Improving Community Ambulation After Hip Fracture

MAIN STUDY

Despite improvements in medical management, significant residual disability remains in older
persons after a hip fracture. The goal of current clinical practice is independent, safe
household ambulation two to three months after surgery. Hip fracture-acquired dependency in
functional activities of daily living persists well beyond three months post-surgery. 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.

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, approximately 6 months (26
weeks) after admission to the hospital for hip fracture. The primary endpoint will be
measured using the Six-Minute Walk Test (SMWT) 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.

Primary Aim The primary aim of the study is to determine if a specific multi-component
16-week intervention based on aerobic conditioning, specificity of training, and muscle
overload (the PUSH intervention), initiated within 26 weeks of admission to the hospital for
hip fracture, will be more successful in producing community ambulation at 16 weeks after
randomization than a non-specific multi-component intervention of transcutaneous electrical
nerve stimulation (TENS), flexibility activities, and active range of motion exercises (AROM)
(the PULSE intervention).

Secondary Aims

1. To determine whether the proportion of community ambulators differs between the PUSH and
PULSE interventions at 40 weeks post-randomization and whether the difference in
proportions at 40 weeks changed from the difference in proportions at 16 weeks

2. To compare the PUSH and PULSE interventions at 16 weeks and 40 weeks post-randomization
with respect to five secondary outcomes that are thought to be precursors to community
ambulation (endurance, dynamic balance, walking speed, quadriceps strength, and lower
extremity function)

3. To compare the PUSH and PULSE interventions at 16 weeks and 40 weeks post-randomization
with respect to several tertiary outcomes (activities of daily living, 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)

4. To compare the economic value of the PUSH and PULSE interventions by estimating the
impact of the interventions on cost per quality-adjusted life year (QALY) gained over
the follow-up period.

In addition to study outcome measures, expected adverse events (AEs) will be assessed every
four weeks during a telephone interview. Information about reportable adverse events (RAEs),
which include serious adverse events (SAEs), unexpected AEs, or injury that occurs under
supervision by study staff, will be collected throughout the study. 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. Adherence with the
PT interventions will also be monitored.

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. In the description of outcome measures, we
identify the measures that will not be collected for participants consented under protocol
version 11.0 or later.

ANCILLARY STUDIES

ANCILLARY STUDY #1 - MECHANISTIC PATHWAYS TO COMMUNITY AMBULATION (CAP-MP) - Dr. Jay
Magaziner [Ancillary Study #1 Start Date: April 12, 2014; Primary Completion Date: October
19, 2017; n=39] The CAP-MP ancillary study is intended to supplement the information gained
from the parent CAP study, to help investigators understand how older adults recover after
injury. Participants enrolled in the CAP parent study at the Baltimore site are invited to
participate in the CAP-MP ancillary study and undergo additional testing at the same time
points as for the parent CAP study. The objective of the CAP-MP ancillary study is to examine
mechanistic factors hypothesized to be on the pathway between two 16-week interventions
post-hip fracture and recovery and the ability to ambulate independently in the community.
The effect of the interventions on these factors 24 weeks after the intervention ends also
will be evaluated. The outcomes for the CAP-MP ancillary study are secondary or tertiary to
the main CAP study.

Primary Aim. To determine if, at the end of the 16-week intervention, participants in the
PUSH group, compared to the PULSE group, have: a) greater muscle volume and attenuation
(i.e., reduced intra-muscular fat) of the thigh; b) greater lower extremity strength; c)
greater bone mineral density and bone strength; d) more bone formation and less bone
resorption; e) lower levels of circulating inflammatory cytokines; f) higher levels of the
hormones insulin-like growth factor (IGF)-1, testosterone, and estradiol; g) greater aerobic
capacity; h) greater improvement in gait and balance; and i) better cognition and fewer
depressive symptoms.

Secondary Aim 1. To determine the long-term (i.e., 24 weeks after intervention ends) effect
of the intervention on the mechanistic factors detailed in the primary aim.

Secondary Aim 2. To evaluate the relationships between mechanistic factors detailed in the
primary aim above and community ambulatory ability at the end of the intervention and 24
weeks later in order to identify those mechanisms that are most responsible for the ability
to ambulate in the community following delivery of the intervention.

Tertiary Aim. To quantify the mediating effect of mechanistic factors detailed in the primary
aim on the relationship between the intervention and ability to ambulate in the community at
the end of the intervention (16 weeks post-randomization) and 24 weeks later.

ANCILLARY STUDY #2 - DIET AND DIETARY PATTERNS IN OLDER ADULTS UNDERGOING HIP FRACTURE
REHABILITATION - Dr. Anne Kenny [n=11] This ancillary study will analyze dietary patterns for
the nutritional characterization of older adults recovering from a hip fracture. The
identified dietary patterns, as well as motivators and barriers to intake, will be assessed
for their impact on the rate of return to community ambulation in the CAP study.

Hypothesis: Those who consume dietary patterns similar to a Mediterranean style diet will
have less malnutrition with greater likelihood for a return to community ambulation.

Aim 1. At baseline determine degree of Mediterranean style diet intake and dietary patterns
in our sample of hip fracture patients to correlate with nutritional status assessed by the
Mini Nutritional Assessment tool (MNA).

Aim 2. Determine motivators and barriers to intake in the hip fracture rehabilitation
population and associate with dietary patterns and nutritional status.

Aim 3. Diets determined at baseline will be used to predict community ambulation and similar
primary endpoints for CAP.

ANCILLARY STUDY #3 - ROLE OF GLUCOSE METABOLISM IN STRENGTH AND FUNCTIONAL RECOVERY AFTER HIP
FRACTURE - Dr. Anne Kenny [n=21] The goal of this ancillary study is to assess the impact of
glucose metabolism on strength and functional performance following resistance training in
the population. Data on rehabilitation capacity post-fracture in those with diabetes mellitus
(DM) are limited and mixed. Studies focusing on rehabilitation potential in DM demonstrate
either no impact or a decrease in functional recovery.

Hypothesis: Community-dwelling ambulatory hip fracture survivors with impaired glucose
metabolism (measured as homeostasis model assessment-estimated insulin resistance [HOMA- IR]
or diagnosis of DM) will not recover lower extremity strength or function as well as those
with normal glucose metabolism in response to resistance exercise compared to non-resistance
training. Further, investigators propose that higher AGE (measured as pentosidine level and
its receptor) will impair strength and functional improvement with resistance exercise. Those
with IR and DM have lower IGF-1 and higher levels of IGF binding proteins (IGFBP1 and 3)
further limiting the available IGF-1 for tissue use. Investigators hypothesize that the
strength and functional improvement from resistance exercise will be mitigated by higher
IGFBP in those with DM and IR compared to those with normal glucose metabolism.

Aim 1. To compare change in strength and function between those with diabetes mellitus,
insulin resistance, or without either condition compared between two multi-component exercise
interventions in which one includes resistance.

Aim 2. To determine association between baseline AGE and IGF/IGFBP on strength and functional
improvement and evaluate contribution of change in biomarkers to muscle/function response
from resistance exercise.

ANCILLARY STUDY #4 - MUSCLE MECHANISMS UNDERLYING RECOVERY OF FUNCTION AFTER HIP FRACTURE -
Dr. Marty Eastlack [Ancillary Study #4 Start Date: April 6, 2015; Primary Completion Date:
December 13, 2017; n=22] The purpose of this ancillary study is, therefore, to examine the
effect of the two interventions on the precursors to participation in the community.

Hypothesis: Those who participate in the PUSH intervention will have less impairment in body
structure and function (muscle thickness and echo intensity), fewer limitations in activities
(chair rate of rise and fast gait speed) and therefore better likelihood to return to
participation (community ambulation).

Aim 1: To determine if there is a difference between PUSH and PULSE with respect to change in
muscle quality (muscle thickness and echo intensity), muscle power (chair rate of rise) and
fast gait speed.

Aim 2: To see if differences persist 40 weeks post-randomization. Aim 3: To see if changes in
muscle quality predict faster gait speed, chair rate of rise and chair rise strategy (this is
categorical) among all participants.

Aim 4: To describe the quality of movement (chair rise strategy and capacity, standing
symmetry, temporospatial aspects of gait) among all participants.

Aim 5: To confirm that rate of rise in standing is a proxy for instrumented measure of lower
extremity power.

Inclusion Criteria:

- Closed fracture of proximal femur

- Age 60 or older at time of randomization

- Minimal trauma fracture

- Non-pathologic fracture

- Surgical fixation of fracture

- Living in the community at time of fracture

- Ambulating without human assistance 2 months prior to fracture

- Unable to walk 300 m or more in 6 minutes without human assistance at time of
randomization

Exclusion Criteria:

- Not English speaking

- Does not live within reasonable distance of the clinical center

- End stage renal disease on dialysis

- Recent myocardial infarction

- Uncompensated congestive heart failure

- Lower extremity amputation

- Symptoms of angina pectoris

- Chest pain or shortness of breath (including from severe COPD)

- Participant plans to move out of area or otherwise be unavailable during the 16-week
intervention period

- Participation in another clinical trial

- Not community-residing (e.g., resident of a skilled nursing facility) at time of
randomization

- Not fully weight-bearing on fractured leg or non-fractured leg at time of
randomization

- Calculated creatinine clearance < 15 ml/min

- Serum albumin < 2.5 g/dl

- Hemoglobin < 9 g/dl

- Receiving physical therapy for the hip fracture in the hospital or inpatient
rehabilitation facility at time of randomization

- Severely diminished lower extremity sensation or ulceration

- Uncontrolled hypertension

- Denied medical clearance by appropriate medical provider

- Clinical site clinician thinks participant is not a good candidate for study (e.g.,
not likely to survive study period)

- Cognitive impairment (3MS score <73)

- Development of chest pain or substantial shortness of breath or ambulating with severe
pain during baseline SMWT

- Participant walks less than 4 meters in 40 seconds (<0.1 m/sec) during baseline SMWT

- Not randomized by 26 weeks post admission for hip fracture

- Final sign-off from study clinician and/or principal investigator is incomplete

- Incomplete baseline data

- Unable to contact participant

- Participant is unable to provide her/his own informed consent

- Participant refuses the study