Improving Community Ambulation After Hip Fracture
Phase: NA
Conditions: Hip Fracture
Sponsor: University of Maryland, Baltimore

                                    
COMMUNITY AMBULATION FOLLOWING HIP FRACTURE 
PROTOCOL (Version 12.0) 
 
 
Summary of Modifications to Protocol Version 11.0 for Version 12.0 
 
 
Summary of Modifications to Protocol Version 10.0 for Version 11.0 
 
Summary of Modifications to Protocol Version 9.0 for Version 10.0 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 12.0 
(10/19/16) 
9.2, 10.4.9, 11.2, 12.1.8, Table 2 
Prior to Version 12.0 of the protocol, three strategies were used to address 
participants’ nutritional status: 1) Consultation with a study registered 
dietician (RD) at baseline for participants who are malnourished (Mini 
Nutritional Assessment-Short Form (MNA®-SF) score ≤7), at risk for 
malnutrition (MNA®-SF score 8-11), or with serum albumin ≤3.5 g/dl; 2) 
Consultation with a study RD if there is weight loss of 2% or more between 
weight assessments performed every four weeks in the course of the 
intervention visits, and 3) Referral for follow-up and/or medical evaluation 
for possible malnutrition if the MNA®-SF score at follow-up is ≤7.  
 
In Version 12.0, to streamline procedures, we eliminated the third strategy 
(MNA screening for malnutrition at follow-up). Identifying nutritional 
deficiencies at baseline (the first strategy) and monitoring weight loss 
throughout the intervention period (the second strategy) will be sufficient for 
addressing participants’ nutritional status.  
 
In the event that a weight measurement is not obtained at the last PT 
intervention visit, the participant’s weight at the 16-week follow-up 
assessment will be compared to his or her baseline weight and, if there has 
been weight loss of 5% or more, the clinical site principal investigator or 
clinical site clinician will review the participant’s weight trajectory, baseline 
body mass index, baseline MNA®-SF score, and registered dietician’s 
documentation and, if warranted based on clinical judgment, will refer the 
participant to a dietician or medical provider for follow-up of possible poor 
nutritional status. 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 11.0 
(8/26/16) 
 
1, 6.1, 8.1, 10, 11 
In order to conserve resources, we eliminated several secondary and tertiary 
outcome measures, while retaining measures needed for the assessment and 
adjudication of the primary outcome, to determine study eligibility, to ensure 
participant safety, to monitor adverse events, and to describe characteristics 
of the participant population. 
Version 11.0 
(8/26/16) 
9.2, 10.6.1, 11.3 
In order to conserve resources, we eliminated the collection of information 
on use of study-provided dietary supplements. However, procedures for drug 
accountability will remain unchanged.  
Version 11.0 
(8/26/16) 
 
15.6.2 
We expect that, by the time all the approvals for the change described above 
have been obtained, approximately 160 participants will have been 
randomized under the existing protocol. The power calculations have been 
revised accordingly for the secondary and tertiary outcome measures that 
will no longer be collected.  
Version 
(date) 
Section 
Brief Summary of Modification 

 
Summary of Modifications to Protocol Version 8.0 for Version 9.0 
 
Summary of Modifications to Protocol Version 7.0 for Version 8.0 
Version 10.0 
(6/7/16) 
 
All sections 
 
 
Prior to Version 10.0 of the protocol, follow-up assessment visits occurred 
16 weeks and 40 weeks from the date of randomization, telephone 
interviews were conducted every four weeks during the 40-week study 
period for a total of 10 telephone interviews, and participants received 
vitamin D, calcium, and multivitamin supplements for a total of 40 weeks. In 
order to conserve resources and preserve the primary outcome, the protocol 
was revised so that study participation of participants randomized after 
approval of Version 10.0 of the protocol will end after the 16-week follow-
up assessment. The wording of the protocol has been changed accordingly.  
Version 10.0 
(6/7/16) 
 
15.6.2 
We expect that, by the time all the approvals for the change described above 
have been obtained, approximately 150 participants will have been 
randomized under the existing protocol which includes follow-up to 40 
weeks post-randomization. The power calculations for some of the outcome 
variables have been revised accordingly. 
Version 10.0 
(6/7/16) 
 
16.7 
We changed "Monthly reports" to "Regular reports" in the section on study 
performance monitoring. This was done to accommodate a revised schedule 
of reports to the Steering Committee. 
Version 10.0 
(6/7/16) 
 
20 
Updates were made to the Study Team Roster. Dr. Anne Kenny is leaving 
the study and was removed from the study team roster. Dr. Yazeed 
Maghaydah will take her place as the clinical site clinician for the University 
of Connecticut Health Center clinical site. We also updated contact 
information for Dr. Ram Miller. 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 9.0 
(12/18/15) 
1, 6.1, 15.6.1, 15.6.2, Table 5 
The original target sample size was 150 per group. Because of recruitment 
difficulties, the DSMB approved a new target sample size of 105 per group. 
The target sample size was revised in several sections of the protocol and the 
power calculations with the new sample size were updated in section 15.6.1, 
section 15.6.2, and Table 5. As recommended by the DSMB, the revised 
power calculations were based on the rate of loss to follow-up and the rate of 
nonadherence observed among the first 88 study participants.   
Version 9.0 
(12/18/15) 
15.5, Table 4 
Due to the change in target sample size, the DSMB approved a change to the 
critical values used for the four remaining interim analyses. Changes were 
made to section 15.5 and Table 4 to reflect the revised plan.  
Version 9.0 
(12/18/15) 
15, 15.1, 15.6.1 
In version 8.0 of the protocol there was inconsistency with respect to the 
analysis plan for the primary outcome. In several sections it was stated that 
the primary outcome (community ambulation at 16 weeks) would be 
assessed using a two-sided 0.05-level test. However, the interim analysis 
plan (which specified the interim analyses and the final analysis) was to 
perform a one-sided 0.025-level test at each time point.  Therefore, we 
modified the proposal so that it consistently says that for the primary 
analysis we will use a one-sided 0.025-level test. 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 8.0 
(10/2/15) 
9.1 and 9.6 
Ideally participants will receive 2 intervention visits per week for 16 weeks 
post-randomization (32 visits total). Previously, missed visits were not 
replaced. In the proposed protocol, it will be possible for missed visits in a 
given week to be replaced by performing makeup visits in subsequent weeks 
(not to exceed 3 visits in any given week) as long as the visits are on non-
consecutive days. Furthermore, if the participant has not had 32 visits by the 
end of 16 weeks, we are allowing makeup visits to be performed during the 
subsequent two weeks to get as close as possible to the target of 32 visits. 
The purpose of this modification is to increase intervention adherence.   

 
Summary of Modifications to Protocol Version 6.0 for Version 7.0 
 
Summary of Modifications to Protocol Version 5.0.1 for Version 6.0 
Version 8.0 
(10/2/15) 
1, 9.2, 10.4.9, 12.1.7, and Table 
2 
In the previous protocol participants who were at risk of malnutrition and 
those who were malnourished, based on the Mini Nutritional Assessment-
Short Form (MNA®-SF) score and serum albumin level, received an in-
person visit from a registered dietician (RD). However, it was found that 
many participants in the at-risk group did not require an in-person visit. 
Therefore, in the proposed protocol, participants in the at-risk group based 
MNA®-SF score and with a normal serum albumin level will receive a 
phone call from the RD and will only receive a follow-up in-person visit if 
the RD believes it is necessary.  
Version 8.0 
(10/2/15) 
11.5, 15.1 
The protocol was revised to reflect changes in the way adjudication will be 
performed. In the proposed version, all three adjudicators will discuss the 
case if the two assigned adjudicators do not reach consensus. The three 
adjudicators will vote on the case if they are unable to reach consensus. 
Also, cases where the Six-Minute Walk Test was administered but not 
according to protocol (e.g., using a walking course of less than 10 m) will 
now be submitted for adjudication.  
Version 
(date) 
Section 
Brief Summary of Modification 
Version 7.0 
(5/5/15) 
1, 3, 6, 7, 8, 11.4, and 12.2  
In the previous protocol, recruitment of hip fracture patients was limited to 
acute care hospitals.  In this version of the protocol, other mechanisms of 
recruitment have been added in order to supplement efforts in the acute care 
hospitals. In addition to augmenting the pool of potentially eligible patients, 
these approaches will allow us to identify patients who have already 
received a preliminary level of pre-screening and who have a higher 
probability of participation than the unselected hip fracture patients who are 
approached for the study in the acute care hospitals.  The new recruitment 
strategies include screening at rehabilitation facilities, home care agencies, 
and other agencies that care for older persons after hip fracture; advertising 
via flyers, print and web postings, radio, and social media; and referral from 
clinicians (e.g., orthopedic surgeons, physical therapists).  
Version 
(date) 
Section 
Brief Summary of Modification 
Version 6.0 
(11/21/14) 
All sections 
In the previous protocol, participants received three intervention visits per 
week in the first eight weeks of the intervention and two intervention visits 
per week in the second eight weeks. In this version of the protocol, the 
frequency in the first eight weeks has been reduced to two times per week so 
that participants will receive two visits per week for all 16 weeks. The 
intensity and total duration of the interventions will not change and there is 
no evidence in the literature indicating that a frequency of three days per 
week is superior to two days per week for improving strength or function. 
Reducing the frequency may increase participation, may increase 
participants’ willingness to start the intervention earlier in the post-fracture 
period, and may improve adherence to the intervention schedule. Changes 
were made throughout the protocol to reflect the reduction in the total 
number of intervention visits from 40 to 32. 
Version 6.0 
(11/21/14) 
All sections 
Changes were made throughout the protocol to reflect revisions made to the 
inclusion and exclusion criteria. 
Version 6.0 
(11/21/14) 
All sections 
We have removed references to the appendices throughout the protocol and 
removed Section 22 (Supplements/Appendix). Appendices provided with the 
original protocol submission represented draft documents and are no longer 
current, as these items continue to be modified to meet the operational needs 
of the study.   

 
Summary of Modifications to Protocol Version 5.0 for Version 5.0.1 
 
Summary of Modifications to Protocol Version 4.0.1 for Version 5.0 
Version 6.0 
(11/21/14) 
7.2 (criterion 1.1) 
We have removed the ICD codes from this criterion.  The operational 
definition of hip fracture diagnosis is not based on ICD codes since they are 
not available at the time of screening.   
Version 6.0 
(11/21/14) 
7.2 (criteria 1.3 and 1.6) 
Unilateral hip fracture and stress fracture were deleted as eligibility criteria 
since patients with these types of fractures can safely perform and can 
benefit from the study interventions. 
Version 6.0 
(11/21/14) 
7.2 (criterion 1.7) 
Orthopedic surgeon permission to contact patient was deleted as a study-
wide exclusion criterion since this is not required at all sites.  
Version 6.0 
(11/21/14) 
7.3 (criterion 4.5) 
The interval between hospital admission and randomization was extended to 
26 weeks. This may help increase participation of people who need more 
time to complete usual home therapy before starting the study interventions. 
Version 6.0 
(11/21/14) 
7.3 (criteria 5.3-5.10, 5.12, 5.13, 
5.16, and 6.11-6.13) 
These 14 medical criteria were deleted as exclusions to avoid unnecessarily 
screening out patients who could safely perform the study interventions and 
benefit from them. Clinical site clinicians will review all potentially eligible 
patients to ensure that they can safely participate in the study.  
Version 6.0 
(11/21/14) 
7.3 (criterion 5.18) 
Severe lower extremity pain with ambulation was deleted as an exclusion 
criterion. Significant pain while walking will now be assessed during the 
baseline administration of the Six-Minute Walk Test (SMWT) (criterion 
6.10). 
Version 6.0 
(11/21/14) 
7.3 (criterion 6.10) 
This criterion has been revised to exclude patients who develop severe pain 
during the baseline SMWT. 
Version 6.0 
(11/21/14) 
7.3 (criterion 5.21) 
The exclusion criterion was revised to be specific to receiving physical 
therapy in a hospital or inpatient rehabilitation facility at the time of 
randomization. Patients receiving physical therapy at home will be eligible 
to begin the study interventions.   
Version 6.0 
(11/21/14) 
7.3 (criterion 6.7) 
This criterion was revised to exclude people who are not fully weight-
bearing on either the fractured or non-fractured leg at time of randomization. 
Version 6.0 
(11/21/14) 
Tables 1 and 2 
Tables 1 and 2 were removed in order to simplify the study protocol, as this 
information is already presented in the text. 
Version 6.0 
(11/21/14) 
8.2, 11.5, and Table 3 
We have added an out-of-window time interval in order to collect data for 
the 16-week follow-up visit earlier than the allowable window.  The 
additional out-of-window interval is 0-16 weeks post-randomization, which 
covers the period from the date of randomization to the earliest date for the 
16-week visit. Although assessment visits are always done as close as 
possible to the target date, this change will increase the probability of 
obtaining complete follow-up data, even for participants whose assessments 
are difficult to schedule.   
Version 6.0 
(11/21/14) 
15.1 
A few paragraphs were added describing the analysis to address the change 
in intervention frequency during the first eight weeks of the intervention 
from three times per week to twice per week. 
Version 6.0 
(11/21/14) 
15.1 
We modified the category for age at baseline from “65 to 84 years” to “60-
84 years” to reflect the current age eligibility criterion. 
Version 6.0 
(11/21/14) 
20 
Updates were made to the Study Team Roster. 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 5.0.1 
(5/14/14) 
7.3 (criterion 6.11) and Table 1 
Modified the criterion to remove the word “recent”, which was added in 
error in version 5.0. The correct wording of criterion 6.11 is "Total hip 
replacement or prior hip fracture on same side as study index hip fracture." 
The operationalization of criterion 6.11 has not changed. 
Version 
(date) 
Section 
Brief Summary of Modification 

 
Summary of Modifications to Protocol Version 4.0 for Version 4.0.1 
Version 5.0 
(4/17/14) 
All sections 
Changes were made throughout the protocol to capture revisions made to the 
inclusion and exclusion criteria. 
Version 5.0 
(4/17/14) 
7.2 (criterion 1.4)  
Eliminated the restriction for surgical fixation within seven days of 
admission. 
Version 5.0 
(4/17/14) 
7.2 (criterion 2.1) 
Lowered the age limit to 60 and older at time of randomization. 
Version 5.0 
(4/17/14) 
7.3 (criterion 4.5) 
 
Widened the randomization window to 0 to 20 weeks post admission (10± 
10 weeks). This will help maximize participation of people who receive a 
shorter duration of regular PT post hip fracture and of those who receive a 
longer duration of PT. 
Version 5.0 
(4/17/14) 
7.3 (criterion 5.4) 
Modified the BMI cutpoint to 17 and deleted the weight restriction due to 
some older hip fracture patients being of short stature.  
Version 5.0 
(4/17/14) 
7.3 (criterion 5.6) 
This criterion has been broken out into 3 separate items in order to allow for 
specific operationalization related to Parkinson’s Disease and for multiple 
sclerosis. 
Version 5.0 
(4/17/14) 
7.3 (criterion 5.13) 
Deleted this criterion since individuals with contractures will be captured 
with other criteria. 
Version 5.0 
(4/17/14) 
7.3 (criterion 5.20) 
Revised the criterion to be specific to receiving PT related to the hip fracture 
and removed OT since this should not interfere with the study. 
Version 5.0 
(4/17/14) 
7.3 (criteria 6.11-6.13) 
These three items were edited to capture recent surgeries and fractures of 
lower extremities to cover both the period prior to the hip fracture but also 
the period during screening for the study. 
Version 5.0 
(4/17/14) 
7.3 (criteria 7.1-7.3) 
Deleted these three items since they do not cause a safety risk for 
participating in the PT interventions. These items will be handled like 
history of kidney stones and participants will not receive calcium 
supplementation.   
Version 5.0 
(4/17/14) 
Table 1 
Table 1 was updated to reflect the edits to the criteria described above. 
Version 5.0 
(4/17/14) 
Table 3 
Phases 1-3 have been removed from Table 3 since we have widened the 
window for randomization to include 0-20 weeks.   
Version 
(date) 
Section 
Brief Summary of Modification 
Version 4.0.1 
(3/18/14) 
 
When we recently submitted protocol Version 4.0 for approval by the 
DSMB, we inadvertently submitted a version that was not final. We are now 
submitting Version 4.0.1 which includes some minor editorial modifications 
to the version that has already been approved. Edits are limited to the 
summary table below and Table 3. We apologize for the error.     
Version 4.0.1 
(3/18/14) 
All sections 
In consultation with our Clinical Direction Committee, we are allowing non-
physician medical professionals to perform study activities related to 
evaluating medical eligibility and safety and to reviewing RAEs, provided 
those professionals are permitted by law to function autonomously (not 
under physician supervision) in the jurisdiction and the institution in which 
the clinical site is located. This change will facilitate clinical sites’ access to 
appropriate clinicians who are available for time-sensitive study activities. 
“Clinical Site Physician” has been replaced with “Clinical Site Clinician” 
throughout the protocol. 
Version 4.0.1 
(3/18/14) 
Table 3 
The allowable interval for telephone interviews has been widened.  The 
telephone interview can occur up to one week before and up to three weeks 
after the target date. Table 3 has been modified to correctly reflect this time 
window. 

 
Summary of Modifications to Protocol Version 3.0 for Version 4.0 
 
Summary of Modifications to Protocol Version 2.1 for Version 3.0 
Version 4.0.1 
(3/18/14) 
8.2, 11.5, and Table 3 
We have added 2 out-of-window time intervals in order to collect data for 
the 16- and 40-week follow-up visits outside the allowable window.  The 
first out-of-window interval is 18-38 weeks post-randomization, which 
covers the period from the latest date for the 16-week visit to the earliest 
date for the 40-week visit. The second out-of-window interval is 44-68 
weeks post-randomization, which covers the period from the latest date for 
the 40-week visit to 24 weeks later. Although assessment visits are always 
done as close as possible to the target date, this change will increase the 
probability of obtaining complete follow-up data, even for participants 
whose assessments are difficult to schedule.   
Version 
(date) 
Section 
Brief Summary of Modification 
Version 4.0 
(2/28/14) 
All sections 
In consultation with our Clinical Direction Committee, we are allowing 
other medical professionals who can function autonomously (not under 
physician supervision) to perform study activities related to evaluating 
medical eligibility, safety and reviewing RAEs. This will vary according to 
state regulations. This will facilitate clinical sites’ access to appropriate 
clinicians who are available for time-sensitive activities. Clinical Site 
Physician has been replaced with Clinical Site Clinician throughout the 
protocol. 
Version 4.0 
(2/28/14) 
Executive Summary 
Changes were made to the text to clarify that nutritional counseling will be 
provided to ensure adequate nutrient intake of 1.2-1.5 g protein/kg body 
weight inclusive of a healthy diet. 
Version 4.0 
(2/28/14) 
Table 1 
Minor editorial changes were made to the eligibility criteria for clarity. 
Version 4.0 
(2/28/14) 
Table 3 
The allowable interval of telephone interviews has been widened.  The 
telephone interview can occur up to one week prior and up to three weeks 
after the target date.  
Version 4.0 
(2/28/14) 
10.3.3 
A minor editorial change has been made for clarity.  For the quadriceps 
strength test, the participant is not seated on the dynamometer; s/he is seated 
on the strength testing chair. 
Version 4.0 
(2/28/14) 
8.2, 11.5, and Table 3 
We have added 2 out-of-window time intervals in order to collect data for 
the 16- and 40-week follow-up visits beyond the allowable window without 
resulting in a protocol deviation.  The first out-of-window interval is 
between 18-38 weeks post-randomization, which covers the period from the 
maximum window for the 16-week visit to the minimum data for the 40-
week visit. The second out-of-window interval is up to 68 weeks post-
randomization (6 months after the maximum date for the 40-week visit).  
Version 4.0 
(2/28/14) 
13.2.3 and 13.4.3 
Updated text to include review of RAEs for ancillary studies to CAP.   
Version 4.0 
(2/28/14) 
13.6 and 13.6.1 
Minor editorial changes were made to expand the categories for RAE status 
and actions taken in response to the RAE. 
Version 4.0 
(2/28/14) 
20 
Updates made to the Study Team Roster. 
Version 
(date) 
Section 
Brief Summary of Modification 

 
Summary of Modifications to Protocol Version 1.3 for Version 2.0 and 2.1 
[Note: The edits made to protocol Version 2.1 originated from review by KAI] 
 
 
Summary of Modifications to Protocol Version 1.3 for Version 2.0 
Version 3.0 
(2/12/13) 
 
7.1, 7.5, 7.6, 17.2, Figure 2, and 
Table 1 
We have made minor changes to the plan for eligibility screening and 
obtaining informed consent so that it allows for diversity in the procedures 
that will be implemented in the three clinical sites, accounting for local 
differences in staffing and institutional infrastructure. Exclusion criteria 
collected from the medical chart will continue to be obtained at phase 1. 
However, assessment of exclusion criteria requiring patient self-report has 
been moved to phase 2. Each clinical site will follow specific procedures for 
obtaining appropriate HIPAA authorizations and informed consent as 
stipulated and approved by their local IRBs. 
Version 3.0 
(2/12/13) 
 
7.3 (criterion 4.2) 
Minor editorial changes were made to the eligibility criterion for clarity. 
Version 3.0 
(2/12/13) 
 
9.5.2 
Minor editorial changes were made to the schedule for treatment fidelity 
visits based on recommendation from the Intervention Monitor. 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 2.1 
(12/17/12) 
3.2.3 
The plan for distribution of the vitamins and supplements has been modified 
to be consistent with the MOP.  Each treatment kit contains five individual 
packs, numbered 1-5.  Packs 1-4 each contain a 4-week supply of vitamin 
D3, calcium, and a multivitamin. Pack 5 contains a 24-week supply that will 
be provided to participants at the conclusion of the 16-week intervention 
period.   
Version 2.1 
(12/17/12) 
6.2 
We added clarification that randomization will only be performed by 
appropriate unblinded study personnel who have received training and 
certification on randomization procedures, including the clinical site PI, 
clinical site coordinator, or other unblinded personnel not performing 
evaluations.  This is now consistent with the MOP.  Further clarification has 
also been added about blinding of interventionists to study outcomes and 
about restricting access to the participant binder which will contain sensitive 
information about treatment assignment.  
Version 2.1 
(12/17/12) 
6.4 
We added clarification that clinical site PIs and clinical site coordinators 
who are responsible for assigning work and assessing treatment fidelity for 
PTs in both groups are completely unblinded.  Only those who will perform 
evaluations (clinical site visits and telephone interviews) after randomization 
and the Independent Safety Monitor (ISM) will be blinded to treatment 
assignment. 
Version 2.1 
(12/17/12) 
9.2 
The section on the nutritional intervention has been revised to clarify that a 
participant who loses 2% or more body weight in a four-week period will 
receive another telephone consultation by the study RD, regardless of 
whether the participant is trying to lose weight.  Nutritional experts serving 
on the advisory committee providing Specialized Support for Exercise and 
Nutrition believe that loss of 2% or more body weight in this elderly 
population warrants follow-up from a registered dietician, who can 
determine whether weight loss was intentional.   
Version 2.1 
(12/17/12) 
13 and Figures 5b-5d 
Changes were made to this section to indicate that the responsibility for 
determining relatedness of RAEs will entirely be the responsibility of the 
independent safety monitor (ISM), who will remain blinded.  RAE reports 
and supporting documents sent to the ISM will be redacted to conceal 
treatment assignment. 
Version 
(date) 
Section 
Brief Summary of Modification 

Version 2.0 
(10/31/12) 
All sections 
Minor editorial changes and corrections were made throughout the document 
for clarity and consistency with the MOP.  These changes can be seen with 
Track Changes. All significant changes are summarized in the remaining 
sections of this table. 
Version 2.0 
(10/31/12) 
All sections 
Changes were made to the naming of the physical therapy interventions.  
“Shuttle Plus” is now PUSH.  “TENS Plus” is now PULSE. We wanted to 
use names for the interventions that did not include the device name and that 
would be more meaningful and easy for the participants to remember.  
Version 2.0 
(10/31/12) 
All sections 
In the original proposal, data capture, data management, and randomization 
were to be implemented by the Veterans Administration Cooperative Studies 
Program Coordinating Center (CSPCC) in Perry Point, MD. However, 
because of administrative and regulatory changes at the CSPCC, it was 
necessary to identify a different data group to handle these tasks. We have 
contracted with Axio Research, LLC (Seattle, WA) to provide data services. 
Throughout the current protocol version, “CSPCC” has been changed to 
“Axio Research, LLC” or “Axio” to reflect this change. References to 
DataFax (the data capture system that was proposed in the original protocol) 
have been removed to reflect the change to paper- and web-based data entry. 
Version 2.0 
(10/31/12) 
All sections 
The name of the administrative database clinical sites will use to facilitate 
study management activities was changed from “tracking database” to 
“study management database” to more accurately reflect its role.  
Version 2.0 
(10/31/12) 
6.2 
The section on randomization has been revised in light of modified 
procedures related to change to Axio as provider of data services.  
Version 2.0 
(10/31/12) 
6.2 
“The date and time of randomization is the time of study entry for each 
participant” was changed to “The date of randomization will mark the start 
of follow-up for each participant”. This correction was made to avoid 
contradicting the statement that “Date of enrollment in the trial is defined as 
the date of informed consent” (7.6.1).   
Version 2.0 
(10/31/12) 
7.1 (Figure 2) 
The algorithm for screening was updated to include correct terminology for 
the blood values for eligibility.   
Version 2.0 
(10/31/12) 
7.3 and Table 1 
These were updated to include newly added exclusion criteria (4.6, 4.7, 4.8 
and 4.9). The new items are mostly administrative in nature, but need to be 
included as reasons why someone is not eligible.  
A correction was made to item 5.18.  The gait speed is still the same, but it is 
based on walking less than 4 meters in 40 seconds.  
Version 2.0 
(10/31/12) 
9.5.3 and 10.6.1 
We have added Polar heart rate monitoring to our Treatment Fidelity Plan.  
This will allow us to monitor the physiologic response during the 
intervention sessions for all participants.  
Version 2.0 
(10/31/12) 
10.3.5 
The distance of the fast walking speed test was corrected from 50 m to 50 ft. 
Version 2.0 
(10/31/12) 
11.1 (Table 2) 
Table 2 was updated to reflect the current data collection form names and to 
delineate which assessments will be collected on paper forms and which will 
be submitted via web-entry. 
Version 2.0 
(10/31/12) 
11.5 and Figure 4 
The process for adjudication of the primary outcome has been modified. The 
emphasis in the revised adjudication process is on reducing the number of 
participants with a missing primary outcome by assigning treatment failure 
status to participants with a high probability of being unable to walk at least 
300 m in six seconds.  
Figure 4 has been revised to correspond to the modified adjudication 
process. 
Version 2.0 
(10/31/12)) 
13 
Minor editorial changes were made throughout this section to ensure 
consistency with our definitions of reportable adverse events  versus 
expected adverse events,  
Version 2.0 
(10/31/12) 
15.1 
The analysis plan was modified to reflect changes in the adjudication 
procedure. 
Version 2.0 
(10/31/12) 
16.1, 16.2, 16.3, 16.4 
The sections on data capture, data management, and data security have been 
revised in light of modified procedures related to change to Axio as provider 
of data services.  
Version 2.0 
(10/31/12) 
20 
Updates made to the Study Team Roster. 

 
Summary of Modifications to Protocol Version 1.2 for Version 1.3 
 
Summary of Modifications to Protocol Version 1.1 for Version 1.2 
 
Summary of Modifications to Protocol Version 1.0 for Version 1.1 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 1.3 
(5/31/2012) 
15.5 
Changes were made to the text to clarify the inefficacy/harm boundary of the 
interim analysis plan. 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 1.2 
(4/17/2012) 
13.4.3 
Edited this section for clarity using the term injury consistently to delineate 
events that need to be reported while under study supervision.   
Version 1.2 
(4/17/2012) 
7.2 (criterion 1.7) 
Moved this item from eligibility section 6 since it is an initial inclusion 
criterion. 
Version 1.2 
(4/17/2012) 
7.3 (criterion 4.5) 
Added a criterion to capture the maximum randomization date of 14 weeks 
post admission. 
Version 1.2 
(4/17/2012) 
7.3 (criterion 5.20) 
Added a criterion for still receiving PT or OT at time of randomization.  
Version 1.2 
(4/17/2012) 
7.3 (criterion 6.11) 
Added a criterion that excludes patients with a prior hip fracture or total hip 
replacement on the same side as the study index hip fracture to avoid 
misclassification of the injury when the source could be due to failure of 
prior surgery or prosthesis.  
Version 1.2 
(4/17/2012) 
7.3 (criteria 6.12 and 6.13) 
Added 2 criteria to exclude patients who are in the process of recovering 
from another recent lower extremity musculoskeletal event or procedure. 
Version 1.2 
(4/17/2012) 
13.5, 13.6, 13.7, 13.8 
Updated text and figures 5b-5d to incorporate revised plan for reporting 
SAEs such that the CCC will be responsible for reporting SAEs to the 
DSMB and NIA.  Clinical site staff will report SAEs to the CCC which then 
forward to the DSMB and NIA directly.   
Version 1.2 
(4/17/2012) 
15.5  
 
In response to a query from the DSMB, we have clarified that we are not 
proposing a futility analysis and have provided more details about our 
approach to the interim analyses.  
Version 1.2 
(4/17/2012) 
15.6  
Power was re-calculated using R software to account for 1) the group 
sequential design and 2) the impact of non-compliance on variances. 
Version 
(date) 
Section 
Brief Summary of Modification 
Version 1.1 
(1/26/2012) 
 
Incorporates recommendations from the DSMB meeting on 12/12/2011 and 
Steering Committee’s edits 
Version 1.1 
(1/26/2012) 
Executive Summary, 4.2, 10.4.5, 
15.2.2 
Corrected wording of tertiary outcome to be consistent across the protocol: 
"increase of 50 meters or more in distance walked." 
Version 1.1 
(1/26/2012) 
Executive Summary, 3.2.3, 6.3, 
9.3, 12.1.7 
Increased the amount of time participants will receive study medications to 
include the period beyond the 16-week intervention period. Participants will 
now receive vitamin D, calcium, and multivitamin daily for the entire 40-
week study period, as per the DSMB recommendation. 
Version 1.1 
(1/26/2012) 
Executive Summary, 3.2.3, 6.3, 
9.3 
Removed one-time loading dose of 100,000 IU of vitamin D3 at 
randomization due to safety concerns in the recent literature and as per 
DSMB recommendation. 
Version 1.1 
(1/26/2012) 
Executive Summary, 3.2.3, 6.3, 
9.3 
Edited the amount of calcium provided from 1000 mg (500 mg twice a day), 
to 600 mg once a day as per DSMB recommendation.   
Version 1.1 
(1/26/2012) 
Executive Summary, 9.2, 12.1.7 
Changed procedure for nutritional intervention based on recommendation of 
Clinical Direction Committee. If a participant has a serum albumin level 2.5-
3.5, he/she will receive a diet consultation visit from the registered dietitian 
following the same protocol as for those who are at risk according to the 
Mini Nutritional Assessment –Short Form. 

Version 1.1 
(1/26/2012) 
3.1.6 (DCC) 
Added "...implement the data analysis plan" to DCC’s list of responsibilities. 
Version 1.1 
(1/26/2012) 
3.2.3, 12.1.7 
Added calculated creatinine clearance < 30 ml/min obtained from blood 
draw as a contraindication for calcium supplementation.  Participants with 
contraindications for calcium will receive vitamin D and multivitamin. 
Version 1.1 
(1/26/2012) 
6.1 (Figure 1) 
Included revised Figure 1 for clarity. 
Version 1.1 
(1/26/2012) 
4.2 
Corrected an error. "…following initiation of the intervention” was replaced 
by “...following randomization." 
Version 1.1 
(1/26/2012) 
7.1, 10.1, 11.4 (Table 3) 
Based on the DSMB’s recommendations, we have added three exclusion 
criteria: hemoglobin < 9 g/dl, calculated creatinine clearance < 15 ml/min, 
and serum albumin < 2.5 g/dl. The blood can be obtained between phases 2 
and 3, but no more than 4 weeks prior to randomization. 
Version 1.1 
(1/26/2012) 
7.1 
Updated Figure 2 incorporating the blood draw and additional exclusion 
criteria and possibility of phase 2 being an in-person visit. 
Version 1.1 
(1/26/2012) 
7.1, 7.5, 7.6, 17.2 
We are no longer requiring that informed consent be obtained at the baseline 
visit (phase 3 screening). For greater flexibility and to maximize enrollment, 
we are now allowing informed consent to be obtained at any time prior to 
data collection that is not covered by the HIPAA Partial Privacy Waiver. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 3) 
Edited item for clarity. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 3.3) 
Moved this item from eligibility section 5 since it is defining our target 
population. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 5.1) 
As per DSMB, added new exclusion criterion of calculated creatinine 
clearance < 15 ml/min as a medical impediment to participation. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 5.2) 
As per DSMB, added new exclusion criterion of serum albumin < 2.5 g/dl as 
a medical impediment to participation. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 5.5) 
Deleted "legally blind" since we capture this in criterion 5.4 (severe sensory 
impairment (visual or hearing)). 
Version 1.1 
(1/26/2012) 
7.2 (criterion 5.7) 
"History of Parkinson's disease, multiple sclerosis…." moved from 
eligibility section 6 since the criterion captures medical impediments to 
participation. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 6.1) 
As per DSMB, added new exclusion criterion of hemoglobin < 9 g/dl for 
safety. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 7) 
Edited the category so that it is just contraindications for calcium 
supplementation. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 7.2) 
 
Deleted glomerular filtration rate (<30 ml/min) obtained from the medical 
chart  since we are now obtaining a calculated creatinine clearance from 
blood drawn within 4 weeks prior to randomization. A calculated creatinine 
clearance <30 ml/min will be a contraindication for receiving calcium 
supplementation. 
Version 1.1 
(1/26/2012) 
7.2 (criterion 8) 
Deleted "Other" as a criterion. 
Version 1.1 
(1/26/2012) 
7.2 (Table 1) 
Edited Table 1 to reflect all changes to the eligibility criteria. 
Version 1.1 
(1/26/2012) 
9.2, 10.6.1, 11.3 
 Previously, we planned to assess adherence to study medications only 
during the 16-week intervention period. We now propose to also assess 
adherence to study medications during the 24-week post-intervention period 
using self-report questions administered during the 4-week phone calls. 
Version 1.1 
(1/26/2012) 
10.1.1 
Correction: Height will be measured in feet and inches and weight will be 
measured in pounds.  
Version 1.1 
(1/26/2012) 
10.3.2 
Added clarification on the scoring of the balance measure. 
Version 1.1 
(1/26/2012) 
10.3.5 
Clarified that the time required to walk 50 meters is the measure for fast 
walking speed. 
Version 1.1 
(1/26/2012) 
10.4.6 
Removed incorrect statement about summing the scores for obtaining the 
standing balance subscale. 
Version 1.1 
(1/26/2012) 
11 (Table 2) 
Updated the table to reflect the timing of informed consent, addition of a 
blood draw, and assessment of adherence to study medications beyond 
intervention period.    

 
 
Version 1.1 
(1/26/2012) 
11.4 (Table 3) 
With the addition of the blood, the timing of informed consent and phase 2 
screening has been widened.  The new time windows reflect that each can 
occur between 4-14 weeks post-admission 
Version 1.1 
(1/26/2012) 
11.5 
We now require that the Six Minute Walk Test (SMWT) be administered 
only by study staff whereas previously we allowed administration by non-
study staff. We have clarified that, at follow-up, self-report or proxy-report 
of walking ability will be used for participants who cannot perform the 
SMWT because of non-physical reasons (e.g., cognitive or sensory 
impairment).  
We have clarified that our approach to classification will reduce bias by 
maximizing the number of participants who are included in the analysis for 
the primary outcome. 
We have removed the sample self/proxy-report question that will be used to 
assess walking ability. The actual question will be added to the data 
collection forms and the Manual of Procedures.  
The adjudication process has been clarified. 
Version 1.1 
(1/26/2012) 
11.5, 15.1 
At follow-up, participants who cannot perform the SMWT because of 
illness, sickness, or death will be considered treatment failures in both the 
primary and secondary analyses. They were considered missing in secondary 
analysis in the previous version. 
Version 1.1 
(1/26/2012) 
11.5 (Figure 4) 
Updated Figure 4 to reflect changes to the classification of the primary 
outcome as described in section 11.5. 
Version 1.1 
(1/26/2012) 
13.5, 13.8 
Updated text and Figures 5b-5d to incorporate NIH reporting timelines for 
serious adverse events.  SAEs will be reported to the DSMB and NIA by the 
study chair within 48 hours of when the event is known and reported by 
study staff. 
Version 1.1 
(1/26/2012) 
15.1 
Clarified primary outcome as "…able to walk 300 meters or more in six 
minutes..." 
Version 1.1 
(1/26/2012) 
15.5 
 We have replaced "beta spending" with "lower bound spending" because 
the spending is actually computed under the null hypothesis.  
Our interim analysis is asymmetrical, but we plan to perform a two-sided 
(symmetrical) test at the end. To clarify, we have added: “The two-sided test 
with nominal alpha=0.05 will be operationalized at the final analysis by 
rejecting if |Z| > 2.03.” 
Version 1.1 
(1/26/2012) 
15.6.2 
The detectable effect size for the economic evaluation was recalculated with 
alpha=0.05, instead of alpha=0.01. 
Version 1.1 
(1/26/2012) 
16.4 
Clarified that site visit reports will only be sent to the Steering Committee 
(SC) not to the DSMB and the SC. 
Version 1.1 
(1/26/2012) 
20 
Updates made to the Study Team Roster. 

 
 
 
 
Improving Community Ambulation after Hip Fracture  
 
Study Chair and Principal Investigator: 
 
Jay Magaziner, PhD, MSHyg 
 
 
Supported by: 
 
The National Institute on Aging 
 
(R01 AG035009) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 12.0 
October 19, 2016

CAP Protocol version 12.0 
 
ii 
 
Table of Contents 
Section 1: Executive Summary ................................................................................................. 1 
Section 2: Participating Clinical Sites ........................................................................................ 4 
Section 3: Study Organization .................................................................................................. 5 
3.1 Study Administration ....................................................................................................... 5 
3.1.1 Study Chair ............................................................................................................. 5 
3.1.2 National Institute on Aging (NIA) ............................................................................. 5 
3.1.3 Data and Safety Monitoring Board (DSMB) ............................................................. 6 
3.1.4 Steering Committee (SC) ........................................................................................ 6 
3.1.5 Clinical Coordinating Center (CCC) ........................................................................ 7 
3.1.6 Data Coordinating Center (DCC) ............................................................................ 7 
3.1.7 Economic Evaluation Core (EEC) ........................................................................... 8 
3.2 Scientific Oversight ......................................................................................................... 8 
3.2.1 Scientific Oversight Committees (SOC) .................................................................. 8 
3.2.2 Specialized Support for Exercise and Nutrition ....................................................... 9 
3.2.3 UMB Investigational Drug Services (IDS) ................................................................ 9 
3.2.4 Study Clinical Sites ................................................................................................10 
3.3 Organizational Chart ......................................................................................................11 
Section 4: Study Objectives .................................................................................................... 12 
4.1 Primary Objective ..........................................................................................................12 
4.2 Secondary Objectives ....................................................................................................12 
Section 5: Background ........................................................................................................... 12 
5.1 Residual Deficits in Precursors of Community Ambulation.............................................13 
5.2 Exercise Studies in Persons after Hip Fracture ..............................................................14 
5.3 Rationale for the Interventions .......................................................................................15 
5.4 Primary Outcome Measure ............................................................................................17 
5.5 Economic Evaluation of Interventions to Reduce Post-fracture Disability .......................18 
Section 6: Study Design ......................................................................................................... 18 
6.1 Overview of Study Design .............................................................................................18 
6.2 Randomization ..............................................................................................................19 
6.3 Interventions ..................................................................................................................19 
6.4 Blinding of Study Staff ...................................................................................................20 
Section 7: Selection and Enrollment of Participants ................................................................ 20 
7.1 Eligibility ........................................................................................................................20 
7.2 Inclusion Criteria (Target Population) ............................................................................21 
7.3 Exclusion Criteria ..........................................................................................................21 
7.4 Identification of Hip Fracture Patients ............................................................................22 
7.5 Participant Screening and Recruitment..........................................................................23 
7.6 Informed Consent ..........................................................................................................23 
7.6.1 Enrollment .............................................................................................................24 
Section 8: Retention ............................................................................................................... 24 
8.1 Retention Promotion Efforts ...........................................................................................24 
8.2 Drop-out Prevention Efforts ...........................................................................................25 
8.3 Monitoring Recruitment and Retention...........................................................................25 
8.3.1 Monitoring and Quality Control of Recruitment and Retention ................................25 
Section 9: Study Interventions ................................................................................................ 26 
9.1 Overview .......................................................................................................................26 
9.2 Nutritional Intervention ...................................................................................................26 
9.3 PUSH Intervention .........................................................................................................27 
9.4 PULSE Intervention .......................................................................................................29 
9.5 Treatment Fidelity Plan ..................................................................................................29 
9.5.1 Initial Training for Procedural Reliability .................................................................29 
9.5.2 Ensuring Ongoing Competency .............................................................................30 

CAP Protocol version 12.0 
 
iii 
9.5.3 Monitoring Physiologic Response ..........................................................................30 
9.6 Scheduling Intervention Visits ........................................................................................31 
Section 10: Study Measures ..................................................................................................... 32 
10.1 Screening Evaluations ...................................................................................................32 
10.1.1 
Weight, Height, and BMI ....................................................................................32 
10.1.2 
Modified Mini-Mental State Examination (3MS) ..................................................32 
10.2 Primary Outcome Measure: Community Ambulation .....................................................32 
10.3 Secondary Outcome Measures - Precursors to Community Ambulation ........................33 
10.3.1 
Endurance .........................................................................................................33 
10.3.2 
Balance ..............................................................................................................33 
10.3.3 
Quadriceps Muscle Strength ..............................................................................33 
10.3.4 
Lower Extremity Function ...................................................................................33 
10.3.5 
Fast Walking Speed ...........................................................................................34 
10.3.6 
Cost Effectiveness: Health Care Utilization ........................................................34 
10.4 Tertiary Outcomes .........................................................................................................34 
10.4.1 
Activities of Daily Living (ADLs) ..........................................................................34 
10.4.2 
Quality of Life (SF-36) ........................................................................................35 
10.4.3 
Balance Confidence ...........................................................................................35 
10.4.4 
Yale Physical Activity Survey (YPAS) ................................................................35 
10.4.5 
Improvement in Walking .....................................................................................35 
10.4.6 
Short Physical Performance Battery (SPPB) ......................................................35 
10.4.7 
Depressive Symptoms .......................................................................................36 
10.4.8 
Cognitive Status .................................................................................................36 
10.4.9 
Nutritional Status................................................................................................36 
10.5 Clinical and Background Characteristics ........................................................................36 
10.5.1 
Demographic and Surgical Characteristics.........................................................37 
10.5.2 
Functional Comorbidity Index .............................................................................37 
10.5.3 
Psychological Measures ....................................................................................37 
10.6 Other Measures to be Monitored ...................................................................................37 
10.6.1 
Adherence .........................................................................................................37 
10.6.2 
Weight Loss .......................................................................................................38 
10.6.3 
Reportable Adverse Events (RAEs) ...................................................................38 
10.6.4 
Expected Adverse Events (AEs) ........................................................................38 
Section 11: Study Procedures .................................................................................................. 38 
11.1 Baseline Assessments ..................................................................................................38 
11.2 Follow-up Assessment ..................................................................................................39 
11.3 Telephone Interviews ....................................................................................................39 
11.4 Timing of Study Procedures ..........................................................................................39 
11.5 Primary Outcome Classification .....................................................................................40 
Section 12: Safety Assessments .............................................................................................. 43 
12.1 Participant Safety Parameters: Methods and Timing .....................................................43 
12.1.1 
Pre-Intervention Safety Screening .....................................................................43 
12.1.2 
Safety Considerations for Study Assessments ...................................................43 
12.1.3 
Safety Considerations for the PUSH Intervention ...............................................44 
12.1.4 
Safety Measures during the PUSH Intervention .................................................45 
12.1.5 
Safety Considerations for the PULSE Intervention .............................................45 
12.1.6 
Safety Measures for the PULSE Intervention .....................................................47 
12.1.7 
Safety Considerations for the Nutritional Intervention .........................................48 
12.1.8 
Safety Measures for the Nutritional Intervention .................................................48 
12.2 Confidentiality ................................................................................................................49 
12.3 Participant Education about Potential Risks ..................................................................49 
Section 13: Reportable Adverse Events (RAEs) and Expected Adverse Events (AEs) ............. 49 
13.1 Overview .......................................................................................................................49 
13.2 Classifying Adverse Events ...........................................................................................50 

CAP Protocol version 12.0 
 
iv 
13.2.1 
Severity ..............................................................................................................50 
13.2.2 
Expectedness ....................................................................................................50 
13.2.3 
Relatedness .......................................................................................................51 
13.3 Expected AEs ................................................................................................................51 
13.4 Reportable AEs .............................................................................................................51 
13.4.1 
Serious Adverse Event (SAE) ............................................................................51 
13.4.2 
Unexpected Adverse Event ................................................................................52 
13.4.3 
Injury that Occurs while Under the Supervision of Study Related Personnel ......52 
13.5 Expected AE and RAE Collection and Reporting ...........................................................52 
13.6 Evaluation and Follow-up of RAEs ................................................................................57 
13.6.1 
Action Taken ......................................................................................................57 
13.7 Responsibilities .............................................................................................................58 
13.7.1 
Clinical Site Clinician ..........................................................................................58 
13.7.2 
Independent Safety Monitor (ISM) .....................................................................58 
13.8 Reporting Expected AEs and RAEs to the DSMB ..........................................................58 
Section 14: Intervention Discontinuation ................................................................................... 59 
Section 15: Data Analyses ....................................................................................................... 59 
15.1 Primary Aim ...................................................................................................................59 
15.2 Secondary Objectives ....................................................................................................61 
15.2.1 
Delayed and Sustained Effects ..........................................................................61 
15.2.2 
Secondary and Tertiary Outcomes .....................................................................62 
15.2.3 
Cost-Effectiveness of Interventions ....................................................................62 
15.3 Missing Data..................................................................................................................63 
15.4 Nonadherence ...............................................................................................................63 
15.5 Interim Analyses ............................................................................................................64 
15.6 Sample Size Adequacy .................................................................................................64 
15.6.1 
Primary Aim .......................................................................................................64 
15.6.2 
Secondary Aims .................................................................................................65 
Section 16: Data Capture, Data Management, and Quality Assurance ..................................... 66 
16.1 Overview .......................................................................................................................66 
16.2 Data Capture .................................................................................................................67 
16.3 Data Management .........................................................................................................67 
16.3.1 
Processing of Paper Data Forms .......................................................................67 
16.3.2 
Processing of Web-Entry Data ...........................................................................68 
16.3.3 
Reportable Adverse Events Coding ...................................................................68 
16.3.4 
Extraction of Data for Analysis and Reporting ....................................................68 
16.4 Protection of Data ..........................................................................................................69 
16.4.1 
Physical Security and Backup ............................................................................69 
16.4.2 
Software Systems Security ................................................................................71 
16.5 Study Management Database .......................................................................................71 
16.6 Quality Assurance (QA) .................................................................................................71 
16.6.1 
Training ..............................................................................................................72 
16.6.2 
Quality Assurance Oversight ..............................................................................72 
16.6.3 
Protocol Deviations ............................................................................................72 
16.7 Monitoring .....................................................................................................................73 
Section 17: Participant Rights and Confidentiality .................................................................... 74 
17.1 Institutional Review Board (IRB) ....................................................................................74 
17.2 Informed Consent Forms (ICF) ......................................................................................75 
17.2.1 
Disposition of Informed Consent Forms .............................................................75 
17.2.2 
HIPAA Authorization ..........................................................................................75 
17.3 Participant Confidentiality ..............................................................................................75 
Section 18: Research Publication Policy .................................................................................. 76 
Section 19: Ancillary Studies Policies ....................................................................................... 77 
19.1 Concurrent Studies ........................................................................................................77 

CAP Protocol version 12.0 
 
v 
Section 20: Study Team Roster ................................................................................................ 79 
Section 21: References ............................................................................................................ 91 
 
 
 
 

CAP Protocol version 12.0 
 
vi 
List of Tables 
 
Table 
Title 
Section 
Table 1 Timing of Study Procedures 
11.4 
Table 2 Safety Alerts and Actions for Study Assessments 
12.1.2 
Table 3 Safety Alerts and Actions for Interventions 
12.1.5 
Table 4 Anticipated Critical Values for Each Planned Analysis  
15.5 
Table 5 Power to Detect Differences in Proportions 
15.6.1 
 
 
List of Figures 
 
Figure 
Title 
Section 
Figure 1 
Timeline for Recruitment, Randomization, and Follow-up 
6.1 
Figure 2 
Algorithm for Screening 
7.1 
Figure 3 
Shuttle Device  
9.3 
Figure 4 
Classification and Analysis of Primary Outcome 
11.5 
Figure 5a 
Collection and Reporting Process for Expected AEs 
13.5 
Figure 5b 
Collection and Reporting Process for RAEs Collected During 
Standardized Telephone Interviews 
13.5 
Figure 5c 
Collection and Reporting Process for RAEs Identified Anytime Other 
than During a Standardized Telephone Interview 
13.5 
Figure 5d 
CCC Reporting Process for RAEs 
13.6 
 
 

 
CAP Protocol version 12.0 
 
vii 
List of Abbreviations 
 
Term 
Abbr. 
Active range of motion 
AROM 
Activities of daily living 
ADL 
Activities-Specific Balance Confidence  
ABC 
Adverse event 
AE 
Arcadia University 
AU 
Arthrogenic muscle response 
AMR 
Baltimore Hip Studies 
BHS 
Body mass index 
BMI 
Cardiopulmonary resuscitation 
CPR 
Center for Epidemiologic Studies 
Depression scale 
CES-D 
Center for Medicare and Medicaid 
Services 
CMS 
Clinical Coordinating Center 
CCC 
Community Ambulation Project 
CAP 
Data and Safety Monitoring Board 
DSMB 
Data Coordinating Center 
DCC 
Data Management Plan 
DMP 
Diastolic blood pressure 
DBP 
Economic Evaluation Core 
EEC 
Eight-repetition maximum 
8-RM 
Emergency Medical Service 
EMS 
Functional Comorbidity Index 
FCI 
Generalized estimating equations 
GEE 
Health Insurance Portability and 
Accountability Act 
HIPAA 
Heart rate 
HR 
Heart rate reserve 
HRR 
Heating, ventilation and air conditioning 
HVAC 
Incremental net benefits 
INB 
Independent Safety Monitor 
ISM 
Information Technology 
IT 
Informed Consent Form 
ICF 
Institutional Review Board 
IRB 
Investigational Drug Services 
IDS 
Intention-to-treat 
ITT 
Intervention Monitor 
IM 
Term 
Abbr. 
Life Orientation Test-Revised 
LOT-R 
Manual of Procedures 
MOP 
Mini Nutritional Assessment-Short Form 
MNA®-SF 
Modified Mini-Mental State examination 
3MS 
Modified Physical Performance Test 
mPPT 
National Health and Aging Trends Study 
NHATS 
National Institute on Aging 
NIA 
National Institutes of Health 
NIH 
Peak oxygen uptake 
VO2peak 
Pepper Assessment Tool for Disability 
PAT-D 
Physical therapist 
PT 
Primary care provider 
PCP 
Principal investigator 
PI 
Protected Health Information 
PHI 
Publications and Ancillary Studies 
Committee 
PASC 
Quality-adjusted life year 
QALY 
Quality assurance 
QA 
Quality control 
QC 
Randomized controlled trial 
RCT 
Range of motion 
ROM 
Rating of perceived exertion 
RPE 
Redundant Array of Independent Risks 
RAID 
Registered dietician 
RD 
Reportable Adverse Event 
RAE 
Resource-Based Relative Value Scale 
RBRVS 
Scientific Oversight Committee 
SOC 
Serious adverse event 
SAE 
Short Physical Performance Battery 
SPPB 
Six-Minute Walk Test 
SMWT 
Skilled nursing facility 
SNF 
Spine Patient Outcomes Research Trial 
SPORT 
Standard Operating Procedure 
SOP 
Statistical Analysis Software 
SAS 
Steering Committee 
SC 
Systolic blood pressure 
SBP 

CAP Protocol version 12.0 
 
viii 
Term 
Abbr. 
Transcutaneous electrical nerve 
stimulation 
TENS 
University of Connecticut Health Center 
UCHC 
Term 
Abbr. 
University of Maryland Baltimore 
UMB 
Weighted estimating equations 
WEE 
Yale Physical Activity Survey 
YPAS 
 
 

CAP Protocol version 12.0 
 
1 
Section 1: Executive Summary 
 
Despite improvements in medical management, significant residual disability remains in older 
persons after a hip fracture.1-3 The goal of current clinical practice is independent, safe 
household ambulation two to three months after surgery.4  Hip fracture-acquired dependency in 
functional activities of daily living persists well beyond three months post-surgery. One year 
after hip fracture, 20% of patients need help putting on pants, 50% need assistance to walk, and 
90% need assistance to climb stairs.2  This residual disability indicates that current standard 
Medicare-reimbursed post-hip fracture rehabilitation (i.e., usual care) fails to return many 
patients to pre-fracture levels of function. In contrast to stroke and heart disease, other 
commonly occurring acute conditions in the older population, there are few intervention trials 
focused on decreasing disability following hip fracture. None of the trials for hip fracture has 
examined the effect of early post-fracture intervention on the ability to ambulate at a level 
required for independent function in the community (i.e., community ambulation). Thus, there is 
a paucity of evidence to justify extending medical management beyond usual care in persons 
following hip fracture to achieve community, rather than merely household, ambulation.  
 
Study Title 
Improving Community Ambulation after Hip Fracture (hereafter referred to as the Community 
Ambulation Project or “CAP”) 
 
Objectives 
The primary outcome will be ability to walk 300 meters or more in six minutes at the end of the 
16-week intervention period. The goal is to enable older adults who have experienced a hip 
fracture to recover sufficiently to become community ambulators. In addition, the effect of the 
interventions on five precursors for community ambulation will be examined, as will the cost-
effectiveness of the interventions, and the effect on a set of tertiary outcomes. Precursors to 
community ambulation include measures of endurance, dynamic balance, walking speed, 
quadriceps strength, and lower extremity function. Tertiary outcomes include activities of daily 
living (ADLs), quality of life, physical activity, lower extremity physical performance, balance 
confidence, increase of 50 meters or more in distance walked in six minutes, nutritional status, 
cognitive status, and depressive symptoms.  
 
Design and Outcomes 
A randomized controlled trial (RCT) including 210 older adults who have experienced a hip 
fracture will be carried out at three clinical sites with half of the subjects receiving a specific 
multi-component intervention (PUSH) and the other half receiving a non-specific multi-
component intervention (PULSE).  Randomization of 210 participants meeting eligibility criteria 
will take place after post-acute rehabilitation ends, up to 26 weeks after admission to the 
hospital for hip fracture. The primary endpoint will be measured using the Six-Minute Walk Test 
(SMWT) at 16 weeks after randomization. Patients age 60 and older who have had surgical 
repair for hip fracture will be identified at the three clinical sites and evaluated for eligibility. 
Following consent to participate, eligible participants will undergo a comprehensive baseline 
assessment.  Participants completing the entire baseline assessment will be randomized to one 
of the two treatment groups.   
 
The two groups will be compared on measures of endurance, dynamic balance, walking speed, 
quadriceps strength, and lower extremity function using the distance walked in six minutes, 
Short Physical Performance Battery (SPPB), dynamometry for quadriceps strength, and 
Modified Physical Performance Test (mPPT).  Resource utilization will be tracked using 

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telephone calls every four weeks beginning four weeks post-randomization. The economic value 
of the interventions will be determined by assessing the impact on quality-adjusted life years 
(QALYs), cost, and cost per QALY gained over the period following randomization. The cost-
effectiveness analyses will address both the within trial comparison of the study interventions 
and a model-based comparison of the study interventions and usual care. This RCT will also 
compare the effect of the interventions on the following tertiary outcomes that are related to 
community ambulation: ADLs, balance confidence, quality of life, physical activity, lower 
extremity physical performance, depressive symptoms, increase of 50 meters or more in 
distance walked in six minutes, cognitive status, and nutritional status. Telephone interviews 
every four weeks will also obtain information on adverse events (AEs), and will help reduce loss 
to follow-up by maintaining ongoing rapport with participants. 
 
For participants randomized prior to version 10.0 of the protocol, follow-up assessment visits 
occurred 16 weeks and 40 weeks from the date of randomization and telephone interviews were 
conducted every four weeks during the 40-week study period for a total of 10 telephone 
interviews. For participants consented under version 10.0 of the protocol, all follow-up will end at 
16 weeks post-randomization. 
 
In version 11.0 of the protocol, we will eliminate several secondary and tertiary outcome 
measures. 
 
Interventions and Duration 
Participants will be randomly assigned to one of two treatment groups: 1) PUSH or 2) PULSE. 
Within a week of randomization, participants will initiate the intervention with a physical therapist 
(PT) in their home and receive counseling with a registered dietician to ensure body weight 
stability and adequate nutrient intake inclusive of a healthy diet.  Participants in both intervention 
groups will also receive vitamin D, calcium and multivitamin supplements during the 16-week 
study period.   
 
Both groups will receive 32 visits of approximately 60 minutes duration from a study PT. 
Participants will receive two visits per week, on non-consecutive days, for 16 weeks. Visits will 
take place in the participant’s place of residence.  
 
PUSH Intervention 
The PUSH intervention is based on improving specific precursors to community ambulation. The 
intervention addresses endurance with continuous upright exercise for 20 minutes; function by 
improving fast walking needed to navigate streets outdoors, standing from a chair, and stair 
negotiation; muscle performance by exercising to enhance lower extremity strength in 
functionally relevant muscles moving through locomotion-appropriate movements and ranges; 
and balance by performing unilateral activities and activities with decreased base of support. 
The components of exercise are woven together into one program that minimizes participant 
burden.  By the end of the first eight weeks, participants will be instructed to complete the 
endurance component independently one to two times/week by walking for a similar duration 
and intensity as they have been doing with the PT during the supervised visits.  
 
The strength components of the muscle performance intervention will be performed using a 
portable progressive resistive exercise device (Shuttle® MiniPress, Contemporary Design 
Company, P.O. Box 5089, Glacier, WA 98244).  Muscle performance will focus on bilateral hip 
extensors, hip abductors, knee extensors, and plantar flexors because of their role in function, 
specifically gait and transfer activities.  Balance and strength will be addressed with additional 
exercises performed while standing.  The endurance intervention will begin initially with two to 

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3 
three minutes of continuous upper and lower extremity active range of motion (AROM) with the 
participant sitting. These exercises are intended to increase the participants’ heart rate (HR) or 
exertion closer to the target zone. The participant will then be asked to walk on level surfaces 
and up and down a single or multiple steps, if able and available, to keep the HR within the 
training zone for 20 minutes. The PT may also engage the participant in additional exercises 
such as upper and lower extremity AROM exercises to keep the HR elevated. 
 
PULSE Intervention 
The PULSE intervention group will receive flexibility exercises, AROM for the upper and lower 
extremities, breathing exercises and transcutaneous electrical nerve stimulation (TENS). During 
the AROM exercises, participants will be working to increase flexibility and range of motion in 
order to increase the motion the participant produces. The exercises will include the neck, 
shoulders, arms, trunk, hips, knees and ankles.  During all of the AROM exercises, the 
participant will focus on deep breathing techniques. Progression will be gradual by beginning 
with three repetitions and slowly progressing to 10 repetitions. We will add a second set of 
exercises when necessary. This portion of the session will last approximately 20-30 minutes. 
 
After the AROM exercises, the second part of the session will use sensory level electrical 
stimulation on lower extremity muscle groups. The TENS portion of intervention is intended to 
decrease pain thereby allowing greater ease of mobility. Conventional TENS uses low-level 
electrical current to stimulate superficial cutaneous nerve fibers through the skin. The amount of 
current for sensory level stimulation is that level which the participant detects as a "tingling" 
sensation and is not high enough to produce a visible muscle contraction (below motor 
threshold).5  Flexible carbonized, disposable electrodes coated with a self-adhesive conductive 
polymer will be applied to the skin. The electrodes will be placed bilaterally near the motor 
points on muscle bellies (the gluteal complex, the quadriceps, and the gastrocnemius) for seven 
minutes per muscle group. The muscle regions selected are important for function after hip 
fracture.   
 
Nutrition Intervention 
Given the importance of maintaining nutrition in both study groups, we will provide all 
participants (regardless of group) with 2000 IU vitamin D3, 600 mg of calcium, and a 
multivitamin daily for the 16-week study period. Nutritional counseling will also be provided to 
ensure weight stability, adequate nutrient intake of 1.2-1.5 g protein/kg body weight inclusive of 
a healthy diet (50% carbohydrate, 20% protein, 30% fat).  Participants will be screened at the 
time of randomization to assess nutritional risk using the Mini Nutritional Assessment-Short 
Form (MNA®-SF).6 Those who score ≤7 (malnourished) on the MNA®-SF at baseline and 
participants with serum albumin 2.5-3.5 g/dl (regardless of the score on MNA®-SF) will receive 
a visit from a registered dietician (RD) from our study in their place of residence within seven 
days of randomization. The RD will evaluate and counsel them on making dietary modifications 
based on their protein, caloric and other dietary deficiencies using a standardized approach 
across the three study sites.7-9 The RD will follow up with participants by telephone one week 
after the visit to assess understanding and implementation of recommendations. Participants 
who score 8-11 (at risk of malnutrition) at baseline and have serum albumin level >3.5 g/dl will 
receive a telephone dietary consultation with the RD within seven days of randomization. Based 
on the participant's eating habits and food intake, the RD may make the clinical determination 
that an in-person consultation is warranted. In these cases, the RD will schedule an in-person 
dietary consultation, following the same protocol as those who score in the malnourished range. 
Those with a score ≥12 on the MNA®-SF and who have serum albumin level >3.5 g/dl at 
baseline will receive brief telephone contact within seven days of randomization from the RD to 
discuss the importance of calorie and protein intake. Weight will be monitored during home PT 

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visits every four weeks and those who lose 2% or more body weight in a four-week period will 
receive another telephone consultation by the study RD. 
 
Participants randomized prior to version 10.0 of the protocol received vitamin D, calcium, and 
multivitamin supplements for a total of 40 weeks. Participants consented under version 10.0 of 
the protocol will receive vitamin D, calcium, and multivitamin supplements for 16 weeks post-
randomization. 
 
Sample Size and Population 
The target sample size is 210 randomized hip fracture patients across three clinical sites (with 
approximately 35 in each treatment group at each site).  Study inclusion criteria are: 1) Closed, 
non-pathologic, minimal trauma hip fracture with surgical fixation; 2) Age 60 or older at time of 
randomization; 3) Living in the community at time of fracture and at time of randomization; and 
4) Ambulating without human assistance during the two months prior to fracture.  Participants 
for whom it is not safe to participate in the interventions will be excluded, as will those who are 
very unlikely to benefit and in whom the interventions are not feasible. 
 
Section 2: Participating Clinical Sites 
 
Arcadia University (1) 
Kathleen Mangione, PhD, PT, GCS 
Clinical Site PI 
450 S. Easton Road 
Glenside, PA 19038-3295 
 
Phone: (215) 572-2861 
 
Fax:     (215) 572-2157 
 
mangionk@arcadia.edu 
 
University of Maryland Baltimore (2) 
Ann Gruber-Baldini, PhD 
Clinical Site PI 
660 W. Redwood Street, Suite 200 
Baltimore, MD 21201  
Phone: 410-706-2444  
Fax:      410-706-4433 
 
abaldin@epi.umaryland.edu 
 
University of Connecticut Health Center (3) 
Richard Fortinsky, PhD 
Clinical Site PI 
UConn Health Center 
263 Farmington Avenue 
Farmington, CT 06030 
 
Phone: (860) 679-8069 
 
Fax:     (860) 679-1307 
 
fortinsky@uchc.edu 
 
 

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Section 3: Study Organization 
 
The Community Ambulation Project (CAP) is a multi-center clinical trial with a Clinical 
Coordinating Center (CCC) and Data Coordinating Center (DCC) at the University of Maryland 
Baltimore, an Economic Evaluation Core (EEC) at Dartmouth College, and three clinical sites. In 
addition to these units, the project will have a Steering Committee (SC) and three Scientific 
Oversight Committees (SOCs) that will provide expertise needed to conduct this investigation. 
There will also be a sub-committee that includes a group of experts who will provide support on 
exercise and nutrition in older adults. A project Organizational Chart is provided in section 3.3.  
Each clinical site will be affiliated with a university (University of Maryland Baltimore, Arcadia 
University, and University of Connecticut) and will be recruiting older adults who have 
experienced a hip fracture in their surrounding geographic areas. All key personnel have 
collaborated on the design of this trial; most will have multiple roles in its execution, based on 
individual areas of expertise.  Please see Section 20: for a complete Study Team Roster. 
 
3.1 Study Administration 
 
3.1.1 Study Chair  
The principal investigator (PI) of the grant awarded by the National Institute on Aging (NIA) will 
serve as the study chair.  Responsibilities of the study chair will include:  
 
Providing overall organization and scientific direction of the trial 
 
Serving as chair of the SC 
 
Administering logistics for the Data and Safety Monitoring Board (DSMB) in consultation 
with the NIA program official 
 
Working with investigators and staff in the CCC, DCC, EEC, clinical sites, and SOCs to 
maximize collaboration 
 
Providing updates on progress to the NIA 
 
Participating in visits to clinical sites to assess quality and assist with problems 
 
Defining analyses of study data 
 
Overseeing manuscript preparation 
 
In the unlikely event the study chair becomes unable to serve, the next most senior investigator 
from UMB and deputy director of the DCC for the trial will replace the study chair and become 
co-chair of the SC; the current co-chair will become study chair. 
 
3.1.2 National Institute on Aging (NIA) 
This is an investigator-initiated project and funding is provided by an R01 grant.  The funding 
agency is the NIA.  The NIA will appoint members of the DSMB, who will review study data and 
safety and report to the NIA program official.  The NIA program official will then report the 
outcome of DSMB review to the NIA director following established internal procedures.  The PI 
will report study progress to the NIA on an annual basis unless asked to report at a different 
interval.  According to PA-10-067, a Non-Competing Continuation Grant Progress Report 
(PHS 2590) will be completed by the PI annually and financial statements will be provided as 
required in the NIH Grants Policy Statement.  A final progress report, invention statement, 
and Financial Status Report will be submitted by the PI when the award is relinquished or 
when it is terminated. 
 

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3.1.3 Data and Safety Monitoring Board (DSMB)   
Members of the DSMB will be appointed by and report to the NIA. They will monitor accruing 
data in order to confirm that the participants in the trial are being cared for safely. 
Responsibilities of the DSMB will include: 
 
Review the research protocol, informed consent documents and plans for data and     
safety monitoring 
 
Advise the NIA on the readiness of the study staff to initiate recruitment 
 
Evaluate the progress of the trial, including periodic assessments of data quality and 
timeliness, recruitment, accrual and retention, participant risk versus benefit, 
performance of the trial sites, and other factors that can affect study outcome 
 
Consider factors external to the study when relevant information becomes available, 
such as scientific or therapeutic developments that may have an impact on the safety of 
the participants or the ethics of the trial 
 
Review, approve, and monitor ancillary studies 
 
Review study performance, make recommendations and assist in the resolution of 
problems reported by the PI 
 
Protect the safety of the study participants 
 
Report to NIA on the safety and progress of the trial  
 
Make recommendations to the NIA and the PI concerning continuation, termination or 
other modifications of the trial based on the observed beneficial or adverse effects of the 
treatment under study 
 
If appropriate, review the results of interim analyses in accordance with stopping 
guidelines, which are clearly defined in advance of data analysis and have the approval 
of the DSMB 
 
Ensure the confidentiality of the study data and the results of monitoring  
 
Assist the NIA by commenting on any problems with study conduct, enrollment, sample 
size and/or data collection 
 
The DSMB will discharge itself from its duties when the study is complete. Study completion will 
be considered in consultation with the PI and NIA after no further outcome data are being 
collected in the main study and the main paper reporting on the primary outcome has been 
published. 
 
 
3.1.4 Steering Committee (SC)  
The SC will be charged with the overall governance of study conduct.  Responsibilities will 
include:  
 
Approving the final protocol and manual of operations 
 
Supervising the overall execution of the trial 
 
Generating and approving study policies 
 
Considering modifications of the protocol and study operations 
 
Reviewing issues related to protocol deviations and making final determinations 
regarding continued participation by a clinical site 
 
Appointing and charging the oversight committees and subcommittees described below  
 
Implementing recommendations of the DSMB 
 
Voting membership has been established within the SC and includes the co-chairs of the SC, 
CCC director, DCC director, EEC director, and one member from each clinical site.   All major 
scientific decisions will be determined by simple majority vote of the voting members of the SC.  
The study chair and co-chair will share one vote and will only vote if there is a tie. If the study 

CAP Protocol version 12.0 
 
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chair and co-chair disagree, the study chair will make the final decision. The SC will meet 
regularly (no less than monthly) throughout the study.  All voting members, as well other 
investigators and the NIA program official, will be invited to participate.  
 
3.1.5 Clinical Coordinating Center (CCC)  
The CCC will be primarily responsible for managing study operations and ensuring adherence 
to the study protocol.  Responsibilities will include: 
 
Developing protocols and the manual of procedures (MOP) 
 
Tracking protocol amendments and ensuring their implementation 
 
Providing study materials to clinical sites 
 
Procuring equipment and materials 
 
Tracking protocol deviations and developing Corrective Action Plans 
 
Tracking the implementation of the Corrective Action Plans 
 
Organizing and providing staff support for meetings of SOCs 
 
Recording minutes from meetings 
 
Organizing training sessions of site coordinators, evaluators, dieticians, and PTs 
 
Providing training related to clinical operation of study 
 
Producing documents and forms in collaboration with the DCC 
 
Developing study management databases for monitoring study activity at each clinical 
site 
 
Classifying reportable adverse events (RAEs) 
 
Developing quality assurance plans 
 
Participating in quality assurance visits to the clinical sites 
 
Tracking submissions and amendments to the UMB Institutional Review Board (IRB) 
 
Tracking human subjects training and certification 
 
Interfacing with UMB Investigational Drug Services (IDS) to ensure proper dispensing of 
the vitamins/supplements (Please see section 3.2.3 for more information on the IDS.) 
 
3.1.6 Data Coordinating Center (DCC)  
The DCC’s primary responsibility will be to manage data operations, monitor adherence to the 
study protocol and implement the data analysis plan. Responsibilities will include:  
 
Developing, implementing, and monitoring the data and safety monitoring plan, the data 
management plan, and the randomization plan 
 
Overseeing training of clinical site staff with regard to data entry, data correction, and 
randomization procedures 
 
Assisting CCC on development of data collection form templates and overseeing the 
implementation of paper-based and web-based forms  
 
Monitoring completion and timeliness of form submissions and query responses 
 
Developing and implementing data edit specifications 
 
Monitoring distribution of data queries to clinical sites 
 
Monitoring sites’ responsiveness to queries 
 
Participating in quality assurance visits to the clinical sites 
 
Preparing reports on study progress and study results for the DSMB (twice per year and 
on request), the NIA (annually and on request), IRBs (annually and on request), and the 
SC (on request) 
 
Preparing final data files and performing data analyses for publications and 
presentations 
 
Preparing data files for the EEC and to be shared with any ancillary studies that are 
approved by the SC 

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 
Developing and maintaining a website to ensure up-to-date study documents (e.g., data 
collection forms, manuals, protocol, study personnel contact information) 
 
Data capture, data management, and randomization will be implemented through a subcontract 
with Axio Research, LLC (hereafter referred to as Axio) in Seattle, WA. 
 
3.1.7 Economic Evaluation Core (EEC) 
The EEC will be responsible for assessing the cost-effectiveness of the interventions.  The 
economic value of the interventions will be determined by assessing the impact on QALYs, cost, 
and cost per QALY gained over the study period. The EEC will conduct analyses of within trial 
comparisons for the economic endpoints (costs and QALYs) as well as develop and implement 
a decision-analytic modeling framework that will incorporate within trial findings regarding costs 
and QALYs.   
 
3.2 Scientific Oversight 
 
3.2.1 Scientific Oversight Committees (SOC) 
There are four SOCs that will provide scientific oversight for distinct aspects of the trial.  CCC 
and DCC staff and SOC leadership will provide day-to-day guidance on issues pertaining to the 
implementation procedures for recruitment, measurement, intervention delivery, and data 
management and analysis.  SOCs will perform their responsibilities under the guidance of the 
SC and with assistance from CCC and DCC personnel.  The areas of responsibility and 
membership of each committee are described briefly below. 
 
Recruitment and Evaluation   
The Recruitment and Evaluation SOC will refine and optimize procedures and strategies for 
recruitment and retention of study participants and for maintaining adherence to the protocol.  It 
will be this group’s responsibility to oversee recruitment progress at all sites, intervene in cases 
of under-recruitment, and report recruitment progress to the SC. The committee will oversee 
retention efforts and investigate and intervene when a site is having retention problems.  A 
study management database will be developed by the CCC to provide a standardized way for 
clinical sites to monitor study-related activities in a timely way (see section Section 16:).  The 
Recruitment and Evaluation SOC will utilize reports from this database which will allow 
monitoring of recruitment, retention, and data collection by clinical site.  Another responsibility of 
this committee is ensuring that protocols are followed for data collection procedures and that 
each clinical site establishes standard operating procedures and maintains a current version 
throughout the study.  The Recruitment and Evaluation SOC will also monitor data collection for 
the CAP study and approved ancillary studies.  This committee will be led by the director of the 
CCC and will include the clinical site PIs and the director of the EEC.   
 
Clinical Direction    
The Clinical Direction SOC will contribute to protocol implementation from the perspective of 
orthopaedic surgery and clinical gerontology, reviewing clinical practice-related issues and 
overseeing the clinical safety of all study participants.  The group will monitor the scientific 
literature, scientific meetings, and input received from colleagues on medical topics that are 
relevant to the project and advise the SC on emerging scientific issues that may affect the 
conduct of the study.  Committee members will be on call on a rotating basis to answer 
questions about eligibility from clinical staff and to serve as Independent Safety Monitors (ISMs) 
to review RAEs. They may be asked to provide medical advice in study-related emergencies 

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9 
and to address IRB issues related to participant safety.   
 
Intervention   
The Intervention SOC will finalize and refine the intervention protocols and work closely with the 
CCC and clinical sites to ensure the QC procedures and training for the intervention. The 
committee will develop the Intervention Manual, and together with the Recruitment and 
Evaluation SOC, will implement strategies to enhance and monitor treatment fidelity and 
adherence to the interventions.  This committee will be responsible for selecting, training, and 
certifying all PTs involved in the intervention protocols. 
 
Publications and Ancillary Studies Committee (PASC) 
The PASC will be responsible for: (a) encouraging production of high quality publications and 
presentations in a timely fashion, (b) encouraging broad participation by the study investigators 
in publications, abstracts, and presentations, c) reviewing ancillary studies with regard to 
scientific value and participant burden, paying particular attention to avoiding interference with 
the main study, and (d) assuring accurate maintenance of a database on study publications, 
presentations and ancillary studies.  The PASC will review proposals for and final versions of 
research abstracts, presentations, manuscripts to be submitted to journals, and proposals for 
ancillary studies.  The PASC will report its recommendations to the SC for ratification. Standing 
members will include two committee co-chairs, and the study chair and co-chair of the SC. 
Additional committee members will be recommended by standing members; at a minimum, the 
directors of the DCC and CCC will each be invited to nominate one representative to serve as a 
standing member of the PASC.   
 
3.2.2 Specialized Support for Exercise and Nutrition  
This advisory committee will provide guidance and expertise to the SC and Oversight 
Committee Chairs in the areas of exercise and nutrition in older adults as required during the 
development of the protocol, MOP, and training materials; execution of the project; and 
interpretation of study findings as they relate to the interventions.  The committee will convene 
on an as-needed basis at the request of the SC. This advisory committee will be involved in 
providing guidance on the development and implementation of the dietician protocol and will 
work closely with the Intervention Oversight Committee to ensure the successful and safe 
implementation of the interventions. 
 
3.2.3 UMB Investigational Drug Services (IDS)  
The University of Maryland IDS will be responsible for the purchasing, distributing, and 
accounting procedures for all investigational drugs within the University of Maryland Medical 
Center campus and will be responsible for preparing and shipping the vitamins/supplements for 
this project to each of the clinical sites. The vitamins/supplements for the study will be 
purchased and managed through the University of Maryland IDS.  IDS will prepare “treatment 
kits” for each randomized participant that will include all vitamins/supplements for the 16-week 
study period: 
1.) 2000 IU vitamin D3, one tablet daily  
2.) 600 mg calcium, one tablet daily 
3.) Multivitamin, one tablet daily 
 
Each treatment kit will contain four individual packs numbered 1-4. Each pack contains a 4-
week supply of vitamin D3, calcium, and a multivitamin. The IDS will prepare appropriate 
packaging for each item in the treatment kit, with a label and directions for taking each product 
that complies with legal requirements. Participants who have contraindications for calcium 
supplementation (i.e., calculated creatinine clearance < 30 ml/min, elevated total or ionized 

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calcium, history of kidney stones, primary hyperparathyroidism, or sarcoidosis) will not be given 
calcium. 
 
3.2.4 Study Clinical Sites  
The study has three collaborating clinical sites each with a clinical site PI and coordinator. The 
three clinical sites are Arcadia University (AU), University of Maryland Baltimore (UMB), and 
University of Connecticut Health Center (UCHC). 
 
Responsibilities of the clinical site PI (with assistance from the coordinator) will include:  
 
Maintaining cooperation of study hospitals and other recruitment sites and ensuring that 
medical staff involved with the care of hip fracture patients are well informed about the 
trial 
 
Recruiting study participants according to the study protocol 
 
Ensuring retention and adherence of study participants 
 
Performing all study-related assessments (including complete tracking of outcomes 
during follow-up) 
 
Overseeing completion of data collection forms, enrolling participants using the 
automated randomization system, and entering data and processing data edit queries  
 
Training and supervising staff at the clinical site; assigning tasks to data collectors, PTs, 
and dieticians; and providing day-to-day supervision of their work 
 
Protecting participant safety and verifying that informed consent procedures are followed 
according to Good Clinical Practice guidelines 
 
Properly maintaining all clinical site study materials and records 
 
Reporting all RAEs and protocol deviations 
 
Participating in the study oversight committees and manuscript preparation  
 

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11 
 
National Institute 
on Aging 
 
Data and Safety 
Monitoring Board 
Clinical Sites 
 
Biostatistics and 
Analysis 
 
 
Randomization 
 (Axio) 
 
University of Connecticut 
Health Center 
 
 
Arcadia  
University 
 
 
University of Maryland 
Baltimore 
 
Scientific Oversight Committees
 
Recruitment and Evaluation 
 
Intervention 
 
Clinical Direction 
 
 
Data Capture and  
Management  
 (Axio) 
 
Study Chair and Co-Chair 
Specialized Support for 
Exercise and Nutrition 
 
Economic Evaluation Core 
Investigational 
Drug Services 
(IDS) 
 
Publications and  
Ancillary Studies 
3.3 Organizational Chart 
 
 
 
 
 
 
 
 
Steering Committee 
 
Data Coordinating Center 
 
Clinical Coordinating Center 

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Section 4: Study Objectives 
 
4.1 Primary Objective 
The primary objective will be to determine if a specific multi-component 16-week intervention 
based on aerobic conditioning, specificity of training, and muscle overload (the PUSH 
intervention), initiated up to 26 weeks following admission to the hospital for hip fracture, will be 
more successful in producing community ambulation at 16 weeks after study entry 
(approximately six months post-fracture) compared to a non-specific multi-component 
intervention of transcutaneous electrical nerve stimulation (TENS), flexibility activities, and 
AROM exercises (the PULSE intervention).   
 
The primary hypothesis is that there will be a 20 percentage point or greater difference in the 
proportion of PUSH compared to PULSE participants who achieve community ambulation 16 
weeks after randomization. Community ambulation will be defined as walking at least 300 
meters in six minutes on the Six-Minute Walk Test (SMWT). 
 
4.2 Secondary Objectives 
Delayed and sustained effects. A secondary objective will be to determine whether the 
proportion of community ambulators differs between the PUSH and PULSE interventions at 40 
weeks post-randomization and, for the subset of participants who were followed for 40 weeks, 
whether the difference in proportions at 40 weeks changed from the difference in proportions at 
16 weeks. 
 
Effect on secondary and tertiary outcomes. There are five variables (endurance, dynamic 
balance, walking speed, quadriceps strength, and lower extremity function) that are 
hypothesized to be precursors to community ambulation. To gain a better understanding of the 
interventions’ mechanisms, the two groups will be compared at 16 weeks post-randomization on 
each of these outcomes and at 40 weeks post-randomization for the subset of participants who 
are followed for 40 weeks. In addition, this study will assess the effect of the interventions on 
several tertiary outcomes including ADLs, balance confidence, quality of life, physical activity, 
lower extremity physical performance, depressive symptoms, increase of ≥ 50 meters in 
distance walked in six minutes, cognitive status, and nutritional status. 
 
Cost-effectiveness of the interventions.  The economic value of the interventions will be 
determined by assessing the impact on QALYs, cost, and cost per QALY gained over the follow-
up period. This RCT will provide critical information on whether the specific PUSH intervention 
can improve a hip fracture patient’s ability to ambulate in the community in a cost-effective 
manner compared to the non-specific PULSE intervention. To address the economic value of 
trial interventions versus usual care, a model-based analysis that combines trial data with other 
data sources also will be undertaken. 
 
Section 5: Background  
Current standard Medicare-reimbursed rehabilitation therapy fails to restore community 
ambulation to older persons who have had a hip fracture. A residual mobility disability similar to 
that reported for stroke occurs in the majority of persons who “recover” from hip fracture.10,11  In 
contrast to stroke, heart disease, and cancer, there are few intervention trials focused on 
decreasing disability following hip fracture. The paucity of intervention trials is surprising since 
there are over 325,000 hip fractures per year in the U.S.12 with a predicted increase to over 
650,000 per year by 2040.13 The estimated cost to hip fracture patients, their families and the 

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13 
health care system is between $14 and $20 billion annually.14-19 A Cochrane Collaboration 
review on interventions post-hip fracture concluded that there is not sufficient evidence to 
determine if the interventions evaluated substantially reduce residual disability and enhance 
community ambulation.20 
 
5.1  Residual Deficits in Precursors of Community Ambulation 
Effective community ambulation requires sufficiency in five physical precursors: endurance; 
dynamic balance; lower limb muscle strength; walking speed; and lower extremity function. The 
precursors enable the person to get up out of bed, get out the front door, and participate in 
community activities. Previous studies indicate significant residual impairments for persons with 
hip fracture who have completed “usual” care.  
 
Endurance. Deconditioning is expected following a hip fracture, but there is a paucity of 
evidence on aerobic capacity from maximal treadmill or cycle ergometry exercise tests.21-25 The 
only study that examined peak oxygen uptake (VO2 peak) values in 20 persons within a month 
of fracture, reported significantly lower peak values in hip fracture vs healthy community-
dwelling older adults.26 The SMWT has been used as a proxy for aerobic capacity and is 
considered an endurance measure in elderly, frail and severely compromised patients.27  
Performance on the SMWT by persons post-hip fracture closely resembles that of patients with 
New York Heart Association class III or IV heart failure who walk 217 meters on average.28  
Mangione reported average SMWT distances of approximately 200 meters after usual care for 
hip fracture.29 Work in Baltimore and in the pilot study for this trial indicate an average SMWT 
distance of 154 m and 184 m, respectively, at six months post-fracture. This contrasts to 400 
meters reported for 80-year-olds living in the community30 or 350 meters reported for a sample 
of comparable age in the Cardiovascular Health Study.31 
 
Balance. Dynamic balance is compromised after hip fracture. For example, at the end of usual 
care (2-3 months post-fracture), 20% who had regained independence in ADL reported falling; 
those who had fallen since hospital discharge had poorer balance compared to those who had 
not fallen.10,32  Fifty-three percent of patients who were community dwelling pre-fracture fell one 
or more times in the first six months post-fracture and 18% were readmitted to the hospital for 
fall-related injury.10  Balance deficits remain at seven months33 at a time when physical recovery 
is reported to approach a plateau.1,2  
 
Walking  Speed. The proportion of individuals achieving independence in ambulation one year 
post-fracture is between 30% and 83%, depending on the study.34-37   Reasons for the variation 
in reported ambulatory status include the use of different measures, differences in the length of 
follow-up time and different definitions of recovery. It has also been observed that recovery in 
gait speed does not reach a plateau until almost a year post-fracture (Magaziner 2000) 
suggesting that interventions prior to that time might add to the natural recovery process.  
 
Lower Extremity Muscle Strength. Hip fracture is accompanied by rapid loss of muscle mass 
and weakness.38  Muscle weakness is not the sole impairment accounting for extensive residual 
disability post-fracture, but its contribution is significant. Leg, thigh, and hip muscle weakness 
are related to decreased muscle power and walking speed.39-42  Muscle weakness appears, 
therefore, to be a major factor in producing mobility disability.   
 
Lower Extremity Function. A hip fracture results in limited lower extremity function that, in turn, 
compromises physical, instrumental and social function.43,44  At six months post-fracture when 
physical recovery is reported to plateau, a limited proportion of hip fracture patients report 
climbing a flight of stairs (8%) or walking one half a mile (6%).2,45  The majority of patients who 

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14 
report independent ambulation also report they do not walk as well they did prior to fracture.1,46  
Even at one year, most hip fracture patients do not return to pre-fracture functional status.2,45,47-
50  They walk more unsteadily and more slowly for shorter distances.51,52  
 
Summary: The numbers and costs of hip fracture are significant, and one to two months of 
usual care is inadequate for restoring function to this patient group.  Most hip fracture patients 
do not regain pre-fracture mobility status. Endurance, dynamic balance, walking speed, lower 
extremity muscle strength, and lower extremity function are compromised and contribute to 
failure to achieve community ambulation. 
 
5.2 Exercise Studies in Persons after Hip Fracture 
Based on the results of Mangione’s survey of 1000 home care PTs,53 we propose that a reason 
for the residual disability after hip fracture is an inadequate dose of physical intervention during 
usual care. A limited number of investigations have examined the direct effect of physical 
interventions on increasing community ambulation. Only 15 studies were included in a 
systematic review of physical therapy management of hip fracture. 54 A finding relevant to this 
study is that usual care outcomes were similar for home, acute rehabilitation, or skilled nursing 
facilities.  
 
A Cochrane Collaboration review of exercise interventions 20 identified 13 clinical trials in 1,065 
patients and concluded that there was insufficient evidence to determine if physical intervention 
affected outcome post-hip fracture.  Seven trials26,55-60 provided intervention early 
(approximately two months) after hip fracture. Various combinations of low intensity AROM or 
flexibility exercises, functional training, strengthening, and balance exercise did not produce 
outcomes that were different from “usual care” with three exceptions.26,55,56 Since the Cochrane 
review, two additional trials intervened with exercise programs early after hip fracture. One 
offered a one-month intervention focused on falls efficacy and reported initial improvements in 
walking outdoors and ADLs at two months post-fracture.61 Another trial reported no benefit in 
knee extensor muscle strength or walking speed compared to the control group following a 16-
week, home-based strengthening program.62 We believe that differences were not observed 
because the exercise dose was inadequate. This hypothesis is supported by three small trials 
which reported between-group differences and demonstrate that higher intensity exercise can 
be done early and safely. Two of the studies included high intensity exercise very early after hip 
fracture.55,56 Strength, gait speed, balance, and balance confidence improved in the 
experimental groups. The third trial,26 which included aerobic conditioning during in-patient 
rehabilitation, demonstrated improved endurance (VO2 peak), increased mobility, and improved 
balance.  
 
The other clinical trials began six months or later after hip fracture, with interventions that 
included various combinations of strengthening exercise, balance training, functional training, 
and AROM/flexibility. Three of these included endurance training but lacked at least one of the 
other components of the program we are proposing. Results show positive outcomes in terms of 
function, gait speed, balance, strength, and endurance.22,29,63-68  A study conducted in a gym 
demonstrated improvement in self-reported outdoor mobility in the intervention group who were 
four years post-fracture, but no changes in dynamic balance or walking speed.69 Since hip 
fracture recovery is reported to plateau at six months (which is when the interventions in these 
studies began), the results of these studies are comparable to the exercise findings reported in 
older adults without hip fracture, i.e., that older adults benefit from increased activity. These 
studies indicate that use of higher intensity exercise with endurance training beginning six 
months post-fracture reduces impairments in precursors to community ambulation.  
 

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The unanswered question is whether a higher intensity program performed as soon as usual 
care is complete will return more people to community ambulation. Mangione described a 
program that provided function, strength, balance, and endurance training to a single patient 
three months post-fracture.70  The patient showed dramatic improvements in all physical 
precursors to community ambulation. In addition, the recent pilot study of the intervention 
resulted in a significant between-group difference in distance walked on the SMWT.  
 
A limited number of studies have examined exercise programs post-hip fracture. The most 
successful in terms of strength, balance, and gait speed outcomes were completed over a 6-
month time period in an exercise center.22,68 The majority of the research published is fraught 
with problems including lack of control groups, small samples, and inadequate exercise dose.  
Prior research suggests that more intensive multi-component training as soon as usual care is 
complete should be safe and effective.  
 
5.3 Rationale for the Interventions  
The significant mobility disability that remains post-hip fracture is remarkable and may account 
for failure to return to effective community ambulation. Mangione et al. surveyed physical 
therapists nationally to describe usual home care physical therapy following in-patient sub-acute 
care for hip fracture.53 The results indicated very similar care regardless of fracture fixation, 
weight-bearing status, time when physical therapy started, or geographic location. Functional 
training was one of the most frequently reported interventions. Most of the joint-specific 
therapeutic exercises reported involved AROM, with very few therapists reporting that they used 
any form of resistance (manual, elastic bands, or weights) for a specific exercise. This study will 
compare the effect of two interventions that provide additional supervised exercise in the home 
following completion of post-acute rehabilitation. One intervention will be specific in delivering 
exercise focused on addressing the precursors of ambulation in the community (PUSH). The 
other intervention (PULSE) will be non-specific and will be similar to the joint-specific 
therapeutic exercises described in the Mangione et al. trial71 and will add a modality for pain 
relief.72 Since a systematic review indicates that the evidence is insufficient with respect to best 
practices in rehabilitating hip fracture in older adults, both interventions are plausible for 
improving mobility in patients after hip fracture.  
 
PUSH. Older adults improve functional performance when engaging in high intensity multiple 
component interventions.73-79  Despite disagreement about exercise type, intensity, frequency, 
duration, and mechanism, it is known that the older musculoskeletal system adapts to increased 
demand.80  Several randomized trials have reported effects of exercise interventions on 
improved physical function, balance, endurance, mobility and/or falls in community-dwelling 
elders without hip fracture.22,77,78,81-85  Studies reporting positive outcomes had similar content 
(strength, balance, and endurance), used high exercise intensity, and the exercises were 
tailored to the individual’s needs rather than using a generic protocol. Task-oriented functional 
activities81,83 were more effective in achieving positive outcomes than traditional regimens that 
included isometric or isotonic strength training, static standing balance training, and/or cycle 
ergometry.77,82 
 
Principles derived from exercise physiology will be used to determine the intensity of the 
endurance and muscle performance exercises. According to the overload principle, exercise 
should be performed at an intensity higher than the usual load to increase the metabolic 
demand and facilitate a training response.80,86-88  Overload will be achieved by increasing 
intensity (effort or load), or frequency and duration (number of repetitions, number of sets). 
Manipulation of intensity, frequency, or duration alters the exercise dose - heart rate for 
endurance training or the amount of muscle force produced for muscle strengthening.86 A 

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16 
review and a meta-analysis emphasize the benefits of endurance training and progressive 
resistance training for improvement in functional status, health, and quality of life in older 
adults.89,90 Guidelines suggested by these two reviews recommend combining endurance, 
dynamic balance, and high intensity strength training, which is consistent with the PUSH 
intervention.  
 
The specificity of training principle has been neglected in many hip fracture intervention 
programs. Research suggests that the type of muscle contractions used during exercise should 
match the type of contractions used in the desired activity to achieve the most gain.80,86  The 
multi-component PUSH intervention will address endurance by requiring completion of task-
specific activities for a continuous period of time. Muscle training will be addressed using a 
machine that provides progressive resistance training while the lower extremity performs whole 
limb patterns similar to those used in walking. Upright balance will be challenged in combination 
with muscle training.  Although there is evidence that appropriate training increases endurance 
and muscle performance, the mechanisms for adaptation in response to exercise in older adults 
are still being clarified.91-95  Motor learning principles, theories associated with neural plasticity 
and exercise physiology must all be considered in the design of an intervention focused on 
increasing community ambulation.80 The older person with hip fracture is more complex 
because of the significant newly acquired deconditioning, muscle atrophy, fracture healing, and 
other metabolic changes. 
 
PULSE.  The PULSE intervention emphasizes increased mobility through AROM exercises for 
the whole body. In addition, this intervention will be supervised by a physical therapist so that 
participants perform techniques correctly and proper breathing is ensured throughout. Following 
hip fracture, lower extremity muscle strength is reduced. Many factors have been cited to 
account for this impairment including inactivity, fear of moving the injured limb, and pain. 
Arthrogenic muscle response (AMR), defined as an ongoing reflex reaction of the musculature 
surrounding a joint after distension or damage to structures of that joint, is another reported 
consequence of joint injury.71 AMR has been suggested to be the result of inhibition of a 
muscle’s motoneuron pool excitability and appears to be independent of pain and swelling and 
may persist after the acute injury has resolved. A current hypothesis is that AMR occurs in 
response to distorted articular sensory receptors after joint injury. Although AMR has been 
studied in the knee, shoulder, elbow and ankle, this response may also occur in the hip muscle 
following hip fracture and surgical repair. One reason, therefore, that TENS will be applied to the 
gluteal, quadriceps, and gastroc-soleus muscles is to promote somatosensory input; the goal of 
this input is to induce changes in the excitability of the motor neurons and to somatosensory 
motor cortex to assist in activation of the motor neurons.96  
 
The other reason that we are proposing the use of TENS is to assist in pain management. 
Herrick et al (2004) grouped persons with hip fracture as moderate/severe or mild/no pain.97 
Forty-two percent of the sample reported moderate/severe pain at baseline. The other benefit of 
TENS will be to reduce pain which may lead to an increased activity level. TENS has been 
demonstrated to be effective in managing both acute and chronic pain for a number of 
conditions. Cheing and Hui-Chan (2004), for example, reported that TENS alone applied to 
persons with chronic pain secondary to knee osteoarthritis resulted in an increase in knee ROM 
during walking and increased gait speed.98 TENS was compared with a sham control after 
surgical repair of hip fracture. When TENS was applied after surgery, pain on movement was 
reduced and health-related quality of life improved.99 Gorodetskyi (2007) compared the effect of 
electrical stimulation to a sham control in 60 older people during acute hospitalization following 
hip fracture repair.100 Participants receiving electrical stimulation reported substantially and 
significantly less interference from pain on walking ability after each of the 10 sessions. Pain 

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17 
scores, which decreased over the 10-day treatment period in both groups, were also markedly 
less in the electrical stimulation group. The two studies that have examined the use of TENS for 
pain alleviation have not, however, examined its effect on alleviation of the chronic pain reported 
by persons after hip fracture. 
 
5.4 Primary Outcome Measure 
Community ambulation is a construct that includes the ability to accommodate change in level 
and terrain irregularity (necessary to enter and leave the home and for curb management), 
avoid obstacles and walk a requisite distance.101  Compared to older adults who are active in 
the community, persons with a mobility disability do not travel alone, take fewer trips and 
perform fewer activities per trip, walk shorter distances, cross the street less often, carry fewer 
objects, and have fewer postural transitions (turning the head, extending their reach, or 
changing direction).102  Although community ambulation is complex, covering a minimal distance 
within a specified period of time is a critical feature.103,104 
 
The SMWT is a standardized test that examines both the distance and time components of 
community ambulation.105 The Cardiovascular Health Study106 concluded that the SMWT is safe 
for use in community samples to measure the impact of multiple comorbidities on endurance in 
older adults.31  Harada et al 107 proposed that the SMWT is a useful integrated measure of 
mobility function taking into account any limitations imposed by major body systems.107  Lord 
and Menz108 concluded that the SMWT provides a measure of overall mobility and physical 
function in addition to being a measure of cardiovascular fitness. Sixty-nine percent of the 
variance in the SMWT is explained by physical functioning, lower body strength, standing 
balance, and gait speed.107  Construct and predictive validity and responsiveness to change 
were established for the SMWT in a sample of 108 persons with hip fracture.109 A high positive 
correlation was reported between pedometer-determined physical activity and the SMWT test 
suggesting that both are correlates of community ambulation.110 The SMWT also has been used 
as an outcome measure to determine the effectiveness of exercise interventions for elderly 
patients with and without hip fracture.29,63,111 
 
Distance. Some investigators use a 400 m threshold (2-3 city blocks) for the SMWT to identify 
community-dwelling elders at risk for developing a mobility disability.27,82,107,108,112-114  This 
threshold appears valid to detect early decline in community dwelling elders.27,31,82,107,108  Four 
hundred meters, however, is considered too high for this investigation where the goal is to assist 
participants, with a significant mobility disability due to recent hip fracture, to return to 
community ambulation. Several investigators support a 300 m threshold for community 
ambulation. 102,107  Reasons to adopt a 300 m distance threshold on the SMWT test include:   1) 
at six months post-fracture or post-stroke, average group performance is < 300 m29,63,72,109,115; 2) 
achieving < 300 m on the SMWT is a predictor of mortality;28 3) average distance from parking 
space in a supermarket parking lot to task completion in the supermarket in both urban and rural 
communities is 301 m.103   
 
Time. Usual walking speed has been determined from observing walking speeds of urban 
pedestrians and from human performance laboratory investigations.116-120  Functional walking 
categories have been developed to include the community walker (i.e., independent in all home 
and community activities).  A reported gait speed of 0.8 m/s signifies the community 
walker.121,122  One year post-hip fracture, usual gait speeds range from 0.44 to 0.97 m/s, 
29,33,56,57,64,72,123-125 the average of which is below the community ambulation threshold. Others 
have reported that a speed threshold of 0.8 m/s is a useful and discriminative primary endpoint 
in clinical trials of exercise rehabilitation.125 
 

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Summary and Primary Endpoint: The SMWT is an assessment with excellent psychometric 
properties, and there is sound justification for a 300 m distance threshold on the SMWT 
(equivalent to walking at 0.8 m/s) to serve as an indicator for community ambulatory ability.  
 
5.5 Economic Evaluation of Interventions to Reduce Post-fracture Disability  
The economic consequences of hip fracture are substantial.17 In a society with limited 
resources, each additional expenditure should produce a benefit that is worth the additional 
cost. Although a number of studies have addressed the cost-effectiveness of hip fracture 
prevention through pharmacological and hip-protector interventions,126-134 the value of exercise 
interventions to reduce post-fracture disability has not been evaluated. Nonetheless, the role of 
post-fracture disability in overall economic costs is well-recognized as is the dearth of studies 
that have attempted to characterize indirect costs of fracture.135  Therefore, a secondary aim of 
the study will be to assess the economic value of the interventions compared to each other as 
well as the interventions compared to usual care. This evaluation will estimate the cost per 
additional quality-adjusted life year (QALY) gained.136 
 
Section 6: Study Design 
 
6.1 Overview of Study Design 
A RCT of 210 older adults who have experienced a hip fracture will be carried out at three 
clinical sites (AU, UMB, and UCHC) with half of the subjects receiving a specific multi-
component intervention (PUSH) and the other half receiving a non-specific multicomponent 
intervention (PULSE). Randomization of 210 participants meeting eligibility criteria will take 
place after post-acute rehabilitation ends, up to 26 weeks after admission to the hospital for hip 
fracture. The primary endpoint will be measured 16 weeks after randomization. Patients age 60 
and older who have had surgical repair for hip fracture will be identified at the three clinical sites 
through a variety of recruitment sources and  will be  evaluated for eligibility. Following consent 
to participate, eligible participants will undergo a comprehensive baseline assessment and will 
then be randomized to one of the two treatment groups. The cohort will be measured again 16 
weeks post-randomization. Figure 1 shows the sequence of participant contacts from the time of 
hospitalization until the final assessment approximately 16 weeks after randomization. 
 
Figure 1. Timeline for screening, randomization, and follow-up 
Hospital 
admission 
 
Randomization 
16-week 
follow-up 
Eligibility 
screening  
(3 phases) 
 
16-week intervention 
Telephone interviews every four weeks 

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19 
 
Within a week of randomization, participants will initiate the intervention with a PT in their place 
of residence and receive counseling with a registered dietician. The follow-up assessment will 
take place 16 weeks post-randomization. Telephone interviews will be conducted every four 
weeks, beginning four weeks post-randomization, to obtain information about RAEs and 
expected AEs, and to help reduce loss to follow-up by maintaining ongoing rapport with 
participants. An honorarium will be given at the completion of both study assessment visits. 
 
For participants randomized prior to version 10.0 of the protocol, follow-up assessment visits 
occurred 16 weeks and 40 weeks from the date of randomization and telephone interviews were 
conducted every four weeks during the 40-week study period for a total of 10 telephone 
interviews.  
 
6.2 Randomization 
Randomization will occur up to 26 weeks after admission to the hospital for a hip fracture. The 
randomization schedule for each clinical site will ensure that treatments are randomly assigned 
within blocks of 2, 4, 6, or 8, with equal numbers of participants assigned to each treatment 
within each block. Block sizes (two to eight participants per block) will be randomly selected with 
the probability of each block size specified by DCC staff.  
 
To ensure that those performing evaluations remain blinded to treatment assignment, 
randomization will only be performed by appropriate unblinded study personnel who have 
received training and certification on randomization procedures.  The clinical site PI, clinical site 
coordinator, or another unblinded designee will perform the randomization. Random treatment 
assignments will be obtained using a secure Web-based randomization system. Each member 
of the study staff who has permission to randomize participants will be assigned a unique, 
nontransferable user ID that will be required to obtain random treatment allocations. The study 
staff member will access the system by login on a secure (encrypted) Web site and receive the 
treatment assignment after responding to prompts confirming that the participant meets all 
inclusion and exclusion criteria and has given informed consent for enrollment. A printable 
report will be available as part of the Web system. Site staff will be instructed to print the report 
and retain it in the participant’s binder. Access to the binders is limited to the clinical site PI and 
coordinator.  The date of randomization will mark the start of follow-up for each participant; a 
computer record is maintained for each attempt to randomize a participant. The clinical site 
coordinator will inform participants of their group assignment and will tell them when their PT 
sessions will begin. The coordinator will also provide the name of the PT who will be contacting 
them. The coordinator will then alert the assigned PT who will contact the participant to 
schedule the first intervention visit.  
 
6.3 Interventions 
Over a 16-week period, participants in both groups will receive two visits per week, on non-
consecutive days, for a total of 32 visits. Visits from a study PT will take place in participants’ 
place of residence. The PUSH intervention group will be receiving a specific multi-component 
training intervention and the PULSE intervention group will receive a non-specific multi-
component intervention that stimulates the same muscle groups as in the PUSH group. 
Participants in both intervention groups will receive 2000 IU of vitamin D3, 600 mg of calcium, 
and a multivitamin daily for the duration of the study and nutritional counseling to ensure weight 
stability and adequate nutrient intake inclusive of a healthy diet.  
 

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6.4 Blinding of Study Staff 
Given the nature of the interventions being tested in this study, it will not be possible to blind the 
participants or the PTs providing the interventions. To minimize “contamination” of the 
interventions, each PT will provide only one of the interventions and PTs will not have contact 
with participants in the other group or with PTs providing the intervention to the other group. The 
interventionists will be told that this is a study comparing a specific multi-component intervention 
and a non-specific multi-component intervention to increase mobility following hip fracture, but 
specific hypotheses or rationale of the study will not be discussed with them. The 
interventionists will be blinded to participants’ study outcomes.   
 
Clinical site PIs and clinical site coordinators who are responsible for assigning work and/or 
assessing for treatment fidelity of PTs in both groups are unblinded.  Unblinded study staff 
involved in randomization will not perform follow-up data collection.  
 
Only those who will perform evaluations (clinical site visits and telephone interviews) after 
randomization and the Independent Safety Monitor (ISM) will be blinded to treatment 
assignment.  Blinded study staff performing follow-up assessments or telephone interviews are 
instructed not to ask about treatment assignment when in contact with participants. Participants 
will be asked not to discuss their treatment experience (including the identity of the PT providing 
the intervention) during study visits and telephone calls conducted by blinded staff.  
 
Only a small number of DCC staff members and members of the DSMB will see group-specific 
study results. In the event of inadvertent unblinding of study staff, a protocol deviation will be 
reported and a notation will be made in the participant binder specifying the circumstances of 
the unblinding event and a list of all persons unblinded.  
 
Section 7: Selection and Enrollment of Participants 
 
7.1 Eligibility   
Participants will be evaluated for eligibility in three phases (see Figure 2), all of which must be 
completed no more than 26 weeks after admission to the hospital for a hip fracture.  In phase 1, 
patients will be assessed for inclusion criteria and medical exclusions. Information for phase 1 
will be collected from the patient’s medical chart.  Patients who are provisionally eligible based 
on medical chart review at phase 1 will be approached in the hospital (or soon after discharge) 
and told about the study. Interested patients (or their legally authorized representative) will be 
asked to provide permission to contact for additional screening. Phase 2, which will take place 
any time before the maximum timeframe for randomization (26 weeks post hospital admission) 
will involve contacting the participant to assess for medical, safety, and feasibility criteria.  
 
Blood will be collected and tested for hemoglobin (<9 g/dl), serum creatinine to calculate 
creatinine clearance (<15 ml/min), and serum albumin (<2.5 g/dl). The blood collection can 
occur anytime between phases 2 and 3 screening as long as it occurs after informed consent is 
obtained and no more than 4 weeks prior to randomization. 
 
Phase 3 will assess final eligibility at the clinical site center at the beginning of the baseline visit. 
Phase 3 must be completed no later than 26 weeks after admission to the hospital for hip 
fracture. Prior to the phase 3 visit, the study coordinator will attempt to contact an appropriate 
medical professional (e.g., primary care physician, orthopaedic surgeon, etc.) who has had 
contact with the person since the hip fracture to review medical history and confirm safety for 
participation in the interventions. Phase 3 will include a review of all disqualifying medical 

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     Figure 2. Algorithm for Screening  
Not Eligible  
No 
 Yes 
No 
 Yes 
No 
Randomized 
Phase 1 Screening  
Chart Review  
Phase 2 
Screening 
Interview 
Phase 3 Screening  
 
Exclusion Criteria 
3MS score below 73 
SMWT <4 m in 40 sec  
or ≥300 m in 6 mins 
Yes 
Not Randomized 
Complete  
Baseline Data 
 No 
Blood Draw 
Exclusions 
 Yes 
Exclusion Criteria   
 Hemoglobin <9 g/dl 
Calculated creatinine clearance  
<15 ml/min 
    Serum albumin <2.5 g/dl 
 Yes 
No 
Exclusions 
conditions, measurement of height and body weight to calculate body mass index (BMI), 
assessment of cognitive status with the Modified Mini-Mental State examination (3MS), and 
evaluation of ability to walk 300 meters in six minutes. This final test will be used to exclude 
participants who are unlikely to benefit from the study interventions because their gait speed is 
very low (<0.1 m/s) and to exclude those who are able to walk 300 m or more in six minutes and 
are, therefore, already classified as community ambulators. The clinical site study clinician must 
review all study eligibility documents and sign off on final eligibility for all potential participants 
prior to collection of baseline data. Those individuals for whom a medical provider was not 
consulted for clearance to participate in the study will be seen by the clinical site clinician.   
 
Eligible individuals will receive the baseline assessment consisting of questionnaire items and 
testing of muscle, balance and functional performance. Participants with complete baseline data 
will be randomized to one of two treatment groups.  
 
7.2 Inclusion Criteria (Target Population) 
1.  Minimal trauma, non-pathologic hip fracture with surgical repair 
1.1  Closed fracture of proximal femur 
1.2  Minimal trauma fracture 
1.3  Surgical fixation of fracture   
1.4  Non-pathologic fracture  
  
2.   Age 60 or older 
2.1  Age 60 or older at time of randomization 
 
3.  Community ambulation 
3.1  Living in the community at time of fracture 
3.2  Ambulating without human assistance two months prior to fracture 
3.3 
Unable to walk 300 m or more in six minutes without human assistance at time of 
randomization  
 
 
7.3 Exclusion Criteria 
 
4. Logistical impediments to participation 
4.1. Does not live within reasonable distance of the clinical center 

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4.2. Participant plans to move out of area or otherwise be unavailable during the 16-week 
intervention period 
4.3. Participation in another clinical trial  
4.4. Not English speaking 
4.5. Not randomized by 26 weeks post admission for hip fracture 
4.6. Final sign off from study clinician and/or principal investigator is incomplete 
4.7. Incomplete baseline data 
4.8. Unable to contact participant 
4.9. Participant is unable to provide her/his own informed consent 
4.10. Participant refuses the study 
 
 
5. Medical impediments to participation or low potential for benefit from interventions 
5.1. Calculated creatinine clearance < 15 ml/min 
5.2. Serum albumin < 2.5 g/dl 
5.3. End stage renal disease on dialysis 
5.4. Lower extremity amputation 
5.5. Cognitive impairment (3MS score <73) 
5.6. Severely diminished lower extremity sensation or ulceration  
5.7. Participant walks less than four meters in 40 seconds (<0.1 m/sec) 
5.8. Not community-residing (e.g., resident of a skilled nursing facility) at time of 
randomization  
5.9. Receiving PT  for the hip fracture in the hospital or in an inpatient rehabilitation facility 
at time of randomization 
 
6. Medical contra-indications for exercise 
6.1. Hemoglobin < 9 g/dl 
6.2. Symptoms of angina pectoris  
6.3. Recent myocardial infarction  
6.4. Uncompensated congestive heart failure  
6.5. Chest pain or shortness of breath (including from severe chronic obstructive 
pulmonary disease) 
6.6. Uncontrolled hypertension 
6.7. Not fully weight-bearing on fractured leg or non-fractured leg at time of randomization 
6.8. Denied medical clearance by appropriate medical provider 
6.9. Clinical site clinician thinks participant is not a good candidate for study (e.g., not likely 
to survive study period) 
6.10. Development of chest pain or substantial shortness of breath or ambulating with 
severe pain during baseline SMWT 
 
7.4 Identification of Hip Fracture Patients 
Potential participants will be identified directly from study hospitals, rehabilitation centers, or 
agencies that care for older adults or they may contact the study directly in response to other 
recruitment methods such as study recruitment flyers, advertisements, social media, or referral 
from a clinician (orthopedic surgeon, physical therapist).   
 
Study hospitals will be chosen based on 1) number of hip fracture patients per hospital per year 
and 2) geographic proximity between hospitals and clinical site.  We will review the number of 
participants recruited in each hospital on a regular basis and initiate enrollment in one or more 
other hospitals if recruitment numbers are lower than expected. We will obtain approval of our 
study protocol from the UMB IRB, from each of the three clinical sites, and from each study 

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hospital.  
 
Clinical site PIs will identify other method(s) of recruitment that are appropriate for their 
respective sites.   
 
7.5 Participant Screening and Recruitment 
Participants will be evaluated for eligibility in three phases to be completed no later than 26 
weeks after admission to the hospital for hip fracture.  Information for phase 1 will be collected 
from the patient’s medical chart. For those identified in acute care hospitals, study staff  with 
adequate medical training and experience reviewing medical records will check the admitting 
records and operating room logs of study hospitals to identify potential hip fracture patients. A 
HIPAA Partial Privacy Waiver (for recruitment) or verbal consent to review the medical chart for 
eligibility will be obtained for patients identified at study hospitals. Patients who are provisionally 
eligible based on medical chart review at phase 1 will be approached in the hospital (or soon 
after discharge) and told about the study.  Written permission from the patient will be obtained to 
allow future contact to collect additional eligibility information. Patients who are identified 
through means of recruitment other than screening in study hospitals will be asked to provide 
written authorization for release of medical records for review of phase 1 eligibility criteria.  
Clinical sites will address specific recruitment methods and content (e.g., customized landing 
pages for websites, print advertisements and flyers) in their local IRB applications.   
 
Phase 2 will assess for additional safety and feasibility criteria prior to the baseline visit.  Phase 
3 will assess eligibility at the beginning of the baseline visit.  This final phase, which will be 
performed at the clinical site, will include a review of new onset medical exclusions, 
measurement of height and weight for BMI, assessment of cognitive status with the 3MS, and 
assessment of ability to walk 300 meters in six minutes. At any point post-admission, potential 
participants and others identified by patients (e.g., caregiver or other family member) will be 
provided with additional information about what participation in the study entails. 
 
7.6 Informed Consent 
Written informed consent and appropriate HIPAA authorizations and/or waivers will be obtained 
in compliance with procedures reviewed and approved by the clinical sites’ IRBs prior to any 
data collection. Informed consent can be obtained anytime upon completion of phase 1 eligibility 
screening and prior to 26 weeks post hospital admission. Regardless of when informed consent 
is obtained, study staff will follow the Good Clinical Practice guidelines for informed consent. A 
copy of the informed consent form (ICF) will always be provided (either in person or by mail) to 
potential participants to allow for adequate review of the information and to allow review with 
family members. Prior to obtaining informed consent, time will be given to the potential 
participant to review the consent form and ask questions. If a participant has vision impairments 
that prevent her/him from reading the ICF, the consent form will be read aloud to them and the 
informed consent process will be witnessed. The witness should also sign and personally date 
the consent form attesting that the information in the consent form and any other written 
information was accurately explained to, and apparently understood by, the participant and that 
informed consent was freely given. Even when the participant reads the consent form on their 
own, study staff will summarize all components of the ICF and remind potential participants that 
participation in the study is voluntary and that s/he has the right to withdraw at any time. It will 
also be explained that signing the consent form allows the study to confirm final eligibility before 
randomization to a treatment group. The consent process will be performed without the use of 
any coercive language or behavior, and with respect for the person's autonomy.  
 

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24 
The goal of the informed consent process is to increase potential participants’ understanding of 
the study in order to better enable them to decide whether or not to enroll.  Therefore, every 
effort will be made to help potential participants understand the research project.  During the 
informed consent process, study staff will provide participants with adequate information 
concerning the study procedures, respond to questions and concerns, and ensure that each 
individual understands all the information provided by assessing ability to provide informed 
consent.   
 
Potential participants who choose to enroll will be assessed for their ability to provide informed 
consent using a local IRB-approved method, such as using the Evaluation to Sign Consent 
measure.  Individuals who do not understand the study purpose, methods, risks, and benefits 
are not able to provide their own informed consent and will not be eligible for participation. The 
informed consent process will be documented by including the following information in the 
research records: that the study was explained, questions (if any) were answered, ability to 
provide informed consent was assessed, subject agreed to participate and signed the consent 
form and HIPAA Authorization, the presence of a witness for individuals with hearing or vision 
impairments, and a copy of the signed consent form and HIPAA Authorization was given to 
participant and, if necessary, left in the chart of facility.  For people who provide informed 
consent, the original signed ICF will be submitted to the study office and a copy of the signed 
ICF will be given to the participant.  If the person provided consent while in a medical facility, a 
copy of the ICF will go into her/his chart. The clinical site PI and/or designee will ensure the 
accuracy, completeness, legibility, and timeliness of the informed consent process conducted by 
the study staff before any phase 3 eligibility data are collected. 
 
7.6.1 Enrollment 
Date of enrollment in the trial is defined as the date of informed consent. 
 
Section 8: Retention 
 
8.1 Retention Promotion Efforts 
At the time of randomization, participants will receive written instructions about the schedule of 
follow-up assessments, PT intervention visits, dietician contact, and four-week telephone 
interviews. To maintain rapport, the same staff member will, whenever possible, contact and 
visit the participant throughout the study. Minimizing waiting time, providing free transportation 
for the baseline and follow-up assessment, and providing comfortable waiting room facilities 
make the visits more pleasant, thereby enhancing participant retention at follow-up. 
 
Participants will be interviewed by telephone every four weeks after randomization for 16 weeks 
to collect information on expected AEs and RAEs. These regular phone contacts also help with 
retention.  Participants will be reminded of the next phone call and follow-up assessment.   
 
If participants are unable to come to the clinical site for the follow-up assessment, a visit at 
another location (home or another facility) will be scheduled. Telephone interviews will be 
scheduled if in-person visits cannot be completed. 
 
Clinical sites will keep detailed records of rescheduled and missed study assessment visits, 
missed phone interviews, and missed intervention visits. Participant retention will be monitored, 
and efforts will be made to provide support and encouragement to participants who are at risk of 
being lost to follow-up. 
 

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25 
8.2 Drop-out Prevention Efforts 
The following procedures will be implemented to minimize and monitor missed follow-up 
assessments, telephone interviews, and intervention visits: 
 
Providing pre-visit reminders (e.g., postcards and phone calls) for upcoming assessment 
visits. Also, reminders about the upcoming follow-up assessment will be provided during 
the four-week phone calls. 
 
Calling participants the night before a follow-up assessment to remind them of the visit 
and the time for transportation pick-up, if appropriate. 
 
Utilizing an Access study management database developed by the CCC to monitor 
participation and attendance within each clinical site, so that staff will be immediately 
alerted to a missed intervention or assessment visit. 
 
Contacting participants (or significant others) when they miss a visit. 
 
Rescheduling the visit within the same window, if possible. 
 
Rescheduling the visit during the out-of-window interval, if necessary. 
 
Some randomized participants may not actively participate in the study, either by declining the 
intervention visits and/or by not attending follow-up assessments. These participants will be 
followed until the end of the study unless they explicitly request not to be contacted. Study staff 
will make contact every four weeks after randomization in order to remind the participant that he 
or she is welcome to rejoin the study at any time. Also, considerable effort will be expended to 
collect data on the primary outcome at the follow-up assessment. 
 
8.3 Monitoring Recruitment and Retention 
The CCC will monitor recruitment and retention with the help of a study management database 
(see Section 16:), which will be used to track all participant contacts, status of participants, 
activity of study staff members, form completion, and form submission. The CCC will track 
screening and recruitment yields against the number expected per site. The CCC will work 
closely with clinical site PIs and the Recruitment and Evaluation SOC to identify and reduce 
barriers to recruitment. We will review the number of patients screened relative to the number of 
participants recruited through each recruitment source quarterly and initiate additional 
enrollment strategies if recruitment goals are not being met. 
 
8.3.1 Monitoring and Quality Control of Recruitment and Retention  
The DCC will collect data to monitor recruitment and retention activities, the number of potential 
participants screened at each site, the yield at the various screening phases, the percent who 
are eligible, and the percent who are randomized. Additionally, a study management database 
will be used by the clinical sites, the Recruitment and Evaluation SOC, and the CCC to monitor 
recruitment to determine if the study hospitals and other recruitment sources are providing the 
expected number of patients. This monitoring will allow early detection of issues and the clinical 
sites will implement procedures for additional recruitment methods, as appropriate. Reports 
from the study management database can also be generated according to individual study staff 
member to identify possible areas for retraining. Retention will be monitored through completion 
rates of follow-up assessment visits, intervention visits, and telephone interviews. Regular 
reports will be available to clinical sites and the CCC.  Members of the CCC maintain regular 
phone contact with clinic staff to: 
1. Review recruitment goals and yields for clinical sites, 
2. Review the recruitment plan and progress in achieving the objectives outlined in 
the plan, 
3. Share successful and unsuccessful recruitment methods, and  
4. Review retention. 

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26 
 
If clinical sites encounter difficulties in recruitment or retention, the CCC (or a subgroup it 
designates) will provide a graduated set of assistance responses that are based on the degree 
of recruitment or retention shortfall. Solutions will be developed that are based on site-specific 
issues. 
 
 
Section 9: Study Interventions 
 
9.1 Overview 
Participants will be assigned to one of two treatment groups: 1) PUSH or 2) PULSE. The PUSH 
intervention group will receive a specific multi-component training intervention and the PULSE 
intervention group will receive a non-specific intervention that stimulates the same muscle 
groups as the PUSH intervention. Both groups will receive 32 visits of approximately 60 minutes 
duration from a study PT. Participants will receive two visits per week, on non-consecutive days, 
for 16 weeks. Missed visits can be replaced during subsequent weeks if there is at least one 
day in between visits and no more than three visits in the week. Visits will take place in the 
participant’s place of residence. 
 
9.2 Nutritional Intervention 
Given the importance of ensuring adequate nutrition in both study groups, we will provide all 
participants with 2000 IU of vitamin D3, 600 mg of calcium, and a multivitamin daily for the 
duration of the 16-week study and nutritional counseling to ensure weight stability, adequate 
nutrient intake of 1 g protein/kg body weight inclusive of a healthy diet (50% carbohydrate, 20% 
protein, 30% fat).  Participants will be screened at the time of randomization to assess 
nutritional risk using the Mini Nutritional Assessment-Short Form (MNA®-SF).6 Those who score 
≤7 (malnourished) at baseline and participants with serum albumin 2.5-3.5 g/dl (regardless of 
the score on MNA®-SF) will receive a visit from a registered dietician (RD) in their place of 
residence within seven days of randomization. The RD will evaluate and counsel them on 
making dietary modifications based on their protein, caloric and other dietary deficiencies using 
a standardized approach across the three study sites.7-9 The RD will follow up with participants 
by telephone one week after the visit to assess understanding and implementation of 
recommendations. Participants who score 8-11 (at risk of malnutrition) at baseline and have 
serum albumin level >3.5 g/dl will receive a telephone dietary consultation with the RD within 
seven days of randomization. Based on the participant's eating habits and food intake, the RD 
may make the clinical determination that an in-person consultation is warranted. In these cases, 
the RD will schedule an in-person dietary consultation, following the same protocol as those 
who score in the malnourished range. Those with a score ≥12 on the MNA®-SF and who have 
serum albumin level >3.5 g/dl at baseline will receive brief telephone contact within seven days 
of randomization from the RD to discuss the importance of calorie and protein intake.  
 
Weight will be monitored during home PT visits every four weeks and those who lose 2% or 
more body weight in a four-week period will receive another telephone consultation by the study 
RD. This protocol applies to anyone who loses 2% or more of body weight, regardless of 
whether the participant is trying to lose weight. In the event that a weight measurement is not 
obtained at the last PT visit, the participant’s weight at the 16-week follow-up assessment will be 
compared to his or her baseline weight and, if there is weight loss of 5% or more, the clinical 
site PI or clinical site clinician will review the participant’s weight trajectory, baseline BMI, 
baseline MNA®-SF score, and registered dietician’s documentation and, if warranted based on 

CAP Protocol version 12.0 
 
27 
clinical judgment, will refer the participant to a dietician or medical provider for follow-up of 
possible poor nutritional status. 
Participants randomized prior to version 10.0 of the protocol received vitamin D, calcium, and 
multivitamin supplements for a total of 40 weeks.  
 
9.3 PUSH Intervention 
This intervention is based on improving specific precursors to community ambulation by 
addressing endurance with continuous upright exercise for 20 minutes in duration; function such 
as walking, standing from a chair, and stair negotiation; muscle performance by exercising to 
enhance lower extremity strength and power in functionally relevant muscles moving through 
locomotion-appropriate movements and ranges; and balance by performing unilateral activities 
and activities with decreased base of support. These components of exercise will be woven 
together into one program that minimizes participant burden. By the end of the first eight weeks 
participants will be instructed to complete the endurance component independently one to two 
times/week by walking for a similar duration and intensity as they have been doing with the PT 
during the supervised visits.  
 
The strength components of the muscle performance intervention will be performed using a 
portable progressive resistive exercise device (Shuttle® MiniPress, Contemporary Design 
Company, P.O. Box 5089, Glacier, WA 98244). The device has six latex bands each with a 
starting load equal to approximately seven pounds. At full excursion one band can provide 
approximately 15 pounds of force. These bands provide the resistance and are attached to the 
machine by a slotted bar on the frame. Inserting more bands into the slotted bar increases the 
resistive load for the participant. A progress monitor strip is located on the top of the machine 
frame. Strips indicate resistance by showing distance that the load is moved. The resistance 
numbers indicate the force for one band as the carriage is moved. When more than one band is 
used, the values will be added.137 
 
Muscle performance will focus on bilateral hip extensors, hip abductors, knee extensors, and 
plantar flexors because of their role in function, specifically gait and transfer activities.138-140  Hip 
and knee extensor muscle will be trained to work hard and fast during the leg press motion 
since this mimics the functional activity of rising from a chair or going up a step. Hip abductors 
will be trained in 5° of adduction and to 10-15° of abduction. Fifteen degrees of movement was 
chosen because it approximates the 8° of motion associated with gait and takes into account 
variations in hip positions while standing.141  Hip extension will also be trained in standing from 
35° of flexion to extension to a neutral position. This ROM approximates the time in the gait 
cycle when the gluteus maximus shows the highest muscle activity, i.e., from heel contact 
through 20% of stride.139  Plantar flexors will be strengthened in standing against body weight77 
because of their role in the push-off phase of gait and the strong association of  plantar flexion 
power and walking speed.77,138-142  The intensity of strength training will be determined during 
Day 1 of intervention at the participant’s residence. The PT will determine the amount of 
resistance the participant can push against so that s/he can complete a maximum of eight 
repetitions (eight repetitions maximum (RM) or 8-RM). 8-RM was chosen because it is strongly 
related to the 1-RM143 and determining the 8-RM will allow the PT to know the training intensity 
without further sub-calculations (e.g. 80% of the 1-RM). Studies have shown that the 8-RM is 
more effective than training at 10-RM or 2-RM88 yet is not so aggressive that it is associated 
with injuries.144,145 This protocol has been used safely and effectively in elders21,73,74,77,140,146 and 
specifically in persons post-hip fracture.29,70 For the first visit, participants will be tested to find 
the load associated with an intensity of 8-RM.  During the second session, participants will 
perform 2 sets of 8 repetitions at the 8-RM intensity. From the third session through the 
remainder of the program, participants will perform 3 sets of 8 repetitions at an intensity of the 8-

CAP Protocol version 12.0 
 
28 
Figure 3. Shuttle Device (arrows indicate direction of lower extremity motion) 
 
 3a 
3b  
3c
RM. The PT will 
provide strong 
verbal 
encouragement 
during each 
repetition for the 
participant to 
move as “fast and 
as hard as possible” during the concentric phase and to move slowly and in a controlled way in 
the eccentric phase. Intensity will be reviewed every two weeks. 
 
The participants will be supine for two exercises: the combination of hip and knee extension 
exercise (leg press) and the hip abduction exercise (Figure 3a & 3b). The device will be placed 
on the bed or floor (if the participant is able to be assisted safely to and from the floor) so that 
the participant’s foot will rest on the footplate and the hip will be flexed to 90°. The participant 
will push the leg out into full hip and knee extension against the pre-determined resistance. For 
the hip abductors, the participant will start in 5° of adduction and move 15° into abduction. The 
participant’s foot will be strapped to the footplate as the participant moves the leg outward.  
 
Balance and strength will be addressed with two additional exercises performed in standing. 
Balance will be addressed by asking the participant to perform one-legged activities or to stand 
upright with a decreased base of support. The first exercise that combines balance training and 
strength training will be standing hip extension (Figure 3c). The leg will be flexed approximately 
35° of flexion and the participant will extend to neutral position. Upright balance will be 
challenged as the participant moves the carriage of the exercise device with one leg as the 
other leg maintains stability. 
 
The second exercise that combines balance and strength training will be standing plantar 
flexion. Initially, participants will be asked to decrease their standing base of support by rising 
onto the balls of feet. This exercise also strengthens the plantar flexors. Balance and strength 
will be progressively challenged by advancing the activity to unilateral heel raises. For hip 
extension and plantar flexion, the person may hold lightly onto an assistive device for balance or 
support. The PT will encourage the participant to use less external support for balance during 
each session. Resistance (load in pounds) and repetitions for each exercise performed will be 
recorded in a training log.29   
 
HR will be measured by palpation of the radial artery recorded every five minutes and it will be 
averaged over 20 minutes of continuous exercise. The PT will calculate the HR training zone 
based on the heart rate reserve (HRR) method (HR max-HR rest) multiplied by 50% and then 
added to HR rest. HR max will be calculated as 220 minus the participant’s age. This 
prescription is consistent with moderate intensity exercise and has been shown to increase 
aerobic capacity in elders.147-149 If the person is taking medication that controls heart rate (e.g., 
beta-blockers), Borg’s Rating of Perceived Exertion (RPE) scale will be used.150  The training 
intensity using the RPE scale will be “moderate” work as consistent with a 3-5 on the 0-10 scale.   
 
The endurance intervention will begin initially with two to three minutes of continuous upper and 
lower extremity AROM with the participant sitting. These exercises are intended to increase the 
participants’ HR or exertion closer to the target zone. The participant will then be asked to walk 
on level surfaces and up and down one or more steps, if able and available, to keep the HR 
within the training zone for 20 minutes. The PT can also engage the participant in additional 
exercises such as upper and lower extremity AROM exercises to keep the HR elevated. The 

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29 
target HR will be 30% of HRR in the first week of the program, 40% of HRR in the second week, 
and 50% of HRR in weeks 3 through 16. 
 
9.4 PULSE Intervention 
The PULSE intervention group will receive flexibility exercises, AROM for the upper and lower 
extremities, breathing exercises and TENS. During the AROM exercises, participants will be 
working to increase flexibility and range of motion in order to increase the motion the participant 
produces. The exercises will include the neck, shoulders, arms, trunk, hips, knees and ankles.  
During all of the AROM exercises, the participant will focus on deep breathing techniques. 
Progression will be gradual by beginning with three repetitions and slowly progressing to 10 
reps. We will add a second set of exercises when necessary. This portion of the session will last 
approximately 20-30 minutes. 
 
The second part of the session will use sensory level electrical stimulation to the lower extremity 
muscle groups.  The TENS portion of intervention is intended to decrease pain and increase 
muscle recruitment thereby allowing greater ease of mobility. Conventional TENS uses low-level 
electrical current to stimulate superficial cutaneous nerve fibers through the skin. The amount of 
current for sensory level stimulation is the level which the participant detects as a "tingling" 
sensation and is not high enough to produce a visible muscle contraction (below motor 
threshold).5 To achieve sensory level stimulation, we will use a frequency of 80 pulses per 
second, pulse duration 50 µsec, and amplitude which produces a comfortable paresthesia 
(tingling or 'pins and needles' sensation).  Flexible carbonized, disposable electrodes coated 
with a self-adhesive conductive polymer will be applied to the skin. The electrodes will be placed 
bilaterally near the motor points on muscle bellies (the gluteal complex, the quadriceps, and the 
gastrocnemius) for seven minutes per muscle group. The muscle regions selected are important 
for function after hip fracture.  Repetitions and duration of the AROM program, as well as TENS 
intensity will be recorded in the training log. 
 
9.5 Treatment Fidelity Plan 
Treatment fidelity151,152 will be evaluated with regard to: (1) design, which focuses on whether 
the interventions are consistent with underlying theories, and whether the study is free of 
contamination such as treatment crossover or unintended motivational interventions; (2) 
training, which addresses skill acquisition and maintenance in PTs; (3) delivery, or the 
assessment that the two interventions were implemented as intended; (4) receipt, which focuses 
on whether or not the participant understood and received the intervention as intended.  Overall, 
treatment fidelity data will provide information on the adherence of the PTs to the interventions, 
and the adherence of the participants to the prescribed activities.  Monitoring treatment fidelity 
also will provide an opportunity to address potential study problems, such as drift from the 
intervention protocols which could threaten the study’s ability to detect treatment differences. 
 
9.5.1 Initial Training for Procedural Reliability 
The Intervention Monitor (IM) will train PTs in either PUSH intervention or PULSE intervention 
procedures.  In order to minimize crossover, the PTs will only be trained on one intervention. 
There will be separate training sessions for each intervention and the PTs will not know the 
details of the other intervention.  
 
Knowledge of procedures will be tested by written examination and by psychomotor skills 
observation via video.  The IM will document that PTs are “CAP certified PTs” and provide a 
certificate of completion after they demonstrate competence on the written exam and video 
observation.  PTs also need to bring evidence to the training session that they are currently 

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30 
CPR certified. As new PTs join the study, training will be conducted on an individualized basis 
following the same procedures.   
 
9.5.2 Ensuring Ongoing Competency  
We will use a multi-faceted approach to ensure ongoing treatment fidelity.  The approaches 
include direct observation of skills by the clinical site coordinators, mandatory monthly telephone 
calls with all active PTs, periodic review of PT log books, access to online discussion boards, 
and face-to-face meetings with the intervention team at least twice per year.  
 
Direct Observation: Direct observations of PTs as they perform the interventions will be 
conducted by the clinical site coordinators who will be trained on both intervention protocols. 
The coordinators will document their observations using a structured checklist that 
addresses data completeness, physical performance, qualitative observations, and verbal 
and non-verbal communication. In the PUSH intervention group, the checklist will also 
document whether the participant completed the necessary repetitions at the appropriate 
intensity and whether the participant completed 20 minutes of aerobic exercise at the proper 
intensity. The checklist for the PULSE intervention group will document that the participants 
completed the AROM exercises, had electrodes placed appropriately, and received the 
TENS at the appropriate level and for the proper amount of time. There will be two 
observation visits during the PT’s first assigned participant’s 16-week intervention period 
and then one observation per quarter for PTs who have conducted a complete 16-week 
intervention period for at least one participant. If the total score on the checklist is less than 
90%, the IM and clinical site PI will be notified. A remediation plan will be proposed that will 
offer refresher training to ensure accurate understanding of the protocol, follow-up 
observation visits, and possible dismissal if warranted.    
 
Mandatory Conference Calls with PTs: The IM will conduct monthly telephone calls with the 
PTs who are currently active with participants. The Treatment Fidelity Manager will take 
minutes of the telephone meetings to document ongoing training. During these calls (which 
will be done separately for the PTs in the two groups), the IM will ask questions to identify 
problems with delivering the intervention. If problems are identified, the IM will schedule an 
individual telephone call and review of PT log books. Additional follow-up will be mandated if 
there are modifications to the exercise prescription that are due to PT factors. A remediation 
plan will be followed if there is ongoing lack of progress. 
 
Periodic Review of Intervention Logs: Clinical site coordinators will review PT intervention 
logs when the PTs come to the study office to pick up study medications or to submit 
completed forms. The coordinator will note if PTs are completing logs and if there are 
modifications to the intervention protocols. This information will be sent to the IM for 
discussion during the monthly phone calls.  
 
IM Site Visits: The IM will visit each site semi-annually to meet with all the PTs, with 
separate meetings for each intervention group. This will be a team building visit emphasizing 
proper delivery of the intervention and discussing issues specific to the site.   
 
9.5.3 Monitoring Physiologic Response 
As a measure of treatment fidelity, we will monitor physiologic response (heart rate) during the 
intervention sessions using Polar heart rate monitors. The monitors will be worn by all 
participants at all intervention sessions. The Polar monitor allows the operator to indicate the 
start and end of distinct time segments referred to as “laps” by the device’s software system. 
Each intervention session will consist of four laps, defined as follows:   

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31 
 
Lap 
PUSH Intervention 
PULSE Intervention 
1 
Greeting, health questions, BP, HR 
Greeting, health questions, BP, HR 
2 
Strength training, BP, HR 
AROM training, BP, HR 
3 
Endurance training 
TENS 
4 
Wrap-up 
Wrap-up 
BP=blood pressure; HR=heart rate; AROM=active range of motion; TENS=transcutaneous 
electrical nerve stimulation.  
 
The Polar monitoring will provide a dichotomous variable reflecting whether, during laps 2 and 3 
of each intervention session, the participant’s average HR was equal to or greater than his or 
her target heart rate (±5 beats). The target heart rate is defined as 50% of heart rate reserve 
and is calculated as follows: 
 
Target HR=(((220-age) – RHR)*0.5)+RHR, where RHR=resting heart rate. 
 
In addition, the IM will perform ongoing qualitative reviews of the HR curves that are generated 
by the software. She will examine the duration of the laps as well as the pattern of activity within 
the laps (height of curve, duration of the rise in HR, number of times HR rises within a lap) and 
compare them to pre-specified criteria established for each intervention. If the pattern of HR 
curves deviates from the pre-established expectations, she will confer with the PT regarding the 
possible reasons and implement appropriate actions as necessary.  
 
9.6 Scheduling Intervention Visits 
There are three requirements for scheduling of intervention visits:  
1. The first intervention visit should occur on Day 7 or earlier, where the day of randomization = 
Day 0.    
2. The schedule of intervention visits is anchored to the date of randomization regardless of 
when the intervention starts.   
3. Intervention visits should never occur on two consecutive days, even when moving from one 
week to the next. 
 
For all randomized participants, Week 1 will begin on the day of the first intervention visit or on 
Day 7 post-randomization, whichever is earlier.  Subsequent weeks will start on the same day of 
the week as Week 1. For example, if the participant’s first intervention visit is on a Wednesday, 
each intervention week for that participant will extend from Wednesday to Tuesday (inclusively).  
Alternatively, if the first visit has not yet occurred by Day 7 and Day 7 is a Monday, then the 
participant’s intervention weeks will extend from Monday to Sunday (inclusively). 
 
In certain circumstances (e.g., illness, travel), the first intervention visit may be scheduled after 
Day 7. 
 
Ideally participants will receive 2 visits per week for 16 weeks post-randomization (32 visits 
total). However, missed visits in a given week can be replaced by makeup visits in subsequent 
weeks (not to exceed 3 visits in any given week) as long as the visits are on non-consecutive 
days. If the participant has not had 32 visits by the end of 16 weeks, makeup visits can be 
performed during the subsequent two weeks to get as close as possible to the target of 32 
visits. 
 

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Section 10: Study Measures 
A list of study measures is provided below. All of the measures will be interview-based or based 
on observations of performance or physiological assessments. No proxy data will be allowed at 
baseline. However, at the 16-week follow-up visit, a proxy may be contacted to provide 
information about the participant’s walking ability. This information will be used as part of the 
adjudication process, as described in section 11.5.   Also, the four-week phone calls will be 
conducted with a proxy when the participant is not available. 
 
In the description of measures below, we identify the measures that will not be collected for 
participants consented under protocol version 11.0 or later. 
 
10.1 Screening Evaluations 
There will be three primary components to the screening process: the chart review in the acute 
care setting (phase 1), the phase 2 screen, and screening for final eligibility (phase 3) that 
includes calculated BMI, the 3MS, and the SMWT.  These components will be typically 
administered over three contacts, in-person or by telephone (phase 2).  Those who qualify after 
phases 1 and 2 will be invited for the first clinic visit for phase 3 screening (see section 7.5). 
 
10.1.1 Weight, Height, and BMI 
Height (in feet and inches) will be measured once at the baseline visit using a standard 
stadiometer. Weight (in pounds) will be measured using a digital scale at baseline and at each 
follow-up visit.  Measured height and weight will be used to calculate BMI. 
 
10.1.2 Modified Mini-Mental State Examination (3MS) 
The 3MS is a test of global cognitive function which assesses a broad variety of cognitive 
dimensions and is an expanded 100 point version of the original Folstein Mini-Mental State 
Exam.153,154 The 3MS will be used at the baseline visit to identify and exclude participants with 
cognitive impairment (3MS score <73).155     
 
10.2 Primary Outcome Measure: Community Ambulation 
The primary study outcome reflects the concept of a minimum distance a person needs to be 
able to walk to carry out usual activities in the community. This will be defined as achieving the 
threshold value of 300 meters or more on the SMWT.  
 
Performance of the SMWT at the baseline assessment also will be used to define final eligibility 
prior to the collection of additional baseline data.  Participants who walk less than four meters in 
40 seconds (<0.1 m/sec) or who walk 300 meters or more in six minutes will be excluded from 
the trial.  Participants with angina, extreme shortness of breath, or ambulating with severe pain 
during the SMWT also will be excluded. 
 
Participants will be asked to walk back and forth on a measured path marked clearly at both 
ends for turning purposes, while being told when each minute has passed, and receiving verbal 
encouragement (“you’re doing well” or “keep up the good work”) every 60 seconds. Test-retest 
reliability in older adults is excellent (r = .95).107 Concurrent validity with V02 peak (r=.64) and 
cycle ergometry (r=.58) have been reported.105,156,157   
 

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10.3 Secondary Outcome Measures - Precursors to Community Ambulation 
 
10.3.1 Endurance 
To assess endurance, the SMWT (described above) will be used to obtain a continuous 
measure of total distance walked in six minutes.158  The SMWT is highly correlated with 
workloads, heart rate, oxygen saturation, and dyspnea responses when compared to bicycle 
ergometry and treadmill exercise tests in older persons.105,156,158  It has been performed by 
elderly, frail and severely compromised participants who cannot perform standard maximal 
treadmill or cycle ergometry exercise tests.31,159   
 
10.3.2 Balance  
We will use an enhanced balance measure that includes the balance subscale of the Short 
Physical Performance Battery (SPPB) and two additional single leg stands (eyes open and eyes 
closed), as used in the National Health and Aging Trends Study (NHATS).160  For the test of 
standing balance, participants are asked to maintain balance in three positions, characterized 
by a progressive narrowing of the base support: with feet together (side-by-side position), the 
heel of one foot beside the big toe of the other foot (semi-tandem position), and the heel of one 
foot in front of and touching the toes of the other foot (tandem position). For each of the three 
positions, participants are timed to a maximum of 10 seconds. Participants are then asked to 
stand on one leg (on the side of the fracture) with eyes open and again with eyes closed. Each 
of the single leg stands are held for up to 30 seconds. The number of seconds is then summed 
across the 5 items to obtain the measure of balance. These tests are hierarchical such that 
when a participant fails an item, the harder ones are not administered and receive a score of 0. 
 
10.3.3 Quadriceps Muscle Strength 
Isometric force for bilateral knee extensors will be measured with a portable, hand-held 
dynamometer (Microfet2 Manual Muscle Tester).  Participants will be seated on the strength 
testing chair, with hip flexion 90° and  knee flexed to 70°, stabilization straps on the pelvis and 
thigh, and resistance applied just proximal to the ankle on the anterior surface of the leg.161  
Participants will be asked to push as hard and as fast as possible for five seconds.  Three 
maximal effort trials, with a one-minute rest between trials, will be performed.  The reported test-
retest reliability with hand-held dynamometry is excellent (r>.90) if tested in one session and in 
subjects with muscle weakness (intraclass correlation coefficient ≥ .90).162-164  The peak force 
will be recorded for each of the three trials and the highest value will be used. 
 
This measure will not be collected for participants consented under protocol version 11.0 or 
later. 
 
10.3.4 Lower Extremity Function 
A modified version of the Physical Performance Test (mPPT)165 will be used to measure lower 
extremity function at baseline and follow-up. The modification, used by Binder et al., substitutes 
a chair-rise task and a balance task for writing and eating tasks, in order to emphasize lower 
extremity function.68  The modified PPT includes nine standardized tasks that will be timed (e.g., 
picking up a penny from the floor, standing up five times from a 16-inch chair). The tasks are 
performed twice and the times from the two trials are averaged. The score for each item ranges 
from 0 to 4, with 36 representing a perfect score. Test-retest reliability for the modified PPT 
score is 0.96.22  Because there is some overlap between the mPPT and SPPB items, we have 
integrated the two scales so that participant burden is minimized but it is still possible to obtain 
scores on each of the scales.   
 

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10.3.5 Fast Walking Speed 
Within the mPPT, participants are asked to walk a distance of 50 feet walking quickly but safely. 
The time required to walk 50 ft will be the measure of fast walking speed.  
 
10.3.6 Cost Effectiveness: Health Care Utilization 
Resource utilization will be tracked every four weeks via telephone interview and unit costs will 
be assigned to each resource for which data are obtained.  Resource use will reflect health care 
use (including both formal and informal care) since the last telephone interview. This interview 
will be patterned after that used in the NIH-sponsored Spine Patient Outcomes Research Trial 
(SPORT).166  In addition to caregiver costs, the questionnaire will document other resource use 
including hospitalizations, other care facilities, health care visits, and diagnostic tests. As in 
SPORT, a health diary will be provided to each participant to assist them in accurately recording 
health care encounters and use of health services.  
 
Effectiveness will be assessed in the QALY framework where health state values will be used to 
reflect the desirability for health outcomes on a scale from 0 (worst imaginable health state) to 1 
(best imaginable health state). To estimate QALYs, health state values will be obtained using 
the SF-6D health state classification system,167 which defines health states using participant 
responses to the SF-36 (described below). QALYs estimated using SF-6D are consistent with 
recommendations to use societal values in economic evaluations in health and medicine.136  
Although current SF-6D scoring uses preference weights from a UK population, use of the SF-
6D will facilitate the planned model-based comparison between trial interventions and usual 
care, because several BHS investigations have utilized SF-36 in similar hip fracture populations. 
 
Costs associated with participant-reported resource utilization will be estimated using the 
Resource-Based Relative Value Scale (RBRVS)168-170, which is used by the Center for Medicare 
and Medicaid Services (CMS) to reimburse physicians for their services.  This approach has the 
advantage of reflecting national fee schedules and relating them to the RBRVS.  To estimate 
costs of other health care services not consistently covered by Medicare, providers will be 
surveyed on charges for services at the geographic locations involved in this study.  For each 
item, units of utilization will be multiplied by prevailing charges to estimate costs for each 
participant. To estimate indirect costs, information about informal caregivers’ employment status 
and job class will be obtained at baseline. This will allow for estimation of the indirect economic 
costs associated with informal caregiving. Costs associated with providing the interventions will 
be estimated based on the amount of physical therapist time required to deliver the 
interventions as recorded during the trial. 
 
This measure will not be collected for participants consented under protocol version 11.0 or 
later. 
 
10.4 Tertiary Outcomes 
A series of outcomes that are relevant for the recovering hip fracture participant also will be 
evaluated. These were selected since: 1) all are affected by a hip fracture; and 2) all are 
important in understanding the degree to which hip fracture patients recover.  
 
10.4.1 Activities of Daily Living (ADLs) 
We will measure ADLs using the Pepper Assessment Tool for Disability (PAT-D)171,172 with two 
modifications.  First, two items (walking a quarter mile and walking across a small room) were 
added to address perceived gaps in the original PAT-D scale. This modification is consistent 
with the version used in the Lifestyle Interventions and Independence for Elders study.173  
Second, two items (walking several blocks and lifting heavy objects) were deleted to avoid 

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duplication with other items in the scale. The resulting 19-item scale allows examination of three 
subscales (basic ADL, functional limitations, and instrumental ADL).  
 
This measure will not be collected for participants consented under protocol version 11.0 or 
later. 
 
10.4.2 Quality of Life (SF-36) 
We will use an interviewer-administered version of the SF-36, a health survey that assesses 
quality of life in eight subscales (physical function, social function, role-physical, role-emotional, 
bodily pain, mental health, general health, and vitality).174  The measure has been validated as a 
generic measure of quality of life in many different populations, including patient and non-patient 
samples.174 68,175,176   
 
This measure will not be collected for participants consented under protocol version 11.0 or 
later. 
 
10.4.3 Balance Confidence 
The Activities-specific Balance Confidence (ABC) scale177 is a 16-item measure that asks 
respondents to rate their confidence in maintaining their balance while doing daily activities. 
Test-retest reliability, internal consistency, and concurrent validity with fall and physical activity 
are high.177,178 This measure has been used successfully in hip fracture patients.32,179  
 
This measure will not be collected for participants consented under protocol version 11.0 or 
later.  
 
 
10.4.4 Yale Physical Activity Survey (YPAS) 
This interviewer-administered questionnaire includes five categories of common activities 
related to work, exercise, and recreation performed during a typical week in the past month.180 
The YPAS increases the sensitivity of other physical activity surveys by describing a wider 
range of lower intensity activities that older adults often engage in.  Participation in each activity 
(hrs/week) will be multiplied by an intensity code (kcal/min) and then summed over all activities 
to calculate a weekly energy expenditure summary. The measure has been validated against 
several physiological variables of habitual activity.180,181 The YPAS has been used to estimate 
change in older adults in an exercise intervention program.182   
 
This measure will not be collected for participants consented under protocol version 11.0 or 
later. 
 
10.4.5 Improvement in Walking 
Whether or not there was an increase of at least 50 meters in the distance walked on the SMWT 
will be assessed as a tertiary outcome. This distance has been shown to be clinically 
meaningful.183,184 
 
10.4.6 Short Physical Performance Battery (SPPB) 
The SPPB evaluates lower extremity performance in older persons based on timed short 
distance walk, repeated chair stands, and a set of balance tests.184-186  Each of the tasks is 
assigned a score ranging from 0 to 4, with 4 indicating the highest level of performance and 0 
an inability to complete the test.  The test takes about 10-15 minutes to administer and was 
designed to be administered by a lay interviewer in a setting with limited space.  The battery has 
an excellent safety record. It has been administered to well over 10,000 persons in various 
studies and no serious injuries are known to have occurred. The SPPB components and total 

CAP Protocol version 12.0 
 
36 
score are derived from normative values obtained from a population-based study.184,186  The 
total score ranges from 0 to 12; there are three subscales embedded in the SPPB.   
 
Standing balance. For the test of standing balance, participants are asked to maintain 
balance in three positions, characterized by a progressive narrowing of the base support:, 
with feet together (side-by-side position), the heel of one foot beside the big toe of the other 
foot (semi-tandem position), and the heel of one foot in front of and touching the toes of the 
other foot (tandem position). For each of the three positions, participants are timed to a 
maximum of 10 seconds.   
 
Walking speed. Walking speed is assessed by asking participants to walk at their usual 
pace over a 4 m course. Participants are instructed to stand with both feet touching the 
starting line and to start walking after a specific verbal command. Participants are allowed to 
use walking aids (cane, walker, or other walking aid) if necessary, but not the assistance of 
another person. Timing begins as soon as the participant starts to walk and the time in 
seconds needed to complete the entire distance is recorded. The faster of two walks is used 
to compute walking speed. 
 
Chair stands. The repeated chair stands test is performed using a straight-backed chair, 
which is placed with its back against a wall. Participants are first asked to stand once from a 
sitting position with their arms folded across their chest. If they are able to perform the task, 
they are then asked to stand up and sit down five times, as quickly as possible. The time to 
complete the task is recorded. 
 
10.4.7 Depressive Symptoms  
Depressive symptoms will be measured  using the 20-item Center for Epidemiologic Studies 
Depression (CES-D) scale,187 which asks about depressive symptoms experienced in the 
previous week.  There is evidence that recovery post-fracture is delayed in the presence of 
depression.188-191 This scale ranges from 0-60 with higher scores indicating greater depression.   
 
10.4.8 Cognitive Status 
Cognitive status will be assessed at follow-up using the 3MS (see section 10.1.2). 
 
This measure will not be collected for participants consented under protocol version 11.0 or 
later. 
 
10.4.9 Nutritional Status 
Nutritional status will be assessed using the Mini Nutritional Assessment-Short Form (MNA®-
SF),6,192 a validated and widely used malnutrition screening tool.192-195 We are using a modified 
version of the MNA®, approved by the scale’s developer (the Nestlé company), to facilitate use 
as an interviewer-administered tool in a research setting. Scores range from 0 to 14; 
participants scoring ≤7 will be considered malnourished; those scoring 8-11 will be considered 
to be at risk of malnutrition; and those scoring 12-14 will be considered to have normal 
nutritional status.6,192   
 
This measure will not be collected at follow-up for participants consented under protocol version 
12.0 or later. 
 
10.5  Clinical and Background Characteristics 
Information on a small number of other patient characteristics will be collected to allow 
description of the study population, to allow analyses of differential effects in subgroups (i.e., 

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effect modification), and to help in the interpretation of results.   
 
10.5.1 Demographic and Surgical Characteristics 
For descriptive purposes, information on the following participant characteristics will be collected 
either during screening or at the baseline assessment: age, gender, race, living situation, marital 
status, educational level, fracture type, and surgery type. 
 
10.5.2 Functional Comorbidity Index 
The Functional Comorbidity Index (FCI) is a clinically based measure developed by Groll et al.  
This index includes a checklist of 18 comorbid conditions scored 1 or 0. A maximum score of 18 
indicates the highest number of comorbid illnesses. The FCI was specifically developed to 
predict physical functioning.196 
     
10.5.3 Psychological Measures 
The following psychological measures will be administered at the baseline assessment to allow 
us to perform pre-specified subgroup analyses. 
 
Life Orientation Test-Revised (LOT-R)  
The LOT-R assesses self-reported optimism and pessimism. A total of six brief statements is 
read to the participant, and response categories range from strongly disagree to strongly agree 
on a 5-point Likert type scale; three items measure optimism and three items measure 
pessimism.197 
 
Brief Resilience Scale 
The Brief Resilience Scale assesses self-reported ability to bounce back after a stressful event. 
A total of six brief statements is read, and response categories range from strongly disagree to 
strongly agree on a 5-point Likert-type scale.198 
 
10.6  Other Measures to be Monitored 
 
10.6.1 Adherence  
Adherence with PT interventions.  PTs will submit a visit form for each of the 32 visits that 
records date of visit; start and end time of the visit; reason for missed visit; what activities were 
performed; and whether activities were performed as prescribed. For the PUSH group, we will 
also obtain information about the intensity of each activity at initiation of the intervention and 
every four weeks during the intervention period. Logs completed by PTs will record the detail of 
each designated activity during intervention sessions as well as any precautions or 
modifications to activities. Reasons for protocol variations will be noted in the PT log books. 
 
Additionally, at the end of each intervention visit, the PT will retrieve the average HRs for laps 2 
and 3 from the Polar heart rate monitor receiver and record them in the logbook and on the 
appropriate data forms. The Polar heart rate monitoring will provide a dichotomous variable 
reflecting whether, during laps 2 and 3 of each intervention session, the participant’s average 
HR was equal to or greater than his or her target heart rate (±5 beats). In addition, the IM will 
perform ongoing qualitative reviews of the HR curves to ensure that the pattern of activity is 
consistent with pre-specified criteria established for each intervention. 
 
Adherence with study vitamins/supplements.  Vitamin D, calcium, and multivitamin adherence 
will be monitored by pill counts every four weeks during the intervention period and by self-
report during the 4-week telephone calls for the entire16-week study period. 
 

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In protocol version 11.0, we will eliminate the collection of information on use of study-provided 
dietary supplements. However, procedures for drug accountability will remain unchanged (see 
section 3.2.3).  
 
10.6.2 Weight Loss    
Weight will be monitored by the PTs every four weeks during the 16-week intervention period 
using a standard digital scale.  
 
10.6.3 Reportable Adverse Events (RAEs) 
Reportable adverse events (RAEs), which include serious adverse events (SAEs), unexpected 
AEs or injury that occurs under supervision by study staff, will also be obtained during the study. 
These events will be tracked in a separate database by the CCC.  RAEs will be captured every 
four weeks during the telephone interviews using standardized questions on the Reportable 
Adverse Events Form.  Participants (or their proxies) will be asked about life-threatening or 
significant medical events and the outcomes of these events.  RAEs will also be asked about by 
study staff prior to each PT visit and clinical site follow-up assessment.  RAEs may be 
spontaneously reported to any study staff member throughout the study (see section 13.4.1).   
 
10.6.4 Expected Adverse Events (AEs) 
Expected AEs will be assessed every four weeks during the telephone interview.  Participants 
(or their proxies) will be asked a series of standardized questions related to pain (feet, hip, back, 
knees); breathing problems or chest pain; skin irritations, rash, or skin tears; numbness or 
tingling; and falls (with and without injury).  
 
Section 11: Study Procedures 
11.1 Baseline Assessments 
The baseline assessments will be performed immediately following screening for phase 3 
criteria.  The following measures will be assessed at the baseline visit.  
 
 
Baseline Weight, Height, and Body Mass Index* 
 
Demographics and Blood Draw Information* 
 
Modified Mini-Mental State Examination* 
 
Six-Minute Walk Test* 
 
Baseline Interview 
 
Activities-Specific Balance Confidence†  
 
Short Physical Performance Battery  
 
SF-36 Health Survey† 
 
Modified Physical Performance Test 
 
Yale Physical Activity Survey†  
 
Weight and Quadriceps Strength†  
 
Center for Epidemiologic Studies-Depression scale 
 
Pepper Assessment Tool for Disability† 
 
Mini Nutritional Assessment-Short Form 
 
Life Orientation Test-Revised 
 
Brief Resilience Scale 
 
* Collected as part of phase 3 screening 
† Eliminated from baseline assessment in protocol version 11.0 
 

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11.2 Follow-up Assessment 
The following measures will be obtained at 16 weeks post-randomization. 
 
Six-Minute Walk Test  
 
Modified Mini-Mental State Examination†  
 
Activities-specific Balance Confidence† 
 
Short Physical Performance Battery 
 
SF-36 Health Survey† 
 
Modified Physical Performance Test 
 
Yale Physical Activity Survey†  
 
Weight and Quadriceps Strength†  
 
Center for Epidemiologic Studies-Depression scale  
 
Pepper Assessment Tool for Disability† 
 
Mini Nutritional Assessment-Short Form^ 
 
† Eliminated from follow-up assessment in protocol version 11.0 
^ Eliminated from follow-up assessment in protocol version 12.0 
 
Note: The subset of participants randomized prior to protocol version 10.0 received a second 
follow-up assessment at 40 weeks post-randomization using the complete list of measures 
above. 
 
 
11.3 Telephone Interviews 
Structured telephone interviews with blinded assessors will be conducted every four weeks for 
16 weeks post-randomization starting four weeks after the date of randomization. Participants 
will be given a health diary at the baseline visit to assist with recall during the telephone 
interviews. The following measures will be administered: 
o Reportable Adverse Events (RAE) Form 
o Health Care Utilization questionnaire† 
o Expected Adverse Events (AE) Form 
o Self-report of study medication adherence† 
† Eliminated from telephone interview in protocol version 11.0 
 
Note: The subset of participants enrolled prior to protocol version 10.0 received telephone calls 
every four weeks for 40 weeks post-randomization using all the measures listed above. 
 
 
11.4 Timing of Study Procedures 
The target date for completion of the pre-randomization (i.e., screening) assessments will be 
anchored to the date of admission to the hospital for hip fracture. The target date for completion 
of all other assessments will be anchored to the date of randomization (see Table 1).   
 

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Table 1. Timing of Study Procedures 
PROCEDURE 
TARGET DATE 
ALLOWABLE INTERVAL 
Phase 3 screening 
As early as possible following 
admission 
Up to 26 weeks post-
admission 
Baseline assessment 
As early as possible following 
admission 
Up to 26 weeks post-
admission 
Randomization 
As early as possible following 
admission 
Up to 26 weeks post-
admission 
Dietitian consult 
1 week post-randomization 
+1 week 
First intervention visit 
1 week post-randomization 
+16 weeks 
First telephone interview 
4 weeks post-randomization 
-1 week, +3 weeks  
Subsequent telephone interviews 
At 4-week intervals from date of 
randomization 
-1 week, +3 weeks  
First follow-up assessment 
16 weeks post-randomization 
+2 weeks 
Out-of-window assessment 
16 weeks post-randomization 
0-16 weeks and 18-38 
weeks post-randomization  
 
11.5 Primary Outcome Classification 
At baseline, all participants will, by design, be tested at the clinical site. At the follow-up visit, we 
will attempt to test all participants at the clinical site. When this is not possible, we will attempt to 
have study staff administer the test in a non-study clinical facility or, failing that, at another non-
study location or the participant’s home. All cases for which, despite intensive efforts, 
administration of the SMWT is not possible will be submitted for adjudication. See Figure 4.  
 
Although there is an absence of highly sensitive and specific surrogate measures for the ability 
to walk ≥ 300 m in six minutes, prior studies suggest that there are factors that are highly 
predictive of the inability to walk at that speed. Therefore, the purpose of the adjudication will be 
to reduce the number of participants with missing outcomes by identifying treatment failures in 
cases where the SMWT could not be administered. Based on the adjudication, participants who 
meet one or more of the following criteria at the follow-up assessment will be classified as 
treatment failures in the primary analysis for the given follow-up time: 
 
1) Participant died 
2) Participant was too sick, based on adjudicators’ review of source documentation, to walk 
300 m or more in six minutes  
3) Gait speed based on SPPB four-meter walk was less than 0.6 m/s (very slow speed 
incompatible with ability to walk 300 m in six minutes) 
4) Participant or proxy reports (a) participant limitation in walking several blocks or (b) in 
walking across a small room without help from another person 
 
Criterion 4a is an item from the Activity Limitations section of the SF-36 and was chosen 
because, in a previous hip fracture study performed by our group, 100% of 27 participants 
meeting the criterion were unable to walk 300 m or more in six minutes (unpublished data). 
Also, in that study, 85% of 26 participants who had a missing SMWT reported this level of 
walking limitation, suggesting that use of this item will allow us to assign a classification to a 
large proportion of those who were not tested on the SMWT. Criterion 4b is an item from the 
Pepper Assessment Tool for Disability and was chosen because it has high face validity for 
predicting treatment failure. To improve our ability to classify the outcome status of participants 
whose SMWT was not administered, we will make intensive efforts to obtain self- or proxy-

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reported information on these two items in person or by telephone, even when other data 
cannot be collected at the given follow-up time. 
 
There will be three adjudicators, all experts in mobility assessment and the clinical management 
of older persons. Each adjudication case will be randomly assigned to two of the adjudicators 
who will independently review all the relevant documents and classify participants as treatment 
failures or indeterminate. If the two adjudicators disagree on the classification, the case will be 
discussed in a meeting with the two adjudicators. If there is no consensus after discussion 
between the two assigned adjudicators, the case will be discussed in a meeting with all three 
adjudicators. Discrepancies will be resolved by a vote if the three adjudicators cannot reach a 
consensus. To monitor the adjudication process, an unblinded statistician will calculate, among 
the cases submitted for adjudication, the outcome of adjudication (proportion classified as 
failure and indeterminate), by treatment group. The incorporation of adjudication results into the 
analysis plan is described in Section 15.1.  
 
Cases where the SMWT was administered but not according to protocol (e.g., using a walking 
course of less than 10 m) will also be submitted for adjudication. The adjudicators will review the 
description of the circumstances and outcome of the testing as recorded by the evaluator and 
will judge whether the participant’s classification (treatment success or treatment failure) based 
on the distance walked is valid. If not, the participant will be classified as ‘indeterminate’. For 
simplicity, this part of the process is not depicted in Figure 4.  
 

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Figure 4.  Classification and Analysis of Primary Outcome 

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Section 12: Safety Assessments 
12.1 Participant Safety Parameters: Methods and Timing  
12.1.1 Pre-Intervention Safety Screening 
Potential participants will be excluded during the screening phases if they have cardiovascular 
diseases or other conditions that would make it unsafe for them to participate in one or both of 
the study interventions. Information about these conditions will be obtained through chart 
review, interviews, and consultation with a medical professional familiar with the potential 
participant (e.g., primary care provider, orthopaedic surgeon). The clinical site study clinician 
and PI will be responsible for giving permission for potential participants to be randomized, 
based on thorough review of all eligibility information. In addition, persons who develop chest 
pain or substantial shortness of breath during the SMWT will be excluded using a protocol to 
evaluate cardiovascular reserve similar to the one suggested by Gill et al.199  
  
12.1.2 Safety Considerations for Study Assessments 
All study assessments will be done by certified staff who will be trained to perform the tests 
safely. If, during the SMWT, the SPPB, or the mPPT, a participant reports chest pain, tightness 
or pressure, significant shortness of breath or difficulty breathing, or feeling faint, lightheaded, or 
dizzy, the test will be stopped. All research staff who come in contact with study participants will 
be CPR certified and will be trained to provide immediate care when faced with medical 
emergencies. Also, institutional and community emergency medical services will be activated if 
needed.  
 
Table 2 describes a summary of safety alerts and the appropriate action during clinical 
assessments. 
 

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Table 2. Safety Alerts and Actions for Study Assessments 
ALERT 
ACTION 
Resting blood pressure 
SBP > 145mm Hg or 
DBP > 90mm Hg 
Qualified staff will inform the participant if 
noted on more than one occasion. 
Resting blood pressure 
SBP > 170mm Hg or SBP < 90mm Hg or 
DBP > 100mm Hg or DBP < 50mm Hg 
Qualified staff will encourage the participant 
to seek additional follow-up and/or medical 
evaluation.  Physical performance testing 
will be deferred until consultation with the 
study clinician. 
Resting blood pressure or after SMWT 
SBP > 185mm Hg or SBP < 90mm Hg or 
DBP > 110mm Hg or DBP < 50mm Hg 
Qualified staff will consult with the study 
clinician and follow up as needed.  
Resting pulse 
Rate > 120 or < 40 beats/min 
Qualified staff will consult with the study 
clinician and follow up as needed.  
Chest pain, dizziness, significant shortness 
of breath, or severe musculoskeletal pain 
during the intervention or study 
assessment. 
Qualified staff will consult with the study 
clinician and follow up as needed.  
CES-D  
Score ≥ 27 
 
Qualified staff will talk to the participant and 
provide a referral for additional follow-up 
and/or medical evaluation for depression.   
Weight loss ≥ 2% in four weeks during 
intervention period 
Participant will be referred to the registered 
dietician for follow-up by telephone. 
Weight not obtained at the final PT 
intervention visit and there is weight loss ≥ 
5% between baseline and follow-up. 
Clinical site PI or clinical site clinician will 
review participant’s weight trajectory, 
baseline BMI, baseline MNA®-SF score and 
registered dietician’s documentation and, if 
warranted, will refer the participant to a 
dietician or medical provider for follow-up of 
possible poor nutritional status. 
Participant expresses desire to commit 
suicide 
Call primary care provider and report 
findings. Report to clinical site 
coordinator/study clinician for follow-up and 
clearance. 
 
12.1.3 Safety Considerations for the PUSH Intervention 
There is no expectation that the PUSH intervention will evoke serious cardiovascular responses; 
however, participants will be warned of a possible risk. Cardiac events are rare, with estimates 
of one event per 60,000 participant-hours in aerobic exercise programs.200  No significant 
cardiac events were reported after performing 1-RM testing for over 6600 healthy subjects.201 
The American Heart Association’s guidelines for resistance training for adults with and without 
cardiovascular disease reports the safety of high intensity resistance training and testing in 
persons with coronary disease which found an absence of anginal symptoms, ischemic ST-
segment depression, abnormal hemodynamics, complex ventricular dysrhythmias, and 
cardiovascular complications.202,203 Less serious risks may include chest pain, fainting, 
hypotension, or muscle strain. We have minimized risk to participants by following the 
guidelines suggested by Gill et al.199  Blood pressure and heart rate will be monitored using a 
standard blood pressure cuff and palpation of peripheral pulse. 
 

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Another concern is the presence of osteoporosis and the risk of inducing a compression fracture 
or a lower extremity fracture. The exercises have been designed to minimize this risk. The risk 
of inducing a compression fracture will be minimized because the exercises are performed in 
supine and upright standing positions with minimal to no trunk flexion.204 The PT will also remind 
the participant to minimize flexion to the spine during all standing exercises. Using an exercise 
device that eliminates the risk of weights falling on a person, and using only voluntary muscle 
contractions during isometric testing, will reduce the risk of lower extremity fracture. We do not 
anticipate additional risk for the PUSH intervention for the following reasons: 1) by 12 weeks 
post-fracture, there is moderate stability from the bone callus formation, 2) participants will only 
be included if they have medical clearance to participate in full weight bearing activities, and 3) 
the device limit is 100 pounds (which in most cases is less than body weight) resulting in less 
load than walking up and down stairs. Delayed onset muscle soreness is a common occurrence 
after the initiation of an exercise program. The soreness occurs in the muscle belly 1-3 days 
after the initiation of exercise and lasts 2-3 days. There is no effective way to eliminate the risk 
of delayed onset muscle soreness, but it is hoped that the orientation process and gradual 
increase in intensity will reduce the risk. The participants will be informed about the condition, 
what it feels like, how long it lasts, and suggested ways of decreasing the pain including the use 
of superficial heat or ice. If a participant reports continued discomfort, the study clinician will 
discuss this with the participant and contact their primary care provider (PCP) as necessary. 
Please see Table 3 below for a summary of alerts and appropriate action during the PT 
intervention visits. 
 
12.1.4 Safety Measures during the PUSH Intervention 
The PUSH intervention will be conducted in the participant’s place of residence and all sessions 
will be conducted and supervised by trained PTs, who monitor potential adverse experiences 
and symptoms. PTs will be trained to deal with medical emergencies that occur during the 
PUSH sessions and will be CPR certified. Also, community EMS services will be activated if 
needed.  
 
In order to minimize discomfort and maximize safety, participants will be taught the proper 
method for performing each exercise and the importance of following the proper method. 
Intensity is gradually increased, and exercise technique is commented on during each session. 
Participants will be instructed to talk with the PTs about any muscle soreness, pain or 
discomfort. 
 
Every effort will be made to prevent harm by stopping intervention activity when the participant 
reports chest pain, dizziness, significant shortness of breath, or severe musculoskeletal pain.  
PTs will monitor blood pressure at the start of the training session, mid-session, and when 
participants are finished with the session. Blood pressure and heart rate will be monitored using 
a standard blood pressure cuff and palpation of peripheral pulse. If blood pressure is elevated 
above 170/100, the participant will rest quietly for a few minutes. The PT will monitor the 
participant for signs of muscle strain, dizziness, or hypotension and appropriate palliative 
methods will be discussed with the participants and appropriate medical referrals will be made.  
 
12.1.5 Safety Considerations for the PULSE Intervention 
TENS is generally considered safe. However, electrical current that is too intense or that is used 
incorrectly can burn or irritate the skin. The electrodes should not be placed over the eyes, 
heart, brain, or front of the throat. Electrodes should not be placed over the chest of persons 
with demand-inhibited synchronous pace makers. People with allergies to adhesives may react 
to the electrode pads. If the participant is allergic to adhesives, carbon electrodes with gel and 
non-allergenic skin tape will be used.  Skin tears may occur when removing the pads.  

CAP Protocol version 12.0 
 
46 
Participants may experience tingling or numbness that only lasts when the electrodes are 
delivering current. Those with implanted pacemakers, defibrillators, infusion pumps, and other 
such devices should not have current passing over the body areas where these devices are 
located.  This should not be a problem in this study since the electrode placements are not on 
the upper body and are restricted to targeted muscle groups on the lower extremities. Please 
see Table 3 for a summary of alerts and appropriate action during the PT intervention visits. 
 
Table 3. Safety Alerts and Actions for Interventions 
ALERT 
ACTION 
Resting blood pressure 
SBP > 170mm Hg or SBP < 90mm Hg or 
DBP > 100mm Hg or DBP < 50mm Hg 
1. If initial BP check is high (systolic > 170; 
diastolic >100), have participant sit for 5 
minutes and rest then check BP again. 
This may be done twice. 
2. If three BP readings are greater than 
170/100, then individual should not 
exercise.  
3. The PCP, clinical site coordinator, and 
study clinician should be called before 
exercise is initiated.   
4. If initial BP is low for that person 
(systolic<90; diastolic<50) follow same 
protocol.   
New chest pain 
 
Reported chest pain that occurred between 
visits 
Call 911. 
 
1. Cancel treatment and call PCP. 
2. Report to clinical site coordinator and 
study clinician to follow-up until cleared. 
Acute shortness of breath 
1. Have participant stop exercising and 
rest. 
2. Take vital signs. 
3. If the shortness of breath does not 
resolve itself in 10 minutes, and vital 
signs are not within normal limits for 
participant, call 911.   
4. Report to PCP, clinical site coordinator, 
and study clinician.  
Fall 
 
1. If there is bleeding/wound, apply 
pressure using emergency kit for wound; 
call 911 if needed.  If participant is  
unable to stand or move the injured part, 
call 911 and keep them warm and 
comfortable. 
2. Report all falls to clinical site coordinator.  
3. Complete an incident report.   
Stroke symptoms 
Call 911 immediately. 

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47 
ALERT 
ACTION 
Dizziness during exercise 
1. Stop exercise and have person sit or lie 
down. 
2. If sitting is not sufficient to resolve 
dizziness, then check vital signs.   
3. Call 911 if clinically unstable. 
4. Report to PCP if heart rate is less than 
60 (and not usually so), the dizziness is 
new in onset; or if the BP is > 160/100 or 
systolic <90.   
5. Report event to clinical site coordinator 
and study clinician.         
Resting pulse 
Rate > 120 or < 40 beats/min 
1. PT will stop delivery of the intervention.  
2. Qualified staff will consult with the study 
clinician and follow up as needed.  
3. PT will resume delivery of the 
intervention only after the participant 
receives medical clearance.   
New irregular heart rate with complaint of 
heart palpitations 
1. Do not exercise and call PCP. 
2. Report to clinical site coordinator and 
study clinician for follow-up. 
3. Wait for medical clearance to resume 
exercise. 
New acute musculoskeletal pain during 
exercise (pain > 5 on VAS) 
1. Have the participant stop the exercise 
and rest.  
2. Attempt to alter position of participant to 
reduce pain. If pain persists, do not 
continue specific exercise. Attempt to do 
other exercises.  
3. If pain does not resolve, refer to PCP or 
orthopedist and study clinician. 
New, acute, non-musculoskeletal pain  
(pain > 5 on VAS) 
1. Do not exercise. 
2. Take pain history and call PCP. 
3. Report to clinical site coordinator and 
study clinician for follow-up and 
clearance. 
Acute change in mental status 
1. Do not exercise. 
2. Call PCP or if unavailable, call 911. 
3. Report to clinical site coordinator and 
study clinician for follow-up and 
clearance. 
Participant expresses desire to commit 
suicide 
1. Call PCP and report findings. 
2. Report to clinical site coordinator and 
study clinician for follow-up and 
clearance. 
 
12.1.6 Safety Measures for the PULSE Intervention 
The intervention visits will be conducted in the participant’s place of residence and all sessions 
will be conducted and supervised by trained PTs, who monitor potential adverse experiences 
and symptoms. PTs will be trained to deal with medical emergencies that occur during the 

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48 
PULSE sessions and will be CPR certified. Also, community EMS services will be activated if 
needed.  
 
In order to maximize safety, participants will be taught the proper method of performing the 
AROM exercises and the importance of following the proper method. Participants will be 
supervised at all times and instructed on technique on all activities during the session. 
Participants will be instructed to talk with the PTs about any muscle soreness, discomfort, 
tingling or numbness. 
 
Every effort will be made to prevent AEs including stopping intervention activity when the 
participant reports discomfort. Precautions for TENS use include not placing the electrodes in 
the thoracic region in the presence of demand-inhibited synchronous pacemakers, checking for 
skin irritation from the electrodes, and keeping the current path outside of open wounds. PTs 
will monitor blood pressure at the start of the training session, mid-session, and when 
participants are finished with the session. Blood pressure and heart rate will be monitored using 
a standard blood pressure cuff and palpation of peripheral pulse. The PT will monitor the 
participant for signs of muscle strain, dizziness, or hypotension and appropriate palliative 
methods will be discussed with the participants and appropriate medical referrals will be made. 
The level of sensory stimulation provided during the intervention will be at a level that should not 
cause pain or muscle contraction.  
 
12.1.7 Safety Considerations for the Nutritional Intervention 
Individuals who have sustained a hip fracture are frequently at risk for protein and calorie 
malnutrition and have low calcium and vitamin D intake.205  Individuals enrolled in the study will 
be screened with the MNA®-SF and if their scores indicate that they are malnourished, they will 
receive in-person nutritional counseling by a registered dietician.  Individuals enrolled that have 
a serum albumin value 2.5-3.5 will also receive in-person nutritional counseling by a registered 
dietician, regardless of score on the MNA®-SF. Participants who are at risk or not at risk for 
malnutrition will receive a telephone consultation from the dietician on maintaining proper diet. 
The RD will schedule an in-person visit for those at risk if he/she feels it is necessary based on 
the telephone consultation, All subjects will receive vitamin D, calcium, and multivitamin 
supplementation for the 16-week study period, all of which represent best practices for this 
disabled group of participants.  There are small risks associated with vitamin D, calcium, and 
multivitamins including gastrointestinal complaints (including mild constipation or diarrhea, 
stomach upset) and kidney stones.  Those with a calculated creatinine clearance <30 ml/min, 
elevated total or ionized calcium, or history of kidney stones, primary hyperparathyroidism, or 
sarcoidosis will not receive calcium supplements. A participant who experiences an episode of 
kidney stones during the study period will stop receiving calcium supplements.  
 
12.1.8 Safety Measures for the Nutritional Intervention 
If a participant loses 2% or more body weight in a four-week period, the participant will be 
referred to the registered dietician for follow-up by telephone.  In the event that a weight 
measurement is not obtained at the last PT visit, the participant’s weight at the 16-week follow-
up assessment will be compared to his or her baseline weight and, if there is weight loss of 5% 
or more, the clinical site PI or clinical site clinician will review the participant’s weight trajectory, 
baseline BMI, baseline MNA®-SF score, and registered dietician’s documentation and, if 
warranted based on clinical judgment, will refer the participant to a dietician or medical provider 
for follow-up of possible poor nutritional status. 

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49 
12.2 Confidentiality  
Confidentiality of data will be maintained by using research identification numbers and letter 
codes that uniquely identify each individual. Safeguards will be established to ensure the 
security and privacy of participants’ study records. Data will be stored in locked files and on 
computer disks, with access limited to the investigators and key study personnel. Computer 
data files will not include participant names, addresses, initials, hospital record number, or any 
other personal identifiers. Computer security procedures, including multiple levels of password 
protection will be instituted. Data for publication will be presented only in aggregate form, 
preventing identification of individual participants. After the study is completed, local data will be 
archived in a secured storage area.  
 
In compliance with the Health Insurance Portability and Accountability Act (HIPAA) and the 
Standards for Privacy of Individually Identifiable Health Information of the Department of Health 
and Human Services, CAP will access personal health information and medical records only 
after receiving approval for a HIPAA Partial Privacy Waiver for Recruitment.  Only information 
necessary for determining eligibility will be obtained.  
12.3 Participant Education about Potential Risks 
Potential risks associated with study-related activities and interventions will be explained to 
each participant by trained study personnel during the informed consent process. Each 
participant will be instructed to report the occurrence of an AE to appropriate study staff at 
scheduled data collection times, to PTs administering the intervention, or spontaneously at any 
other time. Participants also will be encouraged to report concerns about the safety of 
participating in the CAP study.  
 
 
Section 13: Reportable Adverse Events (RAEs) and Expected Adverse 
Events (AEs) 
 
13.1 Overview 
In this study we will capture study-defined expected adverse events (AEs) through structured 
telephone interviews with blinded assessors every four weeks. Reportable AEs (RAEs) are 
defined as serious adverse events (SAEs), AEs that have potential implications for participant 
safety, unexpected AEs, and injury that occurs while a participant is under the supervision of 
study related personnel. These RAEs will require individual event reporting as described in 
section 13.4.  The timely and complete account of RAEs will be a critical requirement for the 
protection of human subjects in the CAP trial.     
 
The CAP DSMB will review and approve study-defined expected AEs and will be involved in 
regular monitoring of the RAE reporting system.  Study-wide reporting of expected AEs to the 
CCC, the DSMB, the NIA, and the clinical site IRBs will be mediated through a central database.  
RAEs will be monitored and tracked separately by the CCC and reviewed by the DSMB and the 
NIA as outlined in section 13.8. 
                                                                                                              
Clinical site staff will have responsibility for reporting RAEs to their own local IRB according to 
local policies. 
 

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50 
13.2 Classifying Adverse Events 
An AE is any unfavorable or unintended medical occurrence in a human study participant that 
has taken place during the course of a research project, including any abnormal sign, symptom, 
or disease, whether or not related to participation in the research   
 
For the purposes of this study, any event that meets the criteria for an SAE, is unexpected, or 
results in injury to the participant while s/he is under the supervision of study related personnel 
will be classified as an RAE.   
 
Adequate review, assessment, and monitoring of RAEs require that they be classified as to 
severity, expectedness, and potential relatedness to the study intervention.   
 
13.2.1 Severity  
The following guidelines will be used to determine level of severity: 
 
Mild: Awareness of signs or symptoms, but easily tolerated and causing no loss of time from 
normal activities. No specific medical intervention is required. 
 
Moderate: Discomfort enough to cause a low level of inconvenience or concern to the 
participant and may interfere with daily activities. Symptoms may require minimal, local, or 
noninvasive medical intervention only. 
 
Severe:  Events interrupt the participant’s normal daily activities and are usually incapacitating. 
Significant symptoms may require hospitalization or invasive medical intervention.  
 
Life threatening: Events that may involve acute, life-threatening metabolic or cardiovascular 
complications (such as circulatory failure, hemorrhage, sepsis) or life-threatening physiological 
consequences. Intensive care or emergent invasive procedure is required. 
 
Fatal: Causing death. 
 
Severity is not synonymous with seriousness. A severe headache is not necessarily an RAE.  
However, mild chest pain may result in a day’s hospitalization and thus would be classified as 
an RAE. 
 
13.2.2 Expectedness  
AEs will be assessed as to whether they were expected or unexpected based on current 
knowledge. Categories are: 
 
Expected: An AE that is anticipated on the basis of prior experience with the intervention under 
investigation; an event that can be attributed to the underlying condition of the participant being 
studied; or an event that can be attributed to the patient population being studied (see section 
13.3). Expected AEs are captured in a standardized way by blinded personnel. 
 
Unexpected: An AE that was not anticipated on the basis of prior experience with the 
intervention under investigation; an event that cannot be attributed to the underlying condition of 
the participant being studied or to the patient population; or an expected event whose frequency 
or severity exceeds what was anticipated (see section 13.4.2).  Unexpected AEs are reportable. 
 

CAP Protocol version 12.0 
 
51 
13.2.3 Relatedness   
An independent safety monitor (ISM) who is blinded to treatment assignment will determine the 
degree to which RAEs are related to CAP study procedures or to procedures conducted as part 
of an ancillary study to CAP using the criteria shown below.  
 
Definitely related: The adverse event is clearly related to the investigational procedure – i.e., an 
event that follows a reasonable temporal sequence from administration of the study intervention, 
follows a known or expected pattern of response to the study intervention, that is confirmed by 
improvement on stopping and reappearance of the event on repeated exposure, and that could 
not be reasonably explained by the known characteristics of the participant’s clinical state. 
 
Possibly related:  An adverse event that follows a reasonable temporal sequence from 
administration of the study intervention or that follows a known or expected pattern of response 
to the study intervention, but that could readily have been produced by a number of other 
factors. 
 
Not related:  The adverse event is clearly not related to the investigational procedure (i.e., 
another cause of the event is most plausible; and/or a clinically plausible temporal sequence is 
inconsistent with the onset of the event and the study intervention and/or a causal relationship is 
considered biologically implausible).      
 
13.3 Expected AEs 
Expected AEs will be captured through telephone interviews every four weeks by blinded 
personnel, using the Expected Adverse Events Form. Following are expected adverse events 
that have been listed in the ICF:   
 
foot pain  
 
hip pain  
 
back pain  
 
knee pain  
 
breathing problems 
 
chest pain or discomfort 
 
skin tears, rash, or skin irritations 
 
numbness or tingling 
 
fall (with or without injury) 
 
13.4 Reportable AEs 
RAEs are events that have potential implications for participant safety and that require individual 
reporting.  RAEs will be defined as events that fall into at least one of the following categories: 
1. Serious adverse events (SAEs) 
2. Unexpected AEs, and 
3. Injury that occurs while a participant is under the supervision of study personnel. 
 
Events that cannot be clearly defined as “reportable” will be discussed with the clinical site 
clinician and clinical site PI to determine if they should be reported. 
 
13.4.1 Serious Adverse Event (SAE)  
SAEs will be defined as any event that: 
 
Results in death 
 
Is life threatening, or places the participant at immediate risk of death (e.g., MI, 
stroke/TIA) 

CAP Protocol version 12.0 
 
52 
 
Requires or prolongs hospitalization 
 
Causes significant disability or incapacity (e.g., torn muscle or ligament) 
 
Requires medical or surgical intervention to prevent significant disability (e.g., hip 
fracture) 
 
SAEs will be captured through telephone interviews every four weeks by blinded personnel, 
using the Reportable Adverse Events Form.  SAEs will also be assessed at the beginning of 
each PT visit and clinical site follow-up visit, and by any study staff who learns of a serious 
event. 
 
13.4.2 Unexpected Adverse Event  
Unexpected AEs will be defined as medical events that occur during study participation, but do 
not commonly occur in the CAP study population and which are not listed in the ICF or study 
protocol (section 13.3).  An unexpected AE may be witnessed by a member of the research 
team, or staff may be told about an unexpected event that may meet the criteria for reporting. 
Unexpected AEs that have a potential relationship to study procedures and activities will be 
captured on an Incident Report and submitted to the clinical site study office where they will be 
logged in the participant binder and then reported to the CCC and the Independent Safety 
Monitor (ISM).   
 
A reportable unexpected AE will be one that meets all of the following criteria: 
 
Unexpected, in terms of nature, severity, or frequency, given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and ICF; and (b) the characteristics of the study 
population;  
 
Related or possibly related to participation in the research (meaning that there is a 
reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research);  
 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
The medical and scientific judgment of the clinical site clinician and the clinical site PI will be 
exercised in deciding whether an occurrence should be reported. In addition, difficulty 
determining whether or not an event is unexpected and/or attributable to the intervention will be 
addressed by the ISM, who will determine if the event is to be reported. 
 
13.4.3 Injury that Occurs while Under the Supervision of Study Related Personnel 
Any injury that occurs while the participant is under the supervision of study-related personnel is 
reportable.  The injury can happen on site (during an assessment visit or during the conduct of 
an ancillary study to CAP) or off-site (in the participant’s home during a PT visit or if the study 
offers supervision during transportation).  These events will be captured on the Reportable 
Adverse Events Form.   
 
13.5 Expected AE and RAE Collection and Reporting 
The requirements for reporting RAEs will begin when the participant provides informed consent 
and will end 30 days after the participant’s involvement in the study has ended. Expected AEs 
will be assessed every four weeks post-randomization.  Figures 5a-d provide algorithms 
describing the reporting process. 
 

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53 
Figure 5a. Collection and Reporting Process for Expected AEs 
Blinded evaluator administers the Expected Adverse Event Form at a scheduled 4-week telephone interview 
Non-serious and expected AE is reported by the participant or proxy 
Blinded evaluator completes the Expected Adverse Event Form and 
submits the data form to Axio 
Expected AE is tracked by the DCC and submitted with the 
routine DSMB report semi-annually 
STOP 
Clinical Site Staff 
DCC 
LEGEND 
 
 

CAP Protocol version 12.0 
 
54 
Has the RAE been previously reported? 
Figure 5b. Collection and Reporting Process for RAEs Collected during Standardized Telephone 
Interviews 
Blinded evaluator administers the Reportable Adverse Events Form at a scheduled 4-week telephone interview 
Blinded evaluator completes a Reportable Adverse Event Record for each event and 
submits documentation to the clinical site coordinator 
Clinical site coordinator records 
RAE ID#, marks as duplicate, 
and files in participant binder 
YES 
Clinical site coordinator assigns new RAE 
ID#, and records event on the RAE Log in 
the participant binder 
Clinical site PI (or designee) redacts 
documents to conceal treatment assignment 
and notifies the CCC in writing (by fax or 
email) within 24 hours of the event being 
reported to the PI 
Event is identified by the participant or proxy & meets the criteria for an RAE 
Clinical site coordinator notifies 
clinical site PI and clinical site 
clinician immediately 
NO 
CCC NOTIFIES DSMB AND NIA IN WRITING 
(BY FAX OR EMAIL) WITHIN 24 HOURS OF THE 
EVENT BEING REPORTED TO THE CCC 
Site Coordinator 
Clinical Site Staff 
LEGEND 
CCC 

CAP Protocol version 12.0 
 
55 
Blinded or unblinded staff is told about an event that meets 
the criteria for an RAE  
Blinded or unblinded staff completes a Reportable Adverse Events Form and Reportable Adverse 
Event Record and submits documentation to the clinical site coordinator 
Clinical site coordinator 
records RAE ID#, marks 
as duplicate, and files in 
participant binder 
Has the event been previously reported? 
NO 
YES 
Blinded or unblinded staff witnesses a 
serious or unexpected event that 
meets the criteria for a reportable AE  
Figure 5c. Collection and Reporting Process for RAEs Identified Anytime Other than During a 
Standardized Telephone Interview 
Clinical site coordinator assigns new RAE 
ID#, and records event on the RAE Log in 
the participant binder 
Clinical site coordinator notifies 
clinical site PI and clinical site 
clinician immediately 
Clinical site PI (or designee) redacts documents to 
conceal treatment assignment and notifies the 
CCC in writing (by fax or email) within 24 hours of 
the event being reported to the investigator 
CCC NOTIFIES DSMB AND NIA IN WRITING 
(BY FAX OR EMAIL) WITHIN 24 HOURS OF THE 
EVENT BEING REPORTED TO THE CCC 
Site Coordinator 
Clinical Site Staff 
LEGEND 
CCC 
 
 

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56 
Figure 5d. CCC Reporting Process for RAEs 
CCC records information on RAEs received from the clinical site in the RAE tracking database 
CCC forwards redacted RAE 
documents to the ISM on call to 
confirm appropriate classification 
CCC notifies the 
DSMB, NIA 
Is this event 
unexpected and 
related or possibly 
related to the study 
and suggest that 
the research places 
participants or 
others at a greater 
risk of harm? 
 
ISM notifies CCC 
that additional 
information is 
needed to make a 
clear determination 
CCC notifies clinical site 
coordinator to request 
additional information 
Clinical site 
coordinator 
gathers 
additional 
information and 
sends to CCC 
YES 
NO 
UNCLEAR 
YES 
ISM submits follow-up 
RAE evaluation 
reports to the CCC as 
new information 
becomes available 
DSMB concludes 
that RAE is of 
universal and of 
immediate 
concern and 
reports their 
findings to CCC 
YES 
CCC notifies clinical site PIs 
for immediate reporting to 
their IRBs  
STOP 
ISM completes a Reportable Adverse Event Evaluation 
and Follow-up form signs off and notifies CCC of RAE 
final status 
CCC provides listing of RAEs to DCC for inclusion in routine DSMB report 
Is this RAE ongoing? 
STOP 
NO 
Site Coordinator 
CCC 
ISM 
LEGEND 
DSMB 
CCC sends RAEs to Axio for MedDRA coding 

CAP Protocol version 12.0 
 
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Timeline for Reporting Events 
The RAE reporting schedule is shown below: 
1. RAEs will be reported to the clinical site PI and clinical site clinician as soon as the event 
is known. 
2. The clinical site PI (or designee) will redact documents to conceal treatment assignment 
and report all RAEs to the CCC in writing (by fax or email) within 24 hours of the event 
being reported to the investigator. 
3. The CCC will report all RAEs to the DSMB and NIA in writing (by fax or email) within 24 
hours of being notified. 
4. The DSMB and NIA will receive notification about all RAEs within 48 hours of when the 
event is known and reported by study staff. 
 
13.6 Evaluation and Follow-up of RAEs 
All RAEs submitted to the CCC will be forwarded to a blinded ISM for adjudication and follow-
up.  The ISM may contact the clinical site coordinator to request additional information from the 
participant, significant other, or their health care provider and may seek medical records from a 
physician or care setting if needed to make a determination about relatedness to the study.  If 
the event is potentially related to the study, the ISM will contact the clinical site PI who will 
consider whether the event was listed in the protocol and ICF and whether modifications to the 
protocol and ICF should be considered. To ensure the appropriate classification of events, the 
clinical site clinician and/or clinical site PI may also be called on to provide additional 
information. 
 
The ISM will be responsible for providing follow-up for ongoing reportable events, as follows: 
 
1. The ISM will follow up on RAEs until a final status has been determined for the event (e.g., 
recovered, ended in death, is still present, or status is unknown). Some RAEs may have a 
status of still present at the conclusion of the study. These are the categories of RAE status:  
a. ‘Resolved’ is an event that has ended, with or without residual deficits. 
b. ‘Still present’ is an event that is ongoing.  
c. ‘Unknown’ should be used when the site is unable to make contact with the 
participant or proxy or to obtain additional information in any other way. 
d. ‘Died’ is for an event that ended in death. 
2. If there are follow-ups to an event (and the event is ongoing), the ISM will use the Reportable 
Event Evaluation and Follow-up Form to record the event follow-up and submit to the CCC.  
3. Once the event is no longer ongoing and a final status for the event has been determined, 
the ISM will record the final status, enter the closed date, and sign and date the Reportable 
Adverse Event Evaluation and Follow-up Form that will be submitted to the CCC. 
 
The CCC will be responsible for reporting RAEs to the DSMB, NIA, and clinical sites, as 
needed.  Clinical sites will be responsible for reporting RAEs to their respective IRBs according 
to local requirements. 
 
13.6.1 Action Taken 
The clinical site PI, in consultation with the study clinician and the ISM, will decide whether or 
not an RAE requires that the participant be removed from the study intervention and will forward 
the decision to the CCC. The DSMB will be notified of the recommended course of action by the 
CCC.  Actions taken in response to the RAE will fall into one of five categories: 
 
Study intervention modified 
 
Study intervention suspended temporarily 
 
Study intervention stopped permanently 
 Study assessment modified 
 No action taken 

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58 
13.7 Responsibilities 
Clinical site PIs have primary responsibility for the safety of participants as it relates to the study 
protocol.  Clinical site coordinators will be responsible for reviewing RAEs and assuring 
accurate and timely reporting of RAEs.  Clinical site clinicians will be responsible for reviewing 
RAEs before they are sent to the CCC.  Blinded ISMs will evaluate and classify RAEs and 
provide follow-up for events until they are resolved. The DSMB will be responsible for reviewing 
monitoring data for evidence of harm attributable to participation in CAP. 
 
13.7.1 Clinical Site Clinician 
The clinical site clinician will be available by telephone for consultation with study personnel 
during all time periods when participants are engaged in the home-based interventions or at 
clinical assessment sites. In addition, the clinical site clinician will be responsible for reviewing 
and RAEs requiring immediate notification of the IRB and CCC and for being “on call” for study-
related emergencies. The clinical site clinician may delegate responsibilities related to 
immediate notification to a “covering” clinician. 
 
13.7.2 Independent Safety Monitor (ISM) 
Physicians serving on the Clinical Direction SOC and who are not affiliated with a clinical site 
will serve as ISMs to review RAEs reported to the CCC on a rotating basis. Other members on 
the Clinical Direction SOC will also serve as an ISM when necessary, but cannot review events 
from their clinical site.  When a RAE is identified by a clinical site the information will be 
redacted to conceal treatment assignment, reported to the CCC, and then forwarded to the on-
call ISM to make a determination.  The ISM will be responsible for: 
 
 
Reviewing reports of RAEs;  
 
Confirming or refuting classification of the event as an RAE; 
 
Making a determination about relatedness of the RAE; 
 
Requesting additional information as needed in order to make a determination;  
 
Providing the CCC with follow-up reports for ongoing RAEs as new information 
becomes available; and 
 
Notifying the CCC of the final status for the event once it has been determined. 
 
13.8 Reporting Expected AEs and RAEs to the DSMB 
The DSMB will review tabulated data on non-serious and expected AEs on a semi-annual basis 
and monitor for adverse event rates out of proportion to those expected. The CCC will forward 
the individual Reportable Adverse Event Records, including a narrative for each event, as well 
as a table showing all RAEs to the DSMB and NIA semi-annually. The DSMB will review all 
RAEs that are temporally related to the interventions in aggregate form at its scheduled 
meetings. 
 
All RAEs that relate to hazards of the study interventions or are cause for urgent concern will be 
reported to the CCC and the CCC will report these to the DSMB chairman, NIA, and the UMB 
IRB immediately after recognition of their importance. If the DSMB chairman concludes that an 
RAE is of universal and immediate concern, the CCC will notify local clinical sites at once. The 
DSMB chairman may recommend convening the DSMB to review participant safety based on 
any individual report or accumulating evidence, including evidence according to treatment 
assignments.  
 

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59 
Section 14: Intervention Discontinuation 
Certain RAEs may result in a temporary interruption or early discontinuation of the trial 
assessments and interventions or components of these assessments and interventions. Please 
refer to the appropriate MOP chapter(s) for specific instructions on stopping criteria during 
screening, intervention, and follow-up assessments.  
 
After such RAEs occur, a participant may resume the trial intervention when the clinical site 
clinician and the primary care provider (if participant has one) agree that it is appropriate. For 
mild problems that require temporary cessation of intervention, the clinical site investigator, in 
consultation with the clinical site clinician and participant, may agree to reintroduce the 
participant to the study intervention.  
 
At any time, the DSMB may recommend discontinuation of any component or intervention group 
of the study for any of the following reasons: 
1)  Compelling evidence from this or any other study of an adverse effect of the 
study intervention(s) that is sufficient to override any potential benefit of the 
interventions to the target population. 
2)  Compelling evidence from this or any other study of a significant beneficial effect 
of the study intervention(s), such that its continued denial to other study group(s) 
would be unethical. 
3)  A very low probability of addressing the study goals within a feasible time frame. 
 
Section 15: Data Analyses 
Analyses for all aims will be performed according to the intention-to-treat (ITT) paradigm. Prior 
to confirmatory analysis, exploratory data analyses will be performed. These exploratory 
analyses will consist of histograms for continuous outcomes to examine whether a 
transformation is needed to meet modeling assumptions and frequencies for categorical data to 
assess whether the data are sparse. With the exception of the statistical test of the primary 
hypothesis, all statistical tests will be two-sided and will not be adjusted for multiple 
comparisons. As described in greater detail below, the test of the primary hypothesis 
(comparing the groups with respect to proportion who are community ambulators at 16 weeks) 
will be based on a one-sided 0.025-level hypothesis test performed at five time points 
throughout the trial. 
 
15.1 Primary Aim 
The primary aim is to determine if a 16-week intervention based on aerobic conditioning, 
specificity of training, and muscle overload for strengthening (the PUSH intervention) is more 
successful in producing community ambulation at 16 weeks post-randomization than an 
intervention of transcutaneous electrical nerve stimulation, flexibility, and AROM exercises (the 
PULSE intervention).  Therefore, the one-sided null hypothesis that the PUSH intervention does 
not result in a higher proportion of community ambulators 16 weeks post-randomization will be 
tested. This hypothesis will be tested at five time points based on a Z-statistic (which is 
equivalent to the square root of the Pearson chi-square statistic). The critical values for each 
time point were chosen to preserve an overall type-1 error rate of 0.025.206 If the exploratory 
analyses reveal data sparseness (expected frequency less than 5 for at least one combination 
of treatment group and community ambulation status), Fisher’s exact test will be performed 
instead of using the chi-square statistic. The difference in proportions with a 95% confidence 
interval will also be reported.  
 

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The binary outcome variable will be ability to walk at least 300 meters in six minutes (yes/no). 
This variable will take the value of ‘yes’ if the participant was tested with the SMWT and walked 
300 m or more in six minutes. This variable will take the value of ‘no’ if 1) the participant was 
tested with the SMWT and walked less than 300 m in six minutes or 2) the participant was not 
tested with the SMWT (or the participant was tested but not according to protocol) and 
adjudication resulted in the participant’s being classified as a treatment failure (see 11.5 for 
description of the adjudication procedure). Participants whose adjudication result is 
‘indeterminate’ will be excluded from the primary analysis.  
 
In a secondary analysis, an alternative outcome variable will be created to represent the 
participant’s community ambulation status at 16-week follow-up. This secondary variable will 
take the value of ‘yes’ if the participant was tested with the SMWT and walked 300 m or more in 
six minutes. The secondary variable will take the value of ‘no’ if 1) the participant was tested 
with the SMWT and walked less than 300 m in six minutes, 2) the participant was not tested 
with the SMWT and adjudication resulted in the participant’s being classified as a treatment 
failure because of death, sickness, or gait speed < 0.6 m/s, or 3) the participant was tested with 
the SMWT but not according to protocol and adjudication resulted in the participant’s being 
classified as a treatment failure, whatever the reason. The secondary variable will take the value 
of ‘missing’ if 1) the participant was not tested with the SMWT and adjudication resulted in the 
participant’s being classified as a treatment failure based only on self- or proxy-reported walking 
limitation or 2) the participant was not tested with the SMWT (or the participant was tested but 
not according to protocol) and adjudication resulted in the participant’s being classified as 
‘indeterminate’. All participants, including those with a missing value for the alternative outcome 
variable, will be included in the secondary analysis. To be consistent with the principle of ITT, 
weighted estimated equations (described below) will be used for this analysis. 
 
Study site will be investigated as a modifier of the effect of the intervention by testing a site-by-
intervention interaction term. If study site is an effect modifier, we will report 1) site-specific 
treatment effects and 2) a summary measure of treatment effect using standardization. 
Standardization will be accomplished using inverse probability of treatment weighting (as a 
function of study site) in a marginal structural model.207 
 
In the fall of 2014, a decision was made to modify the frequency of intervention visits during the 
first 8 weeks from 3 per week to 2 per week. The number of sessions per week in the first 8 
weeks will also be assessed as a potential effect modifier, using the methods described in the 
previous paragraph.  If we find strong evidence that the number of sessions per week modifies 
the comparison of the intervention groups, we will report treatment effects separately for the 
period when there were two sessions per week and the period when there were three sessions 
per week. 
 
This change in number of sessions also affords us an opportunity to assess the impact of visit 
frequency on the intervention outcomes as a secondary analysis.  To do so, assuming no 
significant interaction between site and intervention group, we will assess the statistical 
significance of the effect of number of sessions.  If there is significant interaction between 
number of sessions and intervention group, then we will compare the outcomes obtained during 
the period with two sessions per week in the first 8 weeks to those obtained during the period 
with three sessions per week in the first 8 weeks separately in each intervention group. 
 
In addition, a series of analyses will be performed to examine the differential impact of the 
PUSH intervention relative to the PULSE intervention in subgroups defined by participant 

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characteristics. To do this, a variable-by-intervention interaction term will be tested for each of 
the following variables:  
1. Gender 
2. Age at baseline (≥85 years versus 60-84 years) 
3. Baseline depression (CES-D score ≥ 16 versus CES-D score < 16) 
4. Baseline balance confidence (with median Activities-Specific Balance Confidence scale 
score as the cutpoint to define the subgroups) 
5. Baseline nutritional status (MNA®-SF score <8 versus MNA®-SF score ≥8) 
6. Baseline cognitive status (3MS score <91 versus 3MS score ≥91) 
If the interaction term for any of these subgroup variables is significant, results will be presented 
separately in strata of the subgroup variable. 
 
15.2 Secondary Objectives 
 
15.2.1 Delayed and Sustained Effects 
Generalized estimating equations (GEEs)208 will be used to examine whether the proportion of 
community ambulators differs between the PUSH and PULSE interventions at 40 weeks post-
randomization and, for the subset of participants who were followed for 40 weeks, whether the 
difference in proportions at 40 weeks changed from the difference in proportions at 16 weeks. 
GEE will be used for this analysis because the data are longitudinal and, unlike in likelihood-
based methods, the estimates are robust to misspecification of the working model (e.g., 
binomial, normal, etc.). This approach accounts for intra-participant correlation between 
repeated measures. With the use of GEEs we will be able to relate outcomes, at specific time 
points, to treatment group. For all analyses using GEE, the empirical variance estimate will be 
used because it is robust to model misspecification. The longitudinal model for this aim will be fit 
using a binomial working model and is expressed by the equation: 
 
Logit(p) = a + b1 X + b2 t40 + b3 Xt40, 
 
(Eq. 1) 
 
where p is the probability of a particular outcome, Logit(p) = ln(p/(1-p)), X is the intervention 
indicator (1/0) variable; b1 is the treatment effect at 16 weeks; t40 is the 40-week follow-up time 
post-randomization indicator (0=16 weeks; 1=40 weeks); and Xt40 is the intervention-by-time 
interaction variable. The fitted coefficients in Eq.1 provide estimates of the proportion of 
community ambulators in the PUSH vs PULSE interventions at 16 and 40 weeks post-
randomization. To test the null hypothesis of equal proportion of community ambulators in both 
groups at 40 weeks post-randomization, we will test the null hypothesis H0: (b1+b3)=0 using a 
two-sided test with type I error of 0.05. This test will be performed regardless of results from the 
primary aim. However, the interpretation of results from this test will depend on those from the 
primary aim. If there is evidence for a difference in proportion of community ambulators at 16 
weeks, then rejecting this hypothesis can be interpreted as evidence for a sustained effect of 
the PUSH intervention on community ambulation at 40 weeks; if there is no evidence for a 
difference in proportion of community ambulators at 16 weeks, then rejecting this hypothesis 
can be interpreted as evidence for a delayed effect of the PUSH intervention on community 
ambulation at 40 weeks. We are also interested in describing the trends in community 
ambulation from 16 to 40 weeks post-randomization in both groups. To assess the null 
hypothesis of no change in the between-group difference of proportion of community ambulators 
between 16 and 40 weeks post-randomization, we will test the null hypothesis H0: b3=0 using a 
Wald chi-square test with type I error of 0.05. All treatment effects will be reported with their 
respective 95% confidence intervals. 
 
A similar approach will be used to examine delayed and sustained effects for the secondary and 

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tertiary outcomes described below. 
 
15.2.2 Secondary and Tertiary Outcomes 
Secondary outcomes include five variables (endurance, dynamic balance, walking speed, 
quadriceps strength, and lower extremity function) that are hypothesized to be precursors to 
community ambulation. In addition, we will examine the difference between the treatments with 
respect to the following tertiary outcomes: ADLs, balance confidence, quality of life, physical 
activity, lower extremity physical performance, depressive symptoms, increase of ≥ 50 meters in 
distance walked in six minutes, cognitive status, and nutritional status. GEE will be used to 
compare the PUSH and PULSE interventions at 16 and 40 weeks post-randomization. Increase 
of ≥ 50 m in distance walked, a dichotomous outcome, will be analyzed using the same method 
as the primary outcome. All of the other secondary and tertiary outcomes are continuous; 
therefore, a normal working model will be used to estimate the parameters in the following 
equation:  
                  = a + b1 X + b2 t16 + b3 t40 + b4 Xt16 + b5 Xt40,       (Eq. 2) 
 
where  is the mean of a particular outcome, X is the intervention indicator (1/0) variable; t16 
and t40 are the 16- and 40-week follow-up time post-randomization indicators, respectively; and 
Xt16 and Xt40 are the intervention-by-time interaction variables. This model accounts for 
outcomes at three time points: baseline, 16 weeks, and 40 weeks post-randomization. By 
treating the baseline value as an outcome, we quantify mean changes in the outcome relative to 
baseline levels. Differences between the two groups in changes from baseline to 16 and 40 
weeks post-randomization will be compared using Eq. 2 by testing H0: b4=b5=0 using a Wald 
chi-square test with type-I error of 0.05. All treatment effects will be reported with their 
respective 95% confidence intervals. 
 
15.2.3 Cost-Effectiveness of Interventions 
To assess the cost-effectiveness of study interventions, the EEC will conduct analyses of within-
trial comparisons for the economic endpoints (resource utilization/costs and SF-6D/QALYs) and 
will also undertake a model-based analysis that allows the economic value of both study 
interventions to be assessed relative to usual care. Longitudinal modeling appropriate for 
repeated measures data will be used to make inferences on the overall differences in cost and 
QALYs associated with the study interventions. The basic statistical analyses of cost and 
QALYs will be similar to the approach described for other study endpoints, but will be 
undertaken in the EEC in close collaboration with the DCC.  
 
Statistical analyses of SF-6D will produce an estimate of the incremental QALYs associated 
with the PUSH intervention at each time point where SF-36 is measured. The estimated 
difference in QALYs attributable to the PUSH intervention will be estimated by taking a time-
weighted average of the time-specific intervention effects. Statistical analyses of cost data, 
which will be adjusted to a constant dollar year (e.g., 2012 US dollars), will produce an estimate 
of the incremental costs associated with the PUSH vs.PULSE intervention.  
 
The incremental cost-effectiveness ratio (ICER), which is defined as the net change in cost 
divided by the net change in effectiveness (QALYs) when interventions are ranked in order of 
increasing cost, is the focus of the economic analysis.  When estimated as added cost per 
QALY gained, the ICER allows the value of interventions in hip fracture to be compared with 
interventions in other diseases. ICERs will be estimated using both the statistical analysis of 
cost and QALY data (i.e., trial-based ICER) and a model-based analysis that combines trial 
results with other existing data (i.e., model-based ICER). The trial-based ICER addresses the 
economic value of the PUSH intervention relative to the PULSE, while the model-based ICER 

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estimates the economic value of the study interventions relative to usual care (as described 
below). 
 
The second objective of the cost-effectiveness analysis is to develop and implement a decision-
analytic modeling framework that will incorporate within-trial findings regarding costs and 
QALYs for the purpose of evaluating the cost-effectiveness of the PUSH intervention and 
PULSE relative to usual care. Model-based analyses are commonly employed to extend or 
augment clinical trials because the cost of trials precludes study of all interventions of interest 
and because it is often desirable to consider the value of interventions over a longer time 
horizon than what is observed in the trial. To make inferences about the economic value of the 
study interventions relative to usual care, a Markov state-transition modeling framework that 
incorporates trial results will be developed and utilized. Estimates of the cost of the study 
interventions will be derived from time estimates recorded in the field over the course of the 
study. Estimates of the QALY impact of usual care will be derived from existing hip fracture 
cohorts (control arms of other trials). Estimates of changes in SF-6D for similar patient groups 
are available from the control arms of BHS RCTs. Because these studies have tracked resource 
utilization with few questions and follow up measures, extensive sensitivity analyses that vary 
the impact of the interventions on resource utilization will be undertaken to characterize the 
magnitude of change in costs that would be required to qualitatively affect the conclusions of the 
economic analysis. 
 
The model-based ICER for the study interventions relative to usual care will be compared 
qualitatively with the costs per additional QALY estimates of other commonly accepted medical 
interventions. Uncertainty in the model-based analysis will include estimation of cost-
effectiveness acceptability curves, which represent the probability that a particular cost-
effectiveness threshold (e.g., $100,000 per QALY gained) is achieved when variability in cost 
and QALYs is considered in probabilistic sensitivity analyses. 
 
15.3 Missing Data 
By design, there will be no missing data at baseline because only participants with complete 
baseline data will be randomized. At follow-up, scores for scales that have published rules for 
handling missing scale items (e.g., the CES-D and the SF-36) will be calculated using those 
rules. All other scales will be considered missing if any part of the scale is missing. To correct 
for potential selection bias from missing data, we will perform a weighted estimating equations 
(WEE) analysis.209 This method involves two steps. First the probability of being observed (not 
missing) is calculated as a function of predictors of missingness. Next the relationship of 
treatment group to outcome is assessed using the inverse probability of being observed as a 
weight in the GEE model. WEEs are advantageous because a) they are consistent with the ITT 
principle because participants with missing data are included in the analysis through the 
estimated weight, and b) unlike other methods for addressing missing data, they can be 
performed in conjunction with marginal structural modeling by multiplying both weights together.   
 
15.4 Nonadherence 
In the presence of nonadherence, ITT analyses have the benefit of conservatively estimating 
effects. However, ITT analyses may miss true effects because their results are biased toward 
the null. To address this issue, we will examine adherence (defined as proportion of intervention 
visits completed) in both intervention groups. If adherence is less than 80% in either group, we 
will perform a secondary analysis adapting marginal structural modeling to address 
noncompliance. In this case, the weight will be the inverse probability of treatment received as a 
function of treatment assignment and factors that may affect treatment compliance. This method 
has the benefit of accounting for intermediary factors that may impact compliance without 

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distorting the randomization by conditioning on these factors (i.e., a marginal analysis rather 
than a conditional analysis). Precedents for this approach are available in the literature by 
Cook.210 
 
15.5 Interim Analyses 
Interim analyses will be conducted by an alpha and lower bound spending design. At the time of 
this update, we have already performed an interim analysis based on the first 28.6% of the data. 
We plan to perform three additional interim analyses (based on the first 40%, 60%, and 80% of 
data available), where the boundary values for early stopping will be evaluated using the 
Hwang-Shih-Decani spending function approximation to the O’Brien-Fleming alpha-spending 
function [gamma=-4 for lower-bound alpha spending (inefficacy/harm), and gamma=-4 for 
upper-bound alpha spending (efficacy)].211,212 The upper and lower bounds will be computed for 
a test of efficacy with one-sided nominal alpha=0.025. For example, when testing for efficacy 
(delta>0) at the first interim analysis, Z>3.09 would denote efficacy, and Z<-1.76 would denote 
inefficacy/harm. Table 4 shows the anticipated proportion of the sample accrued at each of the 
remaining interim analyses along with the corresponding critical values for declaring significance 
(or lack thereof) at each time point. The critical values are subject to change if the actual 
information available at the time of the analysis differs from the expected information available. 
These critical values were calculated using the gsDesign package in R version 2.10.1. 
 
Table 4. Anticipated Critical Values for Each Planned Analysis 
Analysis 
Expected % 
of information 
available 
Critical z-value for 
upper-bound alpha 
spending 
(for efficacy) 
Critical z-value for 
lower bound alpha 
spending (for 
inefficacy/harm) 
First interim analysis   
28.6% 
3.09 
-1.76 
Second interim analysis   
40% 
3.03 
-1.57 
Third interim analysis  
60% 
2.69 
 -0.97 
Fourth interim analysis  
80% 
2.37 
 -0.21 
Final analysis 
100% 
2.03 
 2.03 
 
The spending function applies specifically to analysis of the primary outcome (community 
ambulation at 16 weeks post-randomization). However, at each interim analysis, study 
performance and secondary and tertiary outcomes will be examined to aid in the interpretation 
of the primary outcome results.  
 
15.6 Sample Size Adequacy 
  
15.6.1 Primary Aim 
The original power calculations for this study were based on the assumption of a 10% loss to 
follow-up and a 10% rate of nonadherence. However, based on data on the first 88 study 
participants, the estimated rate of loss to follow-up was 6.8% and the rate of nonadherence was 
12.2%. These estimates were used to revise the power calculations using a new total sample 
size of 210. 
 
The threshold defined for the primary outcome, the ability to walk 300 meters or more in six 
minutes, was exceeded by approximately 9% of subjects in the BHS 4 cohort at six months 
post-fracture (which corresponds approximately to the 16-week post-randomization follow-up in 
the proposed trial). Furthermore, 23% of controls in the pilot study for the current project 
surpassed the 300 meter threshold. The midpoint of this range (9% to 23%) is 16% and this was 

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used as the basis for power calculations for the primary outcome, using the R version 2.10.1.213  
Binder et al,68 using a comparable intervention, reported an effect size of approximately 0.6 SD 
on a continuous measure of physical performance. The 0.6 SD effect size corresponds to a 
difference in six-minute walk distances of about 50 meters for hip fracture patients; a 50-meter 
difference has been determined by Perera et al.183 to be clinically meaningful. Assuming normal 
distributions for the SMWT, and with 16% surpassing the 300 meter threshold in the PULSE 
group at 16 weeks, a 0.6 SD effect size projects to a 19 percentage point difference in the 
proportion of community ambulators between the PUSH group and the PULSE group. A 
difference of 20 percentage points or more in the proportion of participants achieving community 
ambulation is thus considered an achievable and clinically meaningful goal.  
 
Using a group sequential design with four interim analyses (see Section 15.5), and assuming an 
overall loss to follow-up of 6.8% and treatment non-compliance of 12.2%, a total sample of 210 
enrolled patients (105 patients per group) is sufficient to achieve over 80% power for the 
detection of a 20 percentage point difference between the groups, with 16% achieving the 300 
m threshold of the SMWT in the PULSE group vs 36% in the PUSH group, using a one-sided 
0.025 significance level. The power specified is for the detection of a time-specific difference at 
the 16-week follow-up. This calculation accounts for the sample size inflation of 2.4% needed to 
account for the group sequential design211,212 and for the impact of noncompliance on the 
variance of treatment differences under the assumption that non-compliers assigned to the 
PUSH group have an equal 16-week proportion achieving community ambulation as participants 
assigned to the PULSE group.214,215 
 
Table 5 shows the power to detect various between-group differences in proportions of 
community ambulators using a one-tailed test of the difference in proportions at the 2.5% 
significance level. The table indicates that the study has adequate power for detecting 
differences down to 20 percentage points.  
 
Table 5. Power to Detect Difference in Proportions 
True Difference in Proportion Achieving 
Community Ambulation at 16 Weeks 
Power (%) 
23 percentage points 
89 
22 percentage points 
87 
21 percentage points 
84 
20 percentage points 
80 
19 percentage points 
76 
18 percentage points 
72 
17 percentage points 
68 
 
15.6.2 Secondary Aims 
Delayed and Sustained Effects. Follow-up will end at 16 weeks post-randomization for those 
consented under version 10.0 of the protocol. We estimate that there will be approximately 150 
participants (not the full 210) for whom the 40-week measure of community ambulation will be 
available.  In addition, based on our experience to date, we estimate that the community 
ambulation outcome will be indeterminate for 10% of the participants at the 40-week 
assessment. If we assume a sample size of 150 then there is 64% power for detecting a 
difference of 20 percentage points at alpha = 0.05 using a two-tailed test.  
 
Effect on Secondary and Tertiary Outcomes. Using a two-sided test with alpha=0.05, a sample 
of 210 patients with 6.8% loss to follow-up and 12.2% treatment noncompliance will provide 

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80% power to detect effect sizes of 0.46 SD at 16 weeks, which are considered moderate in 
size, under the assumption that noncompliers assigned to the PUSH group have an equal mean 
and standard deviation as patients assigned to the PULSE group. Collection of some outcome 
measures will end after implementation of protocol version 11.0 (see Section 11:). For these 
measures, we estimate that there will be approximately 160 participants (not the full 210) for 
whom the 16-week measure will be available. Under the same assumptions, a sample of 160 
will provide 80% power to detect an effect size of 0.53 SD. 
 
Economic Evaluation. Follow-up will end at 16 weeks post-randomization for those consented 
under version 10.0 of the protocol. We estimate that there will be approximately 150 participants 
for whom the full 40-week follow-up will be available. Assuming a mean SF-6D score of 0.62 in 
the PULSE group and between-subject standard deviation of 0.10 (based on unpublished data 
from the fourth BHS cohort study), and assuming that non-compliers assigned to the PUSH 
group have an equal mean and standard deviation as patients assigned to the PULSE group, a 
sample size of 75 per group will allow us to detect a between-group difference in means of 
0.055 with 80% power and using a two-sided 0.05-level test. 
 
Costs will be used in conjunction with information on patient quality of life to make treatment 
outcome comparisons in terms of cost per QALY associated with treatment effects. The primary 
interest in the economic evaluation is to assess the impact of variability in cost and QALYs on 
the ICER. To address power for the economic evaluation, we computed the minimum detectable 
incremental net benefits (INB) for the planned study size.216 To complete this calculation, a 
threshold ICER, , must be specified, which is the maximum one is willing to pay per QALY 
gained. INB is then defined as a function of changes () in QALY and costs as follows: 
*QALY-Cost. We utilized ICER thresholds () of $25,000, $50,000, and $100,000 in these 
computations with α=0.05 (two-sided) and 80% power, and utilized variances and covariances 
between QALYs (estimated by SF-6D) and cumulative costs from the observational, non-
operative treatment arms of the Spine Patient Outcomes Research Trial. Although these 
subjects differ from hip fracture patients, they have similar ongoing musculoskeletal concerns 
and variation in QALYs. For ’s of $25,000, $50,000, and $100,000, minimal detectable INBs 
are $2,638, $4,079, and $7,234, respectively.  
 
Section 16: Data Capture, Data Management, and Quality Assurance 
16.1 Overview 
Data management will be provided under subcontract with Axio Research, LLC, Seattle, WA. 
Axio is a contract research organization with over 30 years of experience providing biostatistical 
and data management support for clinical trials sponsored by the NIH and industry. Axio 
operates under a set of Standard Operating Procedures (SOPs) designed to comply with NIH 
and FDA requirements. 
 
A hybrid system will be employed in which some of the data forms are completed on paper and 
others using a Web form. All data will be stored and cleaned using Clintrial (Oracle/Phase 
Forward, Waltham, MA), a commercial clinical data management system in wide use. Data 
collected during intervention visits and telephone interviews will be entered using a Web system 
developed and validated by Axio. Some forms will be completed on paper and forwarded in 
batches to Axio for processing. This model was chosen to minimize costs and to provide 
maximum flexibility for each of the different types of data collection (clinical assessment, 
intervention visit, telephone interview). All systems used in this study will be validated according 
to Axio’s SOPs prior to being put into production. 
 

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Axio will draft and maintain a Data Management Plan (DMP) for this study. This plan outlines 
the study data management processes including detailed descriptions of the data entry 
systems, the study database, data standards, data edit rules, query processing procedures 
(both automated and manual), and coding procedures. The database annotated data forms and 
details of the edit checks will be included as appendices in the DMP. Minor changes may be 
made to the DMP during the course of the study as appropriate. 
 
16.2 Data Capture 
Data capture will utilize a hybrid system; some of the forms will be completed on paper and 
forwarded to Axio for entry and verification. Others, in particular forms completed at intervention 
visits and during telephone interviews, will be completed online (Web data entry) using a 
validated Web data collection tool. The original of all paper forms submitted will be filed in the 
participant binder and kept at the clinical site. Forms entered using the Web tool will be printed 
from the Web site and filed in the participant binder. It will be the clinical sites’ responsibility to 
ensure that all forms are complete and submitted within the required time frame. For paper 
forms, the person who collected the data will sign and date the form attesting to its accuracy 
and completeness. For the Web-based forms, the person who entered the data will print the 
form after completion and will sign and date the form attesting to its accuracy and 
completeness. If the person who entered the data is not the person who collected the data, the 
latter will review the form and sign and date it to affirm its accuracy and completeness. Source 
documents and other study paperwork will be turned into the office on a regular basis by study 
staff. 
 
16.3 Data Management 
 
16.3.1 Processing of Paper Data Forms 
Paper data forms will be completed by clinical site staff, scanned and emailed to Axio for entry, 
verification and cleaning. The database will be established using Clintrial (version 4.7). This 
clinical data management system is widely used in the pharmaceutical industry. This database 
will reside on the Oracle Database Server, located at Axio. Using Clintrial, Axio will set up a 
logging and tracking system to make sure that each form page received is processed in a timely 
manner. Each table in the database will be carefully checked to ensure that all the variables 
specified on the form have been appropriately entered into the database in the proper format 
(e.g. integer, date/time). Before implementing the data entry system and database, a sampling 
of data will be entered and loaded into the database. The resulting data from each data table 
will be tested to make sure that the entire process results in a database as expected. 
 
Axio staff will program the data entry screens for the study using Clintrial. A screen may 
correspond to a paper data form page or to some portion thereof. The screens are programmed 
to require that numeric fields be re-keyed by a second data entry technician (double-data entry) 
for quality control.  
 
Axio will define a data cleaning system comprised of: 1) computerized data validation rules to 
check for legitimate/expected values, completeness of data forms, and logical consistency; and 
2) manual screening checks. The DCC will review and approve the data edit query definitions 
before Axio begins programming them. A complete list of the data edits will be maintained as an 
appendix to the DMP. 
 
Upon receipt of paper CRF data, the data management staff will log receipt into the study study 
management database and will review the data form prior to data entry. Potential problems with 

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the data (e.g., missing or illegible identification data) will be identified by this screening process 
and entered into Clintrial as “ad hoc” data queries, distributed and tracked for resolution. A data 
technician will enter the data from each data form page received. A separate data technician will 
verify the first entry by entering the data a second time (blinded double entry-verification). Text 
fields will be visually verified during this second pass. 
 
Data edit checks will be run as each batch of data is entered and verified. Axio’s data 
coordinator will review the resulting list of problems, determine which problems should be sent 
as queries, and interact with the clinical site staff to clarify issues and answer questions. 
Queries will be printed to PDF and delivered to the sites via email by the data coordinator. Data 
edit queries will be distributed within one week of receipt of the data forms. Shorter turn-around 
will be provided in advance of DSMB meetings and towards the end of the study in order to 
freeze or close the database. 
 
Using the query tracking reports, the data coordinator will make sure that all queries are 
promptly and completely addressed, following up on data problems and initiating communication 
when necessary to make sure that data problems are promptly addressed. 
 
Clinical site staff and DCC staff may submit “ad hoc” queries that are tracked and processed in 
the same way as the programmed queries. Clinical site staff may also initiate ad hoc 
corrections. 
 
Clintrial provides a complete 21CFR11-compliant electronic audit trail of all changes made to 
the database. The audit trail includes the name of the person making the change, the date/time 
of the change and the reason for the change. 
 
16.3.2 Processing of Web-Entry Data 
Axio will design, program and validate a password-protected Web-based system for data entry 
of certain of the data forms. The Web system will allow the user to select the participant from a 
list of participants randomized at the user’s site. Entry of the letter code by site staff will be used 
to confirm that the proper participant has been selected. The application will display the 
assessment times and allow the user to select the assessment time and form for entry. Edit 
checks will be included for within-form logical, completeness and value/range checks. Once a 
form has been entered and submitted, the link will be disabled. At that point, the application will 
generate a print/readable PDF image of the data form that can be downloaded or printed. 
 
On a daily basis, data from the Web system will be downloaded to the Clintrial (Oracle) 
database. Further edits will be applied to the data in Clintrial. Queries and updates to data 
entered over the Web will be handled as data from paper data forms, as described above. 
 
The Web system is based on a “Survey Tool” that has been in use at Axio for over 5 years. The 
tool has been reliably implemented for a wide range of studies including some involving 
participant reported outcomes. 
  
16.3.3 Reportable Adverse Events Coding 
RAEs will be coded using MedDRA (version 15.1, release date September 1, 2012). The 
MedDRA coding dictionary is integrated with the Clintrial database. 
 
16.3.4 Extraction of Data for Analysis and Reporting 
Data will be extracted to SAS data sets for analysis and reporting.  Where required, data will be 
merged and recoded using validated SAS code to create “analysis data sets”.  Specifications for 

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these analysis data sets will be drafted and updated as needed. Testing will be performed by an 
independent statistician/SAS programmer per Axio’s SOPs. 
 
16.4 Protection of Data 
 
16.4.1 Physical Security and Backup 
Axio 
Axio’s offices remain locked at all times.  Access is controlled by individually-assigned PIN 
codes. Visitors are required to sign in and be accompanied at all times by an Axio staff member. 
Axio maintains a dedicated, access-controlled server room within its facility. The server room is 
supported by three uninterruptable power supplies, a dedicated heating, ventilation and air 
conditioning (HVAC) system, a temperature and humidity monitor and a facility fire detection 
system. 
 
All corporate data and resources including users and computers are administered and secured 
in a Windows domain type network environment using Microsoft’s Active Directory services. 
Access to the data and the programs on the network is secured using group based privileges.  
Passwords are required to be changed every 90 days and the strength and length of the 
passwords are set according to rules specified by the Director of Information Technology (IT). 
 
Internet access is provided by two high-speed connections, a dedicated Ethernet line and a 
Comcast business class connection. The Axio phone system is supported by a separate, 
dedicated T-1 line. The Axio network is isolated from the Internet on each independent provider 
by a router and then subsequently by a Cisco Integrated Services router. The Cisco router 
includes a Cisco IOS Firewall and intrusion prevention, onboard encryption and additional 
security features.   
 
Remote access to the corporate network is provided using the virtual private network services 
supported by the Cisco Integrated Services router. Access to the corporate network is controlled 
by the Microsoft’s Active Directory services in the Axio domain. 
 
Clintrial resides on an Oracle server located inside Axio’s corporate firewall and on a server 
located within Axio’s dedicated access-controlled server room, described above.  Access to the 
Clintrial database is controlled by a security model imposed by the software, which requires 
login with an individually assigned user name and password.  A role-based security model 
assures that staff are allowed to perform only those functions which are appropriate for their role 
(e.g., data entry/verification only, managing data queries, etc.).  Backups are performed as 
described below. 
 
The Axio collocation facility is located at the AdHost data center in Seattle, WA.  The AdHost 
facility is access-controlled, monitored by both interior and perimeter security and all servers are 
located in locked cabinets. The server hardware at AdHost is monitored 24 hours/day, 365 
days/year, by AdHost staff at their network operations center, located on site.  The AdHost 
facility is supported by power from four physically diverse locations: (1) a diesel generation 
backup with rooftop helicopter delivery of fuel, (2) uninterruptable power supplies for each bank 
of cabinets, (3) a carrier neutral environment with nine separate ISPs, and (4) a fully redundant 
HVAC system. The AdHost facility meets or exceeds the California seismic zone 4 standards.  
 
All Axio systems are managed by the Director of IT, a System Administrator and backup System 
Administrator.  The System Administrator duties include configuration and daily monitoring of all 
networks including system performance and intrusion detection, daily monitoring of server 

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systems including server performance and logs, backup and restore, system validation, internal 
user support, software support and network security configuration including permissions and 
network access. The Axio backup plan defines the servers, folders and files that are included in 
the backup. Full backups are performed weekly and differential backups are performed daily.  
All backup tapes are retained onsite for one week and then sent to a hardened, secure offsite 
storage facility, Datasite Northwest.  
 
Axio maintains a disaster recovery plan that addresses all aspects of business activities. The 
technical portion of the plan includes processes for recovery of critical systems, e-mail, data and 
support services under a variety of scenarios. Axio maintains a collocation facility that is capable 
of hosting all critical functions in the event of a disaster.  The disaster recovery plan is reviewed 
yearly and major technical portions of the plan are exercised quarterly. 
 
Data Coordinating Center at University of Maryland, Baltimore 
All files, including programs used for data management functions, are fully archived once every 
week with an incremental backup (one in which only records containing new or modified data 
are archived) as well. The backup system is designed to permit the restoration of the system 
with a minimum expenditure of time and money should any file be destroyed. Every four weeks, 
the backup devices are copied and stored off site. Prior to any major change in the operating 
system, backup devices of the main database are created and saved for as long as needed.  
 
Economic Evaluation Core at Dartmouth University 
The Economic Evaluation Core (EEC) has offices located at Dartmouth-Hitchcock Medical 
Center (DHMC) with computing support provided by The Dartmouth Institute for Health Policy 
and Clinical Practice (TDI) computing services and Geisel School of Medicine Computing. All 
computers operating on the DHMC campus are fully encrypted. TDI provides 7-day, 24-hour 
access to its own Dell PowerEdge 6650 servers, running Red Hat Enterprise Linux.  These 
servers contain four parallel processors, 12 GB of RAM, and 7.2 terabytes of hard disk, along 
with several more terabytes of online tape archives.  Data are protected by the use of Decru 
Dataforts, which provide on-the-fly 256-bit level encryption.  All connections to this server are 
secured by Secure Shell which encrypts all communications to and from the work stations on an 
isolated firewalled network.  Authorized users may access the system only via VPN, or locally 
through the firewalled intranet, using Red Hat Linux workstations.  
 
Current research is supported by a cluster of 2 Dell 2950 servers using the VMWare 
virtualization suite, which allows multiple “virtual machines” to run simultaneously on each 
physical machine. Physical machines communicate together in a cluster to automatically share 
resource load and to assume the work of physical machines that experience hardware failure, 
minimizing possible down-time. Each of the two VMWare servers is configured with two dual-
core 3.2 GHz Pentium processors, dual-power supplies, and 8 GB of memory. The dual 
processors and internal power-supplies prevent shutdown from a single component failure. For 
storage, we have two fault tolerant (RAID-5) Network Attached Disk arrays. The RAID 
(Redundant Array of Independent Disks) configuration prevents a single disk failure from 
affecting data integrity or resulting in data loss. For backup an 80/160 GB tape and another 
400/800 GB tape backup drive are used. Additionally, two external APC 3000 and one 1500 
universal power supply along with PowerChute software minimizes short-term power loss and 
allows for graceful shutdown during extended power outages to prevent corrupted data. In 
addition to the clustered VMWare servers, the Research Computing Service has Dell 
PowerEdge 2600 and 750 systems. Each has its own RAID-5-based internal disk storage and 
the 2600 has dual-CPUs and dual-power supplies for additional fault-tolerance. 
 

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Databases are implemented through Microsoft SQL-Server relational database management 
system. Data on the research workstations is protected through a "near disk" online backup 
strategy along with a tape facility for long-term, off-site storage. All workstations in the CAP 
EEC’s domain are backed up in real time to the server disks to provide short-term file and disk 
recovery using Symantec Backup Exec software. These workstation backups along with all 
server changes are then backed up nightly to tape for long-term and off-site storage. 
Additionally, file copies can be synchronized in real time between laptops and workstations 
using the Symantec Desktop-Laptop Option. 
 
16.4.2 Software Systems Security 
Randomization and Web Data Entry Systems 
The randomization and web data entry systems will be implemented by Axio as a SSL Web 
application on the AdHost collocation facility described above.  Access to these systems will be 
accessible only through successful login using an individually assigned user ID and password.  
Passwords will be required to adhere to specific rules to ensure strong security and will be reset 
every 180 days.  The application will encrypt all transactions (https:// web site).  Data will reside 
on a SQL/Server protected from the internet by firewall.  Separate passwords will protect the 
SQL/Server databases.  All transactions will be logged, recording the user ID of the person 
performing the transaction and the server and local date/time of the transaction. 
 
Analysis Data 
Data for statistical analysis and reporting will be downloaded from the Web systems described 
above and from Clintrial.  All files will be stored to a file server located at Axio.   
 
Access to the directories where study data will be retained will be controlled by a security group 
model, allowing only those Axio staff working on this trial to have access to the files and data.  
Access to unblinded randomization assignment data will be further restricted to those 
specifically designated by the Director of the DCC to have access to the randomization codes. 
 
16.5 Study Management Database 
An Access® database will be used to track study visits, generate schedules of future study visits, 
status of participants, activities of study staff members, form completion, and form submission. 
The database will provide a standard way for the clinical sites to track time-sensitive study 
activities throughout the study and for the CCC to track activities across all three clinical sites.  
Each clinical site will house the study management database on a password-protected 
computer drive that will be automatically backed up daily. Access to the database will be 
restricted to the PI and study coordinator and, if necessary, one other study staff member who 
has no participant contact. There will be several standard reports available in the database for 
the clinical sites to use for a variety of tracking issues.  Additional reports will be created as 
needed.  Data for the tracking database will come from tracking forms completed by study staff.   
 
16.6 Quality Assurance (QA) 
Quality assurance (QA) will be a shared responsibility of all investigators. The goal of QA 
monitoring will be to track study progress and develop the information necessary to ensure: 1) 
enrollment of the required number of participants; 2) adherence to treatment protocol; 3) that 
data are reported completely, verifiably and in a timely fashion; and 4) participant safety, by 
accounting for expected AEs and RAEs and providing regular reports to the DSMB, NIA, and 
IRBs. Study monitoring will be based on early implementation of reviews of accumulating data 
with rapid feedback to the clinical sites regarding problem areas. The Steering Committee will 
regularly review progress. 

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16.6.1 Training 
Staff from each clinical site will be trained at the initial central training session(s). Certification 
and recertification will be required in order to assure that clinic staff have a clear understanding 
of the CAP Protocol and Manual of Procedures (MOP). Separate training sessions will be 
provided for staff conducting study assessments, telephone interviewers, PTs providing the 
PUSH intervention, PTs providing the PULSE intervention, staff conducting screening and 
informed consent procedures, and the registered dieticians.  The clinical site coordinator will 
attend all training sessions. 
 
Training sessions will cover recruitment; obtaining informed consent; collection of protocol-
specified data (both questionnaire and performance-based measures); scoring; completion of 
forms; randomization; capturing and reporting expected AEs and RAEs; administering the 
interventions; performing diet consults; and using the paper-based and web-based data entry 
systems.  
 
In preparation for training, staff will be asked to read background material (e.g., designated 
chapters in the MOP). The training session will involve both didactic and interactive 
components. Training for the different sessions will be provided by investigators with the 
appropriate expertise. For example, training the PTs to deliver the study interventions will be 
provided by the IM, training in consent, enrollment, and assessment procedures will be provided 
by the CCC director, while training in randomization and forms completion will be provided by 
the DCC director. Whenever appropriate, trainees will be required to demonstrate acquired 
skills. These demonstrations will be observed and critiqued by the trainers and other staff. 
Trainees will be certified to perform study procedures after successfully completing written and 
(when appropriate) performance tests.  
 
Local recertification sessions will be held annually for all staff groups. In addition to refresher 
training on all study procedures, these sessions will focus on current issues facing the staff, new 
components implemented in the clinical sites, and problem areas. Recertification procedures 
improve compliance with the protocol and the maintenance of study skills over the course of the 
trial. The clinical site coordinator will be responsible for documenting that certification and 
recertification training has been completed and forwarding that information to the CCC. 
 
16.6.2 Quality Assurance Oversight 
QA will be a major activity of the CCC and DCC throughout the study. Annual visits to each 
clinical site will be carried out by the directors of the DCC and CCC, accompanied by other DCC 
and CCC staff, and the outcome of QA visits will be reported to the study chair and the Steering 
Committee.  Clinical site investigators will be actively engaged in project oversight on an 
ongoing basis via regular meetings of the Recruitment and Evaluation SOC. Conference calls 
will be used to review study progress, exchange information, and engage in joint problem 
solving.  Recruitment, follow-up contact and participant retention, adherence to the 
interventions, protocol deviations and AEs will all be monitored. Please refer to the Treatment 
Fidelity Plan (section 9.5) for QA related to the interventions. 
 
16.6.3 Protocol Deviations 
Protocol deviations may jeopardize the study by breaching assurances made to the participants 
or by diminishing the validity of the study. Major deviations will be those that endanger 
participants, such as failure to protect safety during the interventions, or that undermine 
fundamental premises of the study, such as failure to provide the assigned intervention 
according to protocol or randomizing an ineligible participant. Minor deviations will be those that 

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impede the progress of the study, such as not submitting data in a timely fashion. After the first 
major deviation, a clinical site will be asked to submit a proposal outlining how recurrence will be 
prevented. If remedial efforts fail to correct a problem, access to the randomization system will 
be suspended and the situation will be reviewed by the SC, DSMB, and/or NIA, depending on 
the nature of the deviations.  This review could result either in more aggressive remedial efforts 
or in termination of the clinical site.  The DCC will document minor deviations in performance 
reports, as well as notifying the clinical sites of them. Repeated minor deviations that are not 
corrected may result in suspension of the clinical site. Such a clinical site can only resume study 
activities once a corrective action plan has been submitted and approved by the Steering 
Committee.  Clinical sites with enrolled participants will be required to complete data collection 
for those participants even if randomization is suspended. Prior to separation of a clinical site 
from the study, the directors of the DCC and CCC will visit the clinical site and provide a site 
visit report to the DSMB for recommendation on final action.  
 
Major deviations will be reported promptly by the clinical site to its IRB and to the CCC and will 
be tracked at each site using a protocol deviation log, which will then be stored in a study-wide 
cumulative report in the CCC.  The following classifications of protocol deviations will be 
captured, documented, and reviewed: 
 
1) Enrollment, consent, and randomization deviations 
a. Randomization of an ineligible participant 
b. Failure to obtain informed consent 
c. Enrollment of participant into another study 
 
2) IRB deviations 
a. Failure to keep IRB approval up to date 
b. Failure to submit study modification for approval 
 
3) Intervention deviations 
a. Wrong intervention administered to participant 
b. Required aspects of intervention not administered (e.g., dietician referral) 
 
16.7 Monitoring 
Ongoing QA monitoring will be performed by the DCC and the CCC. The DCC will check study 
forms to confirm that certified staff are performing study procedures and will perform exploratory 
statistical investigations of aggregate data to identify unusual patterns and distributions. Regular 
reports will be generated showing the site-specific frequency of missing data, delinquent forms, 
and other study performance parameters. These reports will be reviewed by CCC staff who will 
promptly initiate action to remedy any problems, and will perform follow-up evaluations of 
actions taken, if necessary.   
 
Each clinical site will be visited before study start-up to ensure readiness for enrollment and 
data collection activities. Each site will then be visited at least once a year during the enrollment 
and follow-up period, and again for a close-out visit six months after the completion of data 
collection. If problems are identified, the CCC will develop a corrective action plan for the clinical 
site with clearly defined tasks and timelines. The CCC will track the implementation of the plan 
and assure that all tasks are completed within the defined timeframe. 
 
Site visitors will discuss any difficulties clinical site staff are having and will work cooperatively to 
try to resolve them. Additional visits will be made to clinical sites experiencing difficulty in 
meeting their goals for recruitment or in delivering the study intervention, and recommendations 

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74 
for improvement will be made to them. Additional visits will also be made if there are concerns 
about data quality or protocol adherence. Following each visit, a report will be sent to the SC. 
The SC will review site deficiencies and protocol deviations; remedial action and/or site 
suspension will be recommended based on severity and frequency of occurrence. 
 
The purposes of the monitoring visits will be to: 
 
assure the rights and safety of participants 
 
assure that informed consent has been obtained and documented in accordance 
with the protocol and NIH regulations  
 
verify adherence to the protocol and examine staff knowledge via interviews and 
formal testing  
 
observe staff performing screening, informed consent, evaluations and 
interventions to confirm that study conduct follows the guidelines of Good Clinical 
Practice 
 
observe office space and procedures to assure secure maintenance of required 
documents  
 
observe location for the storage of study medications and review temperature 
logs 
 
review drug accountability logs 
 
review files for documentation of informed consent and to monitor the quality of 
data collected  
 
review participant binders for completeness 
 
assure the information recorded on the forms is complete and accurate 
 
assure there are no omissions in the reports of specific data elements 
 
assure participant status at study exit is accurately recorded 
 
assure accurate reporting and documentation of all AEs 
 
Clinical site investigators must provide the QC monitors access to all requested study 
documents, including ICFs, drug accountability records, and source documents. During these 
visits, a spot-check of the accuracy of selected participant records will be carried out based on 
data already submitted to the DCC.   
 
Additional QA monitoring will be conducted by audiotaping all four-week telephone calls.  A 
random sample of the recordings will be reviewed centrally to confirm the date, time, and length 
of call; completeness and accuracy of administration of the questions; and completeness and 
accuracy of the responses recorded on the data collection form. 
 
Section 17: Participant Rights and Confidentiality  
 
17.1 Institutional Review Board (IRB) 
The study protocol for scientific oversight and management will be reviewed by the UMB IRB as 
the umbrella protocol (excluding aspects specific to human subjects that will be addressed by 
the clinical sites’ IRBs). Subsequent modifications to the umbrella protocol must be approved by 
UMB IRB before submission to the IRBs at the clinical sites and IRBS at respective study 
hospitals.  
 
The study chair will be responsible for sending DSMB recommendations to individual clinical 
site PIs, who in turn will be required to distribute the report to their local IRBs.  
 

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17.2 Informed Consent Forms (ICF) 
It will be the sole responsibility of each clinical site PI to ensure that informed consent was 
properly obtained for every participant who entered into the study at her/his site.  The ICF will 
describe the purpose of the study, the procedures to be followed, alternatives to participation, 
and the risks and benefits of participation.  It will also be explained that signing the consent form 
allows the study to confirm eligibility before randomization to a treatment group.  Written 
informed consent will be obtained according to procedures reviewed and approved by the 
clinical sites’ IRBs.  Informed consent can be obtained anytime upon completion of phase 1 
eligibility screening and prior to 26 weeks post hospital admission. Consent by a legally 
authorized representative will not be accepted.   
 
In some cases, a local hospital will allow the use of the clinical site’s IRB approved consent form 
and/or the HIPAA Authorization Form.  However, clinical site IRBs and local hospital IRBs may 
require that language be added to the consent form to correspond to local requirements. The 
clinical sites will be responsible for ensuring that the correct version of the ICF is used at their 
site. 
 
If there is a change in any of the study procedures or risks that may affect the participant, the 
ICF must be revised and undergo appropriate IRB review and approval.  Any participants 
enrolled in the study prior to such changes and who are still active in the study must sign the 
amended consent form. 
 
The study consent form will be provided to a potential participant for review prior to obtaining 
informed consent. The ICF may also be mailed to the participant and/or a family member so that 
s/he has sufficient time to read the document and, if desired, to have a family member or friend 
review the form before signing.  During the informed consent process, study staff will provide 
participants with adequate information concerning the study procedures, respond to individuals’ 
questions and concerns, and ensure that each individual understands all the information 
provided by assessing ability to provide informed consent.  A more detailed description of the 
informed consent process can be found in section 7.6.   
 
17.2.1 Disposition of Informed Consent Forms 
Because ICFs contain subject identifiers and protected health information (PHI), these forms will 
not be submitted with the data collection forms.  Originals of the ICF will be filed and maintained 
by the clinical site coordinator in the participant binder which will be secured in a locked cabinet 
or office, separate from source documents that include no PHI.  A copy of the signed consent 
form will be given to the participant and this fact will be documented in the participant’s record.   
 
17.2.2 HIPAA Authorization 
The HIPAA Authorization for Research is an individual's signed permission to allow the study 
investigators to use or disclose the individual's PHI described in the authorization.  Once an 
individual has agreed to participate in the study and written informed consent has been 
obtained, the HIPAA Authorization for Research must also be explained and signed.  The 
HIPAA Authorization may be a stand-alone document or wording for the HIPAA Authorization 
may be incorporated into the text of the ICF.  The original signed authorization will be submitted 
to the study office and a signed copy will be given to the participant.   
 
17.3 Participant Confidentiality 
Potential participants will be provided with a clear understanding of how the information they 
provide will be used.  All investigators and staff involved in the study will be required to complete 
training on the protection of human subjects and HIPAA and to maintain proper certifications.    

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Information may be entered by prospective participants through social media (e.g., Facebook) 
or other online communications. These web-based tools must meet HIPAA guidelines to ensure 
that protected health information is kept private and secure and use of these technologies will 
be subject to approval by the clinical sites’ IRBs.  
 
To ensure confidentiality of study data, completed questionnaires and study forms will be kept in 
participant binders stored in locked offices at each clinical site, no unauthorized person will be 
permitted to see the binder or forms, names will be used only for the necessary purpose of 
making sure that the recorded information is for the person to whom it refers, and data will be 
summarized so that published results cannot be traced to individuals.  
 
On data collection forms, participants will be identified only by a unique study identification 
number and letter code. Clinical sites will record names, contact information, and other direct 
identifiers to enable them to maintain contact with participants. Logs accessible only to the local 
clinical site investigators and key study personnel will link the study identification number to 
names. 
 
To protect study data from theft or unauthorized perusal or alteration, access to all computer 
files will be restricted to designated personnel through the use of passwords.  Access to the 
database and programs will be on a "need to use" basis (e.g., coordination staff cannot access 
main system programs).   
 
Computer security procedures, including multiple levels of password protection will be instituted. 
The study records will be identified by a unique participant identification number. Identification 
numbers will be recorded on each page of the paper forms.  The participant's letter code and a 
study status date (e.g., date of randomization) will be used as a second level of check.  Names 
and addresses of participants corresponding to each identification number will be kept in secure 
files at the clinical sites. Final analysis data sets will not contain any directly or indirectly 
identifying information.   Thus, dates of birth will be converted to age, other dates will be 
changed to counts of days from study entry, identification numbers will be replaced with 
sequence numbers, variables that could lead to deductive disclosure of the identity of individual 
participants will not be included nor will indirect identifiers such as infrequently occurring (e.g., 
fewer than 20 participants) outwardly manifest characteristics. 
 
In the final year of award, after the completion of a final data edit, DCC staff will prepare a data 
file in SAS containing all study variables intended for use in publications; identifying information 
and administrative data (e.g., edit trail) will not be included in this data file. A de-identified data 
set will be created which merges all the essential data from all time points of the study. 
Documentation (including abstracts of published works and calculated variable definitions) and 
form images will be included with the data file. The data file will be provided to the NIA/NIH after 
the end of the period of funding for sharing with other investigators according to NIH policy. 
 
Section 18: Research Publication Policy 
Publications will be operationally defined as manuscripts for publication; abstracts for platform 
or poster presentation at scientific and other professional meetings; slides for presentation at 
scientific and other professional meetings; doctoral dissertations; and master’s theses. 
 
The goal of our publication policy is to encourage and facilitate the publication of study results.  
The purposes of this policy are to ensure the following:  1) CAP publications will be of the 

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highest scientific quality; 2) CAP will be described in a consistent manner across publications; 3) 
measures are reported in consistent ways across publications; 4) proper acknowledgements are 
included; and 4) appropriate authorship credit is determined prior to submission of manuscripts 
for publication consideration. 
 
Publications from CAP will be overseen by the Publications and Ancillary Studies Committee 
(PASC).  In addition to committee co-chairs, the PASC will have at least one representative 
from the DCC, CCC, EEC, and each clinical site.  The PASC will make recommendations to the 
SC.   
 
A document describing the CAP Publication Policy and Procedures appears in the Manual of 
Procedures. 
 
Section 19: Ancillary Studies Policies 
An ancillary study will be defined as a study that (1) uses supplementary data that will be 
collected on participants who are recruited in CAP, over and above the data collection required 
by the CAP protocol, (2) collects biological specimens (e.g., blood) or performs diagnostic tests 
(e.g., bone density scans); and/or (3) collects data on subjects not enrolled in CAP but who may 
be compared to CAP subjects (e.g., participants who receive an alternate intervention).  
Ancillary studies will be distinct from databank studies, which use data previously collected on 
participants who are enrolled in CAP.   
 
Ancillary studies will be reviewed and approved by the PASC and ratified by the SC prior to 
initiation to ensure that they do not conflict with the main study protocol.   All approved ancillary 
studies will also be reviewed by the DSMB and NIA prior to initiation.  If approved, the ancillary 
study PI will report to the DSMB on the same schedule as the main study. Review by the PASC 
(and approval by the SC) will also be required for presentation or publication of ancillary study 
results.   
 
CAP investigators will be encouraged to consider ancillary studies and to involve other 
investigators, within and outside of CAP personnel. Participation in an ancillary study will be 
subject to the approval of the CAP PASC, SC, and DSMB, The following factors will be 
considered in determining approval of a proposed ancillary study:  
1. Participant burden  
a. The proposed study must be acceptable to the participants (e.g. in terms of time, 
discomfort, privacy).  
b. The proposed study must not reduce enrollment or hamper continued participation in 
the main study. 
2. Study interference 
a. The proposed study must not interfere with other parts of the main study.  
b. The proposed study must put no additional demand on CAP resources. 
3. The proposed study must be of the highest scientific merit. 
4. The investigators must have adequate resources to effectively complete the ancillary study, 
including: 
a. Sufficient budget (including enough to offset any costs to CAP). 
b. Staff having the requisite expertise to meet the objectives of the project. 
 
19.1 Concurrent Studies 
Study investigators agree not to conduct studies which would compete with or have a 
detrimental effect on the conduct of CAP during the period of recruitment and follow-up. 

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However, it is understood that each clinical site has the right to conduct concurrent studies with 
participants who do not meet criteria for enrollment into CAP.  Concurrent studies of patients 
who meet eligibility criteria for CAP but are not enrolled in CAP must be disclosed and reviewed 
by the CAP SC.   
 

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Section 20: Study Team Roster 
 
Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Study Chairs 
 
 
 
 
 
 
Jay Magaziner 
Study PI & 
Chair 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-3553 
410-706-4433 
jmagazin@epi.umaryland.edu  
 
 
Rebecca Craik 
Co-Chair 
Arcadia 
Arcadia University 
450 S. Easton Road 
Glenside, PA 19038-
3295 
215-572-2143 
215-572-2157  
craikr@arcadia.edu 
 
NIA Project 
Officer 
 
 
 
 
 
 
Barbara 
Radziszewska 
 
Project 
Officer 
NIA 
National Institute on 
Aging 
7201 Wisconsin Ave. 
Suite 525 A 
Bethesda, MD 20892   
301-435-3046 
301-480-1066 
radziszb@mail.nih.gov  
 
DSMB 
 
 
 
 
 
 
J. Christopher 
Gallagher 
DSMB Chair 
& Safety 
Officer 
Creighton 
University 
Creighton Univ. 
Medical Ctr 
Department of 
Medicine 
601 North 30th St., 
Suite 6718 
Bone Metabolism 
Unit 
Omaha, NE 68131 
402-280-4516 
402-280-4516 
JCG@creighton.edu 
Jennifer Brach 
DSMB 
member 
University of 
Pittsburgh 
University of 
Pittsburgh 
Dept. of Physical 
Therapy 
6035 Forbes Tower 
Pittsburgh, PA 15260 
412-383-6533 
412-648-5970 
jbrach@pitt.edu 
Marybeth Brown 
DSMB 
member 
University of 
Missouri 
University of Missouri 
Dept. of Physical 
Therapy 
112 Lewis Hall 
Columbia, MO 65211 
573-884-7531 
573-884-8000 
brownmb@health.missouri.edu 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Kristine Ensrud 
DSMB 
member 
VAMC 
Veterans Affairs 
Medical Ctr 
General Internal 
Medicine (111-0) 
One Veterans Drive, 
Minneapolis, MN 
55417 
612-467-2676 
612-467-2284 
ensru001@umn.edu 
Michael 
McDermott 
DSMB 
member 
University of 
Rochester 
Medical Center 
 
University of 
Rochester Medical 
Ctr 
Department of 
Biostatistics 
601 Elmwood 
Avenue Box 630 
Rochester, NY 14642 
585-275-6685 
585-273-1031 
mikem@bst.rochester.edu 
Data 
Coordinating 
Center 
 
 
 
 
 
 
Mona 
Baumgarten 
Director, 
Data 
Operation 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-1531 
410-706-4433 
mbaumgar@epi.umaryland.edu 
 
Michael Terrin 
Deputy 
Director, 
Data 
Operation 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-6139 
410-706-4433 
mterrin@epi.umaryland.edu 
 
Sandra Forman 
Assistant 
Director, 
Data 
Operation 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-2406 
410-706-4433 
sforman@epi.umaryland.edu 
Ling Tang 
Coordinator 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-0261 
410-706-4433 
ltang@epi.umaryland.edu 
 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Data 
Management & 
Randomization  
 
 
 
 
 
 
Ruth McBride 
Director, 
Data 
Management 
Unit; 
Scientific 
Director  
Axio Research, 
LLC 
2601 Fourth Ave., 
Suite 200 
Seattle, WA 98121 
206-577-0212 
206-547-4671 
ruthm@axioresearch.com 
 
Anna Leonen 
Director, 
Clinical Data 
Management 
Axio Research, 
LLC 
2601 Fourth Ave., 
Suite 200 
Seattle, WA 98121 
206-577-0248 
206-547-4671 
annal@axioresearch.com  
Biostatistics 
and Analysis 
 
 
 
 
 
 
Michelle Shardell 
Biostatistician 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-8563 
 
410-706-3808 
mshardel@epi.umaryland.edu 
 
Laurence 
Magder 
Biostatistician 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-3253 
410-706-4433 
lmagder@epi.umaryland.edu  
Steering 
Committee 
 
 
 
 
 
 
Jay Magaziner 
PI and Chair 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-3553 
410-706-4433 
jmagazin@epi.umaryland.edu  
Rebecca Craik 
Co-Chair 
Arcadia 
Arcadia University 
450 S. Easton Road 
Glenside, PA 19038-
3295 
215-572-2143 
215-572-2157  
craikr@arcadia.edu 
 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Richard 
Fortinsky 
PI UCHC 
UCHC 
UConn Center on 
Aging 
UConn Health Center 
263 Farmington 
Avenue 
Farmington, CT 
06030 
860-679-8069 
860-679-1307 
fortinsky@uchc.edu 
 
Kathleen 
Mangione 
PI Arcadia 
Arcadia 
Arcadia University 
450 S. Easton Road 
Glenside, PA 19038-
3295 
215-572-2861 
215-572-2157 
mangionk@arcadia.edu 
Ann-Gruber 
Baldini 
PI UMB 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-2444 
410-706-4433 
abaldin@epi.umaryland.edu 
 
Ellen Binder 
Exercise and 
Nutrition 
Expert 
WUSTL 
Washington 
University School of 
Medicine 
Division of Geriatrics 
and Nutritional 
Science 
660 S. Euclid, 
Campus Box 8303 
St. Louis, MO 63108 
314-286-2700 
314-286-2701 
ebinder@dom.wustl.edu 
 
Kenneth Koval 
Orthopedic 
Surgeon 
ORMC 
Orlando Regional 
Medical Ctr 
86 W Underwood 
Street 
MP43 
Orlando FL 32732 
321-841-3479 
321-841-1870 
kenneth.koval@orlandohealth.com 
Denise Orwig 
Director, 
CCC 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-8951 
410-706-4433 
dorwig@epi.umaryland.edu 
 
 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Mona 
Baumgarten 
Director, 
DCC 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-1531 
410-706-4433 
mbaumgar@epi.umaryland.edu 
 
Michael Terrin 
Deputy 
Director  
DCC 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-6139 
410-706-4433 
mterrin@epi.umaryland.edu 
 
Anna Tosteson 
Director, 
Economic 
Evaluation 
Core 
Dartmouth 
Dartmouth Medical 
School 
HB7505 Clinical 
Research 
One Medical Center 
Drive 
Lebanon, NH 03756 
603-653-3568 
603-653-3554 
 
Anna.N.A.Tosteson@Dartmouth.edu  
 
Ram Miller 
Geriatrician 
Novartis 
Institutes for 
Biomedical 
Research 
Novartis Institutes for 
Biomedical Research 
220 Massachusetts 
Ave 260A 
Cambridge, MA 
02139 
617-871-4491 
 
ram.miller@novartis.com  
Brock Beamer 
Geriatrician 
UMB 
Veterans Affairs 
Medical Ctr 
100 N. Greene Street 
Room 4B-192 
Baltimore, MD 21201 
410-605-7000 
EXT. 4870 
410-605-7971 
brock.beamer@va.gov 
Scientific 
Oversight 
Committees 
 
 
 
 
 
 
 
Recruitment 
and Evaluation 
 
 
 
 
 
 
Denise Orwig 
Chair 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-8951 
410-706-4433 
dorwig@epi.umaryland.edu 
 
 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Kathleen 
Mangione 
Member 
Arcadia 
Arcadia University 
450 S. Easton Road 
Glenside, PA 19038-
3295 
215-572-2861 
215-572-2157 
mangionk@arcadia.edu  
Richard 
Fortinsky 
Member 
UCHC 
UConn Center on 
Aging 
UConn Health Center 
263 Farmington 
Avenue 
Farmington, CT 
06030 
860-679-8069 
860-679-1307 
fortinsky@uchc.edu 
 
Anna Tosteson 
Member 
Dartmouth 
Dartmouth Medical 
School 
HB7505 Clinical 
Research 
One Medical Center 
Drive 
Lebanon, NH 03756 
 
603-653-3568 
603-653-3554 
 
Anna.N.A.Tosteson@Dartmouth.edu  
 
Ann Gruber-
Baldini 
Member 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-2444 
410-706-4433 
abaldin@epi.umaryland.edu 
 
 
Clinical 
Direction 
 
 
 
 
 
 
Brock Beamer 
Chair 
UMB 
Veterans Affairs 
Medical Ctr 
100 N. Greene Street 
Room 4B-192 
Baltimore, MD 21201 
410-605-7000 
EXT. 4870 
410-605-7971 
brock.beamer@va.gov 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Kenneth Koval 
 
 
 
Member 
ORMC 
Orlando Regional 
Medical Ctr 
86 W Underwood 
Street 
MP43 
Orlando FL 32732 
321-841-3479 
321-841-1870 
kenneth.koval@orlandohealth.com 
Ellen Binder 
Member 
WUSTL 
Washington 
University School of 
Medicine 
Division of Geriatrics 
and Nutritional 
Science 
660 S. Euclid, 
Campus Box 8303 
St. Louis, MO 63108 
314-286-2700 
314-286-2701 
ebinder@dom.wustl.edu 
 
Ram Miller 
Member 
Novartis 
Institutes for 
Biomedical 
Research 
Novartis Institutes for 
Biomedical Research 
220 Massachusetts 
Ave 260A 
Cambridge, MA 
02139 
617-871-4491 
 
ram.miller@novartis.com  
Andy Goldberg 
Member 
UMB 
Veterans Affairs 
Medical Ctr 
100 N. Greene Street 
Room VA4B186 
Baltimore, MD 21201 
410-605-7183 
410-605-7971 
agoldber@grecc.umaryland.edu 
 
 
Intervention  
 
 
 
 
 
 
Kathleen 
Mangione 
Chair 
Arcadia 
Arcadia University 
450 S. Easton Road 
Glenside, PA 19038-
3295 
215-572-2861 
215-572-2157 
mangionk@arcadia.edu  
Rebecca Craik 
Member 
Arcadia 
Arcadia University 
450 S. Easton Road 
Glenside, PA 19038-
3295 
215-572-2143 
215-572-2157  
craikr@arcadia.edu 
 
Kenneth Koval 
Member 
ORMC 
Orlando Regional 
Medical Ctr 
86 W Underwood 
Street 
MP43 
Orlando FL 32732 
321-841-3479 
321-841-1870 
kjkmd@yahoo.com  

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Denise Orwig 
Member 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-8951 
410-706-4433 
dorwig@epi.umaryland.edu 
 
 
Barbara Resnick 
Member 
UMB SON 
University of MD 
School of Nursing 
655 W. Lombard 
Street 
390D 
Baltimore, MD 21201 
410-706-5178 
410-706-0344 
resnick@son.umaryland.edu 
 
 
 
Publications 
and Ancillary 
Studies 
 
 
 
 
 
 
Richard 
Fortinsky 
Co-chair 
UCHC 
UConn Center on 
Aging 
UConn Health Center 
263 Farmington 
Avenue 
Farmington, CT 
06030 
860-679-8069 
860-679-1307 
fortinsky@uchc.edu 
 
Ann Gruber-
Baldini 
Co-chair 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-2444 
410-706-4433 
abaldin@epi.umaryland.edu 
 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Specialized 
Support for 
Exercise and 
Nutrition 
 
 
 
 
 
 
Andy Goldberg 
Chair 
UMB 
Veterans Affairs 
Medical Ctr 
100 N. Greene Street 
Room VA4B186 
Baltimore, MD 21201 
410-605-7183 
410-605-7971 
agoldber@grecc.umaryland.edu 
 
Ellen Binder 
Member 
WUSTL 
Washington 
University School of 
Medicine 
Division of Geriatrics 
and Nutritional 
Science 
660 S. Euclid, 
Campus Box 8303 
St. Louis, MO 63108 
314-286-2700 
314-286-2701 
ebinder@dom.wustl.edu 
 
Alice Ryan 
Member 
UMB 
Veterans Affairs 
Medical Ctr 
100 N. Greene Street 
Room VA4B203  
Baltimore, MD 21201 
410-605-7851 
 
410-605-7913 
 
aryan@grecc.umaryland.edu 
 
Economic 
Evaluation Core 
 
 
 
 
 
 
Anna Tosteson 
Chair 
Dartmouth 
Dartmouth Medical 
School 
HB7505 Clinical 
Research 
One Medical Center 
Dr., 
Lebanon, NH 03756 
603-653-3568 
603-653-3554 
 
Anna.N.A.Tosteson@Dartmouth.edu  
 
Richard 
Fortinsky 
Investigator 
UCHC 
UConn Center on 
Aging 
UConn Health Center 
263 Farmington 
Avenue 
Farmington, CT 
06030 
860-679-8069 
860-679-1307 
fortinsky@uchc.edu 
 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Loretta Pearson 
 
 
Coordinator 
Dartmouth 
Dartmouth Medical 
School 
HB7505 Clinical 
Research 
One Medical Center 
Dr., 
Lebanon, NH 03756 
603-653-3561 
603-653-3554 
Loretta.Pearson@Dartmouth.edu  
Clinical 
Coordinating 
Center 
 
 
 
 
 
 
Denise Orwig 
Director of 
Clinical 
Operations 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-8951 
410-706-4433 
dorwig@epi.umaryland.edu 
 
 
Lynn Lewis 
Coordinator 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-5144 
410-706-4433 
llewis@epi.umaryland.edu 
 
Clinical Sites 
 
 
 
 
 
 
 
Arcadia 
University 
 
 
 
 
 
 
Kathleen 
Mangione 
Clinical Site 
PI 
Arcadia 
Arcadia University 
450 S. Easton Road 
Glenside, PA 19038-
3295 
215-572-2861 
215-572-2157 
mangionk@arcadia.edu 
Emily DePaul 
Coordinator 
Arcadia 
Arcadia University 
450 S. Easton Road 
Glenside, PA 19038-
3295 
215-572-4689 
215-572-2157 
depaule@arcadia.edu 
Mary Hofmann 
Clinical Site 
Clinician 
Arcadia 
Abington Memorial 
Hospital 
Division of Geriatrics 
1245 Highland Ave 
Suite 302 
Abington, PA 19001 
215-517-8850 
215-572-2157 
 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
 
University of 
MD Baltimore 
 
 
 
 
 
 
Ann Gruber-
Baldini 
Clinical Site 
PI 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-2444 
410-706-4433 
abaldin@epi.umaryland.edu 
 
Laura Mastella 
Coordinator 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-1589 
410-706-4433 
lmastella1@epi.umaryland.edu  
 
Brock Beamer 
Clinical Site 
Clinician 
UMB 
Veterans Affairs 
Medical Ctr 
100 N. Greene Street 
Room VA4B192 
Baltimore, MD 21201 
410-605-7000 
EXT. 4870 
410-605-7971 
brock.beamer@va.gov 
Leslie Katzel 
IRB 
Compliance 
UMB 
Veterans Affairs 
Medical Ctr 
100 N. Greene Street 
Room VA4B189 
Baltimore, MD 21201 
410 605 7248 
410 605 7913 
lkatzel@grecc.umaryland.edu 
 
University of 
Connecticut 
Health Center 
 
 
 
 
 
 
Rick Fortinsky 
Clinical Site 
PI 
UCHC 
UConn Center on 
Aging 
UConn Health Center 
263 Farmington 
Avenue 
Farmington, CT 
06030 
860-679-8069 
860-679-1307 
fortinsky@uchc.edu 
 
Kristen Annis 
Coordinator 
UCHC 
UConn Center on 
Aging 
UConn Health Center 
263 Farmington 
Avenue 
Farmington, CT 
06030 
860-679-3812 
860-679-1307 
annis@uchc.edu 

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Name 
Role 
Site 
Address 
Phone 
number 
Fax number 
E-mail 
Yazeed 
Maghaydah 
Clinical Site 
Clinician 
UCHC 
UConn Center on 
Aging 
UConn Health Center 
263 Farmington 
Avenue 
Farmington, CT 
06030 
860-679-8400 
860-679-1307 
maghaydah@uchc.edu 
Primary 
Outcome 
Adjudicators 
 
 
 
 
 
 
Jack Guralnik 
Adjudicator 
UMB 
University of MD 
Baltimore 
660 W. Redwood 
Street 
Suite 200 
Baltimore, MD 21201 
410-706-2406 
410-706-4433 
jguralnik@epi.umaryland.edu 
Ram Miller 
Adjudicator 
Novartis 
Institutes for 
Biomedical 
Research 
Novartis Institutes for 
Biomedical Research 
220 Massachusetts 
Ave 260A 
Cambridge, MA 
02139 
617-871-4491 
 
ram.miller@novartis.com  
Mary Rodgers 
Adjudicator 
UMB 
University of MD 
Baltimore 
Allied Health Building 
Baltimore, MD 21201 
410-706-5658 
 
mrodgers@som.umaryland.edu 
 

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91 
Section 21: References 
1. 
Magaziner J, Fredman L, Hawkes W, et al. Changes in functional status attributable to hip fracture: a 
comparison of hip fracture patients to community-dwelling aged. Am J Epidemiol 2003;157:1023-31. 
2. 
Magaziner J, Hawkes W, Hebel JR, et al. Recovery from hip fracture in eight areas of function. J 
Gerontol A Biol Sci Med Sci 2000;55:M498-507. 
3. 
Chang KP, Center JR, Nguyen TV, Eisman JA. Incidence of hip and other osteoporotic fractures in 
elderly men and women: Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res 2004;19:532-6. 
4. 
Koval KJ, Cooley MR. Clinical pathway after hip fracture. Disabil Rehabil 2005;27:1053-60. 
5. 
Snyder-Mackler L. Electrical stimulation for pain modulation. In: Robinson AS-M, L, ed. Clinical 
Electrophysiology Electrotherapy and Electrophysiologic Testing. Philadelphia: Lippincott Williams & 
Wilkins; 1995:279-310. 
6. 
Guigoz Y, Vellas B, Garry PJ. Assessing the nutritional status of the elderly: The Mini Nutritional 
Assessment as part of the geriatric evaluation. Nutr Rev 1996;54:S59-S65. 
7. 
Frankenfield D, Roth-Yousey L, Compher C. Comparison of predictive equations for resting metabolic 
rate in healthy nonobese and obese adults: a systematic review. J Am Diet Assoc 2005;105:775-89. 
8. 
Unintended weight loss in older adults. http://www.adaevidencelibrary.com, 2009.  
9. 
Evans WJ. Protein nutrition, exercise and aging. J Am Coll Nutri 2004;23:601S-9S. 
10. 
Shumway-Cook A, Ciol MA, Gruber W, Robinson C. Incidence of and risk factors for falls following hip 
fracture in community-dwelling older adults. PhysTher 2005;85:648-55. 
11. 
Shumway-Cook A, Ciol MA, Yorkston KM, Hoffman JM, Chan L. Mobility limitations in the Medicare 
population: prevalence and sociodemographic and clinical correlates. J Am Geriatr Soc 2005;53:1217-
21. 
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Kozak LJ, Hall MJ, Owings MF. National Hospital Discharge Survey: 2000 annual summary with 
detailed diagnosis and procedure data. Vital Health Stat 13 2002:1-194. 
13. 
Schneider EL, Guralnik JM. The aging of America -- Impact on health care costs. JAMA 
1990;263:2335-40. 
14. 
Tosteson A, Solomon D, King A, Dawson-Hughes B, Burge R, Wong J. Projections of osteoporosis 
fractures and costs by skeletal site in the USA [Abstract]. J Bone Min Res 2005;20:S21. 
15. 
Praemer A, Furner S, Rice D. Musculoskeletal conditions in the United States.  Surgeon General's 
Report. Rosemont, IL: American Academy of Orthopaedic Surgeons; 1992. 
16. 
Brainsky A, Glick H, Lydick E, et al. The economic cost of hip fractures in community-dwelling older 
adults:  A prospective study. J  Am  Geriatr Soc 1997;45:281-7. 
17. 
Ray NF, Chan JK, Thamer M, Melton LJ. Medical expenditures for the treatment of osteoporotic 
fractures in the United States in 1995:  Report from the National Osteoporosis Foundation. J Bone 
Miner Res 1997;12:24-35. 
18. 
Office of Technology Assessment. Hip fracture outcomes in people aged 50 and over:  Mortality, 
service use, expenditures, and long-term functional impairment: Congress of the United States; 1993. 
19. 
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic 
burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone  Miner Res 
2007;22:465-75. 
20. 
Handoll H, Sherrington C. Mobilisation strategies after hip fracture surgery in adults. Cochrane 
Database Syst Rev 2007;23:CD001704. 
21. 
Buchner DM, Cress ME, de Lateur BJ, et al. The effect of strength and endurance training on gait, 
balance, fall risk, and health services use in community-living older adults. J Gerontol A Biol Sci Med 
Sci 1997;52:M218-24. 
22. 
Binder EF, Schechtman KB, Ehsani AA, et al. Effects of exercise training on frailty in community-
dwelling older adults: results of a randomized, controlled trial. J Am Geriatr Soc 2002;50:1921-8. 
23. 
Noonan V, Dean E. Submaximal exercise testing: clinical application and interpretation. PhysTher 
2000;80:782-807. 
24. 
Astrand I. Aerobic work capacity in men and women with special reference to age. Acta Physiol Scand 
1960;49(Suppl 169):1-92. 
25. 
Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and nomographic assessment of functional 
aerobic impairment in cardiovascular disease. Am Heart J 1973;85:546-62. 
26. 
Mendelsohn ME, Overend TJ, Connolly DM, Petrella RJ. Improvement in aerobic fitness during 
rehabilitation after hip fracture. Arch Phys Med Rehabil 2008;89:609-17. 

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92 
27. 
Toraman NF, Erman A, Agyar E. Effects of multicomponent training on functional fitness in older adults. 
J Aging Phys Act 2004;12:538-53. 
28. 
Rostagno C, Galanti G, Romano M, Chiostri G, Gensini GF. Prognostic value of 6-minute walk corridor 
testing in women with mild to moderate heart failure. Ital Heart J 2002;3:109-13. 
29. 
Mangione K, Craik R, Tomlinson S, Palombaro K. Can elderly patients who have had a hip fracture 
perform moderate- to high-intensity exercise at home? PhysTher 2005;85:727-39. 
30. 
Steffen TM, Hacker TA, Mollinger L. Age- and gender-related test performance in community-dwelling 
elderly people: Six-Minute Walk Test, Berg Balance Scale, Timed Up & Go Test, and gait speeds. 
PhysTher 2002;82:128-37. 
31. 
Enright PL, McBurnie MA, Bittner V, et al. The 6-min walk test: a quick measure of functional status in 
elderly adults. Chest 2003;123:387-98. 
32. 
Whitehead C, Miller M, Crotty M. Falls in community-dwelling olders persons following hip fracture: 
impact on self-efficacy, balance and handicap. Clin Rehabil 2003;17:899-906. 
33. 
Sherrington C, Lord SR. Increased prevalence of fall risk factors in older people following hip fracture. 
Gerontology 1998;44:340-4. 
34. 
Magaziner J, Hawkes W, Hebel JR, et al. Recovery from hip fracture in eight areas of function. J 
Gerontol A Biol Sci Med Sci 2000;55:M498-M507. 
35. 
Barnes B, Dunovan K. Functional outcomes after hip fracture. PhysTher 1987;67:1675-9. 
36. 
Miller CW. Survival and ambulation following hip fracture. J Bone Joint Surg Am 1978;60:930-4. 
37. 
Laskin RS, Gruber MA, Zimmerman AJ. Intertrochanteric fractures of the hip in the elderly: a 
retrospective analysis of 236 cases. Clin Orthop Rel Res 1979;141:188-95. 
38. 
Fox KM, Magaziner J, Hawkes WG, et al. Loss of bone density and lean body mass after hip fracture. 
Osteoporos Int 2000;11:31-5. 
39. 
Bean JF, Kiely DK, Herman S, et al. The relationship between leg power and physical performance in 
mobility-limited older people. J Am Geriatr Soc 2002;50:461-7. 
40. 
Herman S, Kiely DK, Leveille S, O'Neill E, Cyberey S, Bean JF. Upper and lower limb muscle power 
relationships in mobility-limited older adults. J Gerontol A Biol Sci Med Sci 2005;60:476-80. 
41. 
Foldvari M, Clark M, Laviolette LC, et al. Association of muscle power with functional status in 
community-dwelling elderly women. J Gerontol A Biol Sci Med Sci 2000;55:M192-M9. 
42. 
Lamb SE, Morse RE, Evans JG. Mobility after proximal femoral fracture: the relevance of leg extensor 
power, postural sway and other factors. Age Ageing 1995;24:308-14. 
43. 
Koval KJ, Skovron ML, Aharonoff GB, Meadows SE, Zuckerman JD. Ambulatory ability after hip 
fracture:  A prospective study in geriatric patients. Clin Orthop Relat Res 1995;310:150-9. 
44. 
Nagi SZ. Disability concepts revisited:  Implications for prevention. In: Pope MT, A.R., ed. Disability in 
America: Toward a National Agenda for Prevention. Washington, DC: Institute of Medicine.  National 
Academy Press; 1991:309-27. 
45. 
Marottoli RA, Berkman LF, Cooney LM. Decline in physical function following hip fracture. J Am Geriatr 
Soc 1992;40:861-6. 
46. 
Tolo ET, Bostrom MP, Simic PM, Lyden JP, Cornell CM, Thorngren KG. The short term outcome of 
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