PUSH Plus Protein Pilot for Hip Fracture Patients

Hip fracture is a common problem among older individuals. The goal of current standard of care after hip fracture is to achieve independent, household ambulation 2-3 months after surgery, yet decreased functional ability typically persists well beyond three months and many patients never resume independent ambulation outside the home. Previous research has established that one must be able to walk at least 300 meters (~330 yards) within 6 minutes to re-establish routine interactions in the community, such as going to the store or to church. In part, this is based on the average distance from handicapped parking spaces into most facilities. Activity and exercise are believed to be of benefit for reducing disability in older adults, yet the majority of older adults does not participate in regular exercise and is not active. This is especially true for older adults following hip fracture after they complete the usual rehabilitation program. This research study is being done to test a 16-week, multi-part exercise intervention for hip fracture patients that will be supervised by specially trained physical therapists (PTs). The exercise intervention uses a novel machine to provide strength and endurance training in the home. This has been shown in smaller studies to be safe and effective at increasing strength. The purpose of this small pilot study is to test whether adding a protein supplement to the exercise intervention leads to more improvements in a person's ability to walk in their own home and in the local community. With this knowledge, investigators hope to help a greater number of hip fracture patients enjoy a more complete recovery and improved overall health. In addition to providing important information on adherence, feasibility, and safety, this pilot study of hip fracture patients has the unique advantage of being able to compare data to two recently completed studies where participants received the PUSH intervention without protein supplementation.

A pilot study including 30 older adults who have experienced a hip fracture will be carried out with participants receiving a specific multi-component intervention with protein supplementation (PUSH Plus Protein). Study activities for participants meeting eligibility criteria will take place after post-acute rehabilitation ends, up to 26 weeks after admission to the hospital for hip fracture. Patients age 60 and older who have had surgical repair for hip fracture will be identified in study hospitals or by self-referral and evaluated for eligibility. Following consent to participate, eligible participants will undergo a comprehensive baseline assessment. Participants completing the entire baseline assessment will be eligible to receive the intervention. All participants will receive the PUSH Plus Protein intervention. The follow-up assessment will occur after the intervention is completed, approximately 16 weeks after baseline testing. The primary endpoint will be measured using the Six-Minute Walk Test (SMWT). Participants in this pilot will receive the same specific multi-component 16-week intervention, PUSH, as participants in the multi-site randomized controlled trial, "Improving Community Ambulation after Hip Fracture (CAP)" (NCT01783704). The purpose of this study is to test whether adding a protein supplement to the PUSH intervention (PUSH Plus Protein) leads to greater improvement in a person's ability to walk in their own home and in the local community compared to the PUSH intervention alone; therefore, data in this pilot study will be compared to data from participants in the CAP study across the three sites who received the PUSH intervention alone (n=105). The working hypothesis is that PUSH Plus Protein will lead to greater improvements in ability to walk in the community compared to PUSH. Investigators will also compare the effect of PUSH Plus Protein intervention to PUSH intervention alone on secondary outcomes in the CAP study believed to be precursors to community ambulation as shown in Aim 2 below. Investigators can also compare participants in the pilot study to participants who received PUSH alone in the ancillary study to CAP, "Mechanistic Pathways to Community Ambulation (CAP-MP)" (n=19) to examine whether PUSH Plus Protein has an impact on the mechanistic factors on the pathway to recovery of ambulatory ability after hip fracture (Aim 3). Aim 1. To test whether PUSH Plus Protein intervention improves community ambulation (as measured by distance walked in six minutes) compared to PUSH intervention alone (from CAP parent study) at the end of 16 weeks. Aim 2. To assess the effects of PUSH Plus Protein on precursors to community ambulation compared to the PUSH intervention alone (CAP study). To determine the effects of PUSH Plus Protein intervention, compared to PUSH, on several other outcomes in CAP including activities of daily living (ADLs), quality of life, lower-extremity physical performance, increase of ≥ 50 meters in distance walked in six minutes, cognitive status, and nutritional status. Aim 3. To determine the effects of PUSH Plus Protein intervention on the mechanistic factors compared to PUSH intervention alone (CAP-MP ancillary study). To determine if, at the end of the 16 week intervention, participants in the PUSH Plus Protein intervention, compared to PUSH alone, have: a) greater muscle volume and attenuation (i.e., reduced intra-muscular fat) of the thigh; b) greater lower extremity strength; c) better gait parameters; d) greater bone mineral density and bone strength; e) more bone formation and less bone resorption; and f) lower levels of circulating inflammatory cytokines. Aim 4. To determine safety and tolerability of delivering the PUSH Plus Protein intervention to hip fracture patients. This pilot study will be used to estimate the sample size requirements for a more definitive study.

Participants will be given a whey-based protein supplement containing 27.6g of protein daily for 16 weeks and receive the PUSH intervention. PUSH is a specific multi-component intervention based on improving specific precursors to community ambulation. The intervention addresses endurance with continuous upright exercise for 20 min.; function by improving fast walking, standing from a chair, and stair negotiation; muscle performance by exercising to enhance lower extremity strength; and balance by performing unilateral activities and activities with decreased base of support. Participants receive 32 visits of approximately 60 minutes in duration from a study PT. Participants will receive two visits a week, on non-consecutive days, for 16 weeks. Visits take place in the participant's place of residence. Participants also receive the nutritional intervention for the duration of the 16-week study.

Strength components of the muscle performance intervention are performed using a portable progressive resistive exercise device (Shuttle® MiniPress, Contemporary Design Company, P.O. Box 5089, Glacier, Washington 98244). Muscle performance focuses on bilateral hip extensors, hip abductors, knee extensors, and plantar flexors. Balance and strength are addressed with additional exercises performed while standing. The endurance intervention begins with 2-3 minutes of continuous upper and lower extremity active range of motion (AROM) with the participant sitting in order to increase the participants' heart rate (HR) or exertion closer to the target zone. The participant is then asked to walk on level surfaces and/or up and down steps to keep the HR within the training zone for 20 minutes.

Participants will receive a whey-based protein supplement in the form of a powder containing 27.6g of protein. This dose induces maximum muscle protein synthesis post-exercise. Participants will mix the supplement in 8 oz of water (or other beverage) or soft food (e.g., yogurt, soup) and consume immediately following each exercise session with the study PT. On days when they do not have a physical therapy visit with the study PT, participants will be instructed to take the supplement at the meal time closest to the time of scheduled PT visits to maintain regular daily dosing schedule.

Participants receive 2000 IU vitamin D3, 600 mg calcium, and a multivitamin daily for the duration of the study. Nutritional counseling is also provided. Participants are screened at baseline to assess nutritional risk using the Mini Nutritional Assessment-Short Form and contacted by a registered dietician (RD) within 7 days of baseline testing Those who score ≤7 (malnourished) and participants with baseline serum albumin 2.5-3.5 g/dl receive a visit from an RD with follow-up a week later. Participants who score 8-11 (at risk of malnutrition) and have serum albumin level >3.5 g/dl receive a phone call from the RD and may receive an in-person visit if warranted. Those screening in the normal range (12-14) and have serum albumin level >3.5 g/dl receive a phone call from the RD. Weight is monitored every 4 weeks. Those who lose 2% or more body weight receive a call from the RD. Those who lose 5% or more body weight between baseline and follow-up may be referred to an RD.

The Six-Minute Walk Test (SMWT) will be used to obtain a continuous measure of total distance walked in six minutes. 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. It has been performed by elderly, frail and severely compromised participants who cannot perform standard maximal treadmill or cycle ergometry exercise tests.

The Mini Mental Status Exam (MMSE) is one of the most widely used screening instruments for dementia. The Modified Mini-Mental State (3MS) test was developed to overcome shortcomings of the MMSE, specifically its narrow range of possible scores and ceiling effects. The 3MS incorporates four additional items (on long-term memory, abstract thinking, category fluency, delayed recall), more uniform administration, and refined scoring, in order to sample a broader variety of cognitive functions, cover a wider range of difficulty levels, and enhance the reliability and validity of the test scores. The 3MS test has a score range of 1-100. It can provide an estimated score of the MMSE, and can also be used to monitor cognitive change over time.

The SPPB evaluates lower extremity performance in older persons based on timed short distance walk, repeated chair stands, and a set of balance tests. 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 score are derived from normative values obtained from a population-based study.

We will measure ADLs using the Pepper Assessment Tool for Disability (PAT-D) 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. Second, two items (walking several blocks and lifting heavy objects) were deleted to avoid duplication with other items in the scale. The resulting 19-item scale allows examination of three subscales (basic ADL, functional limitations, and instrumental ADL).

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). The measure has been validated as a generic measure of quality of life in many different populations, including patient and non-patient samples.

Nutritional status will be assessed using the Mini Nutritional Assessment-Short Form (MNA®-SF), a validated and widely used malnutrition screening tool. 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.

Muscle and lean mass will be estimated using dual-energy x-ray absorptiometry (DXA) (GE LUNAR, Madison, WI). DXA calculates fat mass (g) and lean muscle mass (g) from the total body scan and values are provided in the report produced by the DXA machine. The coefficient of variation of these measurements in our previous studies for fat and lean mass was 1.4% and 1.3%, respectively.

Skeletal muscle area is determined with a thigh CT scan, analyzed using MIPAV (Medical Image Processing, Analysis and Visualization, v.7.0, NIH).

A Biodex System 3 PRO dynamometer will measure concentric isokinetic peak normalized joint torque over the entire range of motion (strength) for bilateral knee flexion-extension. Strength is measured in Newton-meters (Nm). Testing will utilize standardized positioning and joint motion excursions. Subjects will perform two blocks of three repetitions with a rest period between blocks.

A Biodex System 3 PRO dynamometer will measure strength per unit of time (power) for bilateral knee flexion-extension. Power is measured in Watts (W). Testing will utilize standardized positioning and joint motion excursions. Subjects will perform two blocks of three repetitions with a rest period between blocks.

BMD will be estimated using DXA as described above for whole body. DXA of the contralateral (non-fractured) femur will be measured to yield measures of total hip and femoral neck BMD.

Bone formation (serum aminoterminal propeptide of type 1 procollagen; P1NP (mcg/ml)) will be assessed.

Bone resorption (serum cross-linked C-telopeptides of type I collagen; CTx-I (ng/mL)) will be assessed.

a) interleukin-6 (IL-6), b) soluble TNF- α receptor 1 (sTNF- αR1), c) IL-1 receptor antagonist (IL-1ra), and d) interleukin-10 (IL-10). All cytokines will be measured in serum by ELISA (R&D Systems Inc., Minneapolis, MN) and expressed at pg/ml levels.

A GAITrite instrumented walkway system will measure spatial and temporal gait parameters. Subjects will walk at their safest fast and natural speeds. Distance (spatial) variables will include step length (cm).

A GAITrite instrumented walkway system will measure spatial and temporal gait parameters. Subjects will walk at their safest fast and natural speeds. Time (temporal) variables will include: walking speed, single and double leg support time, and cadence.

The Dynamic Gait Index, a clinical assessment of balance and mobility while walking, will be administered.

The Four Square Step Test (FSST) is used to assess dynamic stability and the ability of the subject to step over low objects forward, sideways, and backward. The FSST may be an effective and valid tool for measuring dynamic balance and the subject's fall risk.

The Trail Making Test is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. The test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. It is sensitive to detecting cognitive impairment associated with dementia.

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.

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.

We will monitor adherence to the protein supplement by weighing the container(s) of protein powder every 4 weeks during the 16-week intervention period and by self-report during the 4-week telephone calls.

Reportable adverse events (RAEs), which include serious adverse events (SAEs), unexpected AEs, or injury that occurs under supervision by study staff, will be obtained during the study. 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.

Expected adverse events (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; bloating or puffiness (legs, ankles, feet); drowsiness, dizziness, or confusion; shakiness, anxiety, clammy skin, or irritability; and falls (with and without injury).

Inclusion Criteria: Closed fracture of proximal femur Age 60 or older at time of baseline testing 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 baseline testing 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 baseline testing Not fully weight-bearing on fractured leg or non-fractured leg at time of baseline testing 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 baseline testing Severely diminished lower extremity sensation or ulceration Uncontrolled hypertension Chronic kidney disease Severe liver disease (e.g., hepatitis, fatty liver disease, cirrhosis) Poorly controlled and/or insulin-dependent diabetes Known dairy allergy 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 Baseline testing not done 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

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