Vitamin D and Type 2 Diabetes - Treat-To-Target (D2d-TTT)

Vitamin D and Type 2 Diabetes, Treat-To-Target

This study tests whether taking a weekly dose of vitamin D, with the dose adjusted to reach a target blood vitamin D level, can help control blood sugar levels in adults at high risk of developing type 2 diabetes (prediabetes).

Research suggests that vitamin D may play a role in blood sugar control. The goal of this study is to see whether adjusting the dose of vitamin D to reach a specific blood vitamin D level improves blood sugar control compared with a placebo (a look-alike pill without vitamin D).

One hundred adults aged 30 to 74 with prediabetes will take part. Participants will be randomly assigned (by chance) to receive either weekly vitamin D supplements or a placebo. Neither the participants nor the research team will know which group a participant is in during the study.

Participants in the vitamin D group will start with one specific dose. After three months, a blood test will be used to decide whether the dose should stay the same or be increased to reach the target vitamin D level. Participants in the placebo group will continue taking the placebo each week.

All participants will be followed for about 18 months. During the study, they will attend scheduled study visits, have blood tests, and wear a continuous glucose monitor, a small device that measures blood sugar levels throughout the day and night. The research team will also make periodic phone calls to check on health changes, medication use, and study participation.

The main outcome of the study is the proportion of time that the participants' blood sugar levels remains in a healthy range.

Study Overview

• Status: Not yet recruiting
• Conditions: Prediabetes; Type 2 Diabetes (T2DM)
• Intervention / Treatment: Drug: Vitamin D (Cholecalciferol ); Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Tufts Medical Center Endocrine Research Team; Phone Number: 617-636-3232; Email: endocrine-research@tuftsmedicine.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
      • Contact: Tufts Medical Center Endocrine Research Team; Phone Number: 617-636-3232; Email: endocrine-research@tuftsmedicine.org
      • Principal Investigator: Anastassios Pittas, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. High-risk prediabetes ("at high risk for type 2 diabetes") defined by meeting the following 2 prediabetes criteria established by the American Diabetes Association (ADA) in the 2010 clinical practice guidelines:

   1. Fasting plasma glucose (FPG) 100-125 mg/dL, inclusive
   2. Hemoglobin A1c (HbA1c) 5.7-6.4%, inclusive
2. Age 30-74 years, inclusive
3. Body Mass Index ≥ 23.0 and ≤ 35.0 kg/m2

4. Provision of signed and dated written informed consent prior to any study procedures.

   Exclusion Criteria:

5. History of diabetes (ICD10 diabetes code E08.X through E13.X) or meeting a diabetes glycemic criterion at screening, as defined by the ADA guidelines (FPG ≥ 126 mg/dL or HbA1c ≥ 6.5%).
6. History (past 2 years) of hyperparathyroidism, symptomatic or asymptomatic (i.e., radiographic) nephrolithiasis or hypercalcemia.
7. Any medical condition (past 2 years) that in the opinion of the site investigator may increase risk for nephrolithiasis or hypercalcemia during the trial (e.g., sarcoidosis).
8. If older than 70 years, history (past 1 year) of a fall.

9. Use of tanning devices within 12 weeks of the baseline visit and unwilling to stop use of tanning devices for the duration of the study.

   Medications and Supplements

10. Use (past 6 months) of hypoglycemic pharmacotherapy (oral or injectable medication approved by the FDA for type 2 diabetes) for any condition (e.g., prediabetes, diabetes, polycystic ovarian syndrome, MASLD, sleep apnea) or any other medication that may affect glycemia (e.g., hydroxychloroquine)
11. Current use of medications approved by the FDA for weight management (e.g., incretin receptor agonists) or planned use during the study.
12. Use of supplements containing vitamin D at total doses higher than 1000 IU/day within 8 weeks of the baseline visit and unwillingness to limit vitamin D supplementation dosage to no higher than 1000 IU/day during the study. Because supplements vary widely in vitamin D content (e.g., may include cod liver or cod liver oi), participants will bring all supplements to the site for a review by the research team.
13. Use of supplements containing calcium at total doses higher than 600 mg/day within 1 week of the baseline visit and unwillingness to limit calcium supplementation dosage to no higher than 600 mg/day during the study.
14. Current use of medications or conditions (e.g., untreated celiac disease) that would interfere with the absorption or metabolism of vitamin D.
15. Use of an anticonvulsant drug started within 6 months of screening. Stable regimen of anticonvulsants is allowed.

16. History of intolerance to vitamin D supplements, allergic to any content of the study drug or unwilling to take vitamin D supplements (e.g., someone who eats a vegan diet and would object to the cholecalciferol ingredient which is produced from cholesterol extracted from sheep wool harvested from healthy living sheep).

    Other Medical History

17. Severe symptomatic cardiovascular disease based on history (unstable angina, dyspnea on exertion, paroxysmal nocturnal dyspnea, arrhythmia, congestive heart failure NYHA class II or higher, claudication)
18. History (past 1 year) of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft.
19. History (past 1 year) of cerebrovascular disease (stroke, transient ischemic attack).
20. Any type of cancer (past 5 years) except for basal cell skin cancer. Prostate cancer (for men over age 55) or well-differentiated thyroid cancer not expected to require treatment (except for suppression with thyroid hormone) over the next 3 years, are not exclusions. People with history of squamous cell cancer of the skin, which was completely excised and with no evidence of metastases, are eligible.
21. History (past 6 months) of treatment with oral (for > 7 days) or intravenous glucocorticoids or disease likely to require oral or intravenous glucocorticoid therapy during the study. Inhaled glucocorticoid use is not an exclusion. Epidural or intra-articular glucocorticoid injections are not exclusions, but study visits need to be conducted at least two weeks after the injection. Persons with adrenal insufficiency treated with physiologic doses of glucocorticoids who are otherwise stable are not excluded.
22. History (past 1 year) of substance abuse or unstable psychiatric disorder that in the opinion of the site investigator would impede competence or adherence with study procedures or hinder completion of the study or increase risk.
23. History of bariatric surgery (e.g., Roux-en-Y gastric bypass, gastric sleeve) or planned bariatric surgery in the next 2 years.
24. Extreme (over 18 hours) intermittent fasting diets because prolonged fasting downregulates CYP2R1 activity.
25. A life-threatening event within 30 days of screening or currently planned major surgery.
26. Any other active medical condition (including but not limited to liver disease, wasting illness, HIV, tuberculosis, oxygen-dependent chronic obstructive pulmonary disease, organ transplant, Cushing's syndrome) that in the opinion of the site investigators would interfere with the study objectives, impede competence or adherence with study procedures or increase risk.
27. Uncontrolled hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg).

28. Poor venous access.

    Laboratory Evaluation

29. Serum liver transaminase higher than 3 times the normal range for the clinical site's laboratory, within 18 months of screening.
30. Anemia (hematocrit < 32 for women, < 36 for men), whole blood transfusion (within 18 months of screening) or chronic requirement, whole blood donation (within 3 months of screening) or other condition (hemolysis, hemoglobinopathy) rendering HbA1c results unreliable as indicator of chronic glycemia. Participants who donate platelets are not excluded.
31. Low platelet count (< 100,000) within 18 months of screening.
32. Chronic kidney disease, defined as estimated glomerular filtration rate [GFR] < 50 mL/min per 1.73 m2 from creatinine level and GFR calculated by the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations that omit race within 18 months of screening.
33. Hypercalcemia, defined as serum calcium concentration ≥ upper limit of normal within 18 months of screening.
34. Hypercalciuria, defined as spot urine (morning void) calcium-creatinine ratio > 0.275 within 18 months of screening.

35. Baseline serum 25(OH)D level greater than 100 ng/mL.

    Other

36. Participation (within 30 days of screening) in another interventional research study, and unwillingness to refrain from participating in another intervention study during the study.
37. Previous randomization in the study. Participants who did not qualify after screening may be screened again if the prior reason for exclusion has been addressed (e.g., high blood pressure is treated).

38. Any other reason that in the opinion of the site investigator would interfere with the study objectives, impede adherence with study procedures or hinder completion of the study or increase risk.

    Women only

39. Pregnancy (past 1 year by report or positive pregnancy test at screening), intent to become pregnant in the next 2 years. History of gestational diabetes is not an exclusion criterion.
40. Currently breastfeeding.

41. Use of oral contraceptives or menopausal hormone therapy started within 3 months of baseline. .

    Continuous Glucose Monitoring specific

42. Regular use of personal CGM and unwillingness to refrain from using personal CGM for the duration of the study.
43. Use of hydroxyurea or regular use of high doses of acetaminophen (may impact CGM).
44. Extensive skin changes (e.g., skin breakdown, rash) making CGM sensor use problematic.
45. Significant skin sensitivity to adhesive (making CGM sensor unfeasible).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Vitamin D; Participants will receive oral vitamin D (cholecalciferol) once weekly throughout the study.	Drug: Vitamin D (Cholecalciferol ); Vitamin D (cholecalciferol) will be administered orally once weekly for approximately 18 months. The vitamin D will be provided in liquid form in an ampule. Participants in the intervention group will begin with a dose of 25,000 IU per week. A blood vitamin D level will be measured at 3 months, and the dose will be increased to 50,000 IU per week for participants whose results are below the study target.
Placebo Comparator: Placebo; Participants in this arm will receive an oral placebo taken once weekly throughout the study.	Drug: Placebo; Placebo will be administered orally once weekly for approximately 18 months. The placebo will be provided in an ampule and will be matched in appearance, dosing schedule, and duration to the active study medication.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-in-normoglycemia 140	The cumulative proportion of time that a participant's glucose level is below 140 mg/dL at each CGM measurement period.	Assessed every 6 months from enrollment to the end of the study at 18 months.
Time-In-Normoglycemia 126	The cumulative proportion of time that a participant's glucose level is below 126 mg/dL at each CGM measurement period.	Assessed every 6 months from enrollment to the end of the study at 18 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean glycemia (mg/dL)	The average glucose level at each CGM measurement period.	Assessed every 6 months from enrollment to the end of the study at 18 months
Glycemic variability	Glycemic variability will be assessed using the mean amplitude of glycemic excursions at each CGM measurement period.	Assessed every 6 months from enrollment to the end of the study at 18 months
Hemoglobin A1c (%)		Assessed every 6 months from enrollment to the end of the study at 18 months.
Fasting plasma glucose (mg/dL)		Assessed every 6 months from enrollment to the end of the study at 18 months.
Hypercalcemia		Assessed every 6 months from enrollment to the end of the study at 18 months.
Hypercalciuria		Assessed every 6 months from enrollment to the end of the study at 18 months.
Atherosclerotic cardiovascular risk	Atherosclerotic cardiovascular risk, assessed by the PREVENT risk calculator. The calculator requires a lipid profile and a urine albumin creatinine ratio. Higher PREVENT values generally indicate higher estimated cardiovascular risk.	Assessed at baseline, month 12 and month 18

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin resistance	Insulin resistance by the homeostasis model assessment (HOMA-IR). Higher HOMA-IR values generally indicate greater estimated insulin resistance.	Assessed at baseline, 12 months, and 18 months.
Insulin secretion	Insulin secretion by the homeostasis model assessment (HOMA-beta). Higher HOMA beta values generally indicate greater estimated pancreatic β-cell insulin secretion.	Assessed from enrollment to the end of study at 18 months.

Collaborators and Investigators

• Sponsor: Tufts Medical Center
• Collaborators: Abiogen Pharma

Publications and helpful links

General Publications

• Chatterjee R, Davenport CA, Vickery EM, Johnson KC, Kashyap SR, LeBlanc ES, Nelson J, Dagogo-Jack S, Pittas AG, Hughes BD; D2d Research Group. Effect of intratrial mean 25(OH)D concentration on diabetes risk, by race and weight: an ancillary analysis in the D2d study. Am J Clin Nutr. 2023 Jul;118(1):59-67. doi: 10.1016/j.ajcnut.2023.03.021. Epub 2023 Mar 29.
• Pittas AG, Kawahara T, Jorde R, Dawson-Hughes B, Vickery EM, Angellotti E, Nelson J, Trikalinos TA, Balk EM. Vitamin D and Risk for Type 2 Diabetes in People With Prediabetes : A Systematic Review and Meta-analysis of Individual Participant Data From 3 Randomized Clinical Trials. Ann Intern Med. 2023 Mar;176(3):355-363. doi: 10.7326/M22-3018. Epub 2023 Feb 7.
• Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, Brodsky I, Ceglia L, Chadha C, Chatterjee R, Desouza C, Dolor R, Foreyt J, Fuss P, Ghazi A, Hsia DS, Johnson KC, Kashyap SR, Kim S, LeBlanc ES, Lewis MR, Liao E, Neff LM, Nelson J, O'Neil P, Park J, Peters A, Phillips LS, Pratley R, Raskin P, Rasouli N, Robbins D, Rosen C, Vickery EM, Staten M; D2d Research Group. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019 Aug 8;381(6):520-530. doi: 10.1056/NEJMoa1900906. Epub 2019 Jun 7.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: January 16, 2026
• First Submitted That Met QC Criteria: February 26, 2026
• First Posted (Actual): March 4, 2026

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: type 2 diabetes; vitamin D; diabetes prevention; prediabetes; continuous glucose monitoring; cholecalciferol
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Prediabetic State; Lipids; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Cholestenes; Cholestanes; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Cholecalciferol
• Other Study ID Numbers: D2d-TTT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Consistent with the International Committee of Medical Journal Editors (ICMJE) policy, we will make de-identified individual participant data available, following publication, upon reasonable request to qualified investigators who provide a methodologically sound proposal and agree to a data use agreement to protect participant confidentiality. A data dictionary (a description of the variables collected for each individual) will be provided so that the data can be fully interpreted.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No