Placebo given once daily basis.
Placebo (For imatinib mesylate) | 22 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Imatinib Mesylate | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 22 Participants | 67 Participants |
| Age, Continuous | 28.2 years STANDARD_DEVIATION 7.2 | 26.2 years STANDARD_DEVIATION 6.6 | 27 years STANDARD_DEVIATION 7.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 19 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of Autoantibodies Positive 1 | 8 Participants | 4 Participants | 12 Participants |
| Number of Autoantibodies Positive 2 | 8 Participants | 4 Participants | 12 Participants |
| Number of Autoantibodies Positive 3 | 12 Participants | 1 Participants | 13 Participants |
| Number of Autoantibodies Positive 4 | 8 Participants | 6 Participants | 14 Participants |
| Number of Autoantibodies Positive 5 | 9 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 44 Participants | 21 Participants | 65 Participants |
| Region of Enrollment Australia | 9 Participants | 4 Participants | 13 Participants |
| Region of Enrollment United States | 36 Participants | 18 Participants | 54 Participants |
| Sex: Female, Male Female | 18 Participants | 12 Participants | 30 Participants |
| Sex: Female, Male Male | 27 Participants | 10 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 45 | 0 / 22 |
| other Total, other adverse events | 23 / 45 | 12 / 22 |
| serious Total, serious adverse events | 8 / 45 | 3 / 22 |
Outcome results
Primary
Area Under the Stimulated C-peptide Curve (AUC) Mean Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 1 Year Visit
The primary outcome of each participant is the area under the stimulated c-peptide curve (AUC) mean based on data collected at time 0 to 2 hours of a 4-hour mixed meal tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30, 60, 90, and 120 minutes. The term AUC mean comes from the mean value theorem in calculus. It is the value on the scale of the y-axis that is equal to the AUC divided by the range on the x-axis (in this case 120 minutes).
Time frame: Visit 9 (Week 52) at 0, 15, 30, 60, 90, 120 minutes post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib Mesylate | Area Under the Stimulated C-peptide Curve (AUC) Mean Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 1 Year Visit | 0.834 nmol/L | Standard Deviation 0.446 |
| Placebo | Area Under the Stimulated C-peptide Curve (AUC) Mean Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 1 Year Visit | 0.775 nmol/L | Standard Deviation 0.278 |
p-value: 0.04890% CI: [0.00176, 0.121]ANCOVA
Secondary
Area Under the Stimulated C-peptide Curve (AUC) Mean Over 4 Hours at 24 Months
Area under the MMTT-stimulated peak, 4 hour C-peptide AUC mean at week 104. The units are reported as nano-moles/Liter because this is AUC mean (the AUC is divided by the time internal so that the units return to the c-peptide units of measure).
Time frame: Visit 13 (Week 104)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Imatinib Mesylate | Area Under the Stimulated C-peptide Curve (AUC) Mean Over 4 Hours at 24 Months | 0.472 nmol/L |
| Placebo | Area Under the Stimulated C-peptide Curve (AUC) Mean Over 4 Hours at 24 Months | 0.389 nmol/L |
Secondary
Change in HbA1c Levels Over Time
Change in HbA1c levels from Week 52 to Week 104
Time frame: Visit 9 (Week 52) and Visit 13 (Week 104)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Imatinib Mesylate | Change in HbA1c Levels Over Time | Week 52 | 6.33 percentage of HbA1c level |
| Imatinib Mesylate | Change in HbA1c Levels Over Time | Week 104 | 6.44 percentage of HbA1c level |
| Placebo | Change in HbA1c Levels Over Time | Week 52 | 6.51 percentage of HbA1c level |
| Placebo | Change in HbA1c Levels Over Time | Week 104 | 7.03 percentage of HbA1c level |
Secondary
Change in Insulin Dose (Units/kg) Over Time
Assess insulin use in units per kilogram body weight per day at weeks 52 and 104.
Time frame: Visit 9 (Week 52) and Visit 13 (Week 104)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Imatinib Mesylate | Change in Insulin Dose (Units/kg) Over Time | Week 52 | 0.307 Units per Kg |
| Imatinib Mesylate | Change in Insulin Dose (Units/kg) Over Time | Week 104 | 0.389 Units per Kg |
| Placebo | Change in Insulin Dose (Units/kg) Over Time | Week 52 | 0.413 Units per Kg |
| Placebo | Change in Insulin Dose (Units/kg) Over Time | Week 104 | 0.488 Units per Kg |
Secondary
Number of Adverse Events
Number of adverse events that were reported throughout the study.
Time frame: Adverse Events will be assessed at Visit 0 (week 0), Visit 1 (Week 2), Visit 2 (Week 4), and every month thereafter.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib Mesylate | Number of Adverse Events | 172 events |
| Placebo | Number of Adverse Events | 28 events |
Secondary
Number of Severe Hypoglycemic Events
Major hypoglycemic events occurring from randomization at weeks 0, 52 and 104.
Time frame: Visit 0 (Week 0), Visit 9 (Week 52), and Visit 13 (Week 104)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib Mesylate | Number of Severe Hypoglycemic Events | 2 events |
| Placebo | Number of Severe Hypoglycemic Events | 3 events |