Type 1 Diabetes
Conditions
Keywords
Type 1 diabetes, vitamin D, honeymoon phase
Brief summary
This project is designed to study the role of vitamin D supplementation on the honeymoon phase of type 1 diabetes in children who are on standardized insulin treatment. The results could lead to significant changes in the approach to the early phase of type 1 diabetes with a strong emphasis on prolonging the honeymoon phase by using vitamin D and maintaining these patients on a standardized insulin regimen. The overall goal is to reduce the long-term complications of type 1 diabetes.
Detailed description
Prolonging the duration of the partial clinical remission (PCR), or 'honeymoon' phase, of type 1 diabetes (T1D) improves glycemic control and reduces long-term complications. Recent studies suggest the exciting possibility that vitamin D supplementation, a safe and easy-to-implement therapy in children, may lengthen PCR and increase residual beta cell function (RBCF). However, existing studies employed a suboptimal vitamin D dose or lacked a standardized insulin treatment protocol, precluding solid conclusions and preventing the field from moving forward with translation to clinical practice. This trial's rationale is to securely establish the effect of an adequate dose of vitamin D on PCR and RBCF. We hypothesize that vitamin D will increase RBCF and prolong PCR. The primary aim is to determine the effect of adjunctive vitamin D on RBCF and PCR in youth with T1D maintained on a standardized insulin protocol. We propose a 12-month randomized, double-blind, placebo-controlled, parallel design trial of ergocalciferol vs. placebo in 40 subjects of 10-21 years with newly-diagnosed T1D. The primary outcome is the change over time in stimulated C-peptide (a measure of RBCF). Secondary outcomes include change over time in insulin-dose-adjusted-hemoglobin-A1c (HbA1c) (IDAA1C; a measure of PCR), HbA1c, and total daily dose of insulin. Mechanistic studies will explore whether beneficial effects of vitamin D are associated with increased GLP-1 levels or decreased inflammatory markers, and whether response to vitamin D is impacted by T1D-risk polymorphisms. If our hypotheses are true, these findings may completely alter the approach to the early management of T1D, with strong emphasis on prolonging the honeymoon phase using a readily available and easily affordable vitamin D while maintaining these patients on a standardized insulin treatment regimen.
Interventions
DRUGErgocalciferol
Each subject on the experimental arm will receive one capsule of ergocalciferol per week for 2 months; and then once every 2 weeks for 10 months
OTHERPlacebo
Each subject on the placebo arm will receive one capsule of placebo per week for 2 months; and then once every 2 weeks for 10 months
Sponsors
University of Massachusetts, Worcester
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Benjamin U. Nwosu, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Ergocalciferol and placebo will be prepared as identical capsules by Boulevard Pharmaceutical Compounding Center. Randomization will be conducted by the Investigational Drug Services (IDS), UMMS, using a randomization scheme generated by Dr. Barton. Randomization will be 1:1 (ergocalciferol: placebo) and will use a permuted block design with blocking for every 2 or 4 subjects (at random). IDS will maintain blinding information and PI will contact IDS for emergency unblinding.
Intervention model description
12-month randomized, double-blind, placebo-controlled, parallel design trial
Eligibility
Sex/Gender
ALL
Age
10 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Age: 10-21 years. 2. Sex: male and female subjects will be enrolled. 3. Tanner stage: I-V. 4. T1D duration of \<3 months (i.e., from first insulin injection) to ensure the inclusion of patients in PCR. 5. Presence of at least one diabetes-associated autoantibody. 6. Normal-weight, overweight-, and obese subjects with T1D 7. Fasting serum C-peptide level of \>0.1 nmol/L (0.3 ng/mL)1; or 2-hour post-meal stimulated C-peptide level of 0.2 nmol/L (≥0.6 ng/mL).
Exclusion criteria
1. Subjects on weight altering medications, such as orlistat. 2. Subjects with eating disorders 3. Subjects on medications other than insulin that can affect blood glucose level. 4. Subjects with 25-hydroxyvitamin D \[25(OH)D\] levels of \>70 ng/mL, as this may lead to vitamin D toxicity in the study subjects. 5. Subjects with systemic diseases other than T1D. 6. Subjects with recurrent diabetic ketoacidosis (\>2 episodes since the diagnosis of T1D or in the preceding 3 months); or \>2 episodes of severe hypoglycemia in the preceding 3 mo. 7. Pregnant or breast-feeding female subjects. 8. The receipt of any investigational drug within 6 months prior to this trial. 9. Active malignant neoplasm.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Residual Beta-cell Function (RBCF) | Baseline to 12 months at 3 months interval | Investigation of the effect of vitamin D on residual beta cell function (RBCF) in the first 12 months after the diagnosis of T1D by using stimulated C-peptide levels to quantify RBCF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucagon-like Peptide-1 (GLP-1) | Baseline to 12 months at 3 months interval | Investigation of the effect of vitamin D supplementation on GLP-1 during PCR. |
| Vitamin D Binding Protein (VDBP) | Baseline to 12 months at 3 months interval | Investigation of the effect of vitamin D supplementation on VDBP during PCR. |
| Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Baseline to 12 months | Effect of vitamin D supplementation on glycemic control during the partial clinical remission phase as shown by the change in percent HbA1c from baseline across longitudinal measurements at 0, 3, 6, 9, and 12 months. |
| Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Baseline to12 months 3 monthly | Insulin dose-adjusted hemoglobin A1c (HbA1c) (IDAA1C) |
Countries
United States
Participant flow
Pre-assignment details
Out of 48 enrolled participants, 36 met the inclusion criteria and were randomized to the treatment.
Participants by arm
| Arm | Count |
|---|---|
| Ergocalciferol Oral administration of 50,000 IU of ergocalciferol one capsule per week for 2 months; and then once every 2 weeks for 10 months in 20 subjects of 10-21yr with newly diagnosed T1D
Ergocalciferol: Each subject on the experimental arm will receive one capsule of ergocalciferol per week for 2 months; and then once every 2 weeks for 10 months | 18 |
| Placebo Oral administration of placebo one capsule per week for 2 months; and then once every 2 weeks for 10 months in 20 subjects of 10-21yr with newly diagnosed T1D
Placebo: Each subject on the placebo arm will receive one capsule of placebo per week for 2 months; and then once every 2 weeks for 10 months | 18 |
| Total | 36 |
Baseline characteristics
| Characteristic | Ergocalciferol | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 13.25 years STANDARD_DEVIATION 2.76 | 14.28 years STANDARD_DEVIATION 2.86 | 13.77 years STANDARD_DEVIATION 2.82 |
| Body mass index | 22.03 kg/m^2 STANDARD_DEVIATION 5.41 | 22.01 kg/m^2 STANDARD_DEVIATION 4.15 | 22.02 kg/m^2 STANDARD_DEVIATION 4.73 |
| Body mass index z-score | 0.89 Z-score STANDARD_DEVIATION 0.94 | 0.74 Z-score STANDARD_DEVIATION 0.68 | 0.82 Z-score STANDARD_DEVIATION 0.81 |
| diastolic blood pressure | 64.72 mmHg STANDARD_DEVIATION 9.14 | 64.67 mmHg STANDARD_DEVIATION 6.8 | 64.69 mmHg STANDARD_DEVIATION 7.94 |
| Fasting plasma glucose | 125.83 mg/dl STANDARD_DEVIATION 25 | 111.13 mg/dl STANDARD_DEVIATION 35.78 | 118.91 mg/dl STANDARD_DEVIATION 30.97 |
| HbA1C | 7.62 Percentage of HbA1C STANDARD_DEVIATION 1.35 | 7.47 Percentage of HbA1C STANDARD_DEVIATION 1.69 | 7.54 Percentage of HbA1C STANDARD_DEVIATION 1.52 |
| Height | 156.12 cm STANDARD_DEVIATION 12.77 | 158.65 cm STANDARD_DEVIATION 11.3 | 157.38 cm STANDARD_DEVIATION 11.96 |
| Height Z-score | 0.50 Z-score STANDARD_DEVIATION 0.73 | 0.48 Z-score STANDARD_DEVIATION 1.18 | 0.49 Z-score STANDARD_DEVIATION 0.96 |
| puberty stage, tanner II-V | 12 Participants | 10 Participants | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 12 Participants | 15 Participants | 27 Participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 10 Participants | 14 Participants | 24 Participants |
| systolic blood pressure | 104.94 mmHg STANDARD_DEVIATION 9.06 | 106.44 mmHg STANDARD_DEVIATION 10.6 | 105.69 mmHg STANDARD_DEVIATION 9.74 |
| Total Daily Dose Insulin | 0.51 units/kg/d STANDARD_DEVIATION 0.23 | 0.48 units/kg/d STANDARD_DEVIATION 0.23 | 0.50 units/kg/d STANDARD_DEVIATION 0.23 |
| Total Daily Dose Long-acting insulin only | 18.50 units STANDARD_DEVIATION 14.81 | 14.14 units STANDARD_DEVIATION 7.3 | 16.26 units STANDARD_DEVIATION 11.6 |
| Total Daily Dose (TDD) Insulin | 37 units/d STANDARD_DEVIATION 29.61 | 27.17 units/d STANDARD_DEVIATION 14.41 | 31.94 units/d STANDARD_DEVIATION 23.27 |
| Waist Circumference | 76.16 cm STANDARD_DEVIATION 14.83 | 76.22 cm STANDARD_DEVIATION 11.56 | 76.19 cm STANDARD_DEVIATION 13.14 |
| weight | 53.33 kg STANDARD_DEVIATION 15.19 | 56.16 kg STANDARD_DEVIATION 14.66 | 54.78 kg STANDARD_DEVIATION 14.77 |
| Weight z-score | 0.86 Z-score STANDARD_DEVIATION 0.81 | 0.67 Z-score STANDARD_DEVIATION 0.68 | 0.76 Z-score STANDARD_DEVIATION 0.74 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 1 / 18 | 5 / 18 |
| serious Total, serious adverse events | 7 / 18 | 3 / 18 |
Outcome results
Primary
Residual Beta-cell Function (RBCF)
Investigation of the effect of vitamin D on residual beta cell function (RBCF) in the first 12 months after the diagnosis of T1D by using stimulated C-peptide levels to quantify RBCF.
Time frame: Baseline to 12 months at 3 months interval
Population: individuals aged 10-21 years with newly diagnosed T1D in a 12-month RCT of ergocalciferol vs placebo to determine the effect of vitamin D on RBCF and PR in youth with newly diagnosed T1D.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ergocalciferol | Residual Beta-cell Function (RBCF) | Mo 3 | 1.56 ng/ml | Standard Error 0.25 |
| Ergocalciferol | Residual Beta-cell Function (RBCF) | Mo 9 | 1.25 ng/ml | Standard Error 0.24 |
| Ergocalciferol | Residual Beta-cell Function (RBCF) | Mo 6 | 1.40 ng/ml | Standard Error 0.26 |
| Ergocalciferol | Residual Beta-cell Function (RBCF) | Mo 12 | 1.05 ng/ml | Standard Error 0.22 |
| Ergocalciferol | Residual Beta-cell Function (RBCF) | Baseline | 1.78 ng/ml | Standard Error 0.28 |
| Placebo | Residual Beta-cell Function (RBCF) | Mo 12 | 1.15 ng/ml | Standard Error 0.29 |
| Placebo | Residual Beta-cell Function (RBCF) | Baseline | 2.27 ng/ml | Standard Error 0.31 |
| Placebo | Residual Beta-cell Function (RBCF) | Mo 3 | 1.76 ng/ml | Standard Error 0.21 |
| Placebo | Residual Beta-cell Function (RBCF) | Mo 6 | 1.53 ng/ml | Standard Error 0.25 |
| Placebo | Residual Beta-cell Function (RBCF) | Mo 9 | 1.36 ng/ml | Standard Error 0.31 |
p-value: <0.001generalized linear model with dependent
Secondary
Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR)
Effect of vitamin D supplementation on glycemic control during the partial clinical remission phase as shown by the change in percent HbA1c from baseline across longitudinal measurements at 0, 3, 6, 9, and 12 months.
Time frame: Baseline to 12 months
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ergocalciferol | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Mo 3 | 7.25 percent of HbA1C | Standard Error 0.37 |
| Ergocalciferol | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Mo 9 | 7.48 percent of HbA1C | Standard Error 0.35 |
| Ergocalciferol | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Mo 6 | 7.28 percent of HbA1C | Standard Error 0.27 |
| Ergocalciferol | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Mo 12 | 7.65 percent of HbA1C | Standard Error 0.57 |
| Ergocalciferol | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Baseline | 7.62 percent of HbA1C | Standard Error 0.32 |
| Placebo | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Mo 12 | 8.03 percent of HbA1C | Standard Error 0.41 |
| Placebo | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Baseline | 7.47 percent of HbA1C | Standard Error 0.39 |
| Placebo | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Mo 3 | 6.67 percent of HbA1C | Standard Error 0.28 |
| Placebo | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Mo 6 | 7.15 percent of HbA1C | Standard Error 0.34 |
| Placebo | Change in Percent of HbA1c From Baseline Over Time During Partial Clinical Remission (PCR) | Mo 9 | 7.61 percent of HbA1C | Standard Error 0.32 |
p-value: <0.01generalized linear model
Secondary
Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes
Insulin dose-adjusted hemoglobin A1c (HbA1c) (IDAA1C)
Time frame: Baseline to12 months 3 monthly
Population: individuals aged 10 to 21 years with newly diagnosed T1D in a 12-month RCT of ergocalciferol vs placebo to determine the effect of vitamin D on RBCF and PR in youth with newly diagnosed T1D.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ergocalciferol | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Mo 9 | 10.4 % of IDAA1c | Standard Error 0.5 |
| Ergocalciferol | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Mo 3 | 9.7 % of IDAA1c | Standard Error 0.6 |
| Ergocalciferol | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Baseline | 9.9 % of IDAA1c | Standard Error 0.4 |
| Ergocalciferol | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Mo 12 | 10.6 % of IDAA1c | Standard Error 0.6 |
| Ergocalciferol | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Mo 6 | 10.0 % of IDAA1c | Standard Error 0.5 |
| Placebo | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Mo 12 | 10.7 % of IDAA1c | Standard Error 0.6 |
| Placebo | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Mo 6 | 9 % of IDAA1c | Standard Error 0.5 |
| Placebo | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Mo 9 | 10.1 % of IDAA1c | Standard Error 0.5 |
| Placebo | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Baseline | 9.4 % of IDAA1c | Standard Error 0.6 |
| Placebo | Effect of Vitamin D Supplementation on the Duration of Partial Clinical Remission (PCR) of Type 1 Diabetes | Mo 3 | 8.4 % of IDAA1c | Standard Error 0.4 |
p-value: <0.001generalized linear model
Secondary
Glucagon-like Peptide-1 (GLP-1)
Investigation of the effect of vitamin D supplementation on GLP-1 during PCR.
Time frame: Baseline to 12 months at 3 months interval
Population: individuals aged 10-21 years with newly diagnosed T1D in a 12-month RCT of ergocalciferol vs placebo to determine the effect of vitamin D on RBCF and PR in youth with newly diagnosed T1D.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ergocalciferol | Glucagon-like Peptide-1 (GLP-1) | Mo 3 | 8.58 ng/ml | Standard Deviation 5.02 |
| Ergocalciferol | Glucagon-like Peptide-1 (GLP-1) | Mo 9 | 10.26 ng/ml | Standard Deviation 5.57 |
| Ergocalciferol | Glucagon-like Peptide-1 (GLP-1) | Mo 6 | 10.24 ng/ml | Standard Deviation 5.69 |
| Ergocalciferol | Glucagon-like Peptide-1 (GLP-1) | Mo 12 | 9.11 ng/ml | Standard Deviation 4.44 |
| Ergocalciferol | Glucagon-like Peptide-1 (GLP-1) | Baseline | 10.26 ng/ml | Standard Deviation 7.54 |
| Placebo | Glucagon-like Peptide-1 (GLP-1) | Mo 12 | 9.63 ng/ml | Standard Deviation 5.92 |
| Placebo | Glucagon-like Peptide-1 (GLP-1) | Baseline | 5.81 ng/ml | Standard Deviation 3.38 |
| Placebo | Glucagon-like Peptide-1 (GLP-1) | Mo 3 | 8.4 ng/ml | Standard Deviation 5.48 |
| Placebo | Glucagon-like Peptide-1 (GLP-1) | Mo 6 | 6.86 ng/ml | Standard Deviation 3.01 |
| Placebo | Glucagon-like Peptide-1 (GLP-1) | Mo 9 | 8.89 ng/ml | Standard Deviation 5.69 |
p-value: 0.024195% CI: [0.066, 0.947]General linear models
Secondary
Vitamin D Binding Protein (VDBP)
Investigation of the effect of vitamin D supplementation on VDBP during PCR.
Time frame: Baseline to 12 months at 3 months interval
Population: individuals aged 10-21 years with newly diagnosed T1D in a 12-month RCT of ergocalciferol vs placebo to determine the effect of vitamin D on RBCF and PR in youth with newly diagnosed T1D.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ergocalciferol | Vitamin D Binding Protein (VDBP) | Mo 12 | 141.34 ng/ml | Standard Deviation 32.8 |
| Ergocalciferol | Vitamin D Binding Protein (VDBP) | Baseline | 134.32 ng/ml | Standard Deviation 22.82 |
| Ergocalciferol | Vitamin D Binding Protein (VDBP) | Mo 6 | 135.32 ng/ml | Standard Deviation 27.51 |
| Ergocalciferol | Vitamin D Binding Protein (VDBP) | Mo 3 | 118.11 ng/ml | Standard Deviation 27.93 |
| Ergocalciferol | Vitamin D Binding Protein (VDBP) | Mo 9 | 135.79 ng/ml | Standard Deviation 38.47 |
| Placebo | Vitamin D Binding Protein (VDBP) | Mo 12 | 152.42 ng/ml | Standard Deviation 31.19 |
| Placebo | Vitamin D Binding Protein (VDBP) | Mo 9 | 131.51 ng/ml | Standard Deviation 38.86 |
| Placebo | Vitamin D Binding Protein (VDBP) | Mo 3 | 118.79 ng/ml | Standard Deviation 22.96 |
| Placebo | Vitamin D Binding Protein (VDBP) | Mo 6 | 138.18 ng/ml | Standard Deviation 33.15 |
| Placebo | Vitamin D Binding Protein (VDBP) | Baseline | 111.56 ng/ml | Standard Deviation 28.82 |
p-value: 0.2395% CI: [-6.4, 27.13]Regression, Linear