Study protocol: design and rationale for an exploratory phase II randomized controlled trial to determine optimal vitamin D(3) supplementation strategies for acute fracture healing

BACKGROUND: Observational studies have found that 75% of healthy adult fracture patients (ages 18–50) have serum 25-hydroxyvitamin D (25(OH)D) levels < 30 ng/mL. Although lower serum 25(OH)D levels have yet to be correlated to fracture healing complications or poor fracture outcomes, many orthopedic surgeons are routinely prescribing vitamin D supplements to improve fracture healing in healthy non-osteoporotic patients. To address this gap in the literature, we propose a phase II exploratory randomized controlled trial comparing three vitamin D(3) dosing regimens for early surrogate treatment response. METHODS: We will conduct a 4-arm blinded exploratory phase II trial in 96 adults aged 18–50 years with a closed or low-grade open (Gustilo type I or II) tibial or femoral shaft fracture. Eligible patients will be randomized in equal allocation ratio of 1:1:1:1 to one of the treatment groups: (1) 150,000 IU loading dose vitamin D(3) plus daily dose placebo; (2) loading dose placebo plus 4000 IU vitamin D(3) per day, (3) loading dose placebo plus 600 IU vitamin D(3) per day, or (4) loading dose placebo plus daily dose placebo. The primary outcome is fracture healing, assessed as follows: (1) clinical fracture healing measured using the Function IndeX for Trauma, (2) radiographic fracture healing measured using the Radiographic Union Score for Tibial fractures, and (3) biological fracture healing measured using serum levels of cross-linked C-terminal telopeptides of type I collagen and amino-terminal procollagen propeptides of collagen type I. The main secondary outcome will be assessed by measuring serum 25(OH)D levels. All outcome analyses will be exploratory and adhere to the intention-to-treat principle. Per-protocol sensitivity analyses will also be conducted. DISCUSSION: Study results will be disseminated through a publication in an academic journal and presentations at orthopedic conferences. Study results will inform dose selection for a large definitive randomized controlled trial and provide preliminary clinical data on which dose may improve acute fracture healing outcomes in healthy adult patients (18–50 years) at 3 months. TRIAL REGISTRATION: Vita-Shock (A Blinded Exploratory Randomized Controlled Trial to Determine Optimal Vitamin D(3) Supplementation Strategies for Acute Fracture Healing) was registered at ClinicalTrials.gov (identifier NCT02786498) prior to enrollment of participants.