Conditions: Fracture
Keywords: Tibial Shaft Tibia Femoral Shaft Femur Vitamin D Fracture Healing
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
Healthy volunteers: no

Brief summary:
The objective is to determine the effect of vitamin D3 supplementation on fracture healing at 3 months.

Detailed description:
Vitamin D supplements are increasingly being recommended to healthy adult fracture patients without an osteoporotic injury. Although this is a relatively new practice pattern, the basis for this adjunct therapy is grounded in the high hypovitaminosis D prevalence rates (up to 75%) among healthy adult fracture patients, and the strong biologic rationale for the role of vitamin D in fracture healing. Briefly, experimental animal studies have demonstrated that the concentration of vitamin D metabolites is higher at a fracture callus compared to the uninjured contralateral bone, vitamin D supplementation leads to decreased time to union and increased callus vascularity, and increases mechanical bone strength compared to controls. While evidence to confirm that vitamin D supplementation improves fracture healing in clinical studies does not exist, the pre-clinical data are compelling and worthy of further investigation.

With modern orthopaedic surgical care, rates of complications following tibia and femoral shaft fractures can be as high as 15%. Complications, including delayed union, nonunion, or infection often require secondary surgical procedures and result in profound personal and societal economic costs. While surgeons continue to seek advances in surgical technique, it is becoming increasingly obvious that innovations in orthopaedic techniques or implants are unlikely to eliminate complications. As a result, considerable attention is currently focused on adjunct biologic therapies, such as vitamin D.

A recent survey of 397 orthopaedic surgeons showed that only 26% routinely prescribe vitamin D supplementation to adult fracture patients. Of the 93 surgeons who indicated that they routinely prescribe vitamin D supplementation, 29 different dosing regimens were described ranging from low daily doses of 400 IU to loading doses of 600,000 IU. This suggests a high level of clinical uncertainty surrounding the use and optimal dose of vitamin D supplementation in adult fracture patients. If vitamin D supplementation improves fracture healing outcomes, then there is a large opportunity to increase its use; however, before widespread adoption occurs, research is needed to optimize the dosing strategy, establish the dosing safety in the immobilized fracture healing population, and overcome potential medication adherence issues among the often marginalized patients that suffer trauma.

The long-term goal of our research program is to conduct a large phase III RCT to determine which dose of vitamin D3 supplementation optimally improves acute fracture healing outcomes in healthy adult patients (18-50 years). The current proposed phase II exploratory trial will perform important preliminary work to test the central hypothesis that vitamin D3 dose and timing of administration is critical for improving fracture healing at 3 months. This trial will also inform the feasibility of the large phase III RCT.

Arms:
arm 1: 150,000 IU loading dose vitamin D3 at enrolment and 6 weeks, plus daily dose placebo for 3 months. arm 2: Loading dose placebo at enrolment and 6 weeks, plus 4,000 IU vitamin D3 per day for 3 months. arm 3: Loading dose placebo at enrolment and 6 weeks, plus 600 IU vitamin D3 per day for 3 months. arm 4: Loading dose placebo at enrolment and 6 weeks, plus daily dose placebo for 3 months.

Interventions: intervention 1: Vitamin D3 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Version 2.0 12-Mar-2018 
 
 
A Blinded Exploratory Randomized Controlled Trial to Determine Optimal 
Vitamin D3 Supplementation Strategies for Acute Fracture Healing 
 
 
 
Principal Investigator: 
Dr. Gerard Slobogean  
 
Co-Principal Investigator: 
Dr. Sheila Sprague 
 
 
 
Vita-Shock PROTOCOL 
 
Version: 2.0  
 
Date: 12-Mar-2018 
 
 
The Vita-Shock study will be coordinated jointly by the University of Maryland, Baltimore 
and McMaster University as it is part of an ongoing research program looking at vitamin 
D in fracture patients.  The protocol is the confidential intellectual property of the Principal 
Investigators and study team cannot be used in any form without the expressed written 
permission of the Principal Investigators. 
 
Reviewed and Approved by: 
 
 
Dr. Gerard Slobogean  
(Principal Investigator) 
Signature: 
Date: 
 
Dr. Sheila Sprague  
(Principal Investigator) 
Signature: 
 
Date: 
 


Page 2 of 30 
Version 2.0 12-Mar-2018 
TABLE OF CONTENTS  
 
LIST OF ABBREVIATIONS .......................................................................................... 4 
STUDY SUMMARY ......................................................................................................... 5 
1.0 INTRODUCTION ....................................................................................................... 7 
2.0 STUDY AIMS AND OBJECTIVES .......................................................................... 8 
2.1 Primary Aim .............................................................................................................. 8 
2.2 Secondary Aim .......................................................................................................... 8 
2.3 Other Secondary Objective ....................................................................................... 8 
2.4 Hypotheses for the Primary and Secondary Objectives ............................................ 8 
3.0 METHODS .................................................................................................................. 9 
3.1 Study Setting ............................................................................................................. 9 
3.2 Eligibility Criteria ..................................................................................................... 9 
3.3 Recruitment Strategy and Patient Screening ............................................................. 9 
3.4 Randomization Methods ......................................................................................... 10 
3.5 Vitamin D3 (Cholecalciferol) Treatment Groups .................................................... 10 
3.5.1 Blinded administration ..................................................................................... 10 
3.5.2 Vitamin D3 dose rationale ................................................................................ 10 
3.5.3 Storage and administration............................................................................... 11 
3.5.4 Potential adverse events associated with vitamin D ........................................ 12 
3.5.5 Concomitant calcium supplementation ............................................................ 12 
3.6 Surgical Technique and Post-Operative Rehabilitation .......................................... 12 
3.6.1 Surgical technique ............................................................................................ 12 
3.6.2 Post-operative rehabilitation ............................................................................ 13 
3.7 Primary and Secondary Outcome Measures ........................................................... 13 
3.7.1 Primary outcome .............................................................................................. 13 
3.7.2 Secondary outcome .......................................................................................... 14 
3.7.3 Other secondary outcomes ............................................................................... 14 
3.7.4 Data collection and participant follow-up ........................................................ 14 
3.7.5 Analysis of blood samples ............................................................................... 15 
3.7.6 Analysis of radiographs ................................................................................... 15 
3.8 Participant Retention ............................................................................................... 15 
4.0 STATISTICAL PLAN .............................................................................................. 16 
4.1 Sample Size Determination ..................................................................................... 16 
4.2 Statistical Methods .................................................................................................. 16 
4.2.1 Specific Aim .................................................................................................... 16 
4.2.2 Secondary Aim ................................................................................................. 16 
4.2.3 Other Secondary Outcomes ............................................................................. 17 
4.2.4 As Treated Sensitivity Analyses ...................................................................... 17 
5.0 DATA MANAGEMENT .......................................................................................... 17 
6.0 ETHICS AND DISSEMINATION .......................................................................... 17 
6.1 Research Ethics Approval ....................................................................................... 17 
6.2 Consent.................................................................................................................... 17 
6.3 Confidentiality ........................................................................................................ 18 
6.4 Protocol Amendments ............................................................................................. 18 
6.5 Adverse Event Reporting and Definitions .............................................................. 18 


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6.5.1 Adverse event ................................................................................................... 18 
6.5.2 Serious adverse event ....................................................................................... 18 
6.5.3 Unanticipated problems resulting in risk to participant or others .................... 19 
6.5.4 Adverse drug reactions..................................................................................... 19 
6.6 Dissemination Policy .............................................................................................. 19 
Table 1: Schedule of Events ........................................................................................... 20 
Table 2: Primary Outcome Analysis ............................................................................. 21 
Table 3: Secondary Outcome Analysis.......................................................................... 22 
Table 4: Other Secondary Outcomes Analysis ............................................................. 23 
Figure 1: Femur Fracture .............................................................................................. 24 
Figure 2: Tibia Fracture ................................................................................................. 25 
Figure 3: Unblinding of Personnel for Emergency Medical Management ................ 26 
Figure 4:  Retention Strategies ...................................................................................... 27 
7.0 REFERENCES .......................................................................................................... 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 4 of 30 
Version 2.0 12-Mar-2018 
LIST OF ABBREVIATIONS  
Abbreviation 
Explanation 
AE 
Adverse Event 
ASBMR 
American Society for Bone and Mineral Research  
CEO 
Center for Evidence-Based Orthopaedics 
CDC 
Centers for Disease Control and Prevention  
CI 
Confidence Interval 
CRF 
Case Report Form  
CTX 
C-Terminal Telopeptides of Type I Collagen  
FDA 
US Food and Drug Administration  
FIX-IT 
Function IndeX for Trauma 
IRB 
Institutional Review Board 
PACS 
Picture Archiving and Communication System 
PHI 
Personal Health Information 
PINP 
Amino-Terminal Procollagen Propeptides of Collagen Type I 
PTH 
Parathyroid Hormone 
RCT 
Randomized Controlled Trial 
REB 
Research Ethics Board 
RUST 
Radiographic Union Score for Tibial fractures 
SAE 
Serious Adverse Event  
SD 
Standard Deviation 
STC 
R Adams Cowley Shock Trauma Center 
25(OH)D 
25-hydroxy vitamin D 


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Version 2.0 12-Mar-2018 
STUDY SUMMARY   
 
Methodology 
Phase II exploratory randomized controlled trial (RCT) 
Coordinating Center 
Center for Evidence-Based Orthopaedics (CEO), McMaster 
University, Hamilton, ON 
Clinical Site 
R Adams Cowley Shock Trauma Center (STC), Baltimore, 
MD 
Primary Aim 
The primary objective is to determine the effect of vitamin D3 
supplementation on fracture healing at 3 months. 
Secondary Aim 
The secondary objective is to determine if 25-hydroxy vitamin 
D [25(OH)D] serum levels are associated with fracture healing 
at 3 months.  
Other Secondary 
Objective 
The other secondary objective is to confirm study protocol 
feasibility for a larger definitive phase III efficacy RCT to 
determine the optimal vitamin D3 dosing regimen to reduce re-
operations for fracture healing complications in healthy adult 
patients.  
Diagnosis and Main 
Inclusion Criteria 
Healthy adults ages 18-50 years with non-osteoporotic 
femoral or tibial shaft fractures who are treated with 
intramedullary fixation will be enrolled. Only acute fractures 
will be eligible. 
Treatment Groups and 
Study Products 
Each participant will be randomized to 1 of 4 treatment 
groups: 1) 150,000 IU loading dose vitamin D3 plus daily dose 
placebo; 2) loading dose placebo plus 4,000 IU vitamin D3 per 
day; 3) loading dose placebo plus 600 IU vitamin D3 per day; 
or 4) loading dose placebo plus daily dose placebo. All doses 
of vitamin D3 supplements/placebo will be provided in a 
blinded manner. The daily treatment will commence within 1 
week of injury and will be taken for 3 months.  The loading 
dose vitamin D3 supplements/placebo will be given within 1 
week of injury and at 6 weeks post-injury. All doses of vitamin 
D3 and the placebo will be obtained from Bio-Tech Pharmacal, 
Inc. (Fayetteville, AK). 
Length of Follow-Up  
The primary outcome will be assessed at 3 months post-
fracture. Participants will be followed for 12 months.   


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Version 2.0 12-Mar-2018 
 
 
 
 
 
Study Outcomes 
Fracture healing (primary outcome) will be assessed as 
follows: 1) clinical fracture healing will be measured using the 
Function IndeX for Trauma (FIX-IT), 2) radiographic fracture 
healing will be measured using the Radiographic Union Score 
for Tibial fractures (RUST), and 3) biological fracture healing 
will be measured using serum levels of cross-linked C-
terminal telopeptides of type I collagen (CTX) and amino-
terminal procollagen propeptides of collagen type I (PINP).  
 
The secondary outcome will be assessed by measuring 
25(OH)D serum levels.  Correlations will be assessed between 
participants’ 25(OH)D levels at enrolment, changes in 
25(OH)D levels from enrolment to 3 months, and 25(OH)D 
levels at 3 months and fracture healing as described above. 
 
The other secondary outcomes will include assessing 
supplementation adherence between daily and loading doses, 
confirming participant safety as measured by adverse events 
(AEs) and serum levels of calcium and parathyroid hormone 
(PTH), and assessing protocol adherence (e.g. completion of 
outcome assessment and participant follow-up). 
Sample Size 
96 patients will be included.  


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1.0 INTRODUCTION 
 
Vitamin D supplements are increasingly being recommended to healthy adult fracture 
patients without an osteoporotic injury.1 Although this is a relatively new practice pattern, 
the basis for this adjunct therapy is grounded in the high hypovitaminosis D prevalence 
rates (up to 75%) among healthy adult fracture patients,1 and the strong biologic rationale 
for the role of vitamin D in fracture healing.2–6  Briefly, experimental animal studies have 
demonstrated that the concentration of vitamin D metabolites is higher at a fracture callus 
compared to the uninjured contralateral bone,3–5 vitamin D supplementation leads to 
decreased time to union and increased callus vascularity,2 and increases mechanical bone 
strength compared to controls.6 While evidence to confirm that vitamin D supplementation 
improves fracture healing in clinical studies does not exist, the pre-clinical data are 
compelling and worthy of further investigation. 
 
With modern orthopaedic surgical care, rates of complications following tibia and femoral 
shaft fractures can be as high as 15%. Complications, including delayed union, nonunion, 
or infection often require secondary surgical procedures7–9 and result in profound personal 
and societal economic costs.10–12 While surgeons continue to seek advances in surgical 
technique, it is becoming increasingly obvious that innovations in orthopaedic techniques 
or implants are unlikely to eliminate complications.13 As a result, considerable attention is 
currently focused on adjunct biologic therapies, such as vitamin D.14–16  
 
A recent survey of 397 orthopaedic surgeons showed that only 26% routinely prescribe 
vitamin D supplementation to adult fracture patients.17 Of the 93 surgeons who indicated 
that they routinely prescribe vitamin D supplementation, 29 different dosing regimens were 
described ranging from low daily doses of 400 IU to loading doses of 600,000 IU.17 This 
suggests a high level of clinical uncertainty surrounding the use and optimal dose of 
vitamin D supplementation in adult fracture patients. If vitamin D supplementation 
improves fracture healing outcomes, then there is a large opportunity to increase its use; 
however, before widespread adoption occurs, research is needed to optimize the dosing 
strategy, establish the dosing safety in the immobilized fracture healing population, and 
overcome potential medication adherence issues among the often-marginalized patients 
that suffer trauma. 
 
The long-term goal of our research program is to conduct a large phase III RCT to 
determine which dose of vitamin D3 supplementation optimally improves acute fracture 
healing outcomes in healthy adult patients (18-50 years). The current proposed phase II 
exploratory trial will perform important preliminary work to test the central hypothesis that 
vitamin D3 dose and timing of administration is critical for improving fracture healing at 3 
months. This trial will also inform the feasibility of the large phase III RCT. This trial is 
registered at clinicaltrials.gov (Identifier number: NCT02786498). 
 
 


Page 8 of 30 
Version 2.0 12-Mar-2018 
2.0 STUDY AIMS AND OBJECTIVES 
 
2.1 Primary Aim 
The primary aim is to assess the effect of vitamin D3 supplementation on fracture healing 
at 3 months.  Fracture healing will be assessed as follows: 1) clinical fracture healing will 
be measured using the Function IndeX for Trauma (FIX-IT),18 2) radiographic fracture 
healing will be measured using the Radiographic Union Score for Tibial fractures 
(RUST),19–22 and 3) biological fracture healing will be measured using serum levels of 
cross-linked C-terminal telopeptides of type I collagen (CTX) and amino-terminal 
procollagen propeptides of collagen type I (PINP).23  
 
2.2 Secondary Aim 
The secondary aim is to determine if 25(OH)D serum levels are associated with fracture 
healing at 3 months. 
 
2.3 Other Secondary Objective 
The other secondary objective is to confirm study protocol feasibility for a larger definitive 
phase III efficacy RCT to determine the optimal vitamin D3 dosing regimen to reduce re-
operations for fracture healing complications in healthy adult patients.  
 
2.4 Hypotheses for the Primary and Secondary Objectives 
Primary Objective: Lower extremity shaft fractures heal via callus formation and 
secondary bone healing. This seminal process begins within a few weeks of injury and 
vitamin D metabolites have been extensively implicated in this stage of healing. During 
these early weeks, circulating vitamin D levels are most likely to be critical to bone healing; 
therefore, we hypothesize:  
1) High doses (loading or daily) will increase healing compared to low daily dose. Using 
high doses will rapidly increase the circulating vitamin D available during fracture 
callus formation.  
2) High loading dose increases healing compared to high daily dose. Loading doses will 
overcome medication adherence issues and increase circulating vitamin D even more 
rapidly than daily doses.  
3) Low daily dose will increase healing compared to placebo. While the low daily dose is 
not expected to increase circulating vitamin D as rapidly as the high dose strategies, 
this comparison will determine if rapid serum increases are necessary to improve 
fracture healing.  
 
Secondary Objective: Based on experimental data and the role of vitamin D on bone 
metabolism, a correlation between circulating vitamin D levels and fracture healing is 
expected; however, the efficacy of various supplementation strategies may be dependent 
on the patient’s baseline vitamin D status or other related changes. For example, it is known 
that the dose response of supplementation varies depending on the patient’s serum 
25(OH)D levels, with larger increases seen in patients with serum levels <20ng/ml.  
 


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Version 2.0 12-Mar-2018 
3.0 METHODS 
 
3.1 Study Setting 
This study will be coordinated jointly by the University of Maryland, R Adams Cowley 
Shock Trauma Center (STC), Baltimore, MD and McMaster University, Center for 
Evidence-Based Orthopaedics (CEO), Hamilton, ON. Patients will be enrolled from the 
STC. The CEO will be responsible for the protocol, data management, and data analysis.   
 
3.2 Eligibility Criteria 
The inclusion criteria are: 1) adult men or women ages 18-50 years; 2) closed or low grade 
open (Gustilo type I or II) tibial or femoral shaft fracture;24 3) fracture treated with a 
reamed, locked, intramedullary nail; 4) acute fracture (enrolled within 7 days of injury); 
and 5) provision of informed consent. Fifty years was selected as the upper age limit to 
minimize potential confounding with post-menopausal endocrine changes that affect bone 
metabolism. For the purposes of the study, femoral shaft fractures will be defined as any 
injury in which the majority of fracture line is distal to the lesser trochanter and proximal 
to the distal metaphyseal flare of the femoral condyles (Figure 1). Intertochanteric 
extension or distal articular extension is permitted. Similarly, a tibial shaft fracture will be 
defined as an injury with a primary fracture line between the proximal meta-diaphyseal 
flare to the distal metaphyseal region ending one joint width proximal to the tibial plafond 
(Figure 2). Intra-articular extension is permitted. 
 
The exclusion criteria are: 1) osteoporosis; 2) stress fractures; 3) elevated serum calcium 
(>10.5 mg/dL); 4) atypical femur fractures as defined by American Society for Bone and 
Mineral Research (ASBMR) criteria;25 5) pathological fractures secondary to neoplasm or 
other bone lesion; 6) patients with known or likely undiagnosed disorders of bone 
metabolism such as Paget’s disease, osteomalacia, osteopetrosis, osteogenesis imperfecta 
etc.; 7) patients with hyperhomocysteinemia; 8) patients with an allergy to vitamin D or 
another contraindication to being prescribed vitamin D; 9) patients currently taking an over 
the counter multivitamin that contains vitamin D and are unable or unwilling to discontinue 
its use for this study; 10) patients who will likely have problems, in the judgment of the 
investigators, with maintaining follow-up; 11) pregnancy; 12) patients who are 
incarcerated; 13) patients who are not expected to survive their injuries; and 14) other lower 
extremity injuries that prevent bilateral full weight-bearing by 6 weeks post-fracture. 
 
Patients with multiple injuries or multiple tibial and femoral shaft fractures will be eligible 
for inclusion; however, only the most severe eligible fracture will be included (as 
determined by the treating surgeon using the grade of soft tissue injury using the Tscherne 
classification system for closed fractures26 and the Gustilo classification system for open 
fractures).24    
 
3.3 Recruitment Strategy and Patient Screening 
All patients presenting to participating surgeons between the ages of 18 to 50 years with a 
tibial or femoral shaft fracture will be screened. Potentially eligible patients will be 
approached to participate in the trial. All screened patients will be classified as included or 
excluded.  


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Version 2.0 12-Mar-2018 
 
3.4 Randomization Methods  
Each participant will be randomized to 1 of 4 treatment groups: 1) 150,000 IU loading dose 
vitamin D3 plus daily dose placebo; 2) loading dose placebo plus 4,000 IU vitamin D3 per 
day; 3) loading dose placebo plus 600 IU vitamin D3 per day; or 4) loading dose placebo 
plus daily dose placebo. The daily vitamin D3 supplements/placebo will be provided in a 
blinded manner. The daily treatment will commence within 1 week of injury and will be 
taken for 3 months.  The loading dose vitamin D3 supplements/placebo will be given within 
1 week of injury and at 6 weeks (+/- 2 weeks) post-injury.  
 
Allocation to the 4 study groups will be concealed using a centralized 24-hour 
computerized randomization system that will allow internet-based allocation. The 
treatment allocation will be stratified on the following prognostic factors to ensure balance 
between the intervention groups: fracture type (closed vs. open) and long bone fracture 
(tibia vs. femur). 
 
3.5 Vitamin D3 (Cholecalciferol) Treatment Groups 
3.5.1 Blinded administration  
The loading dose of 150,000 IU will consist of 3 50,000 IU capsules of vitamin D3.  The 
loading dose placebo will consist of 3 capsules that are identical to the 50,000 IU capsules 
with no active ingredient. The loading dose vitamin D3 supplements/placebo will be given 
within 1 week of injury and at 6 weeks (+/- 2weeks) post-injury while in hospital or at the 
outpatient fracture clinic.  
 
The daily vitamin D3 supplements/placebo will be provided in a blinded manner and the 
daily treatment will commence within 1 week of injury.  The daily doses (4,000 IU, 600 
IU, and placebo) will be identical and will be comprised of one capsule.  Patients will be 
given a bottle of either active vitamin D3 or placebo capsules and will be instructed to take 
one capsule daily for 3 months. The placebo capsules will have no active ingredients and 
will be identical to the vitamin D capsules. To measure supplementation adherence, 
participants will be asked to bring their bottles to their follow-up visits. At the 3-month 
visit, participants will return their bottle to the clinical research coordinator.  If the 
participant does not return the bottle, the clinical research coordinator will provide them 
with an envelope to return it via mail.  
 
All doses of vitamin D and placebo will be obtained from Bio-Tech Pharmacal, Inc. 
(Fayetteville, AK). The unblinding protocol can be found in Figure 3. Following the 
completion of the study, participants may be unblinded their treatment group upon request.  
 
3.5.2 Vitamin D3 dose rationale 
The doses selected are based on biologic rationale, current practice patterns, and existing 
guidelines. The goal of the high dose arms is to rapidly increase circulating vitamin D and 
serum 25(OH)D during the early callus fracture healing periods. Conversely, while the low 
daily dose is not expected to increase circulating vitamin D as quickly as the high dose 
strategies, this treatment arm will determine if rapid serum increases are necessary to 
improve fracture healing. Finally, the placebo control arm is needed to demonstrate the 


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relative efficacy of each treatment arm and is also necessary to represent current practice 
at most trauma centers in North America.  
• High loading dose: 150,000 IU D3 loading doses can be administered easily with three 
50,000 IU D3 pills. We expect this dose to increase circulating vitamin D levels the 
fastest. While we acknowledge that many non-orthopaedic clinicians may prefer more 
frequent large doses, such as 50,000 IU weekly, our loading dose strategy has been 
chosen to correspond with the standard post-operative clinical follow-up schedule. This 
is important for generalizability and is likely to overcome potential supplementation 
adherence issues within the adult fracture population that is often predominantly lower 
socioeconomic patients. This high loading dose is also in the mid-range of other 
previous large loading doses used safely in fracture patients and is similar to the total 
cumulative 3-month dose of our high daily dose group.  
• High daily dose: 4,000 IU D3 represents an alternative high dose strategy and it 
corresponds to the tolerable upper daily intake level suggested by the Institute of 
Medicine (IOM).27 While this is the IOM’s upper limit, the Endocrine Society has 
recommended adults can safely take up to 10,000 IU per day,28 further suggesting that 
our 4,000 IU dose should be well-tolerated.  
• Low daily dose: 600 IU D3 is a common dose and approved indication for maintaining 
general bone health. 600 IU is also the IOM’s Recommended Dietary Allowance for 
all individuals ages 1-70 years.27 This represents our most conservative 
supplementation strategy, but its use is common among surgeons prescribing vitamin 
D and previous studies have shown its efficacy for increasing serum 25(OH)D levels. 
• Placebo: Finally, we are including a placebo group because it is important to include 
placebo-controlled comparisons to our active supplements during this exploratory 
phase of research. Not only does placebo reflect our usual clinical practice of no 
supplementation, this Phase II comparison will define our rationale and selection of the 
control group for the definitive trial. If there are no preliminary efficacy differences 
between low dose supplementation and placebo, then the low dose supplement could 
be used as the control group in the Phase III trial. This would obviate potential 
criticisms for performing a Phase III placebo-controlled trial in a population with a high 
prevalence of hypovitaminosis D. Given the small number of patients receiving placebo 
(n=24), the Phase II screening design of this trial, and the fact that receiving placebo 
does not represent an increased risk of study participation since it is our standard 
clinical practice, we do not believe this poses an ethical concern. We have used a similar 
rationale to explain the placebo blinding in the FAITH-2 pilot trial and this has been 
accepted at over 20 research ethics boards, with no clinical site disallowing the 
protocol. 
 
3.5.3 Storage and administration 
As per the standard operating procedures at the STC, the study supplements/placebo will 
be stored at room temperature in accordance with the manufacturer’s recommendations. 
The research personnel will maintain an inventory and temperature log to ensure the 
integrity of the supplements. Study supplementation will begin within 1 week of injury, 
and it is expected that the research personnel will provide the supplementation to the 
participant upon discharge from the hospital. Therefore, the hospital pharmacy will not be 
used to administer this out-patient, over-the-counter medication. The research personnel 


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Version 2.0 12-Mar-2018 
have previous experience administering vitamin D supplements/placebo to study patients 
at the recruiting hospital, the STC. 
 
3.5.4 Potential adverse events associated with vitamin D 
A recent systematic review comprehensively examined the effectiveness and safety of 
vitamin D supplementation among all ages of adult fracture patients.27 The majority of 
research has been performed in elderly fracture populations; however, the safety of a wide 
range of doses is well established. Studies with doses of 4,000 IU daily and loading doses 
from 50,000 IU for up to 7 days or single loading doses up to 500,000 IU have been used 
without complication.29  
 
Since vitamin D regulates PTH and serum calcium levels, it is theoretically possible that 
vitamin D supplementation could lead to hypercalcemia. Of the 1,088 patients included in 
the systematic review, 4 cases of hypercalcemia were reported (0.4%).30 Furthermore, there 
have been no cases of hypercalcemia in several high loading dose clinical trials. 
Regardless, we will monitor serum calcium levels at enrolment, 6 weeks, and 3 months 
post-fracture, and clinical signs of hypercalcemia will be sought at all clinical encounters. 
If hypercalcemia is identified, participants will be instructed to stop their vitamin D 
supplementation immediately and the hypercalcemia will be treated as indicated. 
 
Finally, we will monitor for increased falls among the study participants. While we do not 
expect to observe this adverse event (AE) in our 18 to 50 year-old adult population, a recent 
study of 200 elderly fracture patients found that a 60,000 IU monthly loading dose and 
24,000 IU monthly loading dose plus 300 µg of calcifediol were associated with increased 
falls compared to the control group.31 This single study contradicts several other high 
loading dose clinical trials, and these concerns have not been borne out of the healthy adult 
fracture population. This may be a result of the fact that supplementation in the non-
osteoporotic fracture population has not been extensively studied (highlighting the need for 
the proposed research), or because these concerns regarding the risk of falls do not apply 
to healthy adults without osteoporosis.  
 
3.5.5 Concomitant calcium supplementation 
In addition, although calcium supplementation is often recommended concomitantly with 
vitamin D for osteoporosis prevention, for our non-osteoporotic study population the 
necessity of calcium supplementation is controversial and will not be provided because of 
the increased risk of kidney stones, hypercalcemia, and potential confounding. This 
rationale has also been outlined by other researchers performing RCTs involving vitamin 
D supplementation. 
 
3.6 Surgical Technique and Post-Operative Rehabilitation 
3.6.1 Surgical technique 
The study protocol will not dictate the surgical technique. Based on the study’s eligibility 
criteria, all participants must receive a reamed, locked, intramedullary nail for their tibial 
or femoral shaft fracture. The number and orientation of locking screws is at the discretion 
of the treating surgeon, as there have been no studies that demonstrate clinical superiority 


Page 13 of 30 
Version 2.0 12-Mar-2018 
of any locking screw strategy. Any concomitant fracture lines that extend into the adjacent 
articular areas may be treated with additional fixation as indicated. 
 
3.6.2 Post-operative rehabilitation 
Full weight-bearing as tolerated is recommended for all isolated tibial and femoral shaft 
fractures. In the presence of additional lower extremity fractures, intra-articular extension, 
or other concomitant soft tissue injuries, participants may be restricted to protected weight-
bearing (partial or no weight) for up to 6 weeks post-fracture. If additional contralateral 
injuries are present, both limbs must be eligible for full weight-bearing by 6 weeks post-
fracture. 
 
3.7 Primary and Secondary Outcome Measures 
3.7.1 Primary outcome 
Fracture healing will be assessed as follows: 1) clinical fracture healing will be measured 
using FIX-IT, 2) radiographic fracture healing will be measured using the RUST, and 3) 
biological fracture healing will be measured using serum levels of CTX and PINP. 
 
Clinical Healing: FIX-IT is a standardized measure of weight-bearing and pain in patients 
with lower extremity fractures, specifically tibia and femur fractures.18 Preliminary 
validation of the FIX-IT has demonstrated high inter-rater agreement and moderate 
correlation with the physical scores of the Short Form-36.18 It has been used in other studies 
to assess clinical fracture healing. 
 
Radiographic Healing: The RUST score assesses the presence of bridging callus or a 
persistent fracture line on each of 4 cortices.19–22 This score has been previously validated 
and found to have greater inter-rater reliability when compared with surgeons’ general 
impression of the cortical bridging.19–22 RUST has been widely used to assess radiographic 
fracture healing.19–22 An orthopaedic surgeon who is independent of the study will review 
the images and assign a RUST score. 
 
Biological Healing: CTX is a bone-resorption marker and previous research has found that 
it rises 1 week after fracture of the tibial shaft and remains elevated throughout fracture 
healing.23 PINP is a bone-formation marker and prior research has found that it is highest 
at 12 weeks after fractures of the tibial shaft and proximal femur.32  
 
The primary time point for assessing fracture healing will be at 3 months post-injury. This 
time point was selected because it coincides within the standard clinical follow-up 
schedule, and because it has the greatest potential to detect differences in short-term 
fracture healing. While we expect the 1-year fracture union rate to be approximately 95% 
for the femur fractures32 and 75% for the tibia fractures (unpublished data from the SPRINT 
trial),7 improved early fracture healing is biologically plausible. The median time to 
fracture union for tibia fractures is 4 months; therefore, many patients are still experiencing 
morbidity from their injury at the 3-month visit and decreasing the time to union would be 
an important patient benefit.  


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3.7.2 Secondary outcome 
The secondary outcome will be assessed by measuring 25(OH)D serum levels.  
Correlations will be assessed between participants’ 25(OH)D levels at enrolment, changes 
in 25(OH)D levels from enrolment to 3 months, and 25(OH)D levels at 3 months and 
fracture healing as described above. 
 
3.7.3 Other secondary outcomes 
The other secondary outcomes will include assessing supplementation adherence between 
daily and loading doses, confirming participant safety as measured by AEs and serum 
levels of calcium and parathyroid hormone (PTH), and assessing protocol adherence (e.g. 
completion of outcome assessment and participant follow-up). 
 
Adherence with vitamin D supplementation will be assessed by participant self-report, by 
counting the tablets for the daily doses at each follow-up, and by direct observation for the 
loading doses. 
 
Participant safety will be assessed by AEs, defined as any symptom, sign, illness, or 
experience that develops or worsens in severity during the course of this study.  Within the 
AEs collected, fracture healing complications will be identified, and will include nonunion 
(defined as failure of the fracture to progress towards healing for 2 consecutive months 
and at least 6 months post-fracture), delayed union (defined as a failure of progression of 
fracture healing beyond the expected median healing time of 4 months with pain at the 
fracture site), hardware failure (defined as broken or bent nail or locking screw),33 wound 
healing problems (previously published criteria by Anglen 2005), and infection (superficial 
and deep as defined by Centers for Disease Control and Prevention (CDC) criteria). Wound 
healing problems and infection are a part of the composite fracture healing complication 
outcome because previous animal and infectious disease clinical research has suggested 
that vitamin D can improve wound healing and reduce infections.34–37 In addition to AEs, 
serum levels of calcium and PTH will be monitored and we will record results of the 
participants’ pre-operative metabolic profile. These data will be used to understand the 
baseline metabolic health of the participants and will be used as needed in the event of 
suspected AEs.  
 
Participant adherence with the protocol will be assessed by monitoring the completion of 
outcome measures, including clinic assessments (FIX-IT), radiographs (RUST), and blood 
work (CTX, PINP, 25(OH)D, calcium, and PTH), documentation of AEs and re-operations, 
and completion of follow-up to 12 months.   
 
3.7.4 Data collection and participant follow-up 
Upon providing informed consent, baseline demographics will be collected from the patient 
and from their medical chart (Table 1). This includes demographic, medical history, pre-
operative blood work-up details (e.g. kidney and liver function tests, calcium, phosphate, 
and albumin), injury details, fracture characteristics, details on the surgical management of 
their fracture, and rehabilitation details. Participants will have blood drawn within the 
fracture clinic that will be analyzed for calcium levels and for CTX, PINP, 25(OH)D, and 


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PTH (See Section 3.7.5).  Post-operative x-rays will be taken as per standard of care (See 
Section 3.7.6).   
 
Participants will be followed at standard clinical visit intervals for 12 months post-injury 
including 6 weeks, 3 months, 6 months, 9 months, and 12 months.  The Schedule of Events 
(Table 1) details the requirements and procedures for each visit.  Participants will have 
blood drawn within the fracture clinic that will be analyzed for calcium, CTX, PINP, 
25(OH)D, and PTH serum levels at 6 weeks and 3 months (See Section 3.7.5).  Post-
operative x-rays will be taken as per standard of care at each follow-up visit (See Section 
3.7.6).  Participants will be assessed clinically for FIX-IT at each visit. All study outcomes 
(as defined above) will be documented on the case report forms (CRFs) at each follow-up 
visit. A 12-month follow-up was selected because is a standard follow-up period for 
patients with tibial and femoral shaft fractures and it is a commonly used follow-up period 
for similar fracture trials.7,38 In addition, it is a commonly referenced time period for 
fracture healing complications requiring reoperation, and will further inform decisions 
surrounding the larger, definitive phase III RCT.  
 
3.7.5 Analysis of blood samples 
Serum calcium testing will be performed by the hospital laboratory and will be part of the 
unblinded medical chart for patient safety. The remainder of serum samples (PTH, 
25(OH)D, PINP, CTX) will be analyzed in a blinded manner at the end of the study. 
Laboratory personnel at the University of Maryland’s Muscle Research Laboratory will 
process the samples for storage in the -80 C freezer. Upon completion of all blood work 
for the study, the serum samples will be transferred to the Institute for Clinical and 
Translational Research Clinical Research Unit Core Laboratory to be analyzed as a single 
batch to eliminate inter-batch assay variability.  The results of the analyses will be sent to 
the CEO to be added to the REDCap study database and included within the final data 
analysis. The treating surgeon will remain blinded to these results. Participants may request 
the results of their blood analysis at the end of the study.  
 
3.7.6 Analysis of radiographs 
The radiographs will be stored in the STC Picture Archiving and Communication System 
(PACS) at the STC and then sent to the CEO for the review of radiographic fracture healing 
(RUST) by an independent practicing orthopaedic surgeon.  
 
3.8 Participant Retention 
Once a participant is enrolled in the trial, every reasonable effort will be made to follow 
the participant for the entire duration of the study period.  The expected follow-up rate for 
this study is greater than 90% based on similar fracture trials.7,38–40 To maximize participant 
retention, all possible attempts should be made to collect as much data as possible and to 
reduce loss to follow-up. We have implemented procedures to improve participant 
retention (Figure 4).41   
 
We will only deem participants lost to follow-up after all exhaustive measures have been 
taken to locate the participant. Participants should not be deemed lost to follow-up until the 
12-month visit is due and all attempts to contact the participant have been exhausted. 


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We will not remove participants from the study if the study protocol was not adhered to 
(e.g. participant received wrong treatment arm, early discontinuation of supplements, 
occurrence of protocol deviations, missed follow-up visits, etc.). We will document the 
reasons for participant withdrawal from the trial (e.g. withdrawal of consent or lost to 
follow-up). 
 
4.0 STATISTICAL PLAN  
 
4.1 Sample Size Determination 
This trial will use a phase II randomized screening design to facilitate non-definitive 
comparisons of three vitamin D3 dosing regimens. Using the principles outlined by 
Rubinstein et al, the statistical parameters have been carefully chosen to ensure a 
reasonable sample size and meaningful results.42 Consistent with previous 
recommendations, an  and  of 0.20 was chosen with a target mean difference of 17-20%, 
depending on the fracture healing measure. There will be no adjustments for multiple 
testing given the exploratory nature of the study design. 
 
Based on the original instrument development and validation in tibia and femur fracture 
patients, it is expected that the low dose and control groups will have a mean 3-month FIX-
IT score of 8 (standard deviation (SD) 3).18 Assuming the high dose groups will achieve a 
mean 2 point increase (17% mean difference), 21 patients are required in each group. The 
same sample size requirements will be applied for comparisons using the RUST instrument 
based on similar assumptions and recent literature (2 point mean difference, 8 vs. 6, SD 
3).19–22 Clinically important changes in the PINP and CTX markers are unknown; however, 
in a previous study of tibia fracture healing, Veitch et al observed concentrations of both 
bone turnover markers approximately 100% greater than baseline values.43 Given the large 
changes observed in these bone turnover markers, the same criteria will be applied for 
identifying a potentially clinically beneficial regimen and remain powered to detect a mean 
difference of 20% (SD 30%). Finally, the sample size will be increased to account for a 
10% loss to follow-up, for a total enrolment of 24 patients per allocation group (96 total). 
 
4.2 Statistical Methods 
All outcome analyses will be exploratory and adhere to the intention-to-treat principle.  As 
treated sensitivity analyses will also be conducted. 
 
4.2.1 Specific Aim  
Each measure of fracture healing will be described with its mean and SD. For our primary 
analysis, comparisons for the 3 hypotheses (Section 2.4) will be made using an independent 
t-test and significance set at =0.20 (Table 2). Hypothesis 1 compares high dose 
supplementation versus low dose. To test this hypothesis, we will combine the two high 
dose groups (loading and daily) for a 2:1 comparison against the low daily dose group. All 
other comparisons will be 1:1 based on the treatment groups outlined. 
 
4.2.2 Secondary Aim 
To test the hypotheses of the Secondary Aim, univariate analyses will be used to explore 
associations between 3-month fracture healing and 3 assessments of serum 25(OH)D 


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levels: enrolment, 3 months, and change in levels between enrolment and 3 months. 
Significance will be set at =0.20. Additional descriptive analyses will be performed for 
serum 25(OH)D at each time point (Table 3).  
 
4.2.3 Other Secondary Outcomes 
All other secondary outcomes will be presented using point estimates and appropriate 
measures of variance to describe supplementation adherence, participant safety, and key 
aspects of participant compliance with the protocol (Table 4). Supplement adherence will 
be summarized using means and 95% confidence intervals for participant self-reporting 
and the mean cumulative dose taken at 3 months. The incidence of AEs and re-operations 
for fracture healing complications in each group will be described with counts and 
proportions. Serum levels of calcium and PTH will be summarized using means and 95% 
CIs. Participant compliance with the protocol will be summarized descriptively with counts 
and proportions. 
 
4.2.4 As Treated Sensitivity Analyses 
The specific aim and the relevant other secondary outcome analyses will be repeated 
following as-treated analyses. These sensitivity analyses will be completed after the above 
outcome analyses have been completed and once unblinding has occurred.  As treated will 
be defined as participants who received both loading doses of vitamin D and participants 
who did not miss 20 or more daily doses of vitamin D.  Therefore, participants who missed 
a loading dose of vitamin D and participants who missed 20 or more daily doses of vitamin 
D will not be included in the as-treated sensitivity analyses.   
 
5.0 DATA MANAGEMENT 
 
The CRFs will be the primary data collection tool for the study. All data requested on the 
CRF must be recorded.  All data will be entered into a REDCap study database (McMaster 
University) and double verified.   
 
6.0 ETHICS AND DISSEMINATION 
 
6.1 Research Ethics Approval 
This protocol will be reviewed and approved by the University of Maryland Institutional 
Review Board (IRB) and the McMaster University Research Ethics Board (REB) prior to 
commencement of the study. 
 
6.2 Consent 
Any patients who are deemed to meet all eligibility criteria should be approached to discuss 
participation in the trial by someone on the study team who is knowledgeable about the 
trial.  In order to obtain informed consent, study personnel should follow the below 
procedures: 
• Present study information in a manner that is understandable to the potential 
participant. 
• Discuss the study with the potential participant and answer any questions he or 
she asks. 


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Version 2.0 12-Mar-2018 
• Allow the potential participant an opportunity to discuss participation with their 
family, friends, or family physician if desired.  
• Confirm that the participant understands the risks and benefits of participating 
in the study and that their participation is voluntary. 
• Complete and obtain signatures for informed consent form and obtain contact 
information from the participant. 
 
6.3 Confidentiality 
Information about study participants will be kept confidential and will be managed in 
accordance with the below rules: 
• All study-related information will be stored securely. 
• All study participant information will be stored in locked file cabinets and 
accessible only to study personnel. 
• All CRFs will be identified only by a coded participant number and initials. 
• All records that contain participant names, or other identifying information (e.g. 
consent forms and contact information forms), will be stored separately from 
the study records that are identified only by the coded participant number and 
initials. 
• All databases will be password protected. 
 
In the event that a participant revokes authorization to collect or use personal health 
information (PHI), the clinical site retains the ability to use all information collected prior 
to the revocation of participant authorization. For participants who have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. primary outcome data) at the end of their scheduled study period. 
 
6.4 Protocol Amendments 
Any amendments to the study protocol which may affect the conduct of the study, or the 
potential safety of or benefits to participants (e.g. changes to the study objectives, study 
design, sample size, or study procedures) will require a formal amendment to the protocol.  
Any protocol amendments will be approved by the Principal Investigators and will require 
approval by the University of Maryland IRB and the McMaster University REB. 
Administrative changes (e.g. minor corrections or clarifications that have no effect on the 
way the study is conducted) will not need to undergo a formal amendment process. 
 
6.5 Adverse Event Reporting and Definitions 
6.5.1 Adverse event  
An AE is any symptom, sign, illness, or experience that develops or worsens in severity 
during the course of this study.  
 
6.5.2 Serious adverse event  
AEs are classified as serious or non-serious. A serious adverse event (SAE) is any AE that 
is any of the following: 
• Fatal 
• Life threatening 
• Requires or prolongs hospital stay 


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• Results in persistent or significant disability or incapacity 
• A congenital anomaly or birth defect 
• An important medical event  
All SAEs must be recorded and promptly submitted to the local IRB. 
 
6.5.3 Unanticipated problems resulting in risk to participant or others 
Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in nature, severity, or frequency (e.g. not described in study-related 
documents such as the ethics-approved protocol or consent form, etc.). 
• Related or possibility related to participation in the research (i.e. possibly 
related means there is reasonable possibility that the incident experience, or 
outcome may have been caused by the procedures involved in the research). 
• Suggests that the research places participants or others at greater risk of harm 
(including physical, psychological, economic, or social harm).  
All unanticipated problems resulting in risk to participants or others must be recorded and 
promptly submitted to the local IRB. 
 
6.5.4 Adverse drug reactions 
An adverse drug reaction is an injury caused by taking a medication. All adverse drug 
reactions that are considered both serious and unexpected are to be reported to the US Food 
and Drug Administration (FDA) within the following time periods of the information 
becoming available: 1) within 7 days for events that are fatal or life-threatening and 2) 
within 15 days for all other events that are not fatal or life-threatening. 
 
6.6 Dissemination Policy 
Results from the study will be submitted for publication regardless of whether or not there 
are significant findings.  Every attempt will be made to ensure that the amount of time 
between completion of data collection and release of study findings are minimized.   


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Table 1: Schedule of Events 
 
 
 
 
 
Assessment 
Visit 1: 
Screening 
& Baseline 
Visit 2:  
6 Weeks 
Visit 3:  
3 Months 
Visit 4:  
6 Months 
Visit 5:  
9 
Months 
Visit 6:  
12 
Months 
Screening 
● 
 
 
 
 
 
Serum Calcium Analysis  
●* 
● 
● 
 
 
 
Informed Consent  
● 
 
 
 
 
 
Randomization 
● 
 
 
 
 
 
Collection of Baseline Data (Demographic, Serum Metabolic 
Panel, Fracture, & Surgical Data)  
● 
 
 
 
 
 
Nutritional/Placebo Supplementation** 
● 
● 
● 
 
 
 
Assessment of Clinical Fracture Healing (FIX-IT) 
 
● 
● 
● 
● 
● 
X-Rays of Tibia or Femur 
● 
● 
● 
● 
● 
● 
Assessment of Radiographic Fracture Healing (RUST) 
 
● 
● 
● 
● 
● 
Serum Bone Marker Analysis (CTX & PINP) 
● 
● 
● 
 
 
 
Assessment of Adherence to Supplementation 
 
● 
● 
 
 
 
Laboratory Serum 25(OH)D Analysis 
● 
● 
● 
 
 
 
Assessment for AEs  
 
● 
● 
● 
● 
● 
Serum PTH Level Analysis  
● 
● 
● 
 
 
 
Assessment of Fracture Healing Complications 
 
● 
● 
● 
● 
● 
*To be assessed as eligibility criteria 
**Must occur within 1 week of fracture 
 


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Table 2: Primary Outcome Analysis  
 
Objective 
Hypothesis 
Fracture Healing 
Outcome 
Method of Analysis 
To determine the 
effect of vitamin 
D3 dose on 
fracture healing at 
3 months 
  
High doses of supplementation 
(loading or daily) will increase 
healing compared to low daily dose. 
Using high doses will rapidly 
increase the circulating vitamin D 
available during fracture callus 
formation. 
1. FIXIT  
(Clinical) 
Patients in the high loading dose & 
high daily dose groups will be 
combined for a 2:1 comparison against 
low daily dose group using an 
Independent t-test (alpha=0.20)* 
2. RUST 
(Radiographic) 
3. PINP 
(Biologic) 
4. CTX 
(Biologic) 
To determine the 
effect of vitamin 
D3 frequency on 
fracture healing at 
3 months 
  
High loading dose increases healing 
compared to high daily dose. 
Loading doses will overcome 
medication adherence issues and 
increase circulating vitamin D even 
more rapidly than daily doses. 
1. FIXIT  
(Clinical) 
Comparisons between the high loading 
dose & high daily dose groups will be 
made using an Independent t-test 
(alpha=0.20)* 
2. RUST 
(Radiographic) 
3. PINP 
(Biologic) 
4. CTX 
(Biologic) 
To determine the 
effect of low 
amounts of 
vitamin D3 
supplementation 
on fracture healing 
at 3 months 
  
Low daily dose will increase healing 
compared to placebo. While the low 
daily dose is not expected to 
increase circulating vitamin D as 
rapidly as the high dose strategies, 
this comparison will determine if 
rapid serum increases are necessary 
to improve fracture healing. 
1. FIXIT  
(Clinical) 
Comparisons between the low daily 
dose & placebo groups will be made 
using an Independent t-test 
(alpha=0.20)* 
2. RUST 
(Radiographic) 
3. PINP 
(Biologic) 
4. CTX 
(Biologic) 
*Using Phase II screening trial approach, comparisons are non-definitive and an increased alpha level has been adopted. 
 
 


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Table 3: Secondary Outcome Analysis 
Objective 
Hypothesis 
Fracture Healing Outcome 
Method of Analysis 
To determine if 
25(OH)D serum 
levels are 
associated with 
fracture healing 
at 3 months 
There will be an association between 
fracture healing and:  
1) patients’ enrolment serum 25(OH)D,  
2) their change in 25(OH)D from 
enrolment to 3 months,  
3) their 25(OH)D level at 3 months 
1. FIXIT  
(Clinical) 
Associations will be 
quantified using Univariate 
Analysis (alpha=0.20)*. 
 
2. RUST 
(Radiographic) 
3. PINP 
(Biologic) 
4. CTX 
(Biologic) 
*Using Phase II screening trial approach, comparisons are non-definitive and an increased alpha level has been adopted. 
  
 


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Table 4: Other Secondary Outcomes Analysis  
Objective 
Hypothesis 
Outcome 
Method of Analysis 
Supplementation 
adherence 
Daily vitamin D3 adherence will be <80% 
and loading dose vitamin D3 adherence 
will be >95% 
Self-report 
Summary statistics of 
means and confidence 
interval. 
Count of pills 
Participant 
safety 
Adverse events will be rare across all 4 
treatment groups. 
Adverse event 
Summary statistics of 
proportions. 
Re-operations for a composite of fracture 
healing complications will follow the 
same 3 hypotheses as fracture healing. 
Re-operations for a 
composite of fracture 
healing complications 
Summary statistics of 
proportions. 
Levels of serum calcium will be similar 
across the 4 treatment groups.  Levels of 
serum calcium will be within normal 
reference ranges. 
Serum Calcium 
Summary statistics of 
means and confidence 
interval. 
Levels of serum PTH will be similar 
across the 4 treatment groups.  Levels of 
serum PTH will be within normal 
reference ranges. 
Serum PTH 
Summary statistics of 
means and confidence 
interval. 
Protocol 
adherence 
Protocol adherence will be acceptable. 
Complete follow-up 
assessments including 
x-rays and bloodwork 
Summary statistics of 
proportions. 
 
 
 
 
 


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Figure 1: Femur Fracture 
 
 
BONE: FEMUR (3) 
 
Location: Diaphyseal segment (32) 
 
 
 
 
 
 
 
 
 
 
 
Types: 
A. Simple (32-A) 
 
B. Wedge (32-B)
 
C. Complex (32-C) 
 


Page 25 of 30 
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Figure 2: Tibia Fracture 
BONE: TIBIA/FIBULA (4)  
 
 
Location:  
Diaphyseal segment (42) 
 
 
 
 
 
 
 
 
 
Types: 
A. Simple (42-A) 
B. Wedge (42-B) 
C. Complex (42-C) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 26 of 30 
Version 2.0 12-Mar-2018 
Figure 3: Unblinding of Personnel for Emergency Medical Management  
 
 
1. In the event of a medical emergency that directly affects the health status of the 
participant, it may become necessary to unblind allocation status to determine the 
specific treatment the participant has received while enrolled in the study. A 
medical emergency is defined as an event which necessitates immediate attention 
regarding the treatment of a participant. 
2. The clinical research coordinator should contact the principal investigator (or 
designee) and provide details of the medical emergency as soon as possible after 
the event. The principal investigator (or designee) is responsible for reviewing and 
approving all requests for unblinding.  At no time will the participant’s health be 
compromised or medical treatment delayed.  
3. Once approved, the clinical research coordinator (or designee) will contact the 
unblinded Project Manager and request the participant’s treatment allocation.  The 
unblinded Project Manager will provide the clinical research coordinator with the 
participant’s treatment allocation.  This information is to be provided by telephone.  
No information regarding treatment allocation is to be sent via email or fax. 
4. The unblinded personnel are not to unblind the principal investigator or any blinded 
members of the study team unless deemed necessary by the principal investigator. 
5. Study personnel must keep all information related to the individual unblinding 
cases confidential. 
6. All cases of unblinding must be documented, including: study ID, date of 
unblinding, parties unblinded, and reason for unblinding. 
 


Page 27 of 30 
Version 2.0 12-Mar-2018 
 
 
Figure 4:  Retention Strategies 
 
1) We will exclude individuals who are likely to present problems with follow-up (see 
exclusion criteria).  
 
2) At the time of randomization, as well as their own address and phone number, each 
participant will provide the name and address of their primary care physician, and the 
name, address and phone number of 3 people at different addresses with whom the 
participants does not live who are likely to be aware of the participant’s whereabouts. The 
clinical research coordinator will confirm that these numbers are accurate prior to the 
participant’s discharge from hospital.   
 
3) Participants will receive reminders for upcoming clinic visits from local study 
personnel.   
 
4) Follow-up schedules will coincide with normal surgical fracture clinic visits.   
 
5) Study personnel will contact participants no less frequently than once every 3 months 
to maintain contact and obtain information about any planned change in residence.   
 
 
 
Sprague et al41 
 
 
 
 
 
 
 


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7.0 REFERENCES  
 
1.  
Sprague S, Petrisor B, Scott T, et al. What Is the Role of Vitamin D Supplementation in Acute Fracture 
Patients? A Systematic Review and Meta-Analysis of the Prevalence of Hypovitaminosis D and 
Supplementation Efficacy. J Orthop Trauma. 2016;30(2):53-63. 
2.  
Omeroğlu S, Erdoğan D, Omeroğlu H. Effects of single high-dose vitamin D3 on fracture healing. An 
ultrastructural study in healthy guinea pigs. Arch Orthop Trauma Surg. 1997;116(1-2):37-40. 
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Jingushi S, Iwaki A, Higuchi O, et al. Serum 1alpha,25-Dihydroxyvitamin D3 Accumulates into the 
Fracture Callus during Rat Femoral Fracture Healing. Endocrinology. 1998;139(4):1467-1473. 
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Lidor C, Dekel S, Edelstein S. The metabolism of vitamin D3 during fracture healing in chicks. 
Endocrinology. 1987;120(1):389-393. 
5.  
Lidor C, Dekel S, Hallel T, Edelstein S. Levels of active metabolites of vitamin D3 in the callus of 
fracture repair in chicks. J Bone Joint Surg Br. 1987;69(1):132-136. 
6.  
Omeroğlu H, Ateş Y, Akkuş O, Korkusuz F, Biçimoğlu A, Akkaş N. Biomechanical analysis of the 
effects of single high-dose vitamin D3 on fracture healing in a healthy rabbit model. Arch Orthop 
Trauma Surg. 1997;116(5):271-274. 
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SPRINT Investigators ., Bhandari M, Guyatt G, et al. Study to prospectively evaluate reamed 
intramedullary nails in patients with tibial fractures (S.P.R.I.N.T): Study rationale and design. BMC 
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8.  
Duan X, Al-Qwbani M, Zeng Y, Zhang W, Xiang Z. Intramedullary nailing for tibial shaft fractures 
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9.  
Bhandari M, Guyatt GH, Tong D, Adili A, Shaughnessy SG. Reamed versus nonreamed 
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Bonafede M, Espindle D, Bower AG. The direct and indirect costs of long bone fractures in a working 
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Antonova E, Le TK, Burge R, Mershon J. Tibia shaft fractures: costly burden of nonunions. BMC 
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Axelrad T, Einhorn T. Orthobiologics. In: Bhandari M, ed. Evidence Based Orthopaedics. 1st ed. West 
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Marsell R, Einhorn TA. Emerging bone healing therapies. J Orthop Trauma. 2010;24 Suppl 1:S4-S8. 
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Sprague S, Bhandari M, Devji T, et al. Prescription of Vitamin D to Fracture Patients: A Lack of 
Consensus and Evidence. J Orthop Trauma. 2016;30(2):e64-e69. 
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Bhandari M, Wasserman S, Yurgin N, Petrisor B, Sprague S, Dent R. Development and preliminary 
validation of a Function IndeX for Trauma (FIX-IT). Can J Surg. 2013;56(5):E114-E120. 
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Leow JM, Clement ND, Tawonsawatruk T, Simpson CJ, Simpson AHRW. The radiographic union 
scale in tibial (RUST) fractures: Reliability of the outcome measure at an independent centre. Bone 
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Litrenta J, Tornetta P, Mehta S, et al. Determination of Radiographic Healing: An Assessment of 
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Kooistra BW, Dijkman BG, Busse JW, Sprague S, Schemitsch EH, Bhandari M. The radiographic 


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union scale in tibial fractures: reliability and validity. J Orthop Trauma. 2010;24 Suppl 1:S81-S86. 
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Cekic E. Reliability of the Radiographic Union Score for Tibial Fractures. Acta Orthop Traumatol 
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23.  
Cox G, Einhorn TA, Tzioupis C, Giannoudis P V. Bone-turnover markers in fracture healing. J Bone 
Joint Surg Br. 2010;92(3):329-334. 
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Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg Am. 
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Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: 
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