Clinical trial NCT01908751
Conditions: Femoral Neck Fractures
Sponsor: McMaster University
Start date: 2014-09-01; Completion date: 2019-03-18
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The purpose of this study is to determine the impact of surgical fixation (cancellous screws versus sliding hip screws) and biologic intervention (Vitamin D versus placebo) on patient important outcomes.

Detailed description:
Femoral neck fractures are a type of hip fracture associated with high complication rates and poor functional outcomes. It is estimated that over 300,000 hip fractures occur in patients under age 50 annually. Hip fractures in younger aged patients are particularly devastating with profound impairments of quality of life and function. Virtually all patients require surgical repair of their fractures and unlike elderly hip fractures, failure of surgery offers few options for salvage. Arthroplasty is a successful treatment for elderly patients; however, a hip replacement is not a viable option for younger patients because of their higher functional demands for work and recreational activities that are not tolerated by joint replacements.

There is more than one way to perform internal fixation for femoral neck fractures. Cancellous screws have traditionally been the preferred internal fixation implant for femoral neck fractures. Multiple screws (2 or more) are used during fixation, and advocates of this implant promote the construct's superior torsional stability, limited disruption of femoral head blood supply, minimally invasive insertion, and retention of more viable bone than the larger sliding hip screw (SHS). On the other hand, sliding hip screws have been gaining popularity and there is evidence to suggest that SHS provide greater fracture stability and may reduce patient complications. It is currently unknown which method of internal fixation provides the best outcomes for patients.

Femoral neck fracture treatment is further complicated by vitamin D insufficiency in as many as 8 of 10 trauma patients. Vitamin D plays an important role in musculoskeletal health and bone quality because it regulates serum calcium homeostasis. Laboratory research and human clinical studies suggest important associations between vitamin D, musculoskeletal health, and improved fracture healing. Experimental animal studies have demonstrated the concentration of vitamin D metabolites are higher at a fracture callus compared to the uninjured contralateral bone, vitamin D supplementation leads to decreased time to fracture union and increased callus vascularity, and vitamin D increases mechanical bone strength compared to controls. Clinical studies have also demonstrated that vitamin D supplementation increases the callus volume of proximal humerus fractures, increases the number and diameter of type II muscle fibres, and can improve wound healing, however, the effects of vitamin D supplementation in you patients with femoral neck fractures are unknown.

Using a 2x2 factorial design, participant will be randomly allocated to one of four treatment arms. Participants allocated to the cancellous screw group will receive multiple threaded screws (with a minimum of 3 screws and a minimum diameter of 6.5 mm) and those allocated to the sliding hip screw group will receive a single larger diameter partially threaded screw affixed to the proximal femur with a sideplate using a minimum of 2 screws for fixation. Participants allocated to the vitamin D Group will receive a bottle of 2,000 International Units (IU) vitamin D3 drops. Participants will be instructed to take two drops daily for six months, for a total daily dose of 4,000 IU. Participants in the placebo group will receive an identical bottle of placebo drops with no active ingredient. Similarly, they will be instructed to take two drops daily for six months. All vitamin D3 supplement and placebo bottles will be labeled in a blinded manner according to Health Canada and Good Manufacturing Practice.

Participation in this study will last 12 months. In-person participant follow-up visits will occur at enrollment (baseline), post-surgery, 6 weeks, 3 months, 6 months, 9 months, and 12 months post-surgery. Data for all outcomes and radiographs will be collected at each follow-up visit.

Arms: arm 1: Participants allocated to the vitamin D Group will be given a six-month supply of vitamin D3 supplementation. Participants in the vitamin D Group will receive a bottle of 2,000 International Units (IU) vitamin D3 drops (Ddrops®, Ddrops Company). Participants will be instructed to take two drops daily for six months, for a total daily dose of 4,000 IU. arm 2: Participants in the placebo group will receive an identical bottle of placebo drops with no active ingredient. Similarly, they will be instructed to take two drops daily for six months. The placebo supplement is also manufactured by the Ddrops Company. arm 3: Participants allocated to the vitamin D Group will be given a six-month supply of vitamin D3 supplementation. Participants in the vitamin D Group will receive a bottle of 2,000 International Units (IU) vitamin D3 drops (Ddrops®, Ddrops Company). Participants will be instructed to take two drops daily for six months, for a total daily dose of 4,000 IU. arm 4: Participants in the placebo group will receive an identical bottle of placebo drops with no active ingredient. Similarly, they will be instructed to take two drops daily for six months. The placebo supplement is also manufactured by the Ddrops Company.
Interventions: intervention 1: Sliding Hip Screw intervention 2: Cancellous Screws intervention 3: Vitamin D intervention 4: Vitamin D Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Fixation Using Alternative Implants for the 
Treatment of Hip Fractures (FAITH-2) 
 
NCT01908751 
 
May 28, 2019 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
1 of 45 
Version 2.0 
 
 
 
 
Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2): 
 
A Multi-Centre 2x2 Factorial Randomized Trial Comparing Sliding Hip Screws versus 
Cancellous Screws AND Vitamin D versus Placebo on Patient Important Outcomes and 
Quality of Life in the Treatment of Young Adult (18-60) Femoral Neck Fractures 
 
 
 
 
Principal Investigators: 
Dr. Gerard Slobogean and Dr. Mohit Bhandari 
 
 
 
FAITH-2 PROTOCOL  
Version: 2.0 
 
 
 
The FAITH-2 study protocol is the confidential intellectual property of the FAITH-2 
Principal Investigators, Steering Committee, and McMaster University and cannot be 
used in any form without the expressed permission of the Principal Investigators. 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
2 of 45 
Version 2.0 
SIGNATURE PAGE 
Reviewed and Approved 
by: 
 
 
Dr. Gerard Slobogean 
(Chair and Principal 
Investigator) 
Signature: 
Date: 
Dr. Mohit Bhandari (Co-
Chair and Co-Principal 
Investigator) 
Signature: 
Date: 
Dr. Earl Bogoch 
 
Signature: 
Date: 
Dr. PJ Devereaux  
 
Signature: 
Date: 
Dr. Gordon Guyatt  
 
Signature: 
Date: 
Dr. Martin J. Heetveld  
 
Signature: 
Date: 
Dr. Kyle Jeray  
 
Signature: 
Date: 
Dr. Susan (Sue) Liew 
 
Signature: 
Date: 
Dr. Robert (BobͿ O’Toole  
 
Signature: 
Date: 
Dr. Andrew Pollak  
 
Signature: 
Date: 
Dr. Emil Schemitsch  
 
Signature: 
Date: 
Dr. Marc Swiontkowski  
 
Signature: 
Date: 
Dr. Lehana Thabane  
 
Signature: 
Date: 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
3 of 45 
Version 2.0 
TABLE OF CONTENTS  
 
FAITH-2 PROTOCOL ..................................................................................................... 1 
SIGNATURE PAGE ........................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................... 3 
LIST OF TABLES ........................................................................................................... 5 
LIST OF FIGURES .......................................................................................................... 6 
LIST OF ABBREVIATIONS ............................................................................................. 7 
STUDY SUMMARY ....................................................................................................... 8 
1. INTRODUCTION ....................................................................................................... 9 
1.1 Femoral Neck Fracture in Young Patients................................................................. 9 
1.2 Internal Fixation of Femoral Neck Fractures ............................................................ 9 
1.3 Methods of Internal Fixation .................................................................................. 10 
1.3.1 Multiple Cancellous Screws ............................................................................. 10 
1.3.2 Sliding Hip Screws ............................................................................................ 11 
1.3.3 Inconclusive Clinical Evidence .......................................................................... 11 
1.4 Adjuvant Nutritional Supplementation (Vitamin D) ............................................... 12 
2. STUDY OBJECTIVES ................................................................................................ 13 
2.1 Primary Objective.................................................................................................... 13 
2.2 Secondary Objectives .............................................................................................. 13 
3. TRIAL DESIGN ........................................................................................................ 13 
4. METHODS ............................................................................................................. 14 
4.1 Study Setting ........................................................................................................... 14 
4.2 Eligibility Criteria ..................................................................................................... 14 
4.2.1 Inclusion Criteria .............................................................................................. 14 
4.2.2 Exclusion Criteria.............................................................................................. 14 
4.3 Recruitment Strategy and Patient Screening ......................................................... 15 
4.4 Randomization Methods ......................................................................................... 15 
4.5 Surgical Interventions ............................................................................................. 15 
4.5.1 Multiple Cancellous Screws ............................................................................. 15 
4.5.2 Sliding Hip Screws ............................................................................................ 16 
4.5.3 Ipsilateral Femoral Shaft Fractures .................................................................. 16 
4.5.4 Adherence to Surgical Intervention ................................................................. 16 
4.6 Nutritional Supplementation .................................................................................. 16 
4.6.1 Administration of Nutritional Supplementation .............................................. 16 
4.6.2 Vitamin D Supplementation............................................................................. 16 
4.6.3 Placebo Supplementation ................................................................................ 17 
4.6.4 Adherence to Nutritional Supplementation .................................................... 17 
4.7 Standardization of Peri-Operative Care .................................................................. 17 
4.8 Primary and Secondary Outcome Measures .......................................................... 17 
4.8.1 Primary Outcome ............................................................................................. 17 
4.8.2 Secondary Outcome ......................................................................................... 18 
4.9 Frequency and Duration of Follow-Up ................................................................... 18 
4.10 Participant Retention ............................................................................................ 19 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
4 of 45 
Version 2.0 
4.11 Blinding ................................................................................................................. 19 
5.0 STATISTICAL PLAN ............................................................................................... 20 
5.1 Sample Size Determination ..................................................................................... 20 
5.2 Statistical Methods ................................................................................................. 21 
5.2.1 General ............................................................................................................. 21 
5.2.2 Primary Analyses .............................................................................................. 21 
5.2.3 Secondary Analyses ......................................................................................... 21 
5.2.4 Planned Exploratory Analyses .......................................................................... 22 
5.2.5 Interim Analysis ................................................................................................ 22 
6. DATA MANAGEMENT ............................................................................................ 22 
6.1 Case Report Forms and Data Entry ......................................................................... 22 
6.2 Data Transmissions ................................................................................................. 22 
6.3 Data Discrepancy Inquiries ..................................................................................... 22 
6.4 Security and Back-Up of Data ................................................................................. 23 
6.5 Quality Control Reports .......................................................................................... 23 
7. ETHICS AND DISSEMINATION ................................................................................ 23 
7.1 Research Ethics Approval ........................................................................................ 23 
7.2 Consent ................................................................................................................... 23 
7.3 Confidentiality ......................................................................................................... 24 
7.4 Access to Data ......................................................................................................... 24 
7.5 Protocol Amendments ............................................................................................ 24 
7.6 Adverse Event Reporting and Definitions ............................................................... 25 
7.6.1 Adverse Event .................................................................................................. 25 
7.6.2 Serious Adverse Event ..................................................................................... 25 
7.6.3 Unanticipated Problems Resulting in Risk to Participant or Others ................ 25 
7.7 Reporting of Serious Adverse Events and Unanticipated Problems Resulting in Risk 
to Participants or Others ............................................................................................... 25 
7.7.1 Clinical Site Reporting: Notifying the Methods Centre.................................... 25 
7.7.2 Clinical Site ʹ Institutional Review Board and Research Ethics Board Reporting
................................................................................................................................... 26 
7.8 Potential Risks to Participants ................................................................................ 26 
7.9 Dissemination Policy ............................................................................................... 26 
7.10 Ethical Considerations........................................................................................... 26 
8. STUDY COMMITTEES ............................................................................................. 26 
8.1 Steering Committee ................................................................................................ 26 
8.2 Data Safety and Monitoring Committee................................................................. 26 
8.3 Central Adjudication Committee ............................................................................ 27 
REFERENCES ............................................................................................................. 41 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
5 of 45 
Version 2.0 
LIST OF TABLES 
 
Table 1: Schedule of Events .............................................................................................. 28 
Table 2: Sample Size Estimates ......................................................................................... 29 
Table 3: Summary of Primary Outcome Analyses ............................................................ 30 
Table 4: Summary of Secondary Analyses ........................................................................ 31 
Table 5: Summary of Exploratory Analyses ...................................................................... 32 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
6 of 45 
Version 2.0 
LIST OF FIGURES 
 
Figure 1:  Blood Supply to the Femoral Head ................................................................... 33 
Figure 2: Multiple Cancellous Screws ............................................................................... 34 
Figure 3:  Sliding Hip Screw ............................................................................................... 35 
Figure 4:  Recruitment and Follow-Up Schedule .............................................................. 36 
Figure 5:  Retention Strategies ......................................................................................... 38 
Figure 6: Unblinding of Clinical Site Personnel for Emergency Medical Management .... 39 
Figure 7:  Central Adjudication Process ............................................................................ 40 
 
 
 
 
 
 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
7 of 45 
Version 2.0 
  
LIST OF ABBREVIATIONS  
 
Abbreviation 
Explanation 
ADL 
Activities of Daily Living  
AE 
Adverse Event 
CAC 
Central Adjudication Committee 
CRF 
Case Report Form  
DSMC 
Data Safety and Monitoring Committee 
EDC 
Electronic Data Capture  
FAITH 
Fixation using Alternative Implants for the Treatment of Hip Fractures  
HOS 
Hip Outcome Score  
HRQL 
Health-Related Quality of Life  
IU 
International Units 
MRI 
Magnetic Resonance Imaging  
nmol/L 
Nanomole/Litre  
PHI 
Personal Health Information 
RCT 
Randomized Controlled Trial 
REB 
Research Ethics Board 
RRR 
Relative Risk Reduction 
SAE 
Serious Adverse Event  
SF-12 
Short Form-12 
SHS 
Sliding Hip Screw 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
8 of 45 
Version 2.0 
STUDY SUMMARY   
 
Title 
Fixation using Alternative Implants for the Treatment of Hip 
Fractures 
(FAITH-2): 
A 
Multi-Centre 
2x2 
Factorial 
Randomized Trial Comparing Sliding Hip Screws versus 
Cancellous Screws AND Vitamin D versus Placebo on Patient 
Important Outcomes and Quality of Life in the Treatment of 
Young Adult (18-60) Femoral Neck Fractures 
Short Title 
FAITH-2 
Methodology 
Concealed 2x2 factorial randomized controlled trial 
Clinical Sites 
Multiple international clinical sites 
Primary Objective 
The primary objective is to assess the impact of surgical 
implant (sliding hip screws versus cancellous screw fixation) 
AND nutritional supplementation (vitamin D versus placebo) 
on a composite of patient important outcomes during the 12 
month post-surgery follow-up period. The composite of 
patient important outcomes includes: re-operation, femoral 
head osteonecrosis, severe femoral neck malunion, and 
nonunion. 
Secondary Objectives 
To assess the impact of surgical implant (sliding hip screw 
fixation versus cancellous screw fixation) and nutritional 
supplementation (vitamin D versus placebo) on health-
related quality of life and functional outcomes, fracture 
healing complications, and radiographic fracture healing. 
Sample Size 
We will recruit a sample size of 808 patients with full follow-
up. Based on an anticipated 10% loss to follow-up, 898 
patients will need to be enrolled in the FAITH-2 trial.  
Diagnosis 
and 
Main 
Inclusion Criteria 
Femoral neck fracture in patients between the ages of 18 
and 60. 
Study Products 
Surgical implants: Sliding hip screw versus multiple 
cancellous screws. 
Nutritional supplementation: Vitamin D3 (4,000 International 
Units/day taken for 6 months) versus placebo taken for 6 
months. 
 Length of Follow-Up  
12 months. 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
9 of 45 
Version 2.0 
1. INTRODUCTION 
This document is a protocol for a human research study that seeks to identify a surgical 
and nutritional strategy to minimize fracture fixation complications and optimize bone 
health in order to improve patient outcomes following a femoral neck fracture.  Using a 
concealed 2x2 factorial design, this multi-centre randomized controlled trial (RCT) 
compares two alternative surgical implants (cancellous screws and sliding hip screws 
(SHS)) AND vitamin D supplementation versus placebo for the treatment of femoral 
neck fractures in young adult patients (aged 18-60).  This trial is registered at 
clinicaltrials.gov (Identifier number: NCT01908751). 
 
1.1 Femoral Neck Fracture in Young Patients 
Globally, hip fractures rank in the top 10 of all cause disability adjusted life years lost.1 
Hip fractures predominately affect elderly people, however, it is estimated that over 
300,000 hip fractures occur worldwide in patients under the age of 50 annually.2,3  
Unlike other hip fractures, femoral neck fractures are usually associated with a critical 
vascular injury that impedes local fracture healing and obliterates the blood supply to 
the femoral head.4 This occurs because the important blood vessels of the proximal 
femur are small, fragile, and most vulnerable to injury at the femoral neck (Figure 1). 
Ultimately, this vascular injury is the primary cause of two devastating complications: 
femoral neck nonunion (the fracture does not heal) and femoral head osteonecrosis 
(bone death).  These fractures in younger aged patients are associated with high 
complication rates and profound impairments in quality of life and function.   
 
Virtually all patients with a femoral neck fracture require surgical management of their 
injury.  Surgical options include arthroplasty (joint replacement) or internal fixation.   
Arthroplasty is often a successful treatment for elderly patients because it removes the 
fractured area, obviating the risk of fracture healing complications. However, the 
primary limitation of arthroplasty is the finite lifespan of the implant.  Consequently, 
arthroplasty is not usually considered an optimal treatment option for younger patients.  
In addition, younger patients have higher functional demands for work and recreational 
activities that are not well tolerated by joint replacements. For example, Swedish Hip 
Registry data shows that younger patients experience higher failure rates than elderly 
patients (9-year survival rates 87.6% for patients aged 55 years of age or younger 
compared to 97.0% for patients aged 75 years and older) demonstrating that a revision 
joint replacement is frequently required.5 In addition, revision hip arthroplasty results in 
worse functional outcomes than primary joint replacements, represent increased 
morbidity, and may prevent young patients from returning to their pre-injury function.6 
As result, internal fixation is frequently used to manage the majority of femoral neck 
fractures in younger patients. 
 
1.2 Internal Fixation of Femoral Neck Fractures 
Internal fixation is performed for nearly all femoral neck fractures in young patients to 
allow patient ambulation, promote healing, and preserve the native hip joint. Young 
adult femoral neck fractures are typically the result of road traffic accidents and other 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
10 of 45 
Version 2.0 
high-energy traumas. As a result of their high-energy mechanisms, 80% of these 
fractures are severely displaced; a state in which the fracture ends are widely separated 
from each other.7 During internal fixation surgery, the fracture ends are put together 
and a metal implant is inserted into the bone to secure the fracture. Unfortunately, 
complications following internal fixation are common and include femoral head 
osteonecrosis, early implant failure, and nonunion of the fracture. A previous meta-
analysis that included 18 studies of patients between 15 and 50 years of age with acute 
intracapsular hip fractures has reported that these major fracture healing complications 
occur in approximately 25% of patients.7 Invariably, these patients endure prolonged 
morbidity and require further surgery, as confirmed by a 20% re-operation rate in a 
recent meta-analysis performed by our group.8 Beyond the prolonged morbidity and 
increased healthcare costs associated with re-operations, even patients who do not 
suffer a fracture healing complication frequently experience poor outcomes. This occurs 
because an additional 30% of femoral neck fractures heal in a shortened or non-
anatomic position.9 This alters the mechanics of the hip, causes the leg to be shorter, 
and results in substantially worse functional outcomes and quality of life. Therefore, the 
young femoral neck fracture population is at great risk for experiencing significant 
fracture healing complications, re-operations, and lifelong morbidity. 
1.3 Methods of Internal Fixation 
The most common methods of internal fixation for the management of femoral neck 
fractures are multiple cancellous screws or a single compression screw and sideplate 
(SHS). Both approaches have strong physiologic rationale; however, there is no clinical 
consensus regarding the optimal approach for managing femoral neck fractures in 
young adults. 10 
 
1.3.1 Multiple Cancellous Screws 
Cancellous screws have traditionally been the preferred internal fixation implant for 
femoral neck fractures.11 Multiple screws (2 or more) are used during fixation, and 
adǀocaƚeƐ of ƚhiƐ implanƚ promoƚe ƚhe conƐƚrƵcƚ͛Ɛ ƐƵperior ƚorƐional ƐƚabiliƚǇ͕ limiƚed 
disruption of femoral head blood supply, minimally invasive insertion, and retention of 
more viable bone than the SHS.12,13,14,15,16  Retaining more cancellous bone optimizes 
vascularity and thus may reduce the risk of femoral head osteonecrosis. In addition, 
surgeons can insert cancellous screws using small stab incisions with limited blood loss 
and operating time. This minimally invasive approach may limit damage to the soft 
tissues around the hip and may plausibly lead to better patient function. The use of 
cancellous screws has also been supported by two small RCTs. One study compared 
three cancellous screws versus the larger SHS in patients of all ages and found 3.5-fold 
greater femoral head vascularity at follow-up bone scanning in patients treated with 
cancellous screws.15 The other small RCT compared cancellous screws and SHSs in 30 
young adult patients. This study suggested that the use of cancellous screws led to 
decreased operative time (80% of cases were less than one hour in the cancellous screw 
group vs. 67% in the SHS group), superior functional outcomes (60% of cases were rated 
as excellent using the Judet classification system versus 33% in the SHS group), and 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
11 of 45 
Version 2.0 
fewer complications (2 complications in the cancellous screws group vs. 9 in the SHS 
group).17 The small sample size of this study limits our ability to draw definitive 
conclusions regarding the optimal method of internal fixation. 
 
1.3.2 Sliding Hip Screws 
Although cancellous screw fixation has many theoretical benefits and two small RCTs 
provide evidence supporting its use versus SHS, previous research has suggested that 
cancellous screws typically fail from bending or shear forces. Since a more vertical high-
energy fracture is frequently seen in young adults, proponents of the SHS believe that 
ƚhe implanƚ͛Ɛ biomechanical properƚieƐ and greaƚer fracƚƵre ƐƚabiliƚǇ are imporƚanƚ 
factors to counteract these forces.18  Biomechanical studies have shown SHS constructs 
have 2-fold greater maximal strength and less displacement under physiologic loading 
conditions compared to cancellous screws.19 The SHS also performed better than 
cancellous screws in stabilizing unstable femoral neck fractures using cyclic loading 
models.20,14 In addition, two recent retrospective studies comparing cancellous screws 
and the SHS in young adult fractures have shown substantial reductions in short-term 
complications using the SHS. Gardner et al21 showed a 18% absolute risk reduction for 
re-operation at 6 months (6/29 (21%) patients in the cancellous screw group versus 
1/40 (3%) patients in the SHS group). Chen et al22 reported a 25% absolute risk 
reduction for reoperation at an average of 15 months (7/28 (25%) patients in the 
cancellous screw group versus 0/23 (0%) of patients in the SHS group). Other more 
heterogeneous retrospective studies by Liporace et al23 and Razik et al24 suggest 
Relative Risk Reductions (RRRs) from SHS between 50% to 88% for osteonecrosis of the 
femoral head and 63% for nonunion.  While conclusions from these studies are limited 
by small sample sizes and the fact that the data are not adjusted for risk, these large 
reported treatment effects favouring the SHS suggest that a substantial reduction in 
complications may be achieved by using this alternative surgical implant. 
 
1.3.3 Inconclusive Clinical Evidence 
We have conducted two systematic reviews to characterize the outcomes of femoral 
neck fractures in young patients treated with internal fixation and have performed 
comprehensive reviews of other relevant literature.8 These reviews and a meta-analysis 
by Damany et al7 document a 25% incidence of fracture complications, a 20% re-
operation rate, and a 30% fracture malunion incidence associated with poor quality of 
life. Our reviews also revealed conflicting data from a small number of studies 
comparing the SHS and cancellous screws; however, these studies were too 
heterogeneous to facilitate any quantitative pooling of the results to compare 
cancellous screw and SHS fixation. 
 
The impact of uncertainty in the surgical literature is further demonstrated by a lack of 
surgeon consensus. We recently conducted an international survey of orthopaedic 
surgeons to determine their treatment preferences for the management of young 
femoral neck fractures.10 The survey was completed by 540 orthopaedic surgeons.  For 
displaced fractures, 49% of respondents prefer the SHS and 46% prefer cancellous screw 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
12 of 45 
Version 2.0 
fixation. Despite a near equal split in preference between the SHS and cannulated 
screws, most surgeons indicated they had treated at least one femoral neck fracture 
with each device in the past 12 months.  The majority of respondents endorsed the 
need for a RCT comparing SHS and cannulated screws (268/476, 56.3%).  
 
1.4 Adjuvant Nutritional Supplementation (Vitamin D) 
Vitamin D is a nutrient that helps the body use calcium and phosphorous to build and 
maintain strong bones.25 Vitamin D plays an important role in musculoskeletal health 
and bone quality because it regulates serum calcium homeostasis.  Too little vitamin D 
can cause calcium and phosphorus levels in the blood to decrease, leading to calcium 
shifting out of the bones to help maintain stable blood levels.25    
 
Laboratory research and human clinical studies suggest important associations between 
vitamin D, musculoskeletal health, and improved fracture healing.   Experimental animal 
studies have demonstrated the concentration of vitamin D metabolites are higher at a 
fracture callus compared to the uninjured contralateral bone,26 vitamin D 
supplementation leads to decreased time to fracture union and increased callus 
vascularity,27 and vitamin D increases mechanical bone strength compared to controls.28 
Clinical studies have also demonstrated that vitamin D supplementation increases the 
callus volume of proximal humerus fractures,29 increases the number and diameter of 
type II muscle fibres,2 and can improve wound healing.30 It also has preventative bone 
health benefits in young adult populations.  For example, in a double-blind, placebo-
controlled RCT examining the impact of vitamin D on stress fractures in 3,700 navy 
recruits, a 20% RRR was observed for developing a stress fracture (6.8% experienced a 
stress fracture in the vitamin D group versus 8.6% in the placebo group).31  These 
findings highlight the importance of vitamin D in musculoskeletal health.    
 
By helping to maintain bone health and prevent vitamin D deficiency, the potential 
benefits of vitamin D supplementation are even more relevant in light of recent 
research demonstrating that as many as 8 of 10 trauma patients are vitamin D 
insufficient.32,33,34  In 201 patients admitted to a level 2 trauma centre for fracture 
surgery, Bee et al reported the highest prevalence of vitamin D insufficiency was in 
patients ages 21-40 years (80.5%).32  Additionally, in a sample of 1,830 fracture patients 
from a level 1 trauma centre Crist et al reported that 77.4% had vitamin D 
insufficiency.33,34 Similar age related results were also found: 79.4% in patients ages 26-
35, 81.3% of patients ages 36-45, and 81.6% in patients ages 56-65.34  The high 
prevalence of vitamin D insufficiency among young trauma patients combined with the 
critical microvascular injury at the femoral neck site suggests these fracture patients 
may face significant barriers to healing and achieving good functional outcomes. 
 
Although the biologic rationale to use vitamin D supplementation to nutritionally 
optimize the bone of health of young fracture patients is compelling, more clinical 
research is needed.35  In this clinical trial, an oral daily dose of 4,000 International Units 
(IU) of vitamin D3 has been selected as the route and dose for vitamin D 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
13 of 45 
Version 2.0 
supplementation.  According to a 2010 U.S. Institute of Medicine report jointly 
commissioned by the U.S. and Canadian governments, 4,000 IU is the Tolerable Upper 
Inƚake Leǀel of ǀiƚamin D per daǇ for indiǀidƵalƐ͛ aged ϵ ǇearƐ or older͘36  The rationale 
for using this dose in the current clinical trial is centred upon our goals of quickly 
reversing any potential vitamin D insufficiency in a safe and patient-friendly manner.  
This dose can readily be achieved orally with self-administered pills or drops, and meets 
the Health Canada criteria for appropriate self-care use.36  A vast range of other oral 
dosing regimens have been successfully used in other clinical trials. These include a 
Ɛingle adminiƐƚraƚion ͞megadoƐe͟ ;Ƶp ƚo ϱϬϬ͕ϬϬϬ IU ǀiƚamin D3 given once), a 
͞megadoƐe͟ folloǁed bǇ large monƚhlǇ doƐeƐ ;ϱϬϬ͕ϬϬϬ IU ǀiƚamin D3 once and monthly 
50,000 IU vitamin D3), and even smaller daily doses alone (1,000 IU vitamin).37,38 A RCT 
of hip fracture patients over age 50 demonstrated that there is no advantage of a 
loading dose in addition to daily supplementation with 1,000 IU vitamin D3.38  At 3 
months, there was no difference in the serum vitamin D levels between the treatment 
groups and a similar proportions of patients in each group reached the goal of >75 
Nanomole/Litre (nmol/L).38 Therefore, the daily dose of 4,000 IU of vitamin D3 should be 
sufficient to reverse any nutritional insufficiency during the critical first few months of 
fracture healing. 
 
2. STUDY OBJECTIVES 
The objectives of this study are to determine the impact of surgical implants (SHS versus 
cancellous screw fixation) AND nutritional supplementation (vitamin D supplementation 
versus placebo) on young adults (aged 18-60) with femoral neck fractures. This will be 
assessed through the following objectives.  
 
2.1 Primary Objective 
The primary objective is to assess the impact of surgical implant (SHS versus cancellous 
screw fixation) AND nutritional supplementation (vitamin D versus placebo) on a 
composite of patient important outcomes during the 12 month post-surgery follow-up 
period. The composite of patient important outcomes includes: re-operation, femoral 
head osteonecrosis, severe femoral neck malunion, and nonunion. 
 
2.2 Secondary Objectives 
Secondary objectives are to assess the impact of the surgical implants and nutritional 
supplementation on: 
1. Health-related quality of life (HRQL) and functional outcomes 
2. Fracture healing complications 
3. Radiographic fracture healing  
 
3. TRIAL DESIGN 
FAITH-2 is a multi-centre, concealed 2x2 factorial RCT. Surgeons will use one of two 
surgical strategies in patients who have sustained a femoral neck fracture. The first 
strategy involves fixation using multiple cancellous screws (cancellous screw group). The 
second treatment strategy involves fixation of the fracture with a large single diameter 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
14 of 45 
Version 2.0 
screw and side plate (SHS group). Furthermore, participants will be randomized to 
receive a nutritional supplement (vitamin D supplementation versus placebo). Our 
recruitment target is 808 patients with full follow-up. Based on an anticipated 
conservative 10% loss to follow-up39, 898 patients will need to be enrolled in the FAITH-
2 trial to meet our target sample size. Study personnel at the clinical sites will document 
critical aspects of peri-operative care and rehabilitation. Clinical assessments will occur 
at the time of enrollment (baseline), surgery, post-surgery, and 6 weeks, 3 months, 6 
months, 9 months, and 12 months post-surgery.  
 
4. METHODS 
 
4.1 Study Setting 
The FAITH-2 trial will be conducted at academic and community hospitals across North 
America, Europe, Australia, Asia, and South America that treat femoral neck fractures in 
young adults.   
 
4.2 Eligibility Criteria 
Wide eligibility criteria will be used to increase the generalizability of the trial.  
 
4.2.1 Inclusion Criteria 
1. Adult men or women ages 18 to 60 years. 
2. Fracture of the femoral neck.  
3. Fracture amenable to both surgical treatments (SHS and cancellous screws). 
4. Operative treatment within 7 days of injury. 
5. Provision of informed consent by patient or substitute decision maker. 
 
4.2.2 Exclusion Criteria 
1. Patients with previously diagnosed osteoporosis.  
2. Fracture-dislocation of the femoral neck and hip joint. 
3. Planned antegrade nailing of an ipsilateral femoral shaft fracture (if present). 
4. Current infection around the hip (i.e. soft tissue or bone). 
5. Stress fracture of the femoral neck. 
6. Pathologic fractures secondary to neoplasm or other bone lesion.  
7. Patients with known or likely undiagnosed disorders of bone metabolism 
such as Paget's disease, osteomalacia, osteopetrosis, osteogenesis imperfect, 
etc. 
8. Patients with hyperhomocysteinemia. 
9. Patient has an allergy to vitamin D or another contraindication to being 
prescribed vitamin D. 
10. Patient is currently taking an over counter drug and/or food supplement that 
contains vitamin D and is unable or unwilling to discontinue its use for this 
study. 
11. Likely problems, in the judgment of the attending surgeon, with maintaining 
follow up (e.g. patients with no fixed address, plans to move out of town).  


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
15 of 45 
Version 2.0 
This may include patients with severe mental disorders and drug addictions 
without adequate support. 
12. Pregnancy. 
13. Patient is incarcerated. 
14. Patient is not expected to survive injuries. 
15. The attending surgeon believes the patient should be excluded because they 
are involved in a conflicting clinical trial.  
 
 
We will include all femoral neck fracture patterns (subcapital, midcervical, or 
basicervical).  Ipsilateral femoral shaft fractures treated with retrograde nailing or 
plating will be eligible for inclusion. Patients with multiple traumas will also be eligible 
for inclusion. Patients with bilateral femoral neck fractures will be eligible for inclusion; 
however, only the most severe eligible fracture will be included (defined as the most 
displaced fracture, as determined by the attending surgeon).    
 
4.3 Recruitment Strategy and Patient Screening 
All patients presenting to participating surgeons between the ages of 18 to 60 years 
with a femoral neck fracture will be screened. Potentially eligible patients will be 
approached to participate in the FAITH-2 trial.  All screened patients will be classified as: 
1. Excluded (if they subsequently do not meet the eligibility criteria).  
2. Missed (eligible but not randomized due to error). 
3. Included (eligible and randomized). 
 
4.4 Randomization Methods 
Eligible patients will be randomized in equal proportions to one of four treatment 
groups: 1) cancellous screws with vitamin D3 supplementation, 2) cancellous screws 
with placebo supplementation, 3) SHS with vitamin D3 supplementation, or 4) SHS with 
placebo supplementation.  Allocation 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: 1) undisplaced or displaced femoral neck 
fractures; 2) presence or absence of an ipsilateral femoral shaft fracture; and 3) 
geographic region of recruiting centre (industrializing countries versus industrialized 
countries). 
 
4.5 Surgical Interventions 
 
4.5.1 Multiple Cancellous Screws 
Participants allocated to the cancellous screw group will receive multiple threaded 
screws (with a minimum of 3 screws and a minimum diameter of 6.5 mm) (Figure 2). 
Any threaded screw or hook pin as well as buttress plates will be permitted. The number 
of screws, screw configuration, reduction technique, implant manufacturer, use of 
buttress plates, decision to perform a capsulotomy, use of injectable bone substitutes, 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
16 of 45 
Version 2.0 
use of bone grafts, or aspiration of an intracapsular hematoma will be documented but 
not prescribed due to lack of evidence favouring any of these approaches.   
 
4.5.2 Sliding Hip Screws 
Participants allocated to the SHS group will receive a single larger diameter partially 
threaded screw affixed to the proximal femur with a sideplate using a minimum of 2 
screws for fixation (Figure 3). Surgeons will be permitted to use any fixed-angle plate 
construct which includes a large diameter screw or blade that can slide within the plate.  
Surgeons will be allowed to use derotational screws and buttress plates. The use of a 
compression screw, implant manufacturer, reduction technique, decision to perform a 
capsulotomy, use of injectable bone substitutes, use of bone grafts, and aspiration of 
intracapsular hematoma will be documented but not prescribed.  
 
4.5.3 Ipsilateral Femoral Shaft Fractures 
Ipsilateral femoral shaft fractures will be treated with plating or retrograde nailing. The 
method of fixation will be documented.  We will also document the following outcomes 
on the shaft fracture: 1) the time to radiographic fracture healing of the ipsilateral 
femoral shaft; 2) re-operation; and 3) fracture-related complications.  
 
4.5.4 Adherence to Surgical Intervention 
Crossovers rates between the SHS and multiple cancellous screw groups are likely to be 
low because both implants are inserted with similar techniques and surgeon expertise in 
both techniques is likely to be very similar.  Participants will be randomized as close to 
surgery as possible. Any participants who crossover will be analyzed in the group to 
which they were allocated, maintaining the intention to treat approach for the analysis.   
 
4.6 Nutritional Supplementation 
 
4.6.1 Administration of Nutritional Supplementation 
Nutritional supplementation will be administered upon hospital discharge or within two 
weeks of the participant͛Ɛ femoral neck ƐƵrgerǇ͕ ǁhicheǀer comeƐ firƐƚ͘  IdeallǇ͕ 
participants should be administered the nutritional supplementation as soon as possible 
following their surgery.  Each participant will be provided with a six-month supply of 
vitamin D3 supplementation or placebo. 
 
4.6.2 Vitamin D Supplementation 
Participants allocated to the vitamin D Group will receive a bottle of 2,000 IU vitamin D3 
drops (Ddrops®, Ddrops Company). Participants will be instructed to take two drops 
daily for six months, for a total daily dose of 4,000 IU. All vitamin D3 supplement bottles 
will be labeled in a blinded manner according to Health Canada guidelines and Good 
Manufacturing Practice.   


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
17 of 45 
Version 2.0 
 
4.6.3 Placebo Supplementation  
Participants in the placebo group will receive an identical bottle of placebo drops with 
no active ingredient. Similarly, they will be instructed to take two drops daily for six 
months. The placebo supplement is also manufactured by the Ddrops Company. All 
placebo supplement bottles will be labeled in a blinded manner according to Health 
Canada guidelines and Good Manufacturing Practice. 
 
4.6.4 Adherence to Nutritional Supplementation 
Crossovers are unlikely between the nutritional supplementation groups as participants 
and surgeons will be blinded to the vitamin D and placebo treatments.  Additionally, 
participants will be explained the importance of treatment compliance at each follow-
up visit. Study personnel will be instructed that prescribing study participants vitamin D 
is prohibited. Participants will also be instructed to not take additional supplements 
containing vitamin D for the duration of the trial.  Previous research has demonstrated a 
96% adherence to daily vitamin D self-administration in adults40. Additionally, the 
nutritional treatment arm represents a pragmatic effectiveness comparison, and given 
the placebo-controlled blinding, there is no reason to suspect differential compliance 
between the treatment groups will occur.  We will document any deviations to the 
adherence to nutritional supplementation.  
 
4.7 Standardization of Peri-Operative Care 
To ensure similar peri-operative regimens participants should receive antibiotic 
prophylaxis (i.e. cephalosporin, or equivalent coverage) within one hour prior to 
surgery. Weight bearing status will be determined by the participantƐ͛ aƚƚending 
surgeon and we will document the participantƐ͛ ǁeighƚ bearing ƐƚaƚƵƐ aƚ each ǀiƐiƚ͘ We 
will also document surgical delay and whether the participant received physiotherapy.   
 
4.8 Primary and Secondary Outcome Measures 
 
4.8.1 Primary Outcome 
The primary outcome will be a composite of patient important outcomes that occur 
within the 12 months post-surgery follow-up period.  Specifically, these are limited to:  
1. Re-operation: any unplanned surgery related to the treatment of the femoral 
neck fracture;  
2. Femoral head osteonecrosis: any evidence of osteonecrosis on any follow-up 
medical imaging study (i.e., radiographs, magnetic resonance imaging (MRI), or 
other advanced imaging study);  
3. Severe femoral neck malunion: fracture healing with femoral neck shortening of 
>10 mm in any plane on follow-up x-rays;9 or 
4. Nonunion: failure of the fracture to progress towards healing defined as a 
Radiographic Union Score for Hip (RUSH)41,42 score below a pre-determined 
threshold specific for nonunion at 6 months or greater post-injury.  
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
18 of 45 
Version 2.0 
4.8.2 Secondary Outcome 
The secondary outcomes will include: 
1. HRQL and patient-reported function as measured by the: 
x Short Form-12 (SF-12)43 which measures self-reported quality of life through 
an 8-domain profile of functional health and well-being, physical and mental 
health summary measures and a preference-based health utility index. 
x Hip Outcome Score (HOS)44 which measures self-reported functional status 
through 28 items and two sub-scales that pertain to activities of daily living 
(ADLs) or higher level activities such as those necessary to participate in 
sports. 
2. Fracture healing complications: These will include wound healing problems, 
infection (superficial and deep), hardware failure, hardware breakage, painful 
hardware, and peri-prosthetic fracture.  
3. Radiographic fracture healing: The date of healing will be determined by the 
Central Adjudication Committee (CAC).  They will consider a fracture as healed 
when there is obliteration of the fracture line by newly formed bone along the 
cortices and within the trabecular bone on anterior-posterior and lateral 
radiographs.   
 
4.9 Frequency and Duration of Follow-Up 
Participants will be followed for a period of 12 months post-surgery (Figure 4).  
Participant follow-up visits will occur at enrollment (baseline), post-operative  (24 hours 
to 14 days window), 6 weeks (2 week to 8 week window), 3 months (2 to 4 month 
window), 6 months (5 to 7 month window), 9 months (7 to 11 month window), and 12 
months (11 months or greater window) post-surgery.   
 
The Schedule of Assessments (Table 1) details the requirements and procedures for 
each visit.  All study outcomes (as defined in sections 4.8.1 and 4.8.2) will be 
documented on the case report forms (CRFs) at each follow-up visit.  
 
Additionally at all follow-up visits the participant will complete the SF-12 and HOS 
questionnaires.  At the post-surgery follow-up visit participants will answer all 
questionnaires based on their pre-injury status.  Questionnaires for subsequent follow-
up visits will be answered based on the participant͛Ɛ cƵrrenƚ ƐƚaƚƵƐ aƚ ƚhe ƚime of folloǁ-
up.   
 
For participants who have an ipsilateral femoral shaft fracture at each follow-up visit we 
will document: 1) the time to radiographic fracture healing of the ipsilateral femoral 
shaft; 2) re-operation; and 3) fracture-related complications including compartment 
syndrome, wound healing problems, infection (superficial or deep), hardware failure, 
hardware breakage, malunion, nonunion, and prolonged pain at the fracture site.  
 
Serious adverse events (SAEs) will also be documented at each visit.  X-rays of the 
participant͛Ɛ fracƚƵred hip are reqƵired aƚ enrollmenƚ ;baƐelineͿ͕ poƐƚ-surgery, and at, 6 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
19 of 45 
Version 2.0 
weeks, 3 months, 6 months, 9 months, and 12 months post-surgery.  As the primary 
outcome includes radiographic outcomes, it is important that X-rays be obtained at all 
follow-up visits.  MRI or other advanced imaging studies are not required and may be 
ordered at the discretion of the attending surgeon.  Clinical notes may also be 
requested.  If additional imaging studies are obtained, they will be sent to the Methods 
Centre for outcome adjudication. In addition, at the 12-month follow-up visit, any re-
operations that may be planned for the participant will be documented.   
 
4.10 Participant Retention 
Once a patient is enrolled in the trial, the clinical site will make every reasonable effort 
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 
performed by the study investigators.39,45  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 5).46  Clinical site personnel are responsible for implementing these procedures, 
as well as developing their own local procedures, in order to attain this follow-up rate. 
 
Participants may discontinue their participation in the FAITH-2 study at any time. If a 
participant wishes to withdraw their consent from the study, we will use the following 
strategies to reduce the demands of the study and help to retain the study participant:  
1. Ask them to return for a clinic visit at the 12 month follow-up only and ensure 
that the items included in the primary outcome (re-operation status and X-ray) 
are completed. 
2. Ask them if research personnel may contact them by telephone to ask about 
their status. 
3. Ask them for permission to access their medical chart to identify information 
about their status.  
 
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. 
 
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 nutritional 
supplement, 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). 
 
4.11 Blinding 
Surgeons, research personnel, participants, and members of the CAC cannot be blinded 
to the treatment allocation of the surgical interventions (SHS versus cancellous screws). 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
20 of 45 
Version 2.0 
The data analyst and the Steering Committee will be blinded to the surgical treatment 
allocation.  
 
The complete blinding of the nutritional supplement will be achieved by using vitamin 
D3 and placebo liquid products that are indistinguishable. This will ensure that the 
surgeon, participants, research personnel, the CAC members, the data analyst, and the 
Steering Committee are blinded to the participantƐ͛ nutritional supplementation 
allocation.  An unblinding procedure will be made available when necessary (Figure 6). 
 
5.0 STATISTICAL PLAN 
 
5.1 Sample Size Determination 
The choice of sample size is based upon independent comparisons of the SHS versus 
multiple cancellous screw AND vitamin D supplementation versus placebo for the 
primary outcome (patient important outcomes). This is based on the assumption that 
both interventions will act independently. We will use an alpha level of 0.5 for the 
primary outcome and all statistical hypotheses will be 2-sided.  
 
The preliminary sample size calculations are based on the limited published literature. 
As outlined in section 1.2, a pooled estimate from 18 published studies revealed a 
combined femoral head osteonecrosis and fracture nonunion incidence of 25%. In 
addition to femoral head osteonecrosis, the composite primary outcome includes other 
events such as re-operation and severe femoral neck malunion. These additional 
complications are expected to increase the composite event rate to approximately 40%; 
therefore, a conservative event rate of 30% is assumed in the cancellous screw and 
placebo groups. 
 
The trial is powered for a RRR of 33% for each of the treatment comparisons: SHS versus 
multiple cancellous screws AND vitamin D3 supplementation versus placebo. This RRR 
estimate is based on the best available literature and coincides with a 10% absolute risk 
reduction that was deemed to be clinically significant by over 500 surveyed surgeons. 10 
For the surgical comparison, Gardner et al21 and Chen et al22 reported an 86% and 100% 
RRR for reoperation using a SHS. Other more heterogeneous retrospective studies by 
Liporace et al23 and Razik et al24 suggest RRRs from SHS between 50-88% for 
osteonecrosis and 63% for nonunion (Section 1.3). Since these are uncontrolled 
retrospective studies, a conservative effect size estimate is maintained. With regard to 
the expected treatment effect of vitamin D supplementation, there are no clinical 
studies that quantify its efficacy to reduce fracture healing complications. Despite the 
lack of direct data, vitamin D supplementation following acute fractures has 
demonstrated a 40% increase in fracture callus density in human participants29 and an 
80% increase in mechanical strength in animal model.28  Experimental evidence also 
suggests benefits of increased fracture area vascularity and improved healing that may 
also contribute to the treatment effect of vitamin D supplementation. We have also 
assumed the same RRR of 33% in the vitamin D treatment arm.  


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
21 of 45 
Version 2.0 
 
Considering a 30% event rate in the cancellous screw and placebo group, a RRR of 33% 
will give a 20% event rate in the SHS and placebo group.  Therefore, the event rate for 
the total placebo group (combined over cancellous screw and SHS groups) is expected to 
be 25%.  Similarly a RRR of 33% due to vitamin D3 supplementation will result in a 20% 
event rate in the cancellous screw and vitamin D3 supplementation group.  This leads to 
an expected event rate of 25% for the total cancellous screw group (combined over both 
the placebo and vitamin D3 supplementation groups).  Therefore our sample size 
calculation is based on a control group event rate of 25% and a RRR of 33%. 
 
We will recruit a sample size of 808 patients with full follow-up. Based on an anticipated 
10% loss to follow-up39, 898 patients will need to be enrolled in the FAITH-2 trial. Table 
2 demonstrates that the chosen sample size will have a high likelihood of detecting a 
RRR of 33% or greater across a plausible range of expected primary outcome events 
(patient important complication), and moderate power for slightly lower effect sizes. 
Furthermore, if there are synergistic effects between the surgical and vitamin D 
interventions, there will be even greater study power.  
 
5.2 Statistical Methods 
 
5.2.1 General 
The baseline characteristics will be analyzed using descriptive statistics reported as 
mean (standard deviation) or median (first quartile, third quartile) for continuous 
variables depending on the distribution and count (percent) for categorical variables. All 
outcome analyses will adhere to the intention-to-treat principle. The reporting of the 
trial will follow the CONSORT criteria (www.consort-statement.org). We will provide 
estimates of our composite outcome of patient important outcomes using proportions 
with 95% confidence intervals and associated p-values. All p-values will be reported to 
three decimal places with those less than 0.001 reported as p<0.001. The criterion for 
statistical significance will be based on alpha = 0.05. We will use SAS (Cary, NC) to 
perform all analyses. 
 
5.2.2 Primary Analyses 
Two independent comparisons between the treatment groups (SHS versus cancellous 
screws AND vitamin D3 supplementation versus placebo) will be made using the chi-
square statistic and an alpha level of 0.05.  Table 3 shows the details for the analysis of 
primary outcomes. 
 
5.2.3 Secondary Analyses 
All secondary outcomes will be summarized using means and 95% confidence intervals, 
or percentages and 95% confidence intervals.  Longitudinal models will be used to 
explore the effect of treatment group and time on the HOS and SF-12 patient-reported 
outcomes.  Table 4 shows the details for the analysis of secondary outcomes. 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
22 of 45 
Version 2.0 
 
5.2.4 Planned Exploratory Analyses  
Exploratory analyses will be conducted comparing the treatment effects in participants 
with undisplaced versus displaced femoral neck fractures, and emergent (<8 hours) 
versus non-emergent ;шϴ hoƵrƐͿ inƚernal fiǆaƚion͘ We plan ƚo fiƚ logiƐƚic regreƐƐion 
models and include treatment by subgroup interactions to assess whether the 
magnitude of the treatment effect is significantly different between subgroups.  Table 5 
shows the details for the exploratory analyses. 
 
5.2.5 Interim Analysis 
An interim analysis will not be conducted.  The trial will not be stopped early for benefit. 
The Data Safety and Monitoring Committee (DSMC) will monitor Adverse Events (AEs) 
and may make recommendations to the Principal Investigators and Steering Committee 
to stop the study for harm only. 
 
6. DATA MANAGEMENT 
 
6.1 Case Report Forms and Data Entry 
The CRFs will be the primary data collection tool for the study. All data requested on the 
CRF must be recorded.  An Electronic Data Capture (EDC) system will be used to submit 
data to the Methods Centre located at McMaster University.  Upon receipt of the data, 
the personnel at the Methods Centre will make a visual check of the data and they will 
query all missing data, implausible data, and inconsistencies.  
 
6.2 Data Transmissions  
Data will be transmitted from clinical sites to the Methods Centre using an EDC system.  
The data entry screens in the EDC system will be similar to the paper CRFs.  Data 
integrity will be enhanced by using the EDC system through a variety of mechanisms for 
checking data at the time of entry including referential data rules, valid values, range 
checks, and consistency checks against data already stored in the database.  Clinical site 
personnel will be able to view and modify data for participants recruited from their 
clinical site only.  Each time data is submitted or modified, it will be validated by 
Methods Centre personnel. 
 
6.3 Data Discrepancy Inquiries 
Once data are submitted, additional errors will be detected by the program within the 
EDC system to detect missing data or errors.  Clinical site personnel will be notified of 
these errors through regular quality control reports.  Clinical site personnel will be 
required to respond promptly to each query on the quality control report.  To respond 
to queries study personnel should check the original forms for inconsistency and check 
other sources of participant records to determine the correction.  Clinical site personnel 
will then modify the data in the EDC system to reflect the correction and resubmit data 
to the Methods Centre in order to resolve the query. 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
23 of 45 
Version 2.0 
 
6.4 Security and Back-Up of Data 
All CRFs and specimens must be kept secure in locked cabinets or other enclosures that 
are accessible only to study personnel.  All electronic data must be password-protected 
and accessible only to study personnel.  The Methods Centre will be responsible for 
backing up all submitted data. 
 
6.5 Quality Control Reports 
Each clinical site will regularly receive a quality control report showing the number of 
each of the following: 
1. Participants entered into the trial. 
2. Completed follow-ups. 
3. Outstanding data queries and clarification requests. 
4. Participant͛Ɛ neǆƚ folloǁ-up visit. 
5. Overdue follow-up visits. 
Study personnel should review these reports for accuracy and contact the Methods 
Centre if they identify any discrepancies. 
 
7. ETHICS AND DISSEMINATION 
 
7.1 Research Ethics Approval 
This protocol, the consent form template, and the CRFs will be reviewed and approved 
bǇ McMaƐƚer UniǀerƐiƚǇ͛Ɛ ReƐearch EƚhicƐ Board ;REBͿ͘  The proƚocol͕ clinical Ɛiƚe-
specific informed consent forms, and any participant recruitment material will need to 
be reǀieǁed and approǀed bǇ each clinical Ɛiƚe͛Ɛ local eƚhicƐ board͘  Prior ƚo 
commencement of the study the clinical site must provide the Methods Centre with a 
copy of the ethics board approval. 
 
7.2 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: 
x Present study information in a manner that is understandable to the potential 
parƚicipanƚͬƚhe paƚienƚ͛Ɛ legal representative. 
x DiƐcƵƐƐ ƚhe ƐƚƵdǇ ǁiƚh ƚhe poƚenƚial parƚicipanƚͬƚhe paƚienƚ͛Ɛ legal 
representative and answer any questions he or she asks. 
x Alloǁ ƚhe poƚenƚial parƚicipanƚͬƚhe paƚienƚ͛Ɛ legal repreƐenƚaƚiǀe an opporƚƵniƚǇ 
to discuss participation with their family, friends, or family physician if desired. 
x Confirm ƚhaƚ ƚhe parƚicipanƚͬƚhe paƚienƚ͛Ɛ legal repreƐenƚaƚiǀe ƵnderƐƚandƐ ƚhe 
risks and benefits of participating in the study and that their participation is 
voluntary. 
x Complete and obtain signatures for informed consent form and obtain contact 
information from the participant. 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
24 of 45 
Version 2.0 
 
7.3 Confidentiality 
Information about study participants will be kept confidential and will be managed in 
accordance with the below rules: 
x All study-related information will be stored securely at the clinical site. 
x All study participant information will be stored in locked file cabinets and 
accessible only to study personnel. 
x All CRFs will be identified only by a coded participant number and initials. 
x 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. 
x All local 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 that 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. 
 
7.4 Access to Data 
Only the Methods Centre will have access to the full trial dataset.  Data for the primary 
publication will be analyzed exclusively by the Methods Centre.  Requests for access to 
the full trial dataset for secondary publications are encouraged and can be initiated 
through a written request to Methods Centre personnel.  All requests will be reviewed 
by the Principal Investigators. 
 
7.5 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 McMaster UniǀerƐiƚǇ͛Ɛ REB͘  Clinical ƐiƚeƐ ǁill alƐo be reqƵired ƚo 
submit amendment requests to their local ethics boards in order to obtain approval for 
the amendment and to provide the Methods Centre with a copy of this approval.  
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 
and will be communicated to clinical sites when applicable. 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
25 of 45 
Version 2.0 
 
7.6 Adverse Event Reporting and Definitions 
7.6.1 Adverse Event  
An AE is any symptom, sign, illness, or experience that develops or worsens in severity 
during the course of this study. As FAITH-2 is not assessing patient safety, only AEs that 
are study outcomes (i.e. fracture-related) will be recorded as per sections 4.8.1 and 
4.8.2. 
7.6.2 Serious Adverse Event  
AEs are classified as serious or non-serious. A SAE is any AE that is any of the following: 
x Fatal 
x Life threatening 
x Requires or prolongs hospital stay 
x Results in persistent or significant disability or incapacity 
x A congenital anomaly or birth defect 
x An important medical event  
All SAEs must be recorded and promptly submitted to the Methods Centre. 
7.6.3 Unanticipated Problems Resulting in Risk to Participant or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
x Unexpected in nature, severity, or frequency (e.g. not described in study-related 
documents such as the ethics-approved protocol or consent form, etc.). 
x 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). 
x 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 Methods Centre. 
 
7.7 Reporting of Serious Adverse Events and Unanticipated Problems Resulting in Risk 
to Participants or Others  
All fracture-related AEs, SAEs, and unanticipated problems resulting in risk to 
participants or others are to be reported to the Methods Centre immediately.  
7.7.1 Clinical Site Reporting: Notifying the Methods Centre 
All fracture-related AEs and SAEs must be reported to the Methods Centre by 
completing the AE form and submitting it to the Methods Centre. The clinical site will 
keep a copy of this form on file at the clinical site. Significant new information on 
ongoing SAEs should be provided promptly to the Methods Centre by updating the 
form. Unanticipated problems resulting in risk to participants or others are to be 
reported to the Methods Centre. 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
26 of 45 
Version 2.0 
7.7.2 Clinical Site ʹ Institutional Review Board and Research Ethics Board Reporting 
Clinical sites are responsible for reporting fracture-related AEs, SAEs and unanticipated 
problems resulting in risk to participants or others to their local ethic boards. Clinical 
sites are responsible for complying with their local ethic boards reporting requirements. 
Copies of each report and documentation of ethic board notification and receipt will be 
kepƚ in ƚhe clinical Ɛiƚe͛Ɛ ƐƚƵdǇ file͘  
 
7.8 Potential Risks to Participants 
Surgeons worldwide are currently using both surgical techniques (cancellous screws and 
SHS). Both implants have been used for over five decades in the management of hip 
fractures. As with any surgical procedure of the lower extremity, potential risks include 
wound infection, deep vein thrombosis, neurovascular injury, and death. Given that all 
eligible patients require surgery for their acute fracture, there is no anticipated 
increased surgical risk for study participants.  Similarly, the safety of vitamin D3 
supplementation is well established, and 4,000 IU per day is within the tolerable daily 
dose according to Health Canada.36  Participants will be monitored for all SAEs and 
fracture-related AEs following treatment across the surgical and nutritional arms. The 
DSMC will review SAEs and fracture-related AEs at regular intervals.   
 
7.9 Dissemination Policy 
Results from the primary manuscript 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.   
 
7.10 Ethical Considerations 
This study is to be conducted according to US and international standards of Good 
Clinical Practice and International Conference on Harmonization guidelines, applicable 
government regulations, and institutional research policies and procedures. 
 
8. STUDY COMMITTEES 
 
8.1 Steering Committee 
The Steering Committee is comprised of orthopaedic surgeons, vitamin D experts, a 
statistician, and research methodologists.  The Steering Committee will provide 
guidance and direction to the overall trial.   
 
8.2 Data Safety and Monitoring Committee 
The DSMC is comprised of 3 members who remain completely independent of the study 
investigators. The DSMC members include a biostatistician (Chair) and two orthopaedic 
surgeons with prior trial experience. The DSMC will review accumulated safety data (i.e. 
SAEs and fracture-related AEs) from the trial and advise the Principal Investigators and 
the Steering Committee on items related to participant safety. 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
27 of 45 
Version 2.0 
 
8.3 Central Adjudication Committee 
The CAC will be comprised of four orthopaedic surgeons with prior adjudication 
experience and they will independently adjudicate the following: 
x Situations where eligibility is in doubt 
x Radiographic characteristics and quality of the surgery 
x Patient important outcomes that define the primary outcome (re-operation, 
femoral head osteonecrosis, severe femoral neck malunion, or nonunion)  
x Fracture healing complications 
x Radiographic fracture healing  
 
All clinical sites will submit X-Rays and any additional imaging studies (such as a hip MRI 
or other advanced imaging studies) to be included in the adjudication process (Figure 7).  
Clinical notes may also be requested.  Any disagreements between the CAC members 
will be resolved during regular conference calls. If consensus cannot initially be reached, 
additional information will be requested from the clinical site to clarify areas of 
uncertainty.  


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
28 of 45 
Version 2.0 
Table 1: Schedule of Events 
 
Assessment 
Screening 
 
Enrollment 
(Baseline) 
Surgery 
Post-
operative 
Week 6 
Month 3 
Month 6 
Month 9 
Month 12 
Informed Consent  
X 
 
 
  
  
  
  
  
  
Medical History 
X 
 
 
 
  
  
  
  
  
AP & Lateral X-Rays of Proximal Femur  
X 
 
 
X 
X 
X 
X 
X 
 X 
Physical Exam/Injury Assessment 
X 
 
 
 
 
 
 
 
 
Screening Form  
X 
 
 
  
  
  
  
  
  
Randomization Form  
 
X 
 
  
  
  
  
  
  
Pre-Operative Form  
  
X 
 
 
 
 
 
 
 
Surgery (SHS or Cancellous Screws) 
  
 
X 
 
  
  
  
  
  
Surgical Forms 
  
 
X 
 
  
  
  
  
  
Hospital Discharge Form  
  
 
 
X 
  
  
  
  
  
Vitamin D or Placebo Supplementation**  
  
 
 
X 
X 
X 
X  
 
 
Follow-up Visit Forms 
  
 
 
X 
X 
X 
X 
X 
X 
Assessment for Re-Operations 
 
 
 
X 
X 
X 
X 
X 
X 
Assessment of Fracture Healing Complications 
 
 
 
 
X 
X 
X 
X 
X 
Assessment of Fracture Healing  
 
 
 
 
X 
X 
X 
X 
X 
Hip Outcome Score (HOS) 
 
 
 
X* 
X 
X 
X 
X 
X 
Short Form-12 (SF-12) 
 
 
 
X* 
X 
X 
X 
X 
X 
Assessment of Fracture Healing of the Ipsilateral 
Femoral Shaft Fracture*** 
 
 
 
 
X 
X 
X 
X 
X 
Assessment for Fracture-Related Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
Assessment for Serious Adverse Events 
  
 
X 
X 
X 
X 
X 
X 
X 
Assessment for Planned Re-operations 
 
 
 
 
 
 
 
 
X 
*AƐkƐ aboƵƚ parƚicipanƚ͛Ɛ fƵncƚion prior ƚo ƚheir hip fracƚƵre͘ 
** Nutritional supplementation will be administered upon hospital discharge or within two weeks of the participant͛Ɛ ƐƵrgerǇ͕ ǁhicheǀer comeƐ firƐƚ͘  IdeallǇ͕ participants should 
be administered the nutritional supplementation as soon as possible following their surgery to repair their femoral neck fracture. 
***For parƚicipanƚ͛Ɛ ǁiƚh an ipƐilaƚeral femoral Ɛhafƚ fracƚure. 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
29 of 45 
Version 2.0 
Table 2: Sample Size Estimates 
 
 
Relative Risk Reduction 
from the SHS and vitamin D supplementation 
20% 
25% 
30% 
33% 
35% 
40% 
Incidence of 
Patient Important 
Outcomes 
in the control 
groups 
20% 
2994 
1890 
1294 
1060 
936 
706 
25% 
2266 
1434 
984 
808 
714 
540 
30% 
1782 
1130 
778 
638 
566 
428 
35% 
1436 
914 
630 
518 
460 
348 
40% 
1178 
752 
520 
428 
380 
288 
x Total sample size required to achieve 80% power for the independent comparisons of the SHS versus cancellous screws AND 
vitamin D supplementation versus placebo.   
x Grey highlighted boxes denote scenarios where we have more than 80% power (alpha=0.05, 2-sided) to detect the 
hypothesized difference, given our proposed sample size of 808. 
x Control groups: cancellous screws and placebo supplementation  
 
 
 
 
 
 
 
 
 
 
 
 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
30 of 45 
Version 2.0 
Table 3: Summary of Primary Outcome Analyses 
 
Variable/Outcome 
Hypothesis for 
Surgical Treatments 
Hypothesis for 
Nutritional 
Supplementation  
Outcome Measures 
Method of Analysis 
Re-operation  
The incidence of re-
operation, femoral 
head osteonecrosis, 
severe femoral neck 
malunion, or 
nonunion will be 
lower in patients 
receiving a SHS 
compared to 
cancellous screws. 
The incidence of re-
operation, femoral 
head osteonecrosis, 
severe femoral neck 
malunion, or nonunion 
will be lower in patients 
receiving vitamin D 
versus placebo. 
Re-operation anytime within 
12 months 
Chi-square statistic with 
independent comparison 
for the surgical treatments 
and nutritional treatments 
(alpha=0.05) 
Femoral head 
osteonecrosis 
Evidence of femoral head 
osteonecrosis on X-Rays or 
MRI  
Severe malunion 
Evidence of severe femoral 
neck malunion on X-Rays 
Nonunion 
Failure of the fracture to 
progress towards healing 
defined as a Radiographic 
Union Score for Hip (RUSH)41,42 
score below a pre-determined 
threshold specific for 
nonunion at 6 months or 
greater post-injury 
 
*The primary outcome is a composite of re-operation, femoral head osteonecrosis, severe femoral neck malunion, or nonunion. 
 
 
 
 
 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
31 of 45 
Version 2.0 
Table 4: Summary of Secondary Analyses  
 
Variable/Outcome 
Hypothesis for Surgical 
Treatments 
Hypothesis for Nutritional 
Supplementation 
Outcome Measures 
Method of Analysis 
HRQL and function 
HRQL and function will 
be better in patients 
receiving SHS versus 
cancellous screws. 
HRQL and function will be 
better in patients receiving 
vitamin D versus placebo. 
HOS and SF-12 
Summary statistics of 
means and confidence 
interval 
Longitudinal modeling to 
include treatment and 
time 
Fracture healing 
complications 
Rates of fracture healing 
complications will be 
lower in patients 
receiving SHS versus 
cancellous screws. 
Rates of fracture healing 
complications will be lower in 
patients receiving vitamin D 
versus placebo. 
Evidence of 
complications reported 
by patients or evident on 
X-Rays 
Summary statistics of 
proportions 
Chi-square statistic with 
independent comparison 
for the surgical 
treatments and 
nutritional treatments  
Fracture healing  
Fractures will heal faster 
in patients receiving SHS 
versus cancellous 
screws. 
Fractures will heal faster in 
patients receiving vitamin D 
supplementation.   
A fracture will be 
considered as healed 
when there is 
obliteration of the 
fracture line by newly 
formed bone along the 
cortices and within the 
trabecular bone on 
anterior-posterior and 
lateral X-rays 
Time to event analysis 
with treatment group as 
an independent variable 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
32 of 45 
Version 2.0 
Table 5: Summary of Exploratory Analyses  
 
Fracture/Surgical 
Characteristics 
Hypothesis for Surgical Treatments 
Hypothesis for 
Nutritional 
Supplementation 
Outcome Measures 
Method of Analysis 
Undisplaced versus 
displaced femoral 
neck fractures 
The magnitude of treatment effect 
favouring SHS will be higher in 
displaced fractures vs. undisplaced 
fractures 
The magnitude of 
treatment effect 
favouring vitamin D 
will be higher in 
displaced fractures 
vs. undisplaced 
fractures 
Composite primary 
outcome as above 
(reoperation, femoral 
head osteonecrosis, 
severe femoral neck 
malunion, and nonunion) 
Logistic regression 
models with an 
interaction term 
between treatment 
and femoral neck 
displacement 
Emergent (<8 hours) 
versus non-emergent 
;шϴ hoƵrƐͿ inƚernal 
fixation 
The magnitude of treatment effect 
favouring SHS will be higher in 
fractures treated emergently vs. non-
emergently. 
Not Applicable 
Composite primary 
outcome as above 
(reoperation, femoral 
head osteonecrosis, 
severe femoral neck 
malunion, and nonunion) 
Logistic regression 
models with an 
interaction term 
between treatment 
and internal fixation 
type 
 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
33 of 45 
Version 2.0 
Figure 1:  Blood Supply to the Femoral Head 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
34 of 45 
Version 2.0 
Figure 2: Multiple Cancellous Screws 
 
 
 
 
 
 
2a 
2a 
 
2b 
2b 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
35 of 45 
Version 2.0 
Figure 3:  Sliding Hip Screw 
 
 
 
3a 
3b 
3a 
 
3b 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
36 of 45 
Version 2.0 
Figure 4:  Recruitment and Follow-Up Schedule 
 
  
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
37 of 45 
Version 2.0 
Figure 4:  Recruitment and Visit Schedule (continued) 
 
 
 
 
 
 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
38 of 45 
Version 2.0 
Figure 5:  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 three people at different addresses with whom the 
participants does not live who are likely to be aware of the participant͛Ɛ ǁhereaboƵƚƐ͘ 
The research coordinator will confirm that these numbers are accurate prior to the 
participant͛Ɛ diƐcharge from hoƐpiƚal͘   
 
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 three 
months to maintain contact and obtain information about any planned change in 
residence.   
 
6) If a participant refuses to return for a follow-up assessment, study personnel will 
reduce the burden of the study assessments and aim to have the participant complete 
the primary outcome only. 
 
 
 
Sprague et al46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
39 of 45 
Version 2.0 
Figure 6: Unblinding of Clinical Site 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. Clinical sites are instructed to contact the Methods Centre and provide 
details of the medical emergency as soon as possible after the event. At no 
time will the participant͛Ɛ healƚh be compromiƐed or medical ƚreaƚmenƚ 
delayed.  
3. When a request for unblinding is received by the Methods Centre, the 
Research Coordinator (or designee) is responsible for contacting the 
Principal Investigator (or designee). 
4. The Principal Investigator (or designee) is responsible for reviewing and 
approving all requests for unblinding.  Once approved, the Research 
Coordinator (or designee) ǁill proǀide ƚhe Ɛiƚe ǁiƚh ƚhe parƚicipanƚ͛Ɛ 
treatment allocation.  This information is to be provided by telephone.  No 
information regarding treatment allocation is to be sent via email or fax. 
5. The unblinded FAITH-2 personnel are not to unblind the Principal 
Investigator or any blinded members of the FAITH-2 team unless deemed 
necessary by the Principal Investigator. 
6. FAITH-2 personnel must keep all information related to the individual 
unblinding cases confidential. 
7. All cases of unblinding must be documented, including; clinical site ID, 
study ID, date of unblinding, parties unblinded, and reason for unblinding. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
40 of 45 
Version 2.0 
Figure 7:  Central Adjudication Process 
 
1. Methods Centre personnel will request the following from each clinical site: 
x 
X-Rays 
x 
MRI or other advanced imaging study (if available) 
 
 
 
2. Clinical sites remove participant idenƚifierƐ prior ƚo ƐƵbmiƐƐion ƚo ƚhe Meƚhod͛Ɛ 
Centre.   
 
 
 
3. X-Rays will be blinded and adjudication materials will be uploaded to the secure, 
password protected adjudication website by Method Centre personnel for the CAC 
to review. 
 
 
 
4. Each CAC member will independently adjudicate all posted cases.  They will 
independently submit their answers in the EDC section of the adjudication website.  
 
 
 
5. After all CAC members have completed the web-based adjudication, a consensus 
ƚable ǁiƚh each member͛Ɛ reƐƵlƚƐ ǁill be prepared͘ 
 
 
 
6. Following each adjudication batch the CAC members will communicate via 
conference call (or in person if coinciding with a scheduled meeting) and discuss all 
disagreements.  The chair of the CAC will lead each consensus meeting. 
 
 
 
7. Consensus will be achieved for all cases.  Occasionally, the CAC may request 
additional information from a clinical site to achieve consensus.  In situation 
where a consensus cannot be achieved, a majority vote will be taken. 
 
 
 
 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
41 of 45 
Version 2.0 
REFERENCES  
 
1. Cooper C, Campion G, Melton LJ III. Hip fractures in the elderly: A world-wide 
projection. Osteoporosis International. 1992;2:285-289. 
 
2. Hamilton B. Vitamin D and human skeletal muscle. Scandinavian Journal of Medicine 
and Science in Sports. 2010;20:182-190. 
 
3. Johnell O, Kanis JA. An estimate of the worldwide prevalence, mortality, and disability 
associated with hip fracture. Osteoporosis International. 2004;15:897-902. 
 
4. Mussbichler H. Ateriographic studies in fractures of the femoral neck and trochanteric 
region: Type and incidence of findings in pre- and postoperative examinations, relation 
to fracture dislocation and prognostic value. Angiograpy. 1970;21:285-402. 
 
5. Malchau H, Herberts H, Eisler T, Garellick G, Soderman P. The Swedish total hip 
replacement register. Journal of Bone and Joint Surgery – American Volume. 2002;84-
A:2-20. 
 
6. Patil S, Garbuz DS, Greidanus NV, Masri BA, Duncan CP. Quality of life outcomes in 
revision vs. primary total hip arthroplasty. The Journal of Arthroplasty. 2008;23:550-553. 
 
7. Damany DS, Parker MJ, Chojnowski A. Complications after intracapsular hip fractures 
in young adults: A meta-analysis of 18 published studies involving 564 fractures. Injury. 
2005;36:131-141. 
 
8. Slobogean GP, Sprague SA, Scott T, Bhandari M.  Incidence of Reoperation Following 
Internal Fixation of Femoral Neck Fractures in Adults Age 60 Years or Less: A Meta-
Analysis. Presented at the Orthopaedic Trauma Association Annual Meeting. October 10 
to 12, 2013, Phoenix, Arizona.  
 
9. Zlowodzki M, Brink O, Switzer J, Wingerter S, Woodall J Jr, Petrisor BA, Kregor PJ, 
Bruinsma DR, Bhandari M. The effect of shortening and varus collapse of the femoral 
neck on function after fixation of intracapsular fracture of the hip: a multi-centre cohort 
study. Journal of Bone and Joint Surgery British. 2008;90:1487-1494. 
 
10. Slobogean G, Sprague S, Scott T. McKee M. Bhandari, M.  Treatment Preferences in 
the Management of Femoral Neck Fractures in Young Adults.  Journal of Orthopaedic 
Trauma.  In review, 2013. 
 
11. Bhandari M, Devereauz PJ, Swiontkowski MF, Torneta P, Obremskey W, Koval KJ, 
Nork S, Sprague S, Schemitsch EH, Guyatt GH. Internal fixation compared with 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
42 of 45 
Version 2.0 
arthroplasty for displaced fractures of the femoral neck. A meta-analysis. Journal of 
Bone and Joint Surgery American Volume. 2003;85-A:1673-1681. 
 
12. Johansson A, Stroqvist B, Bauer G, Hansson LI, Pettersson H. Improved operations 
for femoral neck fracture. A radiographic evaluation. Acta Orthopaedica Scandinavica. 
1986;57:505-509. 
 
13. Lindequist S. Cortical screw support in femoral neck fractures. A radiographic 
analysis of 87 fractures with a new mensuration technique. Acta Orthopaedica 
Scandinavica. 1993;65:89-293. 
 
14. Linke B, Schwieger K, Bursick D, Ulrich D. Treatment of unstable femoral neck 
fractures: Is the dynamic hip screw a superior alternative to three cannulated screws? 
[Abstract] Presented at the 2004 Orthopaedic Trauma Association Annual Meeting. 
Hollywood, FL. Available at: http://www.hwbf.org/ota/am/ota04/otapo/OTP04055.htm. 
Accessed February 27, 2012. 
 
15. Linde F, Andersen E, Hvass I, Madsen F, Pallesen R.  Avascular femoral head necrosis 
following fracture fixation. Injury. 1986;17:159-63. 
 
16. Swiontkowski MF, Harrington RM, Keller TS, Van Patten PK. Torsion and bending 
analysis of internal fixation techniques for femoral neck fractures: The role of implant 
design and bone density. Journal of Orthopaedic Research. 1987;5:433-444. 
 
17. Srivastava KP, Chandra H, Gupta R. Assessment of comparative results of methods of 
compression fixation of femoral neck fractures ʹ A preliminary report. Indian Journal of 
Orthopaedics. 1989;23:141-144. 
 
18. Aminian A, Gao F, Fedoriw WW, Zhang L-Q, Kalainov DM, Merk BR. Vertically 
oriented femoral neck fractures: Mechanical analysis of four fixation techniques. Journal 
of OrthopaedicTrauma. 2007;21:544-548. 
 
19. Bhandari M, Tornetta P, Hanson B Swintkowski MF. Optimal internal fixation for 
femoral neck fractures: Multiple screws or sliding hip screws? Journal of Orthopaedic 
Trauma. 2009;23:403-407. 
 
20. Baitner AC, Maurer SG, Hickey DG, Jazrawi LM, Kummer FJ, Jamal J, Goldman S, 
Koval KJ. Vertical shear fractures of the femoral neck. A biomechanical study. Clinical 
Orthopaedics and Related Research. 1999;367:300-305. 
 
21. Gardner ST, Weaver MJ, Jerabek SA, Vrahas MS, Appleton PT, Harris MB. Displaced 
femoral neck fractures in patients <60 years of age. [Abstract] Presented at the 2012 
Orthopaedic 
Trauma 
Association 
Annual 
Meeting. 
Available 
at: 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
43 of 45 
Version 2.0 
http://www.hwbf.org/ota/am/ota12/otapa/OTA120133.htm. Accessed February 27, 
2013. 
 
22. Chen Z, Wang G, Lin J, Yang T, Fang Y, Liu L, Zhang H. Efficacy comparison between 
dynamic hip screw combined with anti-rotation screw and cannulated screw in treating 
femoral neck fractures. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2011;25:26-29. 
 
23. Liporace R, Gaines C, Collinge C, Haidukewych GJ. Results of internal fixation of 
Pauwels type-3 vertical femoral neck fractures. Journal of Bone and Joint Surgery 
American Volume. 2008;90-A:1654-1659. 
 
24. Razik F, Alexopoulos A-S, El-Osta B, Connolly MJ, Brown A, Hassan S, Ravikumar K. 
Time to internal fixation of femoral neck fractures in patients under sixty years ʹ does 
this matter in the development of osteonecrosis of the femoral head? International 
Orthopaedics. 2012;36:2127-2132. 
 
25. Health Canada. Vitamin D and calcium: Updated dietary reference intakes. Updated 
March 22, 2012. Available at: http://www.hc-sc.gc.ca/fn-an/nutrition/vitamin/vita-d-
eng.php. Accessed February 27, 2012. 
 
26. Lidor C, Dekel S, Hallel T, Edelstein S. Levels of active metabolites of vitamin D3 in 
the callus of fracture repair in chicks. Journal of Bone and Joint Surgery-British Volume. 
1987;69-B:132-136. 
 
27. Ömeroglu S, Erdogan D, Ömeroglu H. Effects of a single high-dose vitamin D3 on 
fracture healing: An ultrastructural study in healthy guinea pigs. Archives of Orthopaedic 
Trauma Surgery.1997;116:37-40. 
 
28. Ömeroglu H, Ates Y, Akkus O, Korkusuz F, Biçimoglu A, Akkas N. Biomechanical 
analysis of the effect of single high-dose vitamin D3 on fracture healing in a healthy 
rabbit model. Archives of Orthopaedic Trauma Surgery. 1997;116:271-274. 
 
29. Doetsch AM, Faber J, Lynnerup N, Wätjen I, Bliddal H, Danneskiold-Samsoe B. The 
effect of calcium and vitamin D3 supplementation on the healing of the proximal 
humerus fracture: A randomized placebo-controlled study. Calcified Tissue International. 
2004;75:183-188. 
 
30. Burkiewicz CJ, Guadagnin FA, Skare TL do Nascimento MM, Servin SC, de Souza GD. 
Vitamin D and skin repair: A prospective, double-blind and placebo controlled study in 
the healing of leg ulcers. Revista do Colégio Brasileiro de Cirurgiões. 2012;39:401-407. 
 
31. Lappe J, Cullen D, Haynatzki G, Recker R, Ahlf R, Thompson K. Calcium and vitamin D 
supplementation decreases incidence of stress fractures in female Navy recruits. Journal 
of Bone and Mineral Research. 2008;23:741-749. 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
44 of 45 
Version 2.0 
 
32. Bee C, Sheerin DV, Wuest TK, Fitzpatrick DC. Serum vitamin D levels in orthopaedic 
trauma patients living in the northwestern United States. Journal of Orthopaedic 
Trauma. E-pub ahead of print, 10 May 2012. 
 
33. Crist BD, Hood MA, Della Rocca GJ, Stannard JP, Volgas DA, Murtha YM. Prevalence 
of vitamin D insufficiency in orthopaedic trauma patients. Presented at the 2012 
Orthopaedic Trauma Association Annual Meeting. 6 October 2012, Minneapolis, MN. 
Available at: http://www.hwbf.org/ota/am/ota12/otapa/OTA1207104.htm. Accessed 
January 28, 2013. 
 
34. Maureen LeahyVitamin D Insufficiency Common Among Orthopaedic Trauma 
Patients:Low levels not confined to the elderly.  AAOS Now. January 2013 Issue.  
Accessed at: http://www.aaos.org/news/aaosnow/jan13/clinical2.asp 
 
35. Eschle, D, Aeschlimann, G. Is supplementation of vitamin D beneficial for fracture 
healing? A short review of the literature.  Geriatric Orthopaedic Surgery. 2011;2:90-93. 
 
36. Institute of Medicine of the National Academics.  Consensus Report: Dietary 
Reference 
Intakes 
for 
Calcium 
and 
Vitamin 
D. 
 
2010. 
 
Available 
at: 
http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-
Vitamin-D/DRI-Values.aspx.  Accessed on: October 15, 2013. 
 
37. Bacon CJ, Gamble GD, Horne AM, Scott MA, Reid IR. High-dose oral vitamin D3 
supplementation in the elderly. Osteoporosis International. 2009;20:1407-1415. 
 
38. Papaioannou A, Kennedy CC, Giangregorio L, Ioannidis G, Pritchard J, Hanley DA, 
Farrauto L,DeBeer J, Adachi JD. A randomized controlled trial of vitamin D dosing 
strategies after acute hip fracture: No advantage of loading doses over daily 
supplementation. BMC Musculoskeletal Disorders. 2011;12:135. 
 
39. Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial 
Fractures Investigators, Bhandari M, Guyatt G, Tornetta P 3rd, Schemitsch EH,  
Swiontkowski M, Sanders D, Walter SD. Randomized trial of reamed and unreamed 
intramedullary nailing of tibial shaft fractures.  Journal of Bone Joint Surgery American 
Volume.  2008;90-A:2567-78.  
 
40. Zwart SR, Parsons H, Kimlin M, Innis SM, Locke JP, Smith SM.  A 250 ʅgͬǁeek doƐe of 
vitamin D was as effective as a 50 ʅgͬd doƐe in healƚhǇ adƵlƚƐ͕ bƵƚ a regimen of foƵr 
weekly followed by monthly doses of 1250 ʅg raiƐed ƚhe riƐk of hǇpercalciƵria͘ British 
Journal of Nutrition. 2013:1-7. Epub ahead of print. 
 
41. Chiavaras MM, Bains S, Choudur H, Parasu N, Jacobson J, Ayeni O, Petrisor B, 
Chakravertty R, Sprague S, Bhandari M. The Radiographic Union Score for Hip (RUSH): 


FAITH-2 Protocol 
 
Confidential  
11-Aug-2014 
45 of 45 
Version 2.0 
the use of a checklist to evaluate hip fracture healing improves agreement between 
radiologists and orthopedic surgeons. Skeletal Radiology. 2013;42:1079-88.  
 
42. Bhandari M, Chiavaras MM, Parasu N, Choudur H, Ayeni O, Chakravertty R, Bains 
S, Hak A, Sprague S, Petrisor B. Radiographic union score for hip substantially improves 
agreement between surgeons and radiologists. BMC Musculoskeletal Disorders. 
2013;14:70.  
 
43. Ware, J.E., Jr., Kosinski, M., Turner-Bowker, D.M., Gandek, B. How to Score Version 2 
of the SF-12v2® Health Survey (With a Supplement Documenting SF-12® Health Survey) 
Lincoln, RI: QualityMetric Incorporated, 2002. 
 
44. Martin RL, Kelly BT, Philippon MJ.  Evidence of validity for the hip outcome score.  
Arthroscopy. 2006;22:1304-11. 
 
45. FLOW Investigators, Petrisor B, Sun X, Bhandari M, Guyatt G, Jeray KJ, Sprague 
S, Tanner S, Schemitsch E, Sancheti P, Anglen J, Tornetta P, Bosse M, Liew S, Walter S. 
Fluid lavage of open wounds (FLOW): a multicenter, blinded, factorial pilot trial 
comparing alternative irrigating solutions and pressures in patients with open fractures. 
Journal of Trauma. 2011;71:596-606.  
 
46. Sprague S, Leece P, Bhandari M, Tornetta 3rd P, Schemitsch E, Swiontkowski MF, 
SPRINT Investigators. Limiting loss to follow-up in a multicenter randomized trial in 
orthopedic surgery. Controlled Clinical Trials. 2003;24:719-725. 
 
 
 
 
 
 


Page 1 of 54 
26-Oct-2018 
 
 
Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2): 
 
A Multi-Centre 2x2 Factorial Randomized Trial Comparing Sliding Hip Screws versus 
Cancellous Screws AND Vitamin D versus Placebo on Patient Important Complications and 
Quality of Life in the Treatment of Young Adult (18-60) Femoral Neck Fractures 
 
Principal Investigators: 
Dr. Gerard Slobogean and Dr. Mohit Bhandari 
 
 
Statistical Analysis Plan (SAP) 
Confidential 
The FAITH-2 SAP is the confidential intellectual property of the Principal Investigators and 
study team and cannot be used in any form without the expressed written permission of the 
Principal Investigators. 
 
Version: 1.0 
Date: October 26, 2018 


Page 2 of 54 
26-Oct-2018 
 
Document History 
Date 
(dd-mmm-
yyyy) 
Drafted/  
Revised By: 
Version  
Number 
Description of Amendments 
26-Oct-2018 
S. Sprague, S. Bzovsky 
1.0 
Initial version  
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 3 of 54 
26-Oct-2018 
 
Table of Contents 
List of Tables ................................................................................................................................................ 4 
List of Figures .............................................................................................................................................. 5 
1.0 
PURPOSE ......................................................................................................................................... 6 
2.0 
STUDY SUMMARY ....................................................................................................................... 6 
3.0 
SCREENING AND ENROLMENT ............................................................................................... 7 
4.0 
PARTICIPANT DEMOGRAPHICS CHARACTERISTICS ................................................... 11 
5.0 
INJURY AND FRACTURE CHARACTERISTICS ................................................................. 13 
6.0 
SUMMARY OF SURGICAL PROCEDURES ........................................................................... 14 
 
 
 
 


Page 4 of 54 
26-Oct-2018 
 
List of Tables 
Table 1: Reasons for Exclusion at Screening .............................................................................................. 10 
Table 2: Participant Demographics ............................................................................................................. 11 
Table 3: Fracture Characteristics ................................................................................................................. 13 
Table 4: Summary of Pre-Operative and Post-Operative Care Details ....................................................... 14 
Table 5: General Surgical Characteristics ................................................................................................... 14 
Table 6: CS Surgical Management .............................................................................................................. 16 
Table 7: SHS Surgical Management ............................................................................................................ 17 
Table 8: Feasibility Outcomes ..................................................................................................................... 18 
Table 9: Primary Clinical Endpoint Components and Reasons for Secondary Procedures ........................ 19 
Table 10: Primary Clinical Endpoint, According to Surgical Treatment (No Significant Interaction 
Between Implant Type and Supplementation Present) ................................................................................ 20 
Table 11: Primary Clinical Endpoint, According to Nutritional Supplementation (No Significant 
Interaction Between Implant Type and Supplementation Present) ............................................................. 21 
Table 12: Primary Clinical Endpoint (Significant Interaction Between Implant Type and Supplementation 
Present) ........................................................................................................................................................ 22 
Table 13: HRQL (SF-12), According to Surgical Treatment (No Significant Interaction Between Implant 
Type and Supplementation Present) ............................................................................................................ 33 
Table 14: HRQL (SF-12), According to Nutritional Supplementation (No Significant Interaction Between 
Implant Type and Supplementation Present) ............................................................................................... 33 
Table 15: HRQL (SF-12) (Significant Interaction Between Implant Type and Supplementation Present) 36 
Table 16: Summary of HOS, According to Surgical Treatment (No Significant Interaction Between 
Implant Type and Supplementation Present) ............................................................................................... 37 
Table 17: Summary of HOS, According to Nutritional Supplementation (No Significant Interaction 
Between Implant Type and Supplementation Present) ................................................................................ 38 
Table 18: Summary of HOS (Significant Interaction Between Implant Type and Supplementation Present)
 ..................................................................................................................................................................... 39 
 
 
 


Page 5 of 54 
26-Oct-2018 
 
List of Figures 
Figure 1: Flow Diagram ± Surgical Treatment .............................................................................................. 8 
Figure 2: Flow Diagram ± Nutritional Supplementation ............................................................................... 9 
Figure 3: Kaplan-Meier Curves for Primary Clinical Endpoint (Significant Interaction Between Implant 
Type and Supplementation Present) ............................................................................................................ 32 
Figure 4: SF-12 PCS Scores Over Time by Surgical Treatment Group (No Significant Interaction 
Between Implant Type and Supplementation Present) ................................................................................ 33 
Figure 5: SF-12 MCS Scores Over Time by Surgical Treatment Group (No Significant Interaction 
Between Implant Type and Supplementation Present) ................................................................................ 34 
Figure 6: SF-12 PCS Scores Over Time by Nutritional Supplementation Group (No Significant 
Interaction Between Implant Type and Supplementation Present) ............................................................. 34 
Figure 7: SF-12 MCS Scores Over Time by Nutritional Supplementation Group (No Significant 
Interaction Between Implant Type and Supplementation Present) ............................................................. 35 
Figure 8: SF-12 PCS Scores Over Time by Treatment Group (Significant Interaction Between Implant 
Type and Supplementation Present) ............................................................................................................ 36 
Figure 9: SF-12 MCS Scores Over Time by Treatment Group (Significant Interaction Between Implant 
Type and Supplementation Present) ............................................................................................................ 37 
Figure 10: HOS Over Time by Surgical Treatment Group (No Significant Interaction Between Implant 
Type and Supplementation Present) ............................................................................................................ 38 
Figure 11: HOS Over Time by Nutritional Supplementation Group (No Significant Interaction Between 
Implant Type and Supplementation Present) ............................................................................................... 39 
Figure 12: HOS Over Time by Treatment Group (Significant Interaction Between Implant Type and 
Supplementation Present) ............................................................................................................................ 40 
 
 


Page 6 of 54 
26-Oct-2018 
 
1.0 PURPOSE 
The purpose of this statistical analysis plan (SAP) is to outline the primary statistical analyses for the 
Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2): A Multi-Centre 2x2 
Factorial Randomized Trial Comparing Sliding Hip Screws versus Cancellous Screws AND Vitamin D 
versus Placebo on Patient Important Complications and Quality of Life in the Treatment of Young Adult 
(18-60) Femoral Neck Fractures manuscript. This SAP includes review of all data collected.  The FAITH-
2 Writing Committee will determine which data points will be included in the primary manuscript and 
supplemental documents. We will adhere to the CONSORT 2010 guideline when reporting the results of 
FAITH-2. Additional SAPs will be developed for secondary analyses.  
 
2.0 STUDY SUMMARY 
Title 
Fixation using Alternative Implants for the Treatment of Hip 
Fractures (FAITH-2): A Multi-Centre 2x2 Factorial Randomized 
Trial Comparing Sliding Hip Screws versus Cancellous Screws 
AND Vitamin D versus Placebo on Patient Important Outcomes and 
Quality of Life in the Treatment of Young Adult (18-60) Femoral 
Neck Fractures 
Short Title 
FAITH-2 
Methodology 
Concealed 2x2 factorial randomized controlled trial 
Clinical Sites 
Multiple international clinical sites 
Primary Objective 
The primary objective is to assess the impact of surgical implant 
(sliding hip screws (SHS) versus cancellous screw (CS) fixation) 
AND nutritional supplementation (vitamin D versus placebo) on a 
composite of patient important outcomes during the 12 month post-
surgery follow-up period. The composite of patient important 
outcomes includes: re-operation, femoral head osteonecrosis, severe 
femoral neck malunion, and nonunion. 
Secondary Objectives 
To assess the impact of surgical implant (sliding hip screw fixation 
versus cancellous screw fixation) and nutritional supplementation 
(vitamin D versus placebo) on health-related quality of life and 
functional 
outcomes, 
fracture 
healing 
complications, 
and 
radiographic fracture healing. 
Sample Size 
We will recruit a sample size of 808 patients with full follow-up. 
Based on an anticipated 10% loss to follow-up, 898 patients will 
need to be enrolled in the FAITH-2 trial.  
Diagnosis 
and 
Main 
Inclusion Criteria 
Femoral neck fracture in patients between the ages of 18 and 60. 
Study Products 
Surgical implants: Sliding hip screw versus multiple cancellous 
screws. 
Nutritional supplementation: Vitamin D3 (4,000 International 
Units/day taken for 6 months) versus placebo taken for 6 months. 
 Length of Follow-Up  
12 months. 
 
 


Page 7 of 54 
26-Oct-2018 
 
3.0 SCREENING AND ENROLMENT 
The number of participants screened, included, and excluded will be presented in separate flow diagrams 
by surgical treatment and nutritional supplementation groups (Figures 1 and 2). The figure will include the 
number of patients who were eligible, ineligible, and randomly assigned to the two treatment groups. It will 
also include the number of participants who are lost to follow-up over the course of the study. The number 
of patients excluded by reason will be summarized in Table 1.  
 
 
 
 


Page 8 of 54 
26-Oct-2018 
 
Figure 1: Flow Diagram – Surgical Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients screened (N=) 
Patients ineligible (N=) 
Patients randomized (N=) 
Allocated to SHS (N=) 
Allocated to CS (N=) 
Randomization Errors (N=) 
 
Randomization Errors (N=) 
Included in primary analysis (N=   ) 
Included in primary analysis (N=   ) 
Participants completed 12-month follow-up (N=) 
Participants completed 12-month follow-up (N=) 
Participants lost to follow 
up at: 
Hospital discharge (N=) 
6 weeks (N=) 
3 months (N=) 
6 months (N=) 
9 months (N=) 
12 months (N=) 
Participants lost to follow 
up at: 
Hospital discharge (N=) 
6 weeks (N=) 
3 months (N=) 
6 months (N=) 
9 months (N=) 
12 months (N=) 


Page 9 of 54 
26-Oct-2018 
 
Figure 2: Flow Diagram – Nutritional Supplementation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients screened (N=) 
Patients ineligible (N=) 
Patients randomized (N=) 
Allocated to Vitamin D (N=) 
Allocated to Placebo (N=) 
Randomization Errors (N=) 
 
Randomization Errors (N=) 
 
Included in primary analysis (N=   ) 
Included in primary analysis (N=   ) 
Participants completed 12 month follow-up (N=   ) 
Participants completed 12 month follow-up (N=   ) 
Participants lost to follow 
up at: 
Hospital discharge (N=) 
6 weeks (N=) 
3 months (N=) 
6 months (N=) 
9 months (N=) 
12 months (N=) 
Participants lost to follow 
up at: 
Hospital discharge (N=) 
6 weeks (N=) 
3 months (N=) 
6 months (N=) 
9 months (N=) 
12 months (N=) 


Page 10 of 54 
26-Oct-2018 
 
Table 1: Reasons for Exclusion at Screening 
Reasons for Exclusion 
Number 
of 
Patients 
N= 
Number of Patients Excluded Due to Randomization Errors 
Surgical  
Treatment 
X 
N= 
Surgical  
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
Inclusion Criteria 
 
 
The patient is not between 
the ages of 18 and 60 years 
 
 
 
 
 
 
The patient does not have a 
femoral neck fracture 
 
 
 
 
 
 
The fracture is not amenable 
to both surgical treatments 
(SHS and cancellous screw) 
 
 
 
 
 
 
Operative treatment will not 
take place within 7 days of 
injury 
 
 
 
 
 
 
Exclusion Criteria 
 
 
The patient has previously 
been diagnosed with 
osteoporosis 
 
 
 
 
 
 
The patient has a fracture-
dislocation of the femoral 
neck and hip joint 
 
 
 
 
 
 
The patient has planned 
antegrade nailing of an 
ipsilateral femoral shaft 
fracture (if present) 
 
 
 
 
 
 
The patient has an infection 
around the hip (i.e. soft 
tissue or bone) 
 
 
 
 
 
 
The patient has a stress 
fracture of the femoral neck 
 
 
 
 
 
 
This is a pathological 
fracture secondary to 
neoplasm or other bone 
lesion 
 
 
 
 
 
 
The patient has a known or 
likely undiagnosed disorder 
of bone metabolism such as 
PageW¶V diVeaVe, 
osteomalacia, osteopetrosis, 
osteogenesis imperfect, etc 
 
 
 
 
 
 
The patient is currently 
taking an over counter drug 
and/or food supplement that 
contains vitamin D and is 
unable or unwilling to 
discontinue its use for this 
study 
 
 
 
 
 
 
There are likely problems, in 
the judgement of the 
attending surgeon, with 
 
 
 
 
 
 


Page 11 of 54 
26-Oct-2018 
 
maintaining follow-up (e.g. 
patients with no fixed 
address, plans to move out 
of town). This may include 
patients with severe mental 
disorders and drug 
addictions without adequate 
support 
The patient is pregnant 
 
 
 
 
 
 
The patient is incarcerated 
 
 
 
 
 
 
The patient is not expected 
to survive their injuries 
 
 
 
 
 
 
The patient or substitute 
decision maker has not 
provided informed consent 
 
 
 
 
 
 
The patient is eligibile, but 
was not randomized due to 
error 
 
 
 
 
 
 
 
4.0 PARTICIPANT DEMOGRAPHICS CHARACTERISTICS 
Participant demographic, baseline characteristics, and major comorbidities of the population will be 
summarized by surgical treatment and nutritional supplementation groups (Table 2). Descriptive statistics 
will be used to summarize the demographic data. Means and standard deviations (SDs) will be used for 
continuous data, and categorical data will be presented as frequencies and proportions. 
 
Table 2: Participant Demographics 
Characteristic 
Variable 
Surgical 
Treatment X 
N=43 
Surgical 
Treatment 
Y 
N=43 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N=86 
Age, mean (SD) (years) 
2.1 Q5, 
3.1 Q1 
 
 
 
 
 
Sex, n (%) 
  Male 
  Female 
3.1 Q2 
 
 
 
 
 
Ethnicity, n (%) 
  Native/Aboriginal 
  South Asian 
  East Asian 
  Southeast Asian (Filipino) 
  Hispanic/Latino 
  White/Caucasian 
  Black (African/Caribbean) 
  Mixed (Black & White) 
  Middle Eastern 
3.1 Q3 
 
 
 
 
 


Page 12 of 54 
26-Oct-2018 
 
Characteristic 
Variable 
Surgical 
Treatment X 
N=43 
Surgical 
Treatment 
Y 
N=43 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N=86 
Body Mass Index (BMI) (kg/m2), n 
(%) 
  Underweight <18.5 
  Normal weight 18.5-24.9 
  Overweight 25-29.9 
  Obese 30-39.9 
  Morbidl\ ObeVe 40  
3.1 Q4, 
Q5 
 
 
 
 
 
Work-Related Injury, n (%) 
3.1 Q7 
 
 
 
 
 
History of Smoking, n (%) 
  Yes 
  Previously smoked but quit 
  No 
3.1 Q8 
 
 
 
 
 
Consumption of Alcohol, n (%) 
3.1 Q9 
 
 
 
 
 
Current Medications, n (%) 
  None 
  Nonsteroidal Anti-   
  Inflammatory Drugs  
  Steroid Medications 
  Calcium 
  Vitamin D 
3.2 Q11 
 
 
 
 
 
Major Comorbidities, n (%)  
  None 
  One 
  Two 
  Three 
  Four 
  Five  
3.2 Q12 
 
 
 
 
 


Page 13 of 54 
26-Oct-2018 
 
5.0 INJURY AND FRACTURE CHARACTERISTICS  
Injury details and fracture characteristics will be summarized in Table 3. Pre-operative and post-operative 
care details (Table 4) will be presented for each surgical treatment and nutritional supplementation group. 
Means and SDs will be used for continuous data, and categorical data will be presented as frequencies and 
proportions.  
Table 3: Fracture Characteristics 
Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
Level of the Fracture Line, n (%) 
  Subcapital 
  Midcervical 
  Basal 
  Unable to assess 
Adjudicated 
Data 
 
 
 
 
 
Garden Classification, n (%) 
  Garden I (undisplaced) 
  Garden II (undisplaced) 
  Garden III (displaced) 
  Garden IV (displaced) 
  Unable to assess 
Adjudicated 
Data 
 
 
 
 
 
PaXZelV¶ ClaVVificaWion, n (%) 
  Type I 
  Type II 
  Type III 
  Unable to assess 
Adjudicated 
Data 
 
 
 
 
 
Mechanism of Injury, n (%) 
  Motor Vehicle Accident  
   (Driver/Passenger)  
  Motor Vehicle Accident  
   (Pedestrian)  
  Motorcycle Accident  
  Recreational Vehicle (4    
  Wheeler,  
  Snowmobile, ATV, etc) 
  Bicycle Accident 
  Fall from Height (>1m)  
  Fall from HeighW (1m)  
  Fall from Standing 
  Direct Trauma (Blunt)  
  Direct Trauma (Penetrating) 
3.3 Q15 
 
 
 
 
 
Additional Fractures, n (%) 
  Upper extremity  
  Lower extremity  
  Spine and sacrum 
  Pelvis 
3.4 Q20 
 
 
 
 
 
Additional Injuries, n (%) 
  Chest Injury 
  Abdominal Injury 
  Head/Neck Injury 
  Soft Tissue Injuries to Extremities 
3.4 Q24 
 
 
 
 
 


Page 14 of 54 
26-Oct-2018 
 
Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
Ipsilateral Femoral Shaft Fracture, 
n (%) 
3.5 Q23 
 
 
 
 
 
 
Table 4: Summary of Pre-Operative and Post-Operative Care Details 
Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
Pre-operative Antibiotic 
Prophylaxis, n (%) 
3.5 Q26 
 
 
 
 
 
Discharge Location, n (%) 
  Home 
  Rehabilitation Facility 
  Other Hospital 
  Medical Respite 
7.1 Q2 
 
 
 
 
 
Provided with Nutritional 
Supplement, n (%) 
7.1 Q3 
 
 
 
 
 
Received Nutritional 
Supplement Within Two 
Weeks of Femoral Neck 
Surgery, n (%) 
7.1 Q5 
 
 
 
 
 
Nutritional Instructions and 
Importance of Complying with 
Nutritional Supplementation 
Discussed with Participant, n 
(%) 
7.1 Q6 
 
 
 
 
 
 
6.0 SUMMARY OF SURGICAL PROCEDURES 
The following sections will summarize the surgical procedures. General surgical characteristics and the 
surgical details for each surgical treatment and nutritional supplementation group will be presented. Means 
with SDs will be used for continuous data, and categorical data will be presented as frequencies and 
proportions (Tables 5, 6, and 7).  
Table 5: General Surgical Characteristics  
Surgery Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
Time from Injury to Surgery, 
mean (SD) (hours) 
3.3 Q13, 
4.1 Q1/Q2 
 
 
 
 
 
Length of Procedure, mean 
(SD) (minutes) 
4.1 Q2/Q3 
 
 
 
 
 
Attending Surgeon Present in 
Operating Room for Critical 
Aspects of Procedure, n (%) 
4.1 Q5 
 
 
 
 
 


Page 15 of 54 
26-Oct-2018 
 
Surgery Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
Who Performed Majority of 
Procedure, n (%) 
  Surgeon 
  Fellow 
  Resident 
4.1 Q6 
 
 
 
 
 
Total Blood Loss, mean (SD) 
(mL) 
4.1 Q7 
 
 
 
 
 
Type of Reduction Used, n 
(%) 
  Closed 
  Open 
  None 
4.1 Q8 
 
 
 
 
 
Procedure Performed, n (%) 
  CS 
  SHS 
  Cephalomedullary Nail 
4.1 Q9 
 
 
 
 
 
Implant Manufacturer, n (%) 
  Synthes 
  Biomet 
  Stryker 
  Smith & Nephew    
  DePuy 
  Hansson 
  Zimmer   
4.1 Q10 
 
 
 
 
 
Capsulotomy Performed, n 
(%) 
4.2 Q11 
 
 
 
 
 
Aspiration of Intracapsular 
Hematoma, n (%) 
4.2 Q12 
 
 
 
 
 
Additional Buttress-type 
Plates Used, n (%) 
4.2 Q13 
 
 
 
 
 
Injectable Bone Substitutes 
Used, n (%) 
4.2 Q14 
 
 
 
 
 
Bone Graft Used, n (%) 
4.2 Q15 
 
 
 
 
 
Other Procedures Performed 
During Same Operation as 
Femoral Neck Fracture 
Internal Fixation, n (%) 
4.2 Q16 
 
 
 
 
 
Treatment of Ipsilateral 
Femoral Neck Fracture, n (%) 
  N/A (No Ipsilateral Shaft 
Fracture) 
  Plating 
  Retrograde Nailing 
  Antegrade Nailing 
4.2 Q18 
 
 
 
 
 
Re-operations Planned For 
PaWienW¶V FracWXred Hip, n (%) 
  Irrigation and Debridement 
  Wound Closure 
  Implant Revision 
  Implant Exchange 
  Implant Adjustment 
4.3 Q19 
 
 
 
 
 


Page 16 of 54 
26-Oct-2018 
 
Surgery Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
  Bone Graft  
  Femoral Shaft Fracture  
  Surgery 
 
Table 6: CS Surgical Management 
*to be completed only after unblinding 
CS Characteristic 
Variable 
CS 
N= 
Number of Screws Used, n (%) 
   Three 
   Four 
5.1 Q2 
 
Diameter of Screws, mean (SD) (mm) 
5.1 Q3 
 
Number of Partially Threaded Screws with 
Short Threads Used, n (%) 
   Zero 
   One 
   Two 
   Three 
   Four 
5.1 Q4 
 
Number of Partially Threaded Screws with 
Long Threads Used, n (%) 
   Zero 
   One 
   Two 
   Three 
   Four 
5.1 Q5 
 
Formation of Screws (or Pins), n (%) 
   Triangle (Apex at Top) (3 Screws) 
   Inverted Triangle (Apex at Bottom) (3  
   Screws) 
   Square (4 Screws) 
   Diamond (4 Screws) 
   Other 
5.1 Q6 
 
Aiming of Screws (or Pins), n (%) 
   Parallel 
   Crossed 
5.1 Q7 
 
Number of Washers Used, n (%) 
   Zero 
   One 
   Two 
   Three 
   Four 
5.1 Q8 
 
Use of Hook Pins or Any Other Non-Screw 
Implants, n (%) 
5.1 Q9 
 


Page 17 of 54 
26-Oct-2018 
 
 
Table 7: SHS Surgical Management 
*to be completed only after unblinding 
SHS Characteristic 
Variable 
SHS 
N= 
Type of Sliding Fixed-Angle Plate Construct 
Used, n (%) 
   Traditional Large Diameter Hip Screw     
   Spiral/Helical Blade  
   Dynamic Hip Screw 
6.1 Q2 
 
Implant Position in Head of Femur, n (%)  
   Centre-Centre Position 
   Superior Position 
   Anterior Position  
   Inferior Position  
   Posterior Position 
Other (specify): 
6.1 Q3 
 
 
Number of Holes in Side Plate, n (%) 
   Two 
   Three 
   Four 
6.1 Q4 
 
Number of Cortical Screws in Side Plate, n (%) 
   Two 
   Three 
   Four 
6.1 Q5 
 
Supplemental (Derotational) Screws Included in 
Fixation, n (%) 
   With Washer  
   Without Washer 
6.1 Q6 
 
Used of Compression Screw, n (%) 
6.1 Q7 
 
Final Tip Apex Distance, mean (SD) (mm)  
6.1 Q8 
 
 
7.0 FEASIBILITY OUTCOME MEASURES 
Feasibility outcomes will be analyzed using descriptive statistics, reported as count and percentage or mean 
and standard deviation depending on the type of variable to summarize the FAITH-2 feasibility outcomes 
of 1) initiation of clinical sites (locations and timelines), 2) rate of participant enrolment, 3) rate of protocol 
adherence (the number of errors in randomization, 4) the number of crossovers between SHS and cancellous 
screw treatment groups, 5) adherence to the daily vitamin D supplementation), 6) proportion of participants 
with complete follow-up at 12 months post-fracture, 7) and level of data quality (Table 8). 
 
 


Page 18 of 54 
26-Oct-2018 
 
Table 8: Feasibility Outcomes 
Feasibility Outcomes 
Variable 
N= 
Time to Initiation of Clinical Sites, median 
(IQR) (months) 
Clinical site initiation 
tracker 
 
Time to Enroll 60 Participants, n (months) 
2.1 Q5 of first and last 
enrolled participant  
 
Rate of Protocol Adherence: Number of Errors 
in Randomization, n (%) 
14.1 Q2 
 
Rate of Protocol Adherence: Number of 
Crossovers between SHS and CS treatment 
groups, n (%) 
5.1 Q1, 6.1 Q1 
 
Rate of Protocol Adherence: Adherence to the 
daily vitamin D supplementation, n (%) 
8.2 Q10/Q11 (6 
weeks, 3 months, 6 
months) 
 
Proportion of Participants with Complete 
Follow-up at 12 Months Post-Fracture, n (%) 
8.1 (12 months) 
 
Level of Data Quality, n (%) 
Completeness of CRFs  
 
8.0 PRIMARY CLINICAL ENDPOINT 
The primary analyses will first be completed using only blinded treatment groups. All outcome analyses 
will be performed using the intention to treat approach. The FAITH-2 study primary clinical endpoint is a 
composite of patient important outcomes that occur within the 12 months post-surgery follow-up period 
(Table 9). Specifically, these are limited to 1) re-operation, 2) femoral head osteonecrosis, 3) severe femoral 
neck malunion, and 4) nonunion.  
 
The first analysis of clinical outcomes will be a Cox regression with main effects for implant type and 
supplementation, and the interaction between the two. If the interaction is not significant at alpha=0.05 we 
will perform two independent comparisons between the treatment groups (SHS versus cancellous screws 
AND separately vitamin D3 supplementation versus placebo) using the chi-square statistic and an alpha 
level of 0.05 for the composite of patient important outcomes (Tables 10 and 11).  
 
If the interaction is significant we will keep this interaction term in all subsequent analyses, and present 
two hazard ratios (HRs) with 95% confidence intervals (CIs) for the surgical intervention and two HRs for 
the nutritional supplementation (i.e. We will report an HR for SHS versus cancellous screws in those who 
receive vitamin D, and a separate HR for SHS versus cancellous screws in those who receive placebo. We 
will also report an HR for vitamin D versus placebo in those who receive SHS, and a separate HR for 
vitamin D versus placebo in those who receive cancellous screws) The results will be summarized in Table 
12. Kaplan-Meier curves will also be constructed.  
 
 
 
 
 
 
 
 


Page 19 of 54 
26-Oct-2018 
 
Table 9: Primary Clinical Endpoint Components and Reasons for Secondary Procedures 
Outcome 
Definition 
Unplanned Secondary Procedures 
(study event) 
Any unplanned surgery related to the treatment of the femoral neck 
fracture. Specific unplanned secondary procedures include: 
x 
Implant removal  
x 
Bone graft  
x 
Wound closure  
x 
Proximal femur osteotomy 
x 
Implant exchange ± THA  
x 
Implant exchange ± HA  
x 
Implant exchange ± CS 
x 
Implant exchange ± SHS  
x 
Implant exchange ± Other IF 
x 
Soft tissue procedure  
x 
Dynamization 
x 
Osteochondroplasty 
Reasons for Secondary Procedures 
x 
Shortening  
x 
Nonunion  
x 
Femoral head osteonecrosis  
x 
Deep infection  
x 
Superficial infection  
x 
Painful implant  
x 
Implant failure/breakage  
x 
Hip dislocation 
x 
Peri-prosthetic femur fracture  
x 
Hip instability  
x 
Wound healing problem  
x 
Screw penetration  
x 
Screw cut-out  
x 
Post traumatic arthritis 
x 
IT Fracture 
x 
Relieve pain 
Femoral Head Necrosis 
Any evidence of osteonecrosis on any follow-up medical imaging 
study (i.e., radiographs, magnetic resonance imaging (MRI), or 
other advanced imaging study) 
Severe Femoral Neck Malunion 
Fracture healing with femoral neck shortening of >10 mm in any 
plane on follow-up x-rays1 
Nonunion 
Failure of the fracture to progress towards healing defined as a 
Radiographic Union Score for Hip (RUSH)2,3 score below a pre-
determined threshold specific for nonunion at 6 months or greater 
post-injury.  
 
 
 
 
 


Page 20 of 54 
26-Oct-2018 
 
Table 10: Primary Clinical Endpoint, According to Surgical Treatment (No Significant Interaction 
Between Implant Type and Supplementation Present) 
End Point 
 
Variable 
Overall 
 
N= 
Surgical 
Treatment X 
 
N= 
Surgical 
Treatment Y 
 
N= 
 
P-Value 
Primary Clinical Endpoint of Re-operation 
Re-operation 
Adjudicated 
Data 
 
 
 
 
Procedure for Nonunion  
  Implant removal 
  Bone graft  
  Proximal femur osteotomy      
  Implant exchange ± THA  
  Implant exchange ± IF     
Adjudicated 
Data 
 
 
 
 
Procedure for Femoral Head 
Osteonecrosis 
  Implant removal 
  Implant exchange ± THA 
Adjudicated 
Data 
 
 
 
 
Procedure for Deep Infection 
  Wound closure    
  Implant exchange ± SHS 
  Soft tissue procedure  
Adjudicated 
Data 
 
 
 
 
Procedure for Painful Hardware 
  Implant removal 
  Bone graft  
  Implant exchange ± THA 
Adjudicated 
Data 
 
 
 
 
Procedure for Screw Penetration 
  Implant removal 
Adjudicated 
Data 
 
 
 
  
Procedure for Post-Traumatic 
Arthritis  
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
Procedure for IT Fracture 
  Implant exchange ± IF    
Adjudicated 
Data 
 
 
 
 
Procedure for Relieving Pain 
  Implant exchange ± THA 
Adjudicated 
Data 
 
 
 
 
 
Femoral head osteonecrosis  
 
Adjudicated 
Data 
 
 
 
 
 
Severe femoral neck malunion 
Adjudicated 
Data 
 
 
 
 
 
Nonunion 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
 


Page 21 of 54 
26-Oct-2018 
 
Table 11: Primary Clinical Endpoint, According to Nutritional Supplementation (No Significant 
Interaction Between Implant Type and Supplementation Present) 
 
End Point 
 
Variable 
Overall 
 
N= 
Nutritional 
Supplementation 
X 
 
N= 
Nutritional 
Supplementation 
Y 
 
N= 
 
P-Value 
Primary Clinical Endpoint of Re-operation 
Re-operation 
Adjudicated 
Data 
 
 
 
 
Procedure for Nonunion  
  Implant removal 
  Bone graft  
  Proximal femur osteotomy      
  Implant exchange ± THA  
  Implant exchange ± IF     
Adjudicated 
Data 
 
 
 
 
Procedure for Femoral Head 
Osteonecrosis 
  Implant removal 
  Implant exchange ± THA 
Adjudicated 
Data 
 
 
 
 
Procedure for Deep Infection 
  Wound closure    
  Implant exchange ± SHS 
  Soft tissue procedure  
Adjudicated 
Data 
 
 
 
 
Procedure for Painful Hardware 
  Implant removal 
  Bone graft  
  Implant exchange ± THA 
Adjudicated 
Data 
 
 
 
 
Procedure for Screw Penetration 
  Implant removal 
Adjudicated 
Data 
 
 
 
  
Procedure for Post-Traumatic 
Arthritis  
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
Procedure for IT Fracture 
  Implant exchange ± IF    
Adjudicated 
Data 
 
 
 
 
Procedure for Relieving Pain 
  Implant exchange ± THA 
Adjudicated 
Data 
 
 
 
 
 
Femoral head osteonecrosis  
 
Adjudicated 
Data 
 
 
 
 
 
Severe femoral neck malunion 
Adjudicated 
Data 
 
 
 
 
 
Nonunion 
Adjudicated 
Data 
 
 
 
 
 
 


Page 22 of 54 
26-Oct-2018 
 
Table 12: Primary Clinical Endpoint (Significant Interaction Between Implant Type and Supplementation Present) 
End Point 
 
Variable 
Overall 
N= 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation 
Y 
N= 
Hazard Ratio (95% CI) 
 
P-
Value 
Surgery X + 
Supplement 
X vs. Surgery 
Y + 
Supplement 
X 
Surgery X + 
Supplement 
Y vs. Surgery 
Y + 
Supplement 
Y 
Surgery X + 
Supplement 
X vs. Surgery 
X + 
Supplement 
Y 
Surgery Y + 
Supplement 
X vs. Surgery 
Y + 
Supplement 
Y 
Primary Clinical 
Endpoint: re-operation, 
femoral head 
osteonecrosis, severe 
femoral neck malunion, 
nonunion 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Primary Clinical Endpoint Components 
Malunion 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Nonunion 
  Implant removal 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 23 of 54 
26-Oct-2018 
 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Femoral Head 
Osteonecrosis 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 24 of 54 
26-Oct-2018 
 
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Deep Infection 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Superficial Infection 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 25 of 54 
26-Oct-2018 
 
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Painful Hardware 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Hardware 
Failure/Breakage 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 26 of 54 
26-Oct-2018 
 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Hip Dislocation 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Peri-prosthetic Femur 
Fracture 
  Implant removal 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 27 of 54 
26-Oct-2018 
 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Hip Instability 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 28 of 54 
26-Oct-2018 
 
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Wound Healing  
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Screw Penetration 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 29 of 54 
26-Oct-2018 
 
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Screw Cut-Out 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Post-Traumatic Arthritis  
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 30 of 54 
26-Oct-2018 
 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
IT Fracture 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Relieve Pain 
  Implant removal 
  Bone graft  
  Wound closure  
  Proximal femur  
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 31 of 54 
26-Oct-2018 
 
  osteotomy      
  Implant exchange ±  
  THA 
  Implant exchange ±  
  HA 
  Implant exchange ± IF  
   (crossover) 
  Implant exchange ± IF  
   (original)  
  Implant exchange ±  
  Intramedullary nailing 
  Implant exchange ±  
  curved plate and IF  
  Implant exchange ±  
  110 degree blade plate  
  Soft tissue procedure  
  Dynamization 
  Osteochondroplasty 
Femoral Head Necrosis 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Severe Femoral Neck 
Malunion 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Nonunion 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
 
 


Page 32 of 54 
26-Oct-2018 
 
Figure 3: Kaplan-Meier Curves for Primary Clinical Endpoint (Significant Interaction Between 
Implant Type and Supplementation Present) 
 
 
9.0 SECONDARY CLINICAL ENDPOINTS  
The FAITH-2 secondary clinical endpoints include 1) health-related quality of life (HRQL), 2) patient-
reported function, 3) fracture healing complications, and 4) radiographic fracture healing. 
 
9.1 SF-12 Health Survey 
The SF-12 Health Survey is a standardized instrument to measure health-related quality of life. This self-
administered, 12-item questionnaire covers eight main health domains that make up the Physical and Mental 
Health Composite Scores (PCS & MCS). Each domain consists of one or two questions and is scored 
separately from 0 (lowest level) to 100 (highest level).4 The SF-12 will be summarized using means and 
95% CIs at 10-week, 3, 6, 9, and 12-month intervals (Tables 13, 14, and 15). Longitudinal models will be 
used to explore the effect of treatment group and time on the SF-12 patient-reported outcomes (Figures 4-
9). 
 
 
 
 
 
 
 
0
10
20
30
40
50
60
70
80
90
100
Baseline
10 Weeks
3 Months
6 Months
9 Months
12 Months
Probability (%)
Follow-Up
SHS + Vitamin D
CS + Vitamin D
SHS + Placebo
CS + Placebo


Page 33 of 54 
26-Oct-2018 
 
Table 13: HRQL (SF-12), According to Surgical Treatment (No Significant Interaction Between 
Implant Type and Supplementation Present) 
Endpoint 
Surgical 
Treatment X  
Surgical Treatment 
Y  
Total 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Adjusted Mean 
Difference (95% CI) 
Physical Composite Scale (PCS) Scores 
Post-op 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
12 months 
 
 
 
 
 
 
Mental Health Composite Scale (MCS) Scores 
Post-op 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
12 months 
 
 
 
 
 
 
 
Table 14: HRQL (SF-12), According to Nutritional Supplementation (No Significant Interaction 
Between Implant Type and Supplementation Present) 
Endpoint 
Nutritional 
Supplementation 
Treatment X  
Nutritional 
Supplementation 
Treatment Y  
Total 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Adjusted Mean 
Difference (95% CI) 
Physical Composite Scale (PCS) Scores 
Post-op 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
12 months 
 
 
 
 
 
 
Mental Health Composite Scale (MCS) Scores 
Post-op 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
12 months 
 
 
 
 
 
 
Figure 4: SF-12 PCS Scores Over Time by Surgical Treatment Group (No Significant Interaction 
Between Implant Type and Supplementation Present) 


Page 34 of 54 
26-Oct-2018 
 
 
 
Figure 5: SF-12 MCS Scores Over Time by Surgical Treatment Group (No Significant Interaction 
Between Implant Type and Supplementation Present) 
 
 
 
Figure 6: SF-12 PCS Scores Over Time by Nutritional Supplementation Group (No Significant 
Interaction Between Implant Type and Supplementation Present) 
0
10
20
30
40
50
60
70
80
90
100
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
SF-12 PCS Score
Follow-Up
SHS
CS
0
10
20
30
40
50
60
70
80
90
100
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
SF-12 MCS Score
Follow-Up
SHS
CS


Page 35 of 54 
26-Oct-2018 
 
 
 
 
Figure 7: SF-12 MCS Scores Over Time by Nutritional Supplementation Group (No Significant 
Interaction Between Implant Type and Supplementation Present) 
 
 
 
 
0
10
20
30
40
50
60
70
80
90
100
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
SF-12 PCS Score
Follow-Up
Vitamin D
Placebo
0
10
20
30
40
50
60
70
80
90
100
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
SF-12 MCS Score
Follow-Up
Vitamin D
Placebo


Page 36 of 54 
26-Oct-2018 
 
Table 15: HRQL (SF-12) (Significant Interaction Between Implant Type and Supplementation 
Present) 
Endpoint 
Surgical 
Treatment 
X 
Surgical 
Treatment 
Y 
Nutritional 
Supplementation 
Treatment X  
Nutritional 
Supplementation 
Treatment Y  
Total 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Adjusted Mean 
Difference (95% 
CI) 
Physical Composite Scale (PCS) Scores 
Post-op 
 
 
 
 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
 
 
 
 
12 
months 
 
 
 
 
 
 
 
 
 
 
Mental Health Composite Scale (MCS) Scores 
Post-op 
 
 
 
 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
 
 
 
 
12 
months 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 8: SF-12 PCS Scores Over Time by Treatment Group (Significant Interaction Between 
Implant Type and Supplementation Present) 
 
0
10
20
30
40
50
60
70
80
90
100
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
SF-12 PCS Score
Follow-Up
SHS + Vitamin D
CS + Vitamin D
SHS + Placebo
CS + Placebo


Page 37 of 54 
26-Oct-2018 
 
Figure 9: SF-12 MCS Scores Over Time by Treatment Group (Significant Interaction Between 
Implant Type and Supplementation Present) 
 
 
9.2 Hip Outcome Score 
The Hip Outcome Score (HOS)5 measures self-reported functional status through 28 items and two sub-
scales that pertain to activities of daily living (ADLs) or higher-level activities such as those necessary to 
participate in sports. Patient-reported function, measured by the HOS, will be reported as mean differences 
with corresponding 95% CIs and p-values. (Tables 16, 17, and 18). Longitudinal models will be used to 
explore the effect of treatment group and time on the HOS patient-reported outcomes (Figures 10-12). 
Table 16: Summary of HOS, According to Surgical Treatment (No Significant Interaction Between 
Implant Type and Supplementation Present) 
Endpoint 
Surgical 
Treatment X  
Surgical 
Treatment Y  
Total 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Adjusted Mean 
Difference (95% CI) 
Post-op 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
12 months 
 
 
 
 
 
 
 
 
 
0
10
20
30
40
50
60
70
80
90
100
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
SF-12 MCS Score
Follow-Up
SHS + Vitamin D
CS + Vitamin D
SHS + Placebo
CS + Placebo


Page 38 of 54 
26-Oct-2018 
 
Table 17: Summary of HOS, According to Nutritional Supplementation (No Significant Interaction 
Between Implant Type and Supplementation Present) 
Endpoint 
Nutritional 
Supplementation 
Treatment X  
Nutritional 
Supplementation 
Treatment Y  
Total 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Adjusted Mean 
Difference (95% CI) 
Post-op 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
12 months 
 
 
 
 
 
 
 
 
Figure 10: HOS Over Time by Surgical Treatment Group (No Significant Interaction Between 
Implant Type and Supplementation Present) 
 
 
 
 
 
 
 
 
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
HOS
Follow-Up
SHS
CS


Page 39 of 54 
26-Oct-2018 
 
Figure 11: HOS Over Time by Nutritional Supplementation Group (No Significant Interaction 
Between Implant Type and Supplementation Present) 
 
 
Table 18: Summary of HOS (Significant Interaction Between Implant Type and Supplementation 
Present) 
Endpoint 
Surgical 
Treatment X 
Surgical 
Treatment Y 
Nutritional 
Supplementation 
Treatment X  
Nutritional 
Supplementation 
Treatment Y  
Total 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Mean 
(SD) 
N= 
Adjusted Mean 
Difference (95% CI) 
Post-op 
 
 
 
 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
 
 
 
 
3 months 
 
 
 
 
 
 
 
 
 
 
6 months 
 
 
 
 
 
 
 
 
 
 
9 months 
 
 
 
 
 
 
 
 
 
 
12 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
HOS
Follow-Up
Vitamin D
Placebo


Page 40 of 54 
26-Oct-2018 
 
Figure 12: HOS Over Time by Treatment Group (Significant Interaction Between Implant Type 
and Supplementation Present) 
 
 
9.3 Fracture Healing Complications 
Table 19: Fracture Healing Complications 
Fracture Healing Complication 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
Wound Healing Problems 
Adjudicated 
Data 
 
 
 
 
 
Infection - Superficial, n (%) 
Adjudicated 
Data 
 
 
 
 
 
Infection ± Deep, n (%) 
Adjudicated 
Data 
 
 
 
 
 
Infection ± Organ Space, n (%)  
Adjudicated 
Data 
 
 
 
 
 
Implant Failure, n (%)  
Adjudicated 
Data 
 
 
 
 
 
Implant Breakage, n (%) 
Adjudicated 
Data 
 
 
 
 
 
Painful Hardware, n (%) 
Adjudicated 
Data 
 
 
 
 
 
Peri-Prosthetic Fracture, n (%) 
Adjudicated 
Data 
 
 
 
 
 
Other, n (%) 
Adjudicated 
Data 
 
 
 
 
 
 
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
Post-op
10 Weeks
3 Months
6 Months
9 Months
12 Months
HOS
Follow-Up
SHS + Vitamin D
CS + Vitamin D
SHS + Placebo
CS + Placebo


Page 41 of 54 
26-Oct-2018 
 
9.4 Radiographic Fracture Healing 
Table 20: Radiographic Fracture Healing 
Variable 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation  
Y 
N= 
Total 
N= 
Time of Radiographic Fracture 
Healing, mean (SD) (months) 
Adjudicated 
Data 
 
 
 
 
 
Time of Radiographic Healing 
of Ipsilateral Femoral Shaft 
Fracture, mean (SD) (months) 
Adjudicated 
Data 
 
 
 
 
 
 
 
Figure 13: Kaplan-Meier Curves for Radiographic Fracture Healing (Significant Interaction 
Between Implant Type and Supplementation Present) 
 
 
 
 
 
 
 
 
0
10
20
30
40
50
60
70
80
90
100
Baseline
10 Weeks
3 Months
6 Months
9 Months
12 Months
Probability (%)
Follow-Up
SHS + Vitamin D
CS + Vitamin D
SHS + Placebo
CS + Placebo


Page 42 of 54 
26-Oct-2018 
 
Figure 14: Kaplan-Meier Curves for Radiographic Fracture Healing by Surgical Treatment Group 
(No Significant Interaction Between Implant Type and Supplementation Present) 
 
 
Figure 15: Kaplan-Meier Curves for Radiographic Fracture Healing by Nutritional 
Supplementation Group (No Significant Interaction Between Implant Type and Supplementation 
Present) 
 
 
0
10
20
30
40
50
60
70
80
90
100
Baseline
10 Weeks
3 Months
6 Months
9 Months
12 Months
Probability (%)
Follow-Up
SHS
CS
0
10
20
30
40
50
60
70
80
90
100
Baseline
10 Weeks
3 Months
6 Months
9 Months
12 Months
Probability (%)
Follow-Up
Vitamin D
Placebo


Page 43 of 54 
26-Oct-2018 
 
Figure 16: Kaplan-Meier Curves for Radiographic Healing of Ipsilateral Femoral Shaft Fracture 
(Significant Interaction Between Implant Type and Supplementation Present) 
 
 
Figure 17: Kaplan-Meier Curves for Radiographic Healing of Ipsilateral Femoral Shaft Fracture 
by Surgical Treatment Group (No Significant Interaction Between Implant Type and 
Supplementation Present) 
 
 
0
10
20
30
40
50
60
70
80
90
100
Baseline
10 Weeks
3 Months
6 Months
9 Months
12 Months
Probability (%)
Follow-Up
SHS + Vitamin D
CS + Vitamin D
SHS + Placebo
CS + Placebo
0
10
20
30
40
50
60
70
80
90
100
Baseline
10 Weeks
3 Months
6 Months
9 Months
12 Months
Probability (%)
Follow-Up
SHS
CS


Page 44 of 54 
26-Oct-2018 
 
Figure 18: Kaplan-Meier Curves for Radiographic Healing of Ipsilateral Femoral Shaft Fracture 
by Nutritional Supplementation Group (No Significant Interaction Between Implant Type and 
Supplementation Present) 
 
 
9.5 Ipsilateral Femoral Shaft Fractures 
For patients with ipsilateral femoral shaft fractures, a time-to-event analysis will be conducted to assess the 
time to radiographic fracture healing of the ipsilateral femoral shaft fracture (Tables 21-24). 
 
Table 21: Secondary Procedures for Ipsilateral Femoral Shaft Fracture and Reasons 
Outcome 
Definition 
Unplanned Secondary Procedures 
for Ipsilateral Femoral Shaft 
Fracutre (study event) 
Any unplanned surgery related to the treatment of the ipsilateral 
femoral shaft fracture within 12 months of initial surgery. Specific 
unplanned secondary procedures include:  
x 
Wound closure  
x 
Soft tissue procedure  
x 
Bone graft  
x 
Nail removal  
x 
Exchange nailing ± retrograde intramedullary nailing  
x 
Exchange nailing ± antegrade intramedullary nailing 
x 
Exchange nailing ± Other IF  
x 
Nail conversion to plating  
x 
Retaining the nail and augmentation with plates  
x 
Ilizarov external fixation  
x 
Other 
Reasons for Secondary Procedures 
x 
Wound healing problem  
x 
Compartment syndrome  
0
10
20
30
40
50
60
70
80
90
100
Baseline
10 Weeks
3 Months
6 Months
9 Months
12 Months
Probability (%)
Follow-Up
Vitamin D
Placebo


Page 45 of 54 
26-Oct-2018 
 
x 
Deep infection  
x 
Superficial infection  
x 
Shortening  
x 
Nonunion  
x 
Implant failure/breakage  
x 
Prolonged pain at the fracture site  
x 
Other  
 
 
Table 22: Secondary Procedures for Ipsilateral Femoral Shaft Fracture, According to Surgical 
Treatment (No Significant Interaction Between Implant Type and Supplementation Present) 
Secondary Procedure 
 
Variable 
Overall 
N= 
Surgical 
Treatment X 
N= 
Surgical 
Treatment Y 
N= 
 
P-Value 
Re-operation 
Adjudicated 
Data 
 
 
 
 
Procedure for Nonunion 
  Bone Graft 
  Nail Removal 
  Exchange nailing ± IF 
  Proximal femur osteotomy 
Adjudicated 
Data 
 
 
 
 
 
 
Table 23: Secondary Procedures for Ipsilateral Femoral Shaft Fracture, According to Nutritional 
Supplementation (No Significant Interaction Between Implant Type and Supplementation Present) 
 
Secondary Procedure 
 
Variable 
Overall 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation 
Y 
 N= 
 
P-Value 
Re-operation 
Adjudicated 
Data 
 
 
 
 
Procedure for Nonunion 
  Bone Graft 
  Nail Removal 
  Exchange nailing ± IF 
  Proximal femur osteotomy 
Adjudicated 
Data 
 
 
 
 


Page 46 of 54 
26-Oct-2018 
 
Table 24: Secondary Procedures for Ipsilateral Femoral Shaft Fracture (Significant Interaction Between Implant Type and 
Supplementation Present) 
Secondary Procedures 
 
Variable 
Overall 
N= 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation 
Y 
N= 
Hazard Ratio (95% CI) 
 
P-
Value 
Surgery X + 
Supplement 
X vs. Surgery 
Y + 
Supplement 
X 
Surgery X + 
Supplement 
Y vs. Surgery 
Y + 
Supplement 
Y 
Surgery X + 
Supplement 
X vs. Surgery 
X + 
Supplement 
Y 
Surgery Y + 
Supplement 
X vs. Surgery 
Y + 
Supplement 
Y 
Wound Closure 
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Soft Tissue Procedure 
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Bone Graft  
  Wound healing  
  problem  
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 47 of 54 
26-Oct-2018 
 
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Nail Removal 
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Exchange nailing ± 
Retrograde 
Intramedullary Nailing  
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 48 of 54 
26-Oct-2018 
 
Exchange Nailing ± 
Antegrade 
Intramedullary Nailing  
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Nail Conversion to 
Plating  
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Retaining the Nail and 
Augmentation with 
Plates  
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 


Page 49 of 54 
26-Oct-2018 
 
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Ilizarov External 
Fixation  
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
Other 
  Wound healing  
  problem  
  Compartment    
  syndrome 
  Deep infection  
  Superficial infection  
  Shortening  
  Nonunion    
  Implant failure/ 
  breakage  
  Prolonged pain at the  
  fracture site  
  Other 
Adjudicated 
Data 
 
 
 
 
 
 
 
 
 
 
 
 


Page 50 of 54 
26-Oct-2018 
 
Figure 19: Kaplan-Meier Curves for Secondary Procedures for Ipsilateral Femoral Shaft Fracture 
(Significant Interaction Between Implant Type and Supplementation Present) 
 
 
9.6 Other Follow-Up Data 
Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation 
Y 
N= 
Total 
N= 
PaWienW¶V WeighWbearing SWaWXV aW 
Follow-up Visit, n (%) 
 
6 Months 
  Non-Weightbearing 
  Protective Weightbearing or  
  Using Assistive Device 
  Full Weightbearing 
  
12 Months 
  Non-Weightbearing 
  Protective Weightbearing or  
  Using Assistive Device 
  Full Weightbearing 
8.2 Q7 
 
 
 
 
 
Patient Receiving Physiotherapy 
or Rehabilitation at Follow-up 
Visit, n (%) 
 
6 Weeks 
3 Months 
6 Months 
9 Months 
8.2 Q8 
 
 
 
 
 
0
10
20
30
40
50
60
70
80
90
100
Baseline
10 Weeks
3 Months
6 Months
9 Months
12 Months
Probability (%)
Follow-Up
SHS + Vitamin D
CS + Vitamin D
SHS + Placebo
CS + Placebo


Page 51 of 54 
26-Oct-2018 
 
Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation 
Y 
N= 
Total 
N= 
12 Months 
Patient Taking Medications at 
Follow-up Visit, n (%) 
 
6 Months 
  NSAIDS  
  Calcium  
  Steroid Medications  
 
12 Months 
  NSAIDS  
  Calcium  
  Steroid Medications 
8.2 Q9 
 
 
 
 
 
Secondary Procedures Planned 
for Patient After 12 Month 
Follow-up Visit, n (%) 
8.4 Q20 
 
 
 
 
 
 
9.7 Adverse Events and Safety Outcomes 
An adverse event (AE) is defined as any symptom, sign, illness, or experience that develops or worsens in 
severity during the study. AEs and safety outcomes will be reported using descriptive statistics including 
proportions and means with SD (Table 25).  
 
Table 25: General Summary of Adverse Events 
Characteristic 
Variable 
Surgical 
Treatment 
X 
N= 
Surgical 
Treatment 
Y 
N= 
Nutritional 
Supplementation 
X 
N= 
Nutritional 
Supplementation 
X 
N= 
List of AE, n (%) 
  <Insert most common AE> 
  <Insert 2nd most common AE> 
  <Insert 3rd most common AE> 
11.1 Q2 
 
 
 
 
Serious Adverse Events, n (%) 
11.2 Q8 
 
 
 
 
Time from baseline to AE, mean (SD) 
11.1 Q1 
 
 
 
 
Re-Hospitalized for AE, n (%) 
  Yes 
  No 
  N/A ± AE occurred during initial  
  hospitalization 
  N/A ± AE occurred while hospitalized  
  for another problem 
11.2 Q5 
 
 
 
 
Treatment, n (%) 
  No Active Treatment 
  Medication(s) 
  Re-operation 
  Other 
11.2 Q4 
 
 
 
 


Page 52 of 54 
26-Oct-2018 
 
 
 
10.0 
MISSING DATA 
Missing data will be handled using multiple imputation. 
 
11.0 
SUBGROUP ANALYSES 
Two a priori subgroup analyses are planned using logistic regression models for the primary clinical 
outcome: 1) the magnitude of treatment effect of the surgical and nutritional supplementation interventions, 
independently, on undisplaced versus displaced femoral neck fractures and 2) the magnitude of treatment 
effect of the surgical intervention on emergent (<8 hours) versus non-emergenW (8 hoXrV) inWernal fixation 
(Tables 26 and 27). We will use the seven criteria suggested by Oxman and Guyatt to guide inferences 
about the credibility of our subgroup analyses.6 
 
Table 26: Subgroup Analyses Factors, According to Surgical Treatment 
Characteristic 
Variable 
Surgical Treatment 
X 
N= 
Surgical Treatment 
Y 
N= 
Total 
N= 
Fracture Displacement, n (%) 
  Undisplaced 
  Displaced 
3.3 Q17 
 
 
 
Related to Surgical Treatment Arm, n 
(%) 
  Related 
  Probably Related 
  Possibly Related 
  Not Related 
11.2 Q6 
 
 
 
 
Related to Nutritional Supplementation, 
n (%) 
  Related 
  Probably Related 
  Possibly Related 
  Not Related 
11.2 Q7 
 
 
 
 
Event Unexpected, n (%) 
  Yes 
  No 
11.2 Q9 
 
 
 
 
Outcome, n (%) 
  Not yet resolved 
  Fatal 
  Resolved with no impairment 
  Resolved with mild impairment 
  Resolved with moderate impairment 
  Resolved with severe impairment 
11.3 Q11 
 
 
 
 
Operative Adverse Event 
  Yes 
4.2 Q17 
 
 
 
 


Page 53 of 54 
26-Oct-2018 
 
Characteristic 
Variable 
Surgical Treatment 
X 
N= 
Surgical Treatment 
Y 
N= 
Total 
N= 
Time to Internal Fixation, n (%) 
  Emergent (<8 hours) 
  Non-emergenW (8 hoXrV) 
3.3 Q13, 
14, 4.1 
Q1 
 
 
 
 
Table 27: Subgroup Analyses Factors, According to Nutritional Supplementation 
Characteristic 
Variable 
Nutritional 
Supplementation X 
N= 
Nutritional 
Supplementation Y 
N= 
Total 
N= 
Fracture Displacement, n (%) 
  Undisplaced 
  Displaced 
3.3 Q17 
 
 
 
Time to Internal Fixation, n (%) 
  Emergent (<8 hours) 
  Non-emergenW (8 hoXrV) 
3.3 Q13, 
14, 4.1 
Q1 
 
 
 


Page 54 of 54 
26-Oct-2018 
 
12.0 
REFERENCES 
1. Zlowodzki M, Brink O, Switzer J, Wingerter S, Woodall J Jr, Petrisor BA, Kregor PJ, Bruinsma 
DR, Bhandari M. The effect of shortening and varus collapse of the femoral neck on function 
after fixation of intracapsular fracture of the hip: a multi-centre cohort study. Journal of Bone and 
Joint Surgery British. 2008;90:1487-1494. 
2. Chiavaras 
MM, Bains 
S, Choudur 
H, Parasu 
N, 
Jacobson 
J, Ayeni 
O, Petrisor 
B, 
Chakravertty R, Sprague S, Bhandari M. The Radiographic Union Score for Hip (RUSH): the use 
of a checklist to evaluate hip fracture healing improves agreement between radiologists 
and orthopedic surgeons. Skeletal Radiology. 2013;42:1079-88.  
3. Bhandari M, Chiavaras MM, Parasu N, Choudur H, Ayeni O, Chakravertty R, Bains S, Hak A, 
Sprague S, Petrisor B. Radiographic union score for hip substantially improves agreement between 
surgeons and radiologists. BMC Musculoskeletal Disorders. 2013;14:70.  
4. Ware, J.E., Jr., Kosinski, M., Turner-Bowker, D.M., Gandek, B. How to Score Version 2 of the SF-
12v2® Health Survey (With a Supplement Documenting SF-12® Health Survey) Lincoln, RI: 
QualityMetric Incorporated, 2002. 
5. Martin RL, Kelly BT, Philippon MJ. Evidence of validity for the hip outcome score. Arthroscopy. 
2006;22:1304-11. 
6. Oxman AD1, Guyatt GH. A consumer's guide to subgroup analyses. Ann Intern Med. 1992 Jan 
1;116(1):78-84.