A Randomized Controlled Trial of Regional Versus General Anesthesia for Promoting Independence After Hip Fracture
Phase: NA
Conditions: Hip Fractures
Sponsor: University of Pennsylvania

  
 
 
 
 
A RANDOMIZED CONTROLLED TRIAL OF REGIONAL 
VERSUS GENERAL ANESTHESIA FOR PROMOTING 
INDEPENDENCE AFTER HIP FRACTURE (REGAIN TRIAL) 
A multicenter randomized controlled trial to compare survival, functional recovery, and cognitive outcomes, and 
postoperative adverse events among patients aged 50 and older receiving spinal versus general anesthesia for 
hip fracture surgery. 
 
 
 
Principal Investigator  
Mark D. Neuman, MD, MSc 
University of Pennsylvania 
Department of Anesthesiology and Critical Care 
308 Blockley Hall, 423 Guardian Drive 
Philadelphia, PA 19104 
Office: (215) 746-7468 
Cell: (215) 760-7471 
Email: mark.neuman@uphs.upenn.edu 
 
Funding sponsor 
Patient Centered Outcomes Research Institute 
828 L St., NW, Suite 900 Washington, DC 20036 
Phone: (202) 827-7700  Fax: (202) 355-9558 
Grant Number                              PCS 1406-18876 
Interventions 
Standard care spinal anesthesia 
Standard care general anesthesia 
ClinicalTrials.gov Number        NCT02507505 
 
 
Initial version:  A2.2 - August 22, 2015 
Amended version:  A2.3 – March 29, 2016 
 
 

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Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS......................................................................................................................... IV 
INVESTIGATOR APPROVAL STATEMENT ............................................................................................... 1 
STUDY SUMMARY ...................................................................................................................................... 2 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 3 
1.2 
NAME AND DESCRIPTION OF THE INTERVENTIONS ............................................................................ 4 
1.2.1 
Clinical Data to Date ................................................................................................................ 4 
2 
STUDY OBJECTIVES ......................................................................................................................... 5 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 6 
2.2 
SECONDARY OBJECTIVES ............................................................................................................... 6 
3 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................ 6 
3.1 
INCLUSION CRITERIA ...................................................................................................................... 6 
3.2 
EXCLUSION CRITERIA ..................................................................................................................... 6 
3.3 
SUBJECT RECRUITMENT ................................................................................................................. 6 
3.4 
DURATION OF STUDY PARTICIPATION .............................................................................................. 7 
3.5 
TOTAL NUMBER OF SUBJECTS AND SITES........................................................................................ 7 
3.6 
ENROLLMENT OF CHILDREN, PREGNANT WOMEN, FETUSES, NEONATES, OR PRISONERS: .................... 7 
4 
INVESTIGATIONAL PLAN .................................................................................................................. 7 
4.1 
GENERAL DESIGN .......................................................................................................................... 7 
4.1.1 
Screening Phase ..................................................................................................................... 7 
4.1.2 
Study Intervention Phase ........................................................................................................ 8 
4.1.3 
Follow Up Phase ..................................................................................................................... 8 
4.1.4 
Allocation to Interventional Group ........................................................................................... 8 
4.2 
STUDY ENDPOINTS......................................................................................................................... 8 
4.2.1 
Primary Study Endpoints ......................................................................................................... 8 
4.2.2 
Secondary Study Endpoints .................................................................................................... 8 
4.2.3 
Primary Safety Endpoints ...................................................................................................... 10 
5 
STUDY INTERVENTION ................................................................................................................... 10 
5.1 
DESCRIPTION ............................................................................................................................... 10 
5.2 
INTERVENTION REGIMEN .............................................................................................................. 11 
5.3 
BLINDING ..................................................................................................................................... 11 
5.4 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 12 
6 
STUDY PROCEDURES ..................................................................................................................... 12 
6.1 
SCREENING PHASE ....................................................................................................................... 12 
6.2 
STUDY INTERVENTION PHASE ....................................................................................................... 13 
6.2.1 
Randomization....................................................................................................................... 13 
6.3 
FOLLOW UP PHASE ...................................................................................................................... 14 
6.3.1 
Postoperative day 1 and 2 visits ............................................................................................ 14 
6.3.2 
Postoperative day 3 visit ....................................................................................................... 14 
6.3.3 
Post-discharge medical record review .................................................................................. 14 
6.3.4 
60-day, 180-day, and 365-day interviews ............................................................................. 15 
6.3.5 
National death index search .................................................................................................. 16 
6.3.6 
Medicare claims linkage ........................................................................................................ 16 
6.3.7 
End of Study Interview .......................................................................................................... 16 
6.4 
RESCUE THERAPY........................................................................................................................ 16 
6.5 
UNSCHEDULED VISITS .................................................................................................................. 16 

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6.6 
SUBJECT WITHDRAWAL ................................................................................................................ 16 
6.6.1 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 17 
7 
STATISTICAL PLAN ......................................................................................................................... 17 
7.1 
PRIMARY ENDPOINT ..................................................................................................................... 17 
7.2 
SECONDARY ENDPOINTS .............................................................................................................. 17 
7.3 
SAMPLE SIZE AND POWER DETERMINATION ................................................................................... 17 
7.4 
STATISTICAL METHODS ................................................................................................................ 18 
7.4.1 
Baseline Data ........................................................................................................................ 18 
7.4.2 
Efficacy Analysis.................................................................................................................... 18 
7.4.3 
Interim Analysis ..................................................................................................................... 18 
7.4.4 
Safety Analysis ...................................................................................................................... 18 
7.5 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 19 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 19 
8.1 
DEFINITIONS ................................................................................................................................ 19 
8.1.1 
Adverse Event ....................................................................................................................... 19 
8.1.2 
Serious Adverse Event .......................................................................................................... 19 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 20 
8.3 
RELATIONSHIP OF AE TO STUDY ................................................................................................... 20 
8.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................... 20 
8.4.1 
Follow-up report..................................................................................................................... 21 
8.4.2 
Investigator reporting: notifying the study sponsor................................................................ 21 
8.4.3 
INVESTIGATOR REPORTING: NOTIFYING THE IRB ........................................................................... 21 
8.4.4 
Sponsor reporting: Notifying participating investigators ........................................................ 22 
8.5 
UNBLINDING PROCEDURES ........................................................................................................... 22 
8.6 
STOPPING RULES ......................................................................................................................... 23 
8.7 
MEDICAL MONITORING ................................................................................................................. 23 
8.7.1 
Data and Safety Monitoring Plan........................................................................................... 23 
9 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 24 
9.1 
CONFIDENTIALITY ......................................................................................................................... 24 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 24 
9.3 
CASE REPORT FORMS.................................................................................................................. 24 
9.4 
DATA COLLECTION AND MANAGEMENT .......................................................................................... 24 
9.5 
MANAGEMENT OF AUDIO RECORDINGS OF 60, 180, AND 365 DAY INTERVIEWS: ............................... 26 
9.6 
RECORDS RETENTION .................................................................................................................. 26 
9.7 
PUBLIC ACCESS PLAN ................................................................................................................... 26 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 27 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 27 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 27 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 27 
11.1 
RISKS .......................................................................................................................................... 27 
11.2 
BENEFITS .................................................................................................................................... 28 
11.3 
RISK/BENEFIT COMPARISON. ........................................................................................................ 28 
11.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .............................................................. 28 
12 
STUDY FINANCES ............................................................................................................................ 29 
12.1 
FUNDING SOURCE ........................................................................................................................ 29 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 29 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 29 
13 
PUBLICATION PLAN ........................................................................................................................ 29 
14 
REFERENCES ................................................................................................................................... 30 
 
 
 

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List of Abbreviations 
 
3D-CAM: 3-minute Diagnostic Assessment for CAM-Defined Delirium 
AE: Adverse Event 
BPI: Brief Pain Inventory 
CCC: Clinical Coordinating Center 
CRC: Clinical Research Coordinator 
DCC: Data Coordinating Center 
DSMB: Data Safety Monitoring Board 
IRB: Institutional Review Board  
NSQIP: National Surgical Quality Improvement Program 
OAAS: Observer’s Assessment of Alertness/Sedation Scale 
PI: Principal Investigator 
REGAIN: Regional versus General Anesthesia for promoting Independence after Hip Fracture 
SBT: Short Blessed Test of cognition 
WHODAS 2.0: WHO Disability Assessment Schedule 2.0 
 
 
 
 
 
 
 
 

REGAIN TRIAL PROTOCOL 
 
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Version A2 
 
 
 
Investigator Approval Statement 
 
I have read this protocol and agree to conduct this clinical trial as outlined herein.  I will ensure that all 
sub-investigators and other study staff members have read and understand all aspects of this protocol.  I 
agree to cooperate fully with the University of Pennsylvania Clinical Coordinating Center and Data 
Coordinating Center during the study.  I will adhere to the Declaration of Helsinki and its amendments, the 
International Conference on Harmonization (ICH) principles of Good Clinical Practice (GCP; including 
archiving of essential study documents) and all applicable regulations and guidelines of the country in 
which the study is conducted.   
 
 
Principal Investigator: 
 
 
Printed Name: 
 
 
 
Signature: 
 
 
 
Date:  
 
 
 
 
REGAIN 
 
A Randomized Controlled Trial of Regional versus General Anesthesia for Promoting Independence after 
Hip Fracture 
 
 
 
 
Final Protocol Revised: March 29, 2016 
 
 
 
 

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Study Summary 
Title 
A Randomized Controlled Trial of Regional versus General Anesthesia to 
Promote Independence after Hip Fracture (REGAIN Trial) 
Short Title 
REGAIN Trial 
Methodology 
Randomized, active-controlled trial 
Study Duration 
6 years  
Single or multicenter 
design 
Multicenter 
Objectives 
1. To test the effect of spinal versus general anesthesia on recovery of walking 
at 60 days after randomization. 
2. To measure the impact of spinal versus general anesthesia on overall health 
and disability, return to the pre-fracture place of residence, pain, and mortality, 
and cognition at approximately 60, 180 and 365 days after randomization 
3. To assess the tolerability of spinal versus general anesthesia for hip fracture 
surgery, and the association of spinal versus general anesthesia with inpatient 
mortality and major morbidity, including postoperative delirium. 
Number of Subjects 
Total enrollment (consented patients): 2,424; Total randomized sample: 1,600 
Main Inclusion and 
Exclusion Criteria 
Inclusion criteria: Hip fracture requiring surgical treatment; age ≥ 50 years; 
ability to walk without human assistance before fracture 
 
Exclusion criteria: Concurrent surgery not amenable to spinal anesthesia; 
absolute contraindications to spinal anesthesia; patients known or suspected 
to be at elevated risk for malignant hyperthermia; periprosthetic fracture; and 
by determination of the surgeon, the treating anesthesiologist, or the site 
Clinical Director or their designate.  
 
Interventions  
 
Standard care spinal anesthesia  
Standard care general anesthesia  
Statistical 
Methodology 
Data will be analyzed via intent-to-treat (primary) and per-protocol methods; 
binary outcomes will be analyzed using standard two-sample hypothesis tests 
and multivariate regression models accounting for necessary stratification 
factors.  
Safety Evaluations  
Safety evaluations will occur via medical record review on postoperative day 1-
3 and at discharge for selected serious adverse events. 
Data and Safety 
Monitoring Plan  
The PI and the DSMB will be responsible for monitoring the data quality and 
the ongoing safety of subjects.  
 

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Figure 1: Locations of common hip fractures1 
BACKGROUND AND STUDY RATIONALE 
 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (GCP) (International Conference on Harmonization 
ICHE6), the Code of Federal Regulations Title 21, and other applicable government regulations and 
Institutional research policies and procedures. All episodes of noncompliance will be documented.  
 
The purpose of this active comparator study is to evaluate the effect of two different standard care 
approaches to anesthesia care for hip fracture surgery on recovery of ambulation at approximately 60 
days (primary outcome) and other patient-centered outcomes measured at 365 days (plus or minus 60 
days). The two approaches are spinal anesthesia (spinal block) and general anesthesia. Our overarching 
hypothesis is that patients undergoing hip fracture surgery with spinal anesthesia will demonstrate 
improved ambulation at approximately 60 days and better outcomes across a range of patient-centered 
endpoints compared to patients receiving general anesthesia.  
1.1 
Background and Relevant Literature  
 
Hip fracture is a clinical condition that involves a break 
in the femur (hip bone) near where it attaches to the 
pelvis (Figure 1). Over 90% of hip fractures occur in 
individuals aged 50 or older, most commonly resulting 
from low-energy traumatic injuries, such as falls from 
standing in the context of established osteoporosis, 
chronic illness, or disability. Surgical treatment, via 
fixation of the fractured bone or partial or total 
replacement of the hip joint, is indicated for all types of 
hip fractures and approximately 95% of hip fracture 
patients undergo surgery. 
 
Hip fractures occur more than 300,000 times each year 
in the US and over 1.6 million times each year 
worldwide. Hip fractures carry major consequences for 
the individual and society.6, 7 Within 12 months of 
fracture, 25% of patients die,8, 9 and half of previously 
community-dwelling patients either die or require 
nursing home admission.10 Among patients who survive 
to 12 months, 40% of those who could walk 
independently before fracture require human assistance 
to walk 10 feet.11 Hip fractures create substantial needs 
for informal caregiving 12, 13 and post-acute and long-
term care that carry major costs to society;14 the 
estimated costs attributable to hip fractures in the US exceeded $12 Billion in 2005 and will exceed $18 
Billion by 2025.15 Moreover, the disability caused by hip fractures matters to older adults. In a study of 
patient views on hip fracture, 194 women aged 75 or older read hypothetical scenarios describing a 
“good” hip fracture after which they would continue to live independently, and a “bad” hip fracture that 
would require admission to a nursing home. Of women surveyed, 80% stated that they would rather die 
than experience the loss of independence associated with a “bad” hip fracture.16 
 
No evidence-based interventions now exist to improve functional outcomes after hip fracture surgery 
beyond the immediate postoperative period.17, 18 Nearly all hip fracture patients require orthopedic surgery 
and anesthesia,19-21 making the anesthetic care episode a major opportunity to impact outcomes.22  
 

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↓ Exposure to inhaled 
anesthetic agents
↓ Need for airway 
intervention/mechanical 
ventilation
↑ Intraoperative pain control
↓ Introperative opiates 
↓ Postoperative 
confusion 
↓ Pulmonary 
complications
↓ Postoperative 
pain
↑ Recovery of 
locomotion
 ↑Overall health
↓Disability
↑ Return to prior 
residence
↓ Chronic pain 
symptoms
Physiologic advantages
Improved 60-day and 
180-day outcomes 
Decreased postop. 
complications
Figure 2: Proposed causal pathway linking spinal versus general anesthesia 
to improved patient-centered end-outcomes after hip fracture.
Spinal and general anesthesia (defined below) represent the two standard care approaches to anesthesia 
for hip fracture surgery.23 Basic and clinical research has identified multiple plausible mechanisms by 
which spinal anesthesia may improve outcomes after hip fracture; nonetheless, major guidelines and 
systematic reviews have identified key evidence gaps 24-28 and anesthesia care for hip fracture varies 
markedly in practice.29 While spinal and general anesthesia for hip fracture have been previously 
compared in retrospective studies and small randomized trials, much of the available prospective trial 
data is old and may not be reflective of current clinical practice.  
 
REGAIN will be the first pragmatic multicenter prospective randomized trial of spinal versus general 
anesthesia for hip fracture surgery designed to evaluate the association of anesthesia technique with 
functional recovery after hip fracture. As such, it will fill critical evidence gaps to inform policy and 
practice. 
1.2 
Name and Description of the Interventions  
We will compare two widely used approaches to anesthesia for hip fracture surgery.  
General anesthesia uses injected or inhaled medications to keep people unconscious during surgery. 
Since general anesthesia depresses breathing and impairs protective airway reflexes, invasive airway 
interventions such as breathing tube placement and mechanical ventilation are usually required.30  
Spinal anesthesia uses local anesthetic medications injected into the fluid surrounding the spinal cord to 
temporarily numb the legs and lower abdomen. Spinal anesthesia is the most widely used type of regional 
anesthesia for hip fracture surgery.31, 32 While intravenous sedation is typically used for comfort with 
spinal anesthesia, invasive airway interventions are not typically required.33 
1.2.1 
Clinical Data to Date 
Multiple clinical and laboratory 
studies provide evidence for 
physiologic effects of general 
and regional anesthesia that 
may plausibly lead to 
differences in important 
downstream patient-centered 
outcomes. These effects are 
summarized in Figure 2.  
 
Pulmonary effects of general 
versus spinal anesthesia: 
General anesthesia negatively 
impacts lung function by 
impairing natural processes 
that prevent buildup of excess 
mucous,34-36 keep individual lung units (alveoli) open,37, 38 and maintain a normal breathing rate.39-41 
General anesthesia also impairs the function and coordination of muscles involved in breathing.42, 43 In 
contrast, spinal anesthesia has minimal effects on lung function.44-46 Compared to general anesthesia, 
spinal anesthesia is associated with higher blood oxygen levels after hip fracture surgery47-49 and lower 
rates of postoperative pneumonia.48, 50, 51 A recent large retrospective study by the PI found a lower odds 
of pulmonary complications with regional anesthesia among 18,159 patients undergoing hip fracture 
surgery (adjusted odds ratio (OR) 0.75, 95%CI 0.64 to 0.89).52   
 
Effects on pain pathways: With general anesthesia, intravenous opiates like morphine are commonly 
used to treat pain; under-dosing of these drugs and inadequate pain control may lead to the development 
of long-term pain by sensitizing neurons that transmit pain signals to the brain (“central sensitization”).53-55 

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Spinal anesthesia prevents central sensitization by blocking transmission of pain signals at the level of 
the spinal cord, potentially contributing to better short- and long-term pain outcomes.56-58 
 
Effects on cognition: General anesthesia impairs brain cell (neuron) function by influencing neuron gene 
transcription;59, 60 signaling of impulses between neurons;61-64 and systems that balance levels of 
important ions, such as calcium, within neurons.65 General anesthesia has been shown to impair short- 
and long-term memory acquisition.66-69 A 2004 meta-analysis of seven trials47, 48, 50, 51, 70-72 found lower 
rates of postoperative confusion among patients who received spinal versus general anesthesia for hip 
fracture surgery (relative risk (RR), spinal versus general anesthesia: 0.50, 95% confidence interval (CI): 
0.26 to 0.95).26 Additionally, a large retrospective study suggested lower rates of cognitive impairment 
with spinal anesthesia at 6 and 12 months after hip fracture.73  
 
Effects on patient-centered end-outcomes: Few prospective studies to date have examined differences in 
patient-centered end-outcomes with spinal versus general anesthesia for hip fracture surgery.  
 
Mortality: A 2004 meta-analysis of eight small randomized trials of spinal versus general anesthesia for 
hip fracture observed a lower 30-day mortality with spinal anesthesia (RR 0.69, 95% CI: 0.50, 0.95).26 
Nonetheless, the randomized trials included in this meta-analysis have substantial limitations; many were 
completed prior to the 1990’s, and may thus have limited relevance to current practice and the 
methodological quality of included trials was judged to be low overall.25, 26 More recently, in a 
retrospective study of 18,159 hip fracture patients, the PI (Neuman) observed significant decreases in the 
adjusted odds of in-hospital mortality with spinal versus general anesthesia (OR: 0.71, 95% CI 0.54, 
0.93),52 although subsequent non-randomized analyses have yielded equivocal results regarding the 
association of anesthesia type with in-hospital74 or 30-day mortality29 differences. Importantly, even well-
done non-randomized studies of anesthesia care for hip fracture patients are substantially limited by 
potential selection bias: since patients who receive regional anesthesia tend to be older and sicker than 
those who receive general anesthesia,29, 52, 75 non-randomized studies will tend to underestimate any true 
benefits of spinal anesthesia. 
 
Functional endpoints: To date, the association between anesthesia technique and functional endpoints 
has only been investigated in non-randomized studies. Historical cohort studies have shown inconsistent 
associations between anesthesia technique and locomotion after hip fracture.76,73 As a pilot investigation 
for REGAIN, we conducted a retrospective (non-randomized) analysis of data collected in the FOCUS 
trial,77, 78 a 47-center trial of transfusion management strategies in 2,016 hip fracture patients. While we 
found that patients who received spinal anesthesia were older than those who received general 
anesthesia (mean age 82.5 years vs. 80.9 years, P<0.001) they were slightly more likely to be alive and 
able to walk independently at 60 days (65.3% vs 64.9%) although this difference was not statistically 
significant (p=0.86).  
 
Evidence gaps: Major gaps in evidence persist regarding the comparative effectiveness of common 
anesthesia options for hip fracture surgery. A 2011 systematic review by the UK Clinical Guideline Centre 
concluded that “no recent randomized trials were identified that fully address” the clinical effectiveness of 
regional versus general anesthesia for hip fracture surgery, and found that the available evidence “is old 
and does not reflect current practice.”25 The 2014 American Academy of Orthopedic Surgeons’ guidelines 
for hip fracture care also note that available randomized studies are likely to be outdated and that “future 
research involving appropriately randomized patients may yet delineate which anesthesia technique is 
more appropriate in this patient population.”24 
2 
Study Objectives 
 
The purpose of the REGAIN trial is to evaluate the effect of two different standard care approaches to 
anesthesia for hip fracture surgery (spinal and general anesthesia) on recovery of ambulation at 
approximately 60 days (primary outcome) and other patient-centered outcomes measured at up to 
approximately 14 months (365 days plus or minus 60 days) after randomization. The overarching 
hypothesis of this study is that patients who receive spinal anesthesia will demonstrate improved 

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ambulation at approximately 60 days and have better outcomes across a range of patient-centered 
endpoints compared to patients who receive general anesthesia.  
2.1 
Primary Objective 
• To test the effect of spinal versus general anesthesia on recovery of ambulation at 
approximately 60 days after randomization. 
2.2 
Secondary Objectives  
• To measure the impact of spinal versus general anesthesia on overall health and disability, 
cognition, return to the pre-fracture place of residence, pain, and mortality at approximately 60, 
180, and 365 days after randomization.  
• To assess the association of spinal versus general anesthesia for hip fracture surgery with in-
hospital mortality, delirium, medical complications, and pain. 
• To assess the association of spinal versus general anesthesia for hip fracture surgery with 
satisfaction with care. 
3 
Study Population and Duration of Participation  
3.1 
Inclusion Criteria 
 
● Clinically or radiographically diagnosed intracapsular or extracapsular hip fracture 
● Planned surgical treatment via hemiarthroplasty, total hip arthroplasty or appropriate fixation 
procedure 
● Age ≥ 50 years 
● Ability to walk 10 feet or across a room without human assistance before fracture 
3.2 
Exclusion Criteria 
 
●  Planned concurrent surgery not amenable to spinal anesthesia.  
● Absolute contraindications to spinal anesthesia, including: (1) Known or suspected congenital or 
acquired coagulopathy; (2) active use of pharmacologic anticoagulants within a timeframe defined to 
contraindicate neuraxial block placement by available American Society of Regional Anesthesia 
guidelines;79 (2) known or suspected unrepaired critical or severe aortic stenosis; (3) known or 
suspected active skin infection at the planned needle insertion site; (4) known or suspected elevated 
intracranial pressure contraindicating dural puncture. 
● Patient is known or suspected to be at elevated risk for malignant hyperthermia 
● Periprosthetic fracture 
● Prior participation in the REGAIN trial 
● Prisoner status 
● Determination by the attending surgeon, the attending anesthesiologist, or the site Clinical Director 
or their designate, that the patient would not be suitable for randomization. 
 
3.3 
Subject Recruitment  
Hip fracture is an acute condition requiring urgent hospitalization; as such, all subjects will be recruited in 
hospital settings between the time of presentation and the time of surgery. Orthopedic surgeons 
performing hip fracture surgery at each recruiting site will be contacted in advance of the initiation of study 
accrual to assess willingness to allow for patients to be enrolled. Patients under the care of non-
participating orthopedic surgeons will not be recruited into this study. A list of non-participating orthopedic 
surgeons will be maintained by each site Clinical Director. 
 

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Site CRCs, Clinical Directors and other appropriate personnel will use multiple strategies to identify 
potentially eligible patients, potentially including interval calls to the hospital admissions office, specific 
hospital floors or units, relevant attendings, residents, or physician extenders (physician assistants or 
advanced practice nurses); reviews of inpatient census lists and operating room schedules; and requests 
to physicians and physician extenders, emergency room personnel, ward clerks and floor nurses to 
contact site study staff when a hip fracture patient is admitted to the hospital. 
 
For potentially eligible patients, the site CRC, site Clinical Director or other appropriately trained study 
staff member will approach the patient and/or their proxy between the time of diagnosis and the time of 
surgery to explain the study, complete a brief screening evaluation, and obtain informed consent. 
Alternately, members of the healthcare team may initially query patients or their proxies regarding 
potential interest in participation in the REGAIN trial; for interested patients or their proxies, the study 
team will be contacted to initiate recruitment and enrollment.   
3.4 
Duration of Study Participation 
The planned maximum duration of study participation will be approximately 14 months from the date of 
randomization (i.e. 365 days plus or minus 60 days). Additional data on survival beyond this point may be 
obtained from administrative sources (e.g. NDI) where available. 
3.5 
Total Number of Subjects and Sites  
Recruitment will end when approximately 2,424 subjects are enrolled. It is expected that this approximate 
number of subjects will be enrolled (i.e. informed consent for participation will be obtained) in order to 
produce approximately 1,600 randomized patients. This estimate is based on an assumption that one in 
three patients (33%) who undergo consent prior to surgery will be found to be ineligible for randomization 
on the day of surgery due to active clinical issues, timing of medication dosing, or clinical assessments by 
treating physicians or the site Clinical Director or their designate.  
3.6 
Enrollment of children, pregnant women, fetuses, neonates, or prisoners:  
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study. 
4 
Investigational Plan  
4.1 
General Design 
 
Randomized, multicenter, active comparator study of two alternative standard care approaches to 
anesthesia for hip fracture. Study endpoints will be assessed via in-person interview (during 
hospitalization), medical record review, telephone interview (after hospital discharge), and a vital records 
database search. 
4.1.1 
Screening Phase 
Subjects will be screened in person by site CRCs, the site Clinical Director, or other designated study 
staff between the time of presentation and the time of surgery. Written informed consent and HIPAA 
authorization will be obtained in person from patients or their proxies (in cases where patients are unable 
to provide informed consent) by site CRCs, the site Clinical Director, or other designated study staff. A 
series of questions will be asked of patients or their proxies to determine if the potential subject is within 
the correct age range and to assess other inclusion and exclusion criteria. For potential subjects who may 
be eligible based on these criteria, written informed consent will be obtained from patients or (where 
necessary) their proxies.  
 
Consenting patients will undergo an interview, to be carried out by site CRCs, the site Clinical Director, or 
other designated study staff, to collect necessary pre-randomization baseline data. Potentially eligible 
patients will undergo a final pre-randomization screening evaluation on the day of surgery to verify 
eligibility for randomization; since the assigned anesthesiologist is often not known before the day of 
surgery, and since changes in patient clinical status over time may impact eligibility, this evaluation will be 

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required to occur on the day of surgery. Patients deemed eligible for study inclusion at this point will 
proceed to the study intervention phase. 
4.1.2 
Study Intervention Phase  
For randomized patients, the intervention phase will comprise the period in which they are undergoing 
anesthesia care for hip fracture surgery. Prior to the start of anesthesia care, the treating anesthesiologist 
will be notified by the site Clinical Director, CRC, or other designated personnel, regarding the 
randomization status of the patient. As described below, patients will be randomized to one of two 
pragmatic treatment protocols that will instruct the treating anesthesiologist to deliver a standard care 
general anesthetic or a standard care spinal anesthetic. The study intervention phase will comprise the 
intraoperative anesthesia care episode, with the choice of primary anesthetic modality determined by this 
randomization assignment.  
4.1.3 
Follow Up Phase 
The follow up phase will extend from the end of the anesthesia care episode to up to approximately 14 
months (i.e. 365 days +/- 60 days) after the date of randomization.  
4.1.4 
Allocation to Interventional Group  
Participants will be randomly assigned to one of the two treatment regimens in a 1:1 ratio. Randomization 
will occur  on the day of surgery via an automated algorithm constructed by the study Biostatistician. For 
each arm, balanced randomization of subjects, stratified by site, gender, and fracture type (intracapsular 
versus extracapsular), will be achieved by permuted block randomization with a variable block size.80, 81 
The randomization seed and actual algorithm will be kept by the study Biostatistician. Study procedures 
for randomization of subjects are detailed in Section 6.2.1 below. 
4.2 
Study Endpoints  
4.2.1 
Primary Study Endpoints 
Independence in walking at 60 days after randomization (Primary outcome). The primary outcome 
will be assessed by patient and/or proxy telephone interview at 60 days after randomization (+/- 30 days). 
Patients who report being unable to walk 10 feet or across a room without human assistance, or who die 
within 60 days of fracture will be classified as treatment failures; patients who require a cane or walker, 
but not human assistance, will not be classified as treatment failures, although data regarding the need 
for assistive devices will be collected for analysis as a secondary outcome. This outcome will also be 
assessed by telephone interview at 180 days (+/- 45 days) and at 365 days (+/- 60 days) where feasible 
for analysis as secondary study endpoints. 
4.2.2 
Secondary Study Endpoints 
Overall health and disability.  Overall health and disability will be assessed by in-person patient and/or 
proxy interview at baseline and by telephone interview at 60 days (+/- 30 days), 180 days (+/- 45 days), 
and 365 days (+/- 60 days) after randomization via the 12-item World Health Organization Disability 
Assessment Schedule 2.0 (WHODAS 2.0).82 The WHODAS 2.0 is a patient-reported outcome that 
assesses cognition, mobility, self-care, interpersonal relationships, work and household roles, and 
participation in society. It can be administered in person or by telephone in around 5 minutes.83 The 
WHODAS 2.0 is scored on a scale from 0 (no disability) to 4 (extreme disability) for each of 12 items; item 
scores are summed to obtain a total score ranging from 0-48.  The total score is divided by 48 and 
multiplied by 100 to convert it to a percentage of the maximum disability score; disability is classified as 
none (0-4%), mild (5-24%), moderate (25-49%), severe (50-95%) and complete (96-100%).83, 84 The 
WHODAS has been validated across multiple conditions,85-90 and has good criterion and convergent 
validity for assessing postoperative recovery at 3, and 6 months, with excellent responsiveness and 
internal consistency (Chronbach’s Alpha > 0.90).91  
 

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Need for assistive devices for walking. The need for assistive devices for walking (e.g. cane, walker) 
will be assessed by in-person patient and/or proxy interview at baseline and by telephone interview at 60 
days (+/- 30 days), 180 days (+/- 45 days), and 365 days (+/- 60 days) after randomization. 
 
Ability to return home. All patients will be queried by telephone interview regarding location of residence 
at 60 days (+/- 30 days), 180 days (+/- 45 days), and 365 days (+/- 60 days) after randomization. For 
patients not residing in long-term nursing homes prior to fracture (93% of all U.S. hip fracture patients),92 
the percentage returning home at each time point will be assessed as a secondary outcome. 
  
Chronic pain. Pain symptoms will be assessed by patient and/or proxy telephone interview at 60 days 
(+/- 30 days), 180 days (+/- 45 days), and 365 days (+/- 60 days) after randomization using the Numeric 
Rating Scale (NRS), by which pain symptoms are rated from 0 (no pain) to 10 (worst pain imaginable); 
pain items will assess the extent of pain at worst and on average over the past 24 hours, using similar 
wording to selected Brief Pain Inventory items.93, 94An additional item will query patients as to whether 
they are actively taking prescription medications for pain. 
  
All-cause mortality. Vital status will be assessed via patient and/or proxy telephone interview at 60 days 
(+/- 30 days), 180 days (+/- 45 days), and 365 days (+/- 60 days) after randomization. Additionally, a 
National Death Index search will be performed in the final year of the study for all patients enrolled up to 
that point; studies evaluating NDI accuracy in determining mortality have reported rates of 83%-98%.95, 96 
 
Cause of death. Cause of death will be determined via National Death Index search in the final year of 
the study for all patients enrolled up to that point. 
 
Acute postoperative pain. Pain during hospitalization will be assessed by site CRCs or other 
appropriate staff via in-person patient and/or proxy interview before surgery and daily up to postoperative 
day 3 or the day of discharge (whichever occurs first) using a 0-10 Numeric Rating Scale; pain items will 
assess the extent of pain at worst and on average over the past 24 hours, using similar wording to 
selected Brief Pain Inventory items.93, 94.  
 
Satisfaction with care. Satisfaction with anesthesia care will be assessed by site CRCs or other 
appropriate staff via in-person interview on postoperative day 3 or the day of discharge (whichever occurs 
first) via the Bauer Patient Satisfaction Questionnaire,97 as well as additional items assessing to undergo 
or recommend a similar anesthetic in the future. 
 
Cognitive function. Cognitive function will be assessed via in-person interview at baseline, and via 
telephone interview via the Short Blessed Test (SBT), a well-validated brief cognitive screen appropriate 
for telephone administration at 60 days (+/- 30 days), 180 days (+/- 45 days), and 365 days (+/- 60 days) 
after randomization.4, 98 The SBT is summarized in Table 1. 
 
Postoperative delirium.  We will assess patients for the presence of delirium via the 3D-CAM 
assessment tool via in-person interview at baseline and daily up to postoperative day 3 or the day of 
discharge (whichever occurs first). The 3D-CAM is a well-validated brief tool with high sensitivity and 
specificity for delirium.99, 100 
 
Inpatient mortality and major inpatient morbidity.  In-hospital mortality and other major intraoperative 
or postoperative complications will be assessed via chart review by site CRCs or other appropriate staff 
following hospital discharge, death, or at 30 days after randomization, whichever occurs first. We will 
assess the occurrence of major postoperative complications including but not limited to: (1) postoperative 
bleeding requiring transfusion; (2) myocardial infarction; (3) congestive heart failure; (3) stroke or transient 
ischemic attack; (4) pneumonia; (5) urinary tract infection; (6) wound infection; (7) thromboembolic 
complications; (8) unplanned intubation; (9) prolonged mechanical ventilation; (10) acute renal failure; 
(11) cardiac arrest requiring CPR or defibrillation; (12) return to the operating room. Complication 
definitions for use in REGAIN will adapt standard definitions, such as those used by the National Surgical 
Quality Improvement Program.101  

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Table 1: Short Blessed Test of orientation, memory, and concentration4 
Item 
Max. # of 
errors 
Weight 
Maximum score 
(errors x weight) 
1. What year is it now? 
1 
4 
4 
2. What month is it now? 
1 
3 
3 
Memory phrase: Repeat this phrase after 
me: John Brown, 42 Market Street, Chicago 
N/A 
N/A 
N/A 
3. About what time is it? (within 1 hour) 
1 
3 
3 
4. Count backwards from 20 to 1 
2 
2 
4 
5. Say the months of the year in reverse 
order. 
2 
2 
4 
6. Repeat the memory phrase. 
5 
2 
10 
Maximum total score 
28 
To score the SBT, the interviewer records the number of errors on each item up to the 
maximum number of errors allowed for each item. The number of errors on each item is 
multiplied by that item’s weighting factor to obtain the item score. Item scores are summed 
to obtain a total score between 0 and 28.  Scores of 0-4 indicate normal cognition; scores of 
5-9 indicate impairment consistent with early dementia; and scores of 10 or more indicate 
impairment consistent with dementia.5 
 
4.2.3 
Primary Safety 
Endpoints 
Spinal anesthesia and 
general anesthesia are 
standard care approaches 
with longstanding track 
records of safety in 
appropriately selected 
patients. The primary 
safety evaluation will 
assess whether the 
adverse event profile 
associated with 
participation in the 
REGAIN trial differs 
meaningfully from the 
adverse event profile that 
could be expected with spinal and general anesthesia for hip fracture surgery in typical clinical practice. 
We will collect data on the following known or established potential risks of spinal and/or general 
anesthesia: 
 
• 
Intraoperative cardiac arrest requiring CPR caused by anesthetic medications or techniques 
• 
Malignant hyperthermia requiring dantrolene or intraoperative anaphylaxis caused by medications 
used to induce or maintain general or spinal anesthesia 
• 
Intraoperative aspiration resulting in aspiration pneumonia or aspiration pneumonitis 
• 
Epidural hematoma requiring surgical intervention occurring within 24 hours of spinal anesthesia 
• 
Paralysis of the lower extremities lasting greater than 24 hours following spinal anesthesia 
• 
Fall within 12 hours of anesthesia care 
• 
Unplanned postoperative mechanical ventilation lasting greater than 6 hours in a patient not 
previously requiring mechanical ventilation 
These endpoints will be assessed via medical record review for the first 3 postoperative days and at the 
time of discharge; for patients discharged prior to postoperative day 3, these endpoints will be assessed 
through the day of discharge.  
5 
Study Intervention 
5.1 
Description 
Patients will be randomized to receive standard care spinal anesthesia or standard care general 
anesthesia. The administration of anesthesia will be carried out in the course of routine care by practicing 
anesthesiologists, residents, nurse anesthetists and other appropriately trained and credentialed clinical 
staff at each study site. Prior to study initiation, anesthesia staff will be queried by the site Clinical Director 
regarding their willingness to participate in the study and non-participating anesthesia staff will be 
identified by the Clinical Director. Additionally, Clinical Directors will identify anesthesia staff who are 
eligible to provide care for study cases; experience- or skill-based standards for anesthesiologist 
participation in the REGAIN trial will be determined locally based on the judgment of the site Clinical 
Director and other study staff. As anesthesia care for patients enrolled in the REGAIN trial will be 
delivered by participating anesthesiologists as a part of their routine job function, participating 
anesthesiologists will not be considered part of the study team unless involved in other aspects of the 
REGAIN trial. Patients who will be under the care of anesthesia staff at the time of induction of anesthesia 
who are unwilling to participate in REGAIN or who the site Clinical Director has determined to be ineligible 
for participation in REGAIN will be excluded from randomization. 
 

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Table 2: Observer’s Assessment of Alertness/Sedation2, 3 
Score 
Subject responsiveness 
Sedation level 
5 
Responds readily to name spoken in normal 
tone 
Alert 
4 
Lethargic response to name spoken in normal 
tone 
Light sedation 
3 
Responds only after name is called loudly 
and/or repeatedly 
Moderate sedation 
2 
Responds only after mild prodding or shaking 
Moderate sedation 
1 
Does not respond to mild prodding or shaking 
Deep sedation 
The intervention will occur by providing the assigned clinical anesthesia staff instructions directing them to 
perform a standard care spinal anesthetic or a standard care general anesthetic (below). These regimens 
use standard terminology and do not require specialized techniques, drugs, or monitors beyond those 
available and in common use in standard care settings. All participating anesthesia staff will undergo a 
brief orientation to the protocol by the site Clinical Director; instructions will be provided that all aspects of 
anesthesia care within the protocol should adhere to national, local, and individual standards of practice 
for the provision of spinal or general anesthesia, including but not limited to: the location of block 
administration (OR vs. designated block room); medication selection and dosing; decisions to convert 
from spinal to general anesthesia; postoperative analgesia; and decisions regarding the appropriate 
duration and number of attempts permitted to perform a spinal anesthetic or to induce general 
anesthesia. 
5.2 
Intervention Regimen 
At the time of randomization, providers will receive instructions regarding anesthesia care similar to the 
statements shown below, allowing for minor wording changes or revisions for clarity. 
Provider instructions:  
Treatment arm 1 (spinal 
anesthesia): Please perform a 
single-shot spinal anesthetic, with 
sedation as needed for block 
placement and intraoperative 
comfort. Please titrate any 
intraoperative sedation to maintain 
arousability to tactile stimulus or 
voice. Conversion to general anesthesia is permitted if required by clinical circumstances. Please conduct 
all other aspects of anesthesia care, including monitoring, medication selection and dosing, supplemental 
nerve blocks, and management of intraoperative events as per your usual routine.  
 
For patients randomized to receive spinal anesthesia, treating anesthesiologists will receive instructions 
to document the level of sedation based on the Observer’s Assessment of Alertness/Sedation Scale 
(OAAS), a simple, validated measure of alertness among sedated subjects.2, 3 The OAAS scoring system 
to be used in the REGAIN trial appears in Table 2.  
Provider instructions: Treatment arm 2 (general anesthesia): Please perform a general anesthetic. 
Please use an inhaled anesthetic agent for maintenance and use intravenous opiates as needed for 
analgesia. Airway management may be via endotracheal tube, laryngeal mask airway, or other device as 
dictated by clinical circumstances. Please conduct all other aspects of anesthesia care, including 
monitoring, medication selection and dosing, supplemental nerve blocks and management of 
intraoperative events as per your usual routine.  
5.3 
Blinding 
Due to the nature of the study intervention, it will not be possible to blind patients or treating providers 
(anesthesiologists or surgeons) to treatment assignment.   
As permitted by staff availability and site resources, we will encourage site staff to perform the 
postoperative day 1-3 3D-CAM assessments in a blinded fashion by having these assessments 
performed by an individual other than the team member(s) who are responsible for obtaining the 
randomization assignment (see Section 6.2.1, “Randomization”) and conducting chart reviews for adverse 
safety events. Additionally, where appropriate, patients will be instructed to not inform the 3D-CAM 
assessor of the type of anesthesia they received. If this is not possible based on staff availability or site 
resources, we will not require blinded collection of in-hospital outcomes data.  
 

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Post-discharge outcomes, including the primary study outcome, will be assessed by centrally by 
telephone. Telephone follow-up for post-discharge outcomes assessment will be carried out by University 
of Pennsylvania CCC staff who will be blinded to treatment assignment. 
 
Assessments of aggregate data related to patient characteristics and study outcomes will occur in a 
blinded fashion such that investigators cannot determine subject randomization assignment; unblinding at 
the level of the individual patient will be permitted as needed for making determinations of relatedness for 
adverse events (see section 8.3 below). Unblinding procedures for the overall study are described below 
in section 8.5 below.   
5.4 
 Subject Compliance Monitoring 
The PI and/or CCC staff will assess the type of anesthesia actually received via retrospective chart 
review, to be completed by site CRCs or other study personnel following death, hospital discharge, or 
postoperative day 30, whichever comes first. While the type of anesthesia received will be investigated to 
assess for the extent of crossover between study arms, such crossover will not be considered to 
represent protocol non-compliance, since treatment regimens permit deviations from assigned treatments 
based on clinical rationale. Similarly, for patients randomized to spinal anesthesia, sedation beyond 
arousability to voice or tactile stimulus will not be considered to represent non-compliance, since study 
protocols allow for provider selection and dosing of sedation based on clinical rationale.  
 
To assess study performance, data on anesthesia care will be reviewed for each recruiting site after the 
first 10 subjects at each site are randomized. Further site-level analyses as to assess safety events and 
protocol implementation will be performed on an as-needed basis. 
6 
Study Procedures 
6.1 
Screening phase 
 
6.1.1. Initial screening visit 
The initial screening visit will be carried out by site CRCs or other appropriate staff between the time of 
presentation and the time of surgery. It will involve a patient and/or proxy interview and medical record 
review to assess inclusion and exclusion criteria. Data will be recorded on the Initial Screening Visit Form 
and entered into the online DMS. Written informed consent will be obtained at this visit and documented 
in the medical record. Hard copy forms will be stored in secure locked cabinets within offices controlled by 
study personnel and locked when not in use. 
 
• 
Informed Consent 
• 
HIPAA Authorization  
• 
Screening interview (Age; ability to walk 10 feet without assistance prior to fracture; receipt of 
selected anticoagulant or antiplatelet medications; information on malignant hyperthermia risk; 
gender, ethnicity, and race) 
• 
Medical record review (Planned surgical procedures; history of critical or severe aortic stenosis, 
elevated intracranial pressure, or lumbar skin infection; available laboratory data on platelets, INR 
and PTT) 
 
6.1.2. Baseline data collection visit 
The baseline data collection visit will be carried out by site CRCs or other appropriate staff between the 
time of presentation and the time of surgery. It will involve a patient or proxy interview and medical record 
review to assess relevant pre-fracture and pre-randomization covariates. Data will be recorded on the 
Baseline Data Collection Visit Form and entered into the online DMS.  Hard copy forms will be stored in 
secure locked cabinets within offices controlled by study personnel and locked when not in use. 
 
Data will also be collected at this visit regarding patient and proxy contact information as needed to 
facilitate subsequent telephone follow-up; patient social security number and Medicare number as 

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needed to facilitate data linkages to the NDI and Medicare claims; and names and contact numbers of 
two additional contacts who do not live with the patient who may be available to facilitate follow-up in the 
event that we are unable to reach the patient. While information on alternative contact individuals will be 
collected from patients to assist with follow-up, availability of an alternative contact is not a requirement 
for participation in the REGAIN trial.  Contact data will be stored on the Patient Contact Form and entered 
into the online DMS. Hard copy forms will be stored in secure locked cabinets within offices controlled by 
study personnel and locked when not in use. Forms including patient contact information will be stored 
separately from all other CRFs.   
 
• 
Medical history interview and medical record review (Date of birth; comorbidities; height; weight; 
do-not-resuscitate status; most recent available heart rate, blood pressure, and oxygen saturation 
values; fracture location and laterality; supplemental oxygen or mechanical ventilation; most 
recent available serum creatinine; pre-fracture pain medication use) 
• 
Pre-fracture ambulation independence questionnaire 
• 
Pre-fracture residential status assessment (i.e. residence at home, in a nursing home, etc…) 
• 
Short Blessed Test (cognition) 
• 
3D-CAM (delirium) 
• 
WHODAS 2.0 (overall health and disability prior to fracture) 
• 
Pain symptom questionnaire (average and worst pain over past 24 hours; pain prior to hip 
fracture) 
• 
Brief Resilience Scale (resilience to adversity) 
• 
Patient, proxy, and secondary contact information (Patient/proxy telephone numbers, addresses, 
e-mails; patient social security number and Medicare number; names, telephone numbers, and 
home addresses of two additional contacts not living with the patient to facilitate follow-up.)  
 
6.1.3. Day of surgery screening visit 
The day of surgery screening visit will be carried out by site CRCs or other appropriate staff on the day of 
surgery and will involve a medical record review and an interview with treating physicians to assess 
patient appropriateness for randomization. Patients with identified contraindications to spinal anesthesia 
will be excluded prior to randomization. Data will be recorded on the Day of Surgery Screening Form and 
entered into the online DMS. Hard copy forms will be stored in secure locked cabinets within offices 
controlled by study personnel and locked when not in use. 
 
• 
Medical record review (Receipt of selected anticoagulant or antiplatelet medications; available 
laboratory data on platelets, INR and PTT) 
• 
Physician verification of eligibility 
6.2 
Study Intervention Phase 
6.2.1 
Randomization 
Randomization will be carried out on the day of surgery; randomization will be performed centrally 
through the study electronic DMS. The site CRC, Clinical Director or other study staff will obtain the 
randomization assignment electronically from the DMS and will communicate the treatment assignment to 
the anesthesia team on the day of surgery verbally in person or by telephone, e-mail, text, or other 
appropriate modality. Designated alternate study personnel who can access the randomization 
assignment will be identified by the PI and the site Clinical Director to serve as a backup in the event that 
the site Clinical Director is not available. In the event that the DMS is not available or cannot be accessed 
by study personnel, the randomization assignment will be communicated to appropriate site personnel by 
directly by the PI or designated CCC or DCC staff. 
 
6.2.2 
Intraoperative phase 
All intraoperative care will be carried out by practicing clinicians at the study site.   
 
• 
Standard care spinal anesthesia or standard care general anesthesia 

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• 
Measurement of sedation level via OAAS scale 
• 
Monitoring, clinical management, and additional anesthesia procedures as dictated by standard 
care 
6.3 
Follow Up Phase 
6.3.1 
Postoperative day 1 and 2 visits 
Patients will be visited on the first and second postoperative days by site CRCs or other study personnel 
to complete an in-person interview to assess delirium and pain. Data will be recorded onto the 
Postoperative Day 1 and 2 Visit Form and entered into the online DMS. Hard copy forms will be stored in 
secure locked cabinets within offices controlled by study personnel and locked when not in use. 
 
• 
3D-CAM assessment (delirium) 
• 
Pain symptom questionnaire (average and worst pain over past 24 hours) 
• 
Postoperative mortality assessment 
6.3.2 
Postoperative day 3 visit  
Patients will be visited on the third postoperative days by site CRCs or other study personnel to complete 
an in-person interview to assess delirium, pain, and satisfaction with anesthesia. Data will be recorded 
onto the Postoperative Day 3 Visit Form and entered into the online DMS. For patients discharged on 
postoperative day 1 or 2, this interview will be completed on the day of discharge in lieu of the 
postoperative day 1 or 2 interview described above. Hard copy forms will be stored in secure locked 
cabinets within offices controlled by study personnel and locked when not in use. 
 
• 
3D-CAM assessment (delirium) 
• 
Pain symptom questionnaire (average and worst pain over past 24 hours) 
• 
Postoperative mortality assessment 
• 
Anesthesia satisfaction questionnaire (satisfaction with anesthesia care) 
6.3.3 
Post-discharge medical record review 
Site CRCs will complete a detailed chart abstraction to assess intraoperative events and major 
postoperative adverse events occurring up to the date of discharge, death, or at postoperative day 30, 
whichever comes first. Chart abstractions will take place following discharge, death, or postoperative day 
30 within a timeframe to be determined by the PI and site personnel. Data will be recorded on the Medical 
Record Review Form and entered into the online DMS. Hard copy forms will be stored in secure locked 
cabinets within offices controlled by study personnel and locked when not in use. 
 
For each participating site, CCC staff at the University of Pennsylvania will over-read and re-abstract 
chart data for the first 3 randomized patients and additional charts as needed, as determined by the 
results of the initial chart review; for sites other than the University of Pennsylvania, charts will be 
photocopied and mailed via certified mail or scanned and emailed to the CCC. Sites will redact all 
personal identifying information prior to sending.  Data will be re-abstracted by CCC staff and entered into 
the DMS for comparison to the chart abstraction results from individual sites. Following abstraction, 
photocopied or printed scans of charts will be disposed of in a locked cabinet and shredded. Hard copy 
forms will be stored in secure locked cabinets within offices controlled by study personnel and locked 
when not in use. 
 
• 
Medical record review (Date of surgery; anesthesia and surgery start and stop times; surgical 
procedure performed; intraoperative data including but not limited to estimated blood loss; fluids 
and blood products administered in the OR; intraoperative blood pressure and oxygen saturation; 
ASA physical status classification; initial anesthetic type; intrathecal agents administered (for 
patients receiving spinal anesthesia); documented level of arousability; peripheral nerve blocks 
performed; benzodiazepines and intravenous opioids administered in the OR; intraoperative 
adverse events including but not limited to cardiac arrest requiring CPR, anaphylaxis, aspiration; 

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postoperative adverse events including but not limited to bleeding requiring transfusion; 
myocardial infarction, congestive heart failure, stroke or transient ischemic attack,  pneumonia, 
urinary tract infection, wound infection, thromboembolic complications, unplanned intubation, 
prolonged mechanical ventilation, acute renal failure, cardiac arrest requiring CPR or 
defibrillation, epidural hematoma requiring surgical intervention, new permanent paralysis of the 
lower extremities, return to the operating room, inpatient falls, unplanned postoperative 
mechanical ventilation; additional surgeries performed; ICU utilization discharge destination; date 
of first ambulation; discharge status.)  
 
Where relevant, data will also be abstracted from the chart regarding the timing and/or severity of specific 
complications or events, as well as causes of specific events as documented in the medical record. 
6.3.4 
60-day, 180-day, and 365-day interviews 
Interviews for all patients will occur at approximately 60 days, 180 days, and 365 days after 
randomization. Interviews will be conducted centrally via telephone by trained CCC staff overseen by the 
study PI.  
 
CCC staff will call patients and/or proxies using contact information obtained at the time of the baseline 
interview within the following assessment windows: between 30 and 90 days after randomization (for the 
60-day interview); between 135 and 225 days after randomization (for the 180-day interview); and 
between 305 and 425 days after randomization (for the 365 day interview). The listings of patients due for 
follow-up will be generated by the study DCC and will be provided by the DCC to CCC personnel.  
 
Patients or their proxies will complete a structured telephone interview. Additionally, where patients are 
providing their own responses to interview items, we will also conduct a brief interview with a proxy 
respondent (if available) during the same call to verify the patient’s response regarding the primary 
outcome (i.e. degree of independence in ambulation).  A proxy respondent or secondary contact 
(previously provided by the patient) may also be contacted regarding the primary outcome should the 
patient be unable to provide his/her own response at the time of the follow-up. 
 
Participants who are unavailable at the time of the initial attempted contact will receive follow-up calls up 
to five to seven times weekly at variable times over the course of the assessment window; for non-
respondents, CCC staff will place calls to secondary contacts and reminders will be sent via secure e-mail 
and registered mail where feasible to minimize loss to follow-up.  For patients who cannot be reached 
within the assessment window for a particular interview, a letter approved by the IRB may be sent to the 
patient’s and proxy’s address providing CCC contact information and requesting phone contact with the 
patient and/or the proxy with a recommended window of contact.  This process will be repeated once 
every 30 days until either contact is made, a total of 4 letters are sent, or 425 days have passed since the 
date of randomization. All letters will be sent using a method that confirms delivery, either United States 
Postal Service, FedEx, or a similar carrier. Choice of carrier will be at the discretion of the PI. 
 
Calls will be made during business and evening hours of the patient’s residence. Where feasible, calls will 
be audio-recorded with permission for quality assurance; audio files will be kept in digital format on media 
that will be stored in secure, locked cabinets within offices controlled by the PI when not in use. Audio 
files will be accessed for random auditing of interviews and additionally as needed for quality control by 
the study PI and CCC staff. When possible, the results of the follow-up interviews will be entered directly 
into the electronic study DMS via the 60, 180, and 365 Day Follow-up Forms and the 60 Day Proxy 
Interview for the Primary Outcome Form. Hard copy forms will be used in the event that study staff are 
unable to access the online DMS; data will be abstracted from hard copy forms by study staff into the 
online DMS and stored in secure locked cabinets within offices that are controlled by study personnel and 
locked when not in use. 
 
• 
Ambulation independence questionnaire 
• 
Proxy ambulation independence questionnaire. 
• 
Pain symptom questionnaire (pain with ambulation and at rest; pain medication usage) 

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Figure 3. Sample sizes required for 80% power to detect a 
difference in the primary endpoint for patients randomized to 
spinal vs general anesthesia across a range of effect sizes. 
• 
Mortality assessment 
• 
Residential status assessment (i.e. residence at home, in a nursing home, etc…) 
• 
WHODAS 2.0 (overall health and disability) 
• 
Short Blessed Test (cognition) 
6.3.5 
National death index search 
A National Death Index (NDI) search will be performed during the final year of the study to obtain survival 
and cause-of-death data on all patients enrolled up to that point. The following patient-level variables will 
be submitted to the NDI to complete this search where available: first and last name, middle initial, social 
security number (complete or last 4 digits), month, day, and year of birth, race, sex, and state of 
residence. These data will be mailed to the NDI on an encrypted, password-protected CD-ROM or other 
appropriate digital media via certified overnight mail. No more than one individual will have access to 
transmitted data, and all transmitted patient-level data will be destroyed following the completion of the 
NDI search; no patient-level data will be retained at the CDC following completion of the NDI search. 
 
NDI data will be transmitted from the US CDC’s National Center for Health Statistics via password-
protected encrypted CD-ROM or similar media to the CRCU or the CCC or DCC PI via overnight mail, 
and will be transferred directly to the DMS by CRCU staff. Following data transfer, the original NDI disk 
will be stored.  Hard copy forms will be stored in a secure locked cabinet within offices controlled by study 
personnel and locked when not in use. 
 
• 
All-cause mortality 
• 
Cause of death 
6.3.6 
Medicare claims linkage 
Permission will be sought from randomized patients who are Medicare beneficiaries to perform linkage of 
study data to Medicare claims once such claims are available and additional funding can be secured. 
Funding from the present grant will not be used to fund this linkage or related analyses; methods for data 
linkage, data management and analysis will be governed by a separate protocol. 
6.3.7 
End of Study Interview 
Either the 180 day interview or the 365 day interview may represent the end of study interview depending 
on the timing of enrollment into the REGAIN trial and the availability of funding at the time of the 
scheduled interview.  
6.4 
Rescue Therapy 
Management of all intraoperative events will be at the discretion of the treating anesthesiologist and 
surgeon based on clinical expertise and standard 
care.  
6.5 
Unscheduled Visits 
No unscheduled visits will take place over the course 
of the study. 
6.6 
Subject Withdrawal  
Subjects may withdraw from the study at any time 
without impact to their care. They may also be 
discontinued from the study at the discretion of the 
site Clinical Director for lack of adherence to study 
procedures or visit schedules, AEs, due to family 
preferences, or at the discretion of the treating 
physician.  The site Clinical Director may also 

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withdraw subjects for administrative reasons. The date of withdrawal and any known reasons for 
withdrawal will be documented on the Subject Withdrawal Form and entered into the online study DMS.  
6.6.1 
Data Collection and Follow-up for Withdrawn Subjects 
No attempts will be made to collect additional follow-up data from participants who have withdrawn 
consent. 
7 
Statistical Plan 
Statistical analyses using datasets including identifiable patient data will be carried out on secure servers 
maintained by the Penn Clinical Research Computing Unit (see below); analyses will use standard 
statistical software such as R, SAS, and Stata.  
7.1 
Primary Endpoint 
The primary endpoint for this study will be death or inability to walk 10 feet or across a room without 
human assistance at approximately 60 days after randomization. This endpoint will be analyzed as a 
binary outcome. 
7.2 
Secondary Endpoints 
Secondary endpoints include both binary and continuous outcomes and will include but not be limited to: 
• 
Inability to walk 10 feet or across a room without human assistance at 180 and 365 days 
• 
Mortality (in-hospital, 60-day, 180-day, 365-day) 
• 
Need for assistive devices for ambulation (60-day, 180-day, 365-day) 
• 
All cause mortality (via NDI search) 
• 
Cause of death (via NDI search) 
• 
SBT score (60-day, 180-day, 365-day) 
• 
WHODAS 2.0 score (60-day, 180-day, 365-day) 
• 
Pain scores at rest and with movement (in-hospital, 60-day, 180-day, 365-day) 
• 
New utilization of prescription pain medications (in-hospital, 60-day, 180-day, 365 day) 
• 
Satisfaction with anesthesia care (in-hospital) 
• 
Delirium (in-hospital), including presence of delirium and delirium severity score 
• 
Major postoperative morbidity, including selected inpatient adverse events (in-hospital) 
7.3 
Sample Size and Power Determination 
Power and sample size. Our sample size calculation is based on the primary outcome (inability to walk or 
death at 60 days). Figure 3 shows sample size requirements for 80% power to detect a range of relative 
risks for this outcome between two randomized arms (α=0.05). The middle line shows the sample sizes 
required assuming a 34.2% rate of the primary outcome in the general anesthesia arm, (the rate 
observed in the 2,100-patient FOCUS trial);78 the upper and lower lines show required sample sizes 
based on the FOCUS 95% confidence limits for this outcome (i.e., 32.1% and 36.3%).  Our calculations 
assume a 5% loss to follow-up and a 5% crossover rate from spinal to general anesthesia.102, 103 
 
Assuming that the primary outcome occurs in 34.2% of general anesthesia patients our planned sample 
will provide 80% power to detect a relative risk of 0.78 for this outcome among patients receiving spinal 
versus general anesthesia and 90% power to detect a relative risk of 0.76. These effect sizes fall within 
the 95% confidence intervals for the effect of regional anesthesia on in-hospital mortality, pulmonary 
complications and postoperative confusion seen in prior retrospective studies29, 52 and randomized trials,26 
and are of sufficient magnitude to justify changes in practice and policy; while smaller differences could 
exist, effects below this level would be unlikely by themselves to justify large-scale changes in anesthesia 
care. Additional power calculations indicate that the planned sample will have adequate power to detect 
clinically meaningful differences in secondary study endpoints, including survival, delirium, pain, overall 
health and disability, and changes in cognitive status over time.  

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7.4 
Statistical Methods 
7.4.1 
Baseline Data 
The distributions of analysis variables will be examined using tabular and graphical methods, such as 
histograms and boxplots, to identify outliers that may represent errors not captured by automated 
processes. Such values will be verified or corrected prior to analysis. Measures will be summarized using 
appropriate descriptive statistics, including means and standard deviations, medians, ranges, and 
proportions. Analyses will use commercial computing packages including SAS, Stata, and R.  
7.4.2 
Efficacy Analysis  
 
All hypothesis tests will use a two-sided significance level (Type I error) of α = 0.05. As the primary 
outcome (inability to walk or death at approximately 60 days) is binary, the primary analysis will compare 
the proportions of patients meeting this outcome between groups randomized to spinal versus general 
anesthesia using chi-square tests, stratified by site, gender, and fracture type. Secondary analyses will 
use multivariable logistic regression models to control for other covariates such as age, race, and 
baseline WHODAS 2.0 score. Similar approaches will be used to evaluate binary secondary outcomes, 
including mortality at approximately 180 and 365 days, return to the prior residence at approximately 180 
and 365 days, occurrence of any major in-hospital complication, and binary pain, health/disability, and 
satisfaction endpoints.  
 
For continuous endpoints such as overall WHODAS 2.0 score we will use analysis of variance (ANOVA) 
adjusted for age, gender, and fracture type. Further adjusted analysis will be performed using linear 
regression adjusting for potential covariate effects; normalization transformation may be considered if the 
normality assumption is violated.  Standard regression diagnostics, including residual plots, and influence 
statistics will be used to identify outliers and examine the assumptions. We will provide in the analyses, in 
addition to tests of significance, confidence intervals for treatment effect, and various approaches to 
assess the robustness of the estimates to nuisance factors. (IR-6)  Other continuous endpoints such as 
pain and satisfaction scores will be analyzed using similar methods. 
 
Heterogeneity of Treatment Effects (HTE). For the primary outcome, analyses of treatment effects within 
pre-specified subgroups defined by: (1) fracture type; (2) gender; (3) pre-fracture level of overall disability; 
(4) pre-fracture disability in locomotion; (5) age category; (6) baseline cognitive status; (7) surgical 
procedure; (8) baseline pulmonary disease; (9) baseline cardiac disease; (10) nursing home versus non-
nursing home residence prior to fracture. Subgroup comparisons will be conducted if any treatment-
covariate interactions are at least suggestive (p<0.20; HT-3) and sample sizes and numbers of events 
within these subgroups are sufficient for analysis. Secondary outcomes also will be assessed for HTE. If 
there is a treatment difference together with evidence of heterogeneity, the relevant covariates and 
interactions will be added to the relevant regression models to see if an overall difference still exists. 
Additional pre-specified subgroup analyses will be performed for in-hospital delirium outcomes among 
patients for whom assessors were and were not blinded to treatment assignment. 
7.4.3 
Interim Analysis  
As discussed in Section 8.6 below (“Stopping Rules”), we do not plan to perform interim analyses to test 
for superiority or inferiority of either study regimen with regard to any of the primary or secondary study 
outcomes. 
7.4.4 
Safety Analysis  
Randomized subjects will have information collected on defined safety endpoints as described above in 
Section 4.2.3. (“Primary Safety Endpoints”) The overall study safety analysis will assess the rate of all 
combined safety as well as the rates of individual safety events. Reviews of safety data will be performed 
after the enrollment of the first 100 patients, and after accrual of 25%, 50%, and 75% of the study sample. 

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Reviews of safety data will be carried out by the DSMB, the PI, and other appropriate CCC and DCC 
leadership. 
7.5 
Subject Population(s) for Analysis 
 
• All-randomized population: The main analysis for the primary outcome will include the all-
randomized population; this population will also be used for the main analysis of selected 
secondary outcomes including mortality, major intraoperative and postoperative adverse events, 
WHODAS 2.0 score, SBT score, pain at motion and at rest, satisfaction with care, location of 
residence, and severity of delirium as assessed by 3D-CAM.  
• Per-protocol population: Secondary analyses for all of the above named-variables will restrict the 
population under consideration to patients who received the initial anesthesia type (i.e. spinal or 
general anesthesia) to which they were randomized 
• Randomized patients without delirium at baseline: Patients for whom delirium is present prior to 
randomization will not be eligible for inclusion in analyses that examine a binary endpoint 
indicating the presence or absence of new postoperative delirium. As such, this analysis will 
include randomized patients without a baseline diagnosis of delirium prior to randomization. 
• Randomized patients living at home prior to fracture: Patients not living at home prior to fracture 
will not be eligible for inclusion in analyses that examine the percentage returning to home at 60, 
180, and 365 days. As such, this analysis will include only randomized patients living at home 
prior to fracture. 
• Randomized patients not requiring assistive devices for ambulation at baseline: Patients for whom 
assistive devices were required for ambulation prior to fracture will not be eligible for inclusion in 
analyses that examine binary endpoints indicating whether such devices are required for 
ambulation after fracture. As such, this analysis will include randomized patients without a 
requirement for assistive devices for ambulation prior to fracture. 
• Randomized patients without cognitive dysfunction at baseline: Patients for whom cognitive 
dysfunction is present prior to randomization will not be eligible for inclusion in analyses that 
examine a binary endpoint indicating the presence or absence of new cognitive dysfunction at 60, 
180, or 365 days. As such, this analysis will include randomized patients without cognitive 
dysfunction, as defined by SBT score, prior to randomization. 
• Randomized patients not requiring prescription pain medicines at baseline: Patients for whom 
prescription pain medicines are required for pain control prior to fracture will not be eligible for 
inclusion in analyses that examine a binary endpoint indicating the presence or absence of new 
need for prescription pain medicines at 60, 180, or 365 days. As such, this analysis will exclude 
randomized patients reporting use of prescription pain medicines prior to fracture. 
• Additional outcome-specific subpopulations: Additional sub-populations will be defined at the time 
of analysis as required for appropriate secondary analysis of key study endpoints. 
8 
Safety and Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.   
8.1.2 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 
• fatal 

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• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious will be regarded as non-serious 
adverse events.  
8.2 
Recording of Adverse Events 
At each contact with the subject and at the time of hospital discharge, study personnel will seek 
information on adverse events by specific questioning and, as appropriate, by examination and medical 
record review.  Information on all adverse events will be recorded immediately in the source document, 
and also in the appropriate adverse event module of the case report form (CRF).  All clearly related signs, 
symptoms, and abnormal diagnostic procedures results should recorded in the source document, though 
should be grouped under one diagnosis. 
 
All adverse events identified during the study period will be recorded.  The clinical course of each event 
will be followed until resolution, stabilization, or until it has been determined that the study intervention or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
will be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study intervention or study participation will be 
recorded and reported immediately. 
8.3 
Relationship of AE to Study  
The relationship of each adverse event to the study procedures will be determined by an adverse event 
review committee as being definitely related, probably related, possibly related, unlikely to be related or 
unrelated to the study intervention or other study procedures. For purposes of making determinations of 
relatedness, members of the safety monitoring committee may have access as needed to relevant 
intraoperative, preoperative, and postoperative data; additional identifying data not required for 
determinations of relatedness will be suppressed. If needed for determinations of relatedness, unblinding 
with regards to treatment assignment will be permitted at the level of the individual case. The safety 
monitoring committee will include 2-3 members and will be led by the PI or their designate.  
8.4 
Reporting of Adverse Events and Unanticipated Problems 
At each contact with each subject, the study staff will seek information on adverse events by specific 
questioning and, as appropriate, by examination. Information on all adverse events will be recorded 
immediately in appropriate case report forms. All clearly related signs, symptoms, and abnormal 
diagnostic procedure results will be documented. 
 
Initial reports will be submitted as narratives to the PI office; the minimum necessary information to be 
provided at the time of the initial report will include: 
 

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• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study intervention was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study intervention 
 
 
Additionally all other events (unanticipated problems, adverse reactions, unanticipated adverse device 
effects and subject complaints  will be recorded and reported with respect to institutional and federal 
policies. 
 
8.4.1 
Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes the site 
Clinical Director’s or PI’s assessment of the event, a follow-up report including all relevant new or 
reassessed information (e.g., concomitant medication, medical history) will be submitted to the IRB. The 
Clinical Director will be responsible for ensuring that all SAE are followed until either resolved or stable.  
8.4.2 
Investigator reporting: notifying the study sponsor 
Any study-related unanticipated problem posing risk to subjects or others, and any type of serious 
adverse event, will be reported to the Clinical Coordinating Center by telephone within 24 hours of the 
event.  To report such events, a Serious Adverse Event (SAE) form will be completed by the site Clinical 
Director and submitted to the study sponsor within 24 hours.  The investigator will keep a copy of this 
SAE form on file at the study site.  Report serious adverse events by phone and/or email to: 
 
Mark David Neuman, M.D., M.Sc. 
Study Director, REGAIN Trial 
University of Pennsylvania 
308 Blockley Hall 
423 Guardian Drive 
Philadelphia, PA 19104 
Office: (215) 746-7468 
Cell: (215) 760-7471 
Email: mark.neuman@uphs.upenn.edu 
 
Within the following 48 hours, the site Clinical Director will provide further information on the serious 
adverse event or the unanticipated problem in the form of a written narrative.  This will include a copy of 
the completed Serious Adverse Event form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing serious adverse events will be 
provided promptly to the study sponsor. 
8.4.3 
Investigator Reporting: Notifying the IRB  
Reports of the following problems will be reported to the Penn IRB and other appropriate site IRBs within 
10 working days from the time the investigator becomes aware of the event: 
Any adverse event that occurs any time during or after the research study, which in the opinion of 
the principal investigator is: 
• Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document and 
other relevant sources of information, such as product labeling and package inserts.) 
AND 

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• Related to the research procedures (An event is “related to the research procedures” if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be caused 
by the research procedures.) 
The above is required regardless of whether the event is serious or non-serious, on-site or off-site.  
 
Protocol Deviations 
Any protocol deviations initiated without Sponsor and/or Penn IRB approval that may affect the scientific 
soundness of the study, or affect the rights, safety, or welfare of study subjects, will be reported to the 
Sponsor and to the investigator’s IRB as soon as a possible, but no later than 5 working days of the 
protocol deviation. 
Reporting Process 
Unanticipated problems as defined above will be reported to the Penn IRB using the appropriate CRF or 
as a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation). 
Copies of each report and documentation of IRB notification and receipt will be kept in the PI’s office. 
Other Reportable events: 
The following events will also be reported to the Penn IRB: 
• Any adverse event that would cause the modification of the protocol or informed consent form, or 
would prompt other action by the IRB to assure protection of human subjects. 
• Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency, such as: 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected. 
– A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot 
be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased risk, or 
affects the rights or welfare of subjects. 
8.4.4 
Sponsor reporting: Notifying participating investigators  
Investigators at participating sites will be notified by the CCC of any of the above adverse events or 
findings to participating investigators based on the same timing as required for IRB reporting described 
above. 
8.5 
Unblinding Procedures 
Where feasible based on staff availability and site resources, some sites may conduct blinded 
assessments for in-hospital outcomes. As at least one study team member at each site will be unblinded 
to treatment assignment, no unblinding procedures are proposed for the REGAIN trial at the level of the 
individual site. 
 

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Assessments of aggregate data related to patient characteristics and study outcomes will occur in a 
blinded fashion such that investigators cannot determine subject randomization assignment; unblinding at 
the level of the individual patient will be permitted as needed for making determinations of relatedness for 
adverse events (see section 8.3 above). Unblinding with regard to randomization assignment for the full 
study sample will occur at the end of study enrollment, or prior to that point as per the determination of 
the Principal Investigator based on the input of the DSMB and/or the study sponsor.   
8.6 
Stopping Rules 
Spinal and general anesthesia are universally accepted as standard care practices for hip fracture 
surgery. There is no known or expected difference in overall risk or safety to patients between these two 
approaches. For this reason, we do not propose formal stopping rules based on demonstrated superiority 
or inferiority of either treatment with regard to the primary or secondary endpoints. 
8.7 
Medical Monitoring 
The site Clinical Director will oversee the safety of the study at his/her site.  This safety monitoring will 
include careful assessment and appropriate reporting of adverse events as noted above.  
8.7.1 
Data and Safety Monitoring Plan 
 
Data and safety monitoring will be the responsibility of the Study Director/PI (Neuman), the study 
Biostatistician, site Clinical Directors, and a Data Safety Monitoring Board (DSMB). 
 
Data Safety Monitoring Board  
The DSMB roles, responsibilities, and operating procedures are defined by the REGAIN DSMB Charter; 
this charter will be initially drafted by the REGAIN CCC and DCC leads and will be modified and ratified 
by the DSMB prior to the initiation of subject recruitment. The DSMB will be composed of 5-7 patients, 
physicians, and investigators who are not involved in the conduct of the study in any way; who do not 
have subordinate relationships with the PI or any member of the study team; and who are qualified 
through other experience or training  to review the clinical and research data from the study. The 
selection of the DSMB according to these criteria will enable the protection of subjects and the integrity of 
the data through a group which is sufficiently objective yet clinically qualified to fulfill the role. The DSMB 
will be unblinded to subject treatment assignment. 
DSMB Standard Operating Procedures 
The DSMB will be identified by the PI (Neuman), the Biostatistician, and/or the funding sponsor, and will 
be invited to serve in this capacity until the conclusion of the study. The DSMB will meet prior to the 
initiation of enrollment to review the protocol, the DSMB charter and reporting templates. Subsequent 
DSMB meetings will review the protocol, safety and adverse event data, available outcome data, and 
information on subject accrual and protocol compliance; these meetings will take place within 1 month of 
the time of planned interim safety event analyses, which will occur after randomization of the first 100 
patients and after randomization of ¼, ½, and ¾ of the total planned randomized sample of 1,600. The 
study team will prepare all documents and reports in such a manner as to allow complete understanding 
of the study and the results, and will provide the DSMB with the materials in advance of their meeting 
date, which will scheduled by the DSMB at their convenience. As appropriate, the DSMB may consider 
recommending for protocol modifications or revisions to the informed consent document if problems with 
enrollment, accrual, or protocol implementation are identified, or if identified safety events are noted to 
occur at a rate beyond that which would be expected to occur in the course of standard care based on 
available research and clinical experience. 
 
Study enrollment and follow up visits will continue during the period of DSMB review and will proceed until 
study completion unless the sponsor or the PI determines stopping the study is necessary prior to the 
conclusion of the study.  

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9 
Study Administration, Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial as appropriate and applicable to the study. 
9.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. Data will be 
collected using CRFs developed specifically for the REGAIN trial as well as standardized instruments. 
Forms will be made available for completion on paper as well as directly into the electronic data 
management system. Data will be collected from in-person and telephone interviews with study 
participants and their proxy, and from clinical information contained in medical records. When possible 
during the follow-up phase of telephone interviewing, data collected by the CCC will be entered directly 
into the electronic data management system. Hard copy CRFs will be available in case of DMS 
inaccessibility.  
9.4 
Data Collection and Management  
Data Collection Procedures. All data collection procedures for the REGAIN Trial are outlined above in 
Section 6 (“Study Procedures”) 
 
Data management procedures.  The Data Coordinating Center (DCC) at the University of Pennsylvania 
will develop a data management system for the collection, validation, storage and management of trial 
data. The data management system will use a combination of tools to perform the following study 
functions: 
 
• 
Subject tracking – to monitor screening and enrollment and produce subject visit schedules  
• 
Eligibility determination and randomization - to evaluate screening data to determine eligibility and 
randomize subjects according to the randomization schema provided by the Biostatistician 
• 
Comprehensive data collection modules to accommodate all types of trial data 
Data management system.  All research data for this trial will be stored in an electronic database that is 
managed by the Clinical Research Computing Unit (CRCU) of the University of Pennsylvania Center for 

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Clinical Epidemiology and Biostatistics (CCEB). The database will be hosted on secure computing 
servers and will be restricted to only those individuals who are authorized to work on the trial. Individual 
user accounts with passwords will be used to restrict access to the database. Specific privilege 
assignments within the database will also be employed to limit the types of functions that authorized 
users can perform to those functions that are appropriate for their role in the trial. Additional measures to 
prevent unauthorized external access to the database environment will be employed using network 
firewall technologies. 
 
The DMS will exist within an appropriate database structure to support the requirements of the DMS and 
to promote data security and integrity. Electronic audit trails of changes to database contents will be 
incorporated into the design and will capture and record those changes automatically. In addition to the 
trial database where actual results will be maintained, a development database will be created. The 
development database is a working environment that facilitates the development, testing, troubleshooting, 
enhancement, and training for the DMS without adversely affecting the integrity of the collected project 
data. 
 
CRCU servers exist within highly secure computing environments of the CCEB that are the responsibility 
of the Penn Medicine Academic Computing Services group. This group focuses on providing hardware 
and software services, systems administration, business continuity, and security services to research 
projects within the CCEB and other departments in Penn Medicine.  
 
Data Security Measures: The research computing environment has a security component required due to 
HIPAA; federal, state, and research compliance regulations; and CCEB best practices for safeguarding 
research data. The CCEB secures its logical network using virtual private network (VPN) protocols and 
network address translation (NAT) protocols layered on top of the single logical virtual local area network 
(VLAN). The VPN protocols provide encrypted “data in motion” protections and “fire-walled” connections 
between each of the physical network segments of the logical network. Applying VPN/VLAN encrypted 
connections allow all internal CCEB data to “tunnel through” and traverse the University’s physical 
networks as needed, while maintaining security at the logical CCEB network level, thus ensuring the 
privacy of the CCEB data and the availability of the data to only CCEB managed resources and users.  
 
In addition to the VLAN and VPN technologies, the CCEB network utilizes the NAT protocols to provide 
private network addressing within the logical CCEB network. This additional precaution ensures that all 
network protocols running into or out of the logical CCEB network are essentially “proxy” connections that 
are only passed through one of several CCEB firewall devices. Providing a proxy service allows the 
CCEB to monitor, log and control all data and network protocols coming into and going out of its logical 
network.  
 
The physical building environment for supporting the computing environments required by the CRCU is 
co-located within a formal data center facility that is managed by University of Pennsylvania; Penn 
Medicine and Information Systems and Computing personnel. The data center also has uninterrupted 
power supply (UPS)/diesel subsystems to ensure that adequate and constant electrical power 
requirements are met at all times, even during prolonged power outages. The data center has secured 
and limited physical access and is constructed with walls and doors to prevent break-through efforts 
and/or illegal entry. 
 
Data entry. The CRCU will configure a remote data capture (RDC) module to allow remote data entry 
from the participating trial sites. The RDC module will be available to any computer with a persistent 
internet connection and will be run using standard web browser software. The data entry screens will look 
like the data collection forms as closely as possible to allow visual referencing during data entry, 
enhancing accuracy and efficiency. Data entry checks will be included in the entry screen designs where 
appropriate to limit the opportunity for erroneous entries due to mistyping. Such data entry checks would 
include value range comparisons, valid data type checks, required value checks, and skip pattern 
enforcement. This data entry module will be configured for single data entry. 
 

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NDI data will be transmitted from the US CDC’s National Center for Health Statistics to CRCU staff or to 
the DCC or CCC PI via password-protected encrypted CD-ROM or similar media by overnight mail, and 
will be loaded directly onto the DMS. Following data transfer, the original NDI disk will be stored in a 
locked safe or secure locked cabinet within the CRCU. 
 
Data Quality Module: The CRCU will configure a module to assess data entered in to the database in 
relation to a set of rules that describe expectations for those data items. This set of data validation rules 
will be defined by CRCU clinical data management personnel and the study PI and Biostatistician to 
identify data items that may have been collected incorrectly or entered into the database inaccurately. 
The module will run automatically to inspect all newly entered or modified data. Clinical site personnel will 
review the results of the data validation and take any required corrective action for invalid data. Queries 
will be recorded and tracked in the data quality module. Corrections identified for individual data items will 
be managed by the clinical sites. All changes made will be recorded in an electronic audit trail and 
documented using change control procedures. 
 
The DCC and CCC teams will establish specific training and certification procedures to ensure that all 
study personnel are well trained in the performance of study procedures, data collection and data entry 
processes 
 
A Manual of Procedures (MOP) will provide detailed instruction for the performance of screening, 
enrollment, randomization and follow-up procedures. The MOP will provide instruction in case report form 
completion, and use of the electronic data management system,  
 
Reports Module: The CRCU will develop a set of standard reports to clearly illustrate the results of trial 
recruitment efforts and study events, and to document any safety concerns that have occurred during the 
study.  Additional reports may be developed where regular feedback is desirable. Such additional reports 
may include data entry timeliness and data quality assessments. 
9.5 
Management of audio recordings of 60, 180, and 365 day interviews:  
All post-discharge telephone interviews will be audio-recorded with permission for quality assurance; 
audio files will be kept in digital format on removable media (e.g. Flash Drive, DVD-ROM) that will be 
stored in secure, locked cabinets within offices controlled by the PI when not in use. Audio files will be 
accessed for random auditing of interviews and additionally as needed for quality control by the study PI 
and CCC staff using PCs located within offices controlled by the PI. 
9.6 
Records retention 
All investigators will retain study essential documents for at least 7 years after the last subject completes 
the study, or longer if recommended by the IRB, the DSMB or another oversight organization within or 
outside the University of Pennsylvania. 
9.7 
Public access plan 
A complete, cleaned, de-identified copy of the final dataset used in conducting the final analyses will be 
made available within one year after completion of the study. The CRCU will remove any patient, site, or 
other sensitive information from the final database to make it suitable for scientific use. This includes 
removal of all Personal Health Information (PHI) and indirect identifiers that are not listed as PHI but 
could lead to “deductive disclosure” such as comment fields and site numbers. Study specific de-
identification methods will be documented in the final protocol. Documentation regarding the data and 
relevant study details will be provided.  This includes the annotated case report form (CRF); a text file 
outlining the structure, variables and contents of each dataset. The study documentation for this trial will 
include the final protocol, study procedures, data collection forms, descriptions of all variable recoding 
performed, and a list and links to all primary publications. Datasets and accompanying files will be 
available on request from the PI or DCC; key datasets will be archived as appropriate to ensure their 
long-term value and usability.  

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10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according a formal monitoring plan. The investigator will allocate adequate 
time for such monitoring activities.  The Investigator will also ensure that the monitor or other compliance 
or quality assurance reviewer is given access to all the above noted study-related documents and study 
related facilities, and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The PI will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.)  The investigator will ensure the capability for inspections of applicable study-related facilities. 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  
11.1 Risks 
 (1) Risk of Randomization. As treatments will be assigned randomly, the process of randomization will 
necessarily carry the associated risks and benefits of the specific type of anesthesia to be used here. 
Both anesthetic regimens to be used in this study are standard of care, with risks and benefits described 
below;  
 
(2) Anesthesia Regimens. Risks for participation in this study do not go beyond those risks typically 
associated with spinal or general anesthesia as used in routine care. Medications typically used for 
general and regional anesthesia (spinal block) are FDA approved to be used alone and in combination for 
anesthesia. Beyond the study consent, patients will also undergo standard procedural consent to discuss 
the risks and benefits of regional and general anesthesia as per the routine of the local hospital. Risks 
associated with spinal anesthesia: Occasionally, regional anesthesia does not provide sufficient pain 
relief. In these situations, he/she may receive general anesthesia or intravenous pain-relieving drugs to 
supplement regional anesthesia. The risks of regional anesthesia include, but are not limited to, low blood 
pressure, itching or allergic reactions to drugs, obstruction or cessation of breathing, headache, and very 
rarely temporary paralysis, nerve injury, infection or meningitis. Risks of general anesthesia include, but 
are not limited to, nausea and vomiting, awareness under anesthesia, damage to lips or teeth, sore 
throat, headache, eye injury or blindness, infection, transfusion reactions (including excessive bleeding 
and kidney damage), drug reactions (including rash, shock, and cardiac/respiratory arrest), blood clots, 
lung infections, loss of sensation or limb function, paralysis, stroke, or brain injury, heart failure or heart 
attack, and death. Patients will have been screened by both their surgical and anesthesia team for 
allergies to any medications including those commonly used for anesthesia and post operative pain 
control;  
 
(3) Confidentiality breaches. Risks of breaches of confidentiality are small but nonetheless possible. 
However, all possible efforts have been taken to ensure the security of study data and minimize the risks 
of accidental disclosure of identifiable data elements, as outlined below.  

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11.2 Benefits 
At present, insufficient evidence exists to characterize the comparative effectiveness of spinal versus 
general anesthesia for hip fracture surgery among older adults; if a relative difference in comparative 
effectiveness between these two modalities of anesthesia is found in the present study, the potential 
exists that direct benefits of participation could accrue to those patients randomized to a given study arm 
who may have otherwise received a different type of anesthesia. However, research participants may 
also receive no direct benefits from participation in this study. For individuals other than the study 
participants, the present study has substantial potential to yield benefits to individuals with hip fractures. 
As stated above, gaps in knowledge regarding the comparative effectiveness of regional versus general 
anesthesia for improving patient-centered outcomes after hip fracture currently limits efforts to improve 
quality in hip fracture care and has been identified as a key area for hip fracture research by a range of 
stakeholder groups. Our study will address these gaps in knowledge through the first adequately-powered 
prospective study to compare the impact of spinal vs general anesthesia for hip fracture surgery on 
patient-centered outcomes. Given the use of established and conventional anesthesia treatments in both 
arms of the study, and the potential for this study to benefit a large number of patients with hip fracture, 
we judge the risks to study subjects to be reasonable in relation to the anticipated benefits to research 
participants and others. 
11.3 Risk/Benefit Comparison.  
Based on the considerations listed above, the study could be considered greater than minimal risk to 
patients. However, the knowledge that may be gained from the present study may impact the care of over 
300,000 individuals in the US each year and 1.6 million worldwide. Hip fracture represents a critical public 
health concern for older individuals and their families; identification of evidence-based treatments that 
may improve functional and survival outcomes after hip fracture is critical for improving the quality of hip 
fracture care and reducing the massive burden of death and disability attributable to hip fracture. 
Moreover, decreasing the burden of disability associated with hip fractures may have positive effects on 
health care resource use among hip fracture patients. By comparing the effectiveness of two widely used 
approaches to anesthesia care for hip fracture surgery, the present study has the potential to yield a 
transformative impact on how hip fracture care is delivered in the US and other countries. Given these 
considerations, the risks to the study subjects, which will be fully disclosed, and managed and mitigated 
to the maximum extent possible through appropriate study procedures and supervision, are reasonable in 
relation to the importance of the knowledge that may result from this study. 
 
 
11.4 Informed Consent Process / HIPAA Authorization  
The site PI, the site Clinical Research Coordinator, or another member of the orthopedic or anesthesia 
team will obtain informed consent and HIPAA Authorization prior to randomization. The patient will learn 
about the purpose of the study, the study anesthesia regimens, and data collection procedures and timing 
at the time of informed consent. For consenting patients, a note will be written in the chart to indicate 
completion of consent.  
 
Some patients may be too sick or not competent to give permission to enter the study. In these cases, we 
will attempt to recruit the patient by seeking permission of the family or caregiver who is signing informed 
consent for the surgical procedure. We believe it is appropriate and ethical to recruit these patients into 
the trial because these patients are commonly treated with both general and spinal anesthesia in practice. 
Extrapolation of the results from a study excluding seriously ill or cognitively impaired patients may be 
unreliable so it is important that direct evidence be obtained by including such patients in the study. For 
subjects for whom proxy consent is initially obtained, but the patient regains the ability to control medical 
decisions for themselves by postoperative day 3 or the day of hospital discharge (whichever comes first), direct 
written consent will be obtained. For subjects who decline participation at this point, no further data will be 
collected; data collected prior to this point will be retained as per the data management and analysis plan 
outlined above. 
  
For otherwise eligible patients who decline participation, reasons for refusal will be documented. 

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12 Study Finances 
12.1 Funding Source 
This study is funded through a contract with the Patient Centered Outcomes Research Institute 
(Washington, DC) 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study. All University of 
Pennsylvania investigators will follow the applicable University conflict of interest policy(ies). 
12.3 Subject Stipends or Payments 
No stipends or payments will be provided to study subjects.  
13 Publication Plan 
The results of this study in whole or in part will be prepared and submitted for publication to professional 
meetings and/or journals in order to disseminate the information gleaned from this investigation. Subject 
data will be published in aggregate and will be deidentified prior to analysis in order to protect the 
confidentiality of study participants. 
 
The publication of study reports will be governed by the REGAIN Publication Policy, which will be 
developed by a committee to include the PI and selected other investigators. Policies on authorship will 
be determined by committee vote, and will be consistent with available standards and norms regarding 
authorship on scientific publications for multicenter randomized trials.  
 
 

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14 References 
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CONFIDENTIAL 
 
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Protocol #:  822632 
Protocol Title:  A Randomized Controlled Trial of Regional versus General Anesthesia for Promoting 
Independence after Hip Fracture (REGAIN Trial) 
PI:  Mark D. Neuman, MD, MSc 
 
 
Version No. 
Version Date 
Current Approved Protocol 
2.2 
August 22, 2015 
Amended Protocol 
2.3 
March 29, 2016 
 
 
SUMMARY OF CHANGES 
 
Title Page 
• Correction of typo on PI address. 
 
Page 14, Section 6.3.3:  Post-discharge medical record review 
• Added additional method for sending charts for re-abstraction.  This was included to provide sites 
with an option for a more efficient method of document transfer. 
• Clarified that charts sent to CCC will be de-identified by the site prior to sending  
 
Page 15, Section 6.3.4:  60-day, 180-day, and 365-day interviews 
• Added sentence regarding contacting proxy or secondary contact.  This was included to clarify that a 
subject’s proxy or secondary contact will be interviewed if the subject is unable to provide his/her 
own response. 
 
Page 28, Section 11.4:  Informed Consent Process/HIPAA Authorization 
• Deleted end of sentence.  This was removed because a separate consent and study protocol enabling 
the collection of more than a subject’s reason for refusal does not currently exist. 
 
Administrative Changes 
• Updated protocol version number and date throughout the document.