This study is a randomized, placebo-controlled, double-blinded, single-center clinical
trial to elucidate the effects of perioperative essential amino acid nutritional
supplementation in pursuit of the following aim and covariates:
Specific Aim 1: Preserve paraspinal muscle volume and assess impact on spine sagittal
balance through measurement of radiographic parameters. Paraspinal muscle atrophy
following lumbar spine surgery has been correlated with worse clinical outcomes. It is
still not understood whether iatrogenic denervation, immobilization, or nutritional
deficiencies lead to the reduced volume in the paraspinal muscles. Investigators will
utilize pre- and post-operative MRI scans to quantify changes in paraspinal and psoas
muscle cross-sectional area and fatty infiltration, and measure sagittal vertical axis,
pelvic incidence, lumbar lordosis, and pelvic tilt, as muscle quality has been correlated
with spine balance and degeneration, as well as bone quality.
Specific Aim 2: Assess clinical outcomes postoperatively to determine any possible effect
of paraspinal muscle volumes on variability in functional status. Functional assessments
will be made using established, validated clinical outcomes measures at baseline and up
to 2 years postoperatively. Postoperative adverse events will be recorded throughout the
duration of the study, as well as markers of nutritional status using a validated dietary
questionnaire and blood sampling. Results will be compared between treatment and control
groups to determine if functional status is associated with variability in outcomes
related to preservation of native paraspinal muscle volume postoperatively.
Specific Aim 3: Evaluate postoperative pain and opioid consumption postoperatively to
determine any possible effect of pain on variability in paraspinal muscle volumes.
Patient-reported pain and opioid consumption will be evaluated perioperatively with a
daily pain diary, clinician-administered pain assessments, and review of the
state-controlled substances database (CURES). Pain ratings, mean morphine equivalents,
time to baseline preoperative opioid consumption, and time to opioid discontinuation will
be compared between treatment and control groups to determine any relationship between
postoperative pain levels on variability in outcomes related to preservation of native
paraspinal muscle volume following surgery.
Description of Procedures:
Study team members will review the patient medical record for the minimal amount of
health information necessary to determine eligibility in the study prior to obtaining
informed consent. Patients undergoing lumbar spine surgery that meet eligibility
requirements-determined using standard nutritional and lumbar surgical clinical research
inclusion/exclusion criteria applied according to the judgment of the investigator-will
receive standardized written and verbal information about the trial from the
investigators listed in the study team. For non-English speaking participants, an
interpreter will be involved in the consenting process.
A member of the research team will be unblinded and responsible for block randomization
of participants with 1:1 allocation to EAA and placebo groups (N=44 each group) using
Excel 2016 (Microsoft). The University of California Irvine (UCI) Investigational Drug
Services Pharmacy (IDS Pharmacy) is responsible for receiving, labeling, storing, and
distributing the products and will collect product containers/any unused products at the
conclusion of the supplement period as outlined in the study protocol. The remainder of
the study team (including the primary investigator and co-researchers) and the
statistician responsible for data analysis will be blinded to randomization.
Demographic and baseline information regarding nutritional, functional, and frailty
status will be collected at the baseline visit within 6 weeks to 1 week prior to surgery,
including ambulatory status (independent, cane, walker, wheelchair); food preferences
(omnivorous, pescatarian, vegan, vegetarian); Protein Screener 55+ (a validated
questionnaire to screen for low dietary protein intake in the elderly); modified
Fragility Index (a validated risk stratification tool in lumbar spine surgery); and
baseline labs (including serum albumin, prealbumin, and transferrin as markers of
nutritional status and inflammation), functionality, pain scores, and medication use.
From 1 week prior to surgery until 2 weeks postoperatively, patients will consume either
a commercially available EAA supplement-containing L-leucine (3.6g), L-lysine as L-lysine
HCl (3.2g), L-phenylalanine (3.2g), L-valine (2.4g), L-threonine (2.8g), L-isoleucine
(2.0g), L-methionine (0.6g), and L-histidine as L-histidine HCl (2.2g) (Joint
Replacement; Mend Labs, New York, NY) twice daily-or calorically-equivalent placebo
(alanine, 20g twice daily).
Fellowship-trained spine surgeons will perform all lumbar decompression and/or fusion
surgeries using the same posterior operative approach and instrumented fusion of unstable
segments if clinically indicated. All patients are hospitalized from the day of surgery
until discharge, with the total length of stay dependent on postoperative pain control
and progress in physical therapy. Patient-reported pain will be evaluated with a daily
pain diary using the Numerical Pain Rating Scale beginning 1 week prior to surgery for at
least 2 weeks postoperatively or until termination of opioid consumption (for a maximum
of 1 month). Patients will be educated to also record pain levels each time they take an
opioid. Opioid consumption-including oxycodone, hydrocodone, morphine, codeine, fentanyl,
hydromorphone, and tramadol-will be captured simultaneously through a pain medication
diary and compared between treatment groups as mean morphine equivalents. Time to less
than baseline opioid consumption and time to opioid discontinuation will also be compared
between treatment groups. Clinician-administered patient pain ratings using the Visual
Analogue Score will be recorded at baseline, on the day of surgery, and at each
postoperative visit.
Timeline of Study Procedures:
1. Screening visit within 6 months to 6 weeks prior to surgery date: consent, physical
exam, pregnancy test if appropriate, review of lumbar MRI (approximately 1 hour)
2. Preoperative visit within 6 weeks to 1 week prior to surgery: physical exam,
baseline labs, baseline functional mobility and pain assessment, CURES database
review, patient education on self-reporting pain, opioid consumption, consumption of
other medications, and EAA supplementation or placebo consumption (approximately 2
hours). EAA and placebo will be provided by the manufacturer in the same containers
with the same scoop size and the same label instructing patients consume one serving
twice a day beginning one before their surgery and for 2 weeks after. These
instructions and labels will be provided by Mend and they align with previously
studied protocols where the supplement has been fond to be safe. Investigators hope
in using the product as directed by Mend to reduce risk for participants and
decrease confusion as they can follow the package information.
3. Surgery day (all patients are hospitalized from the day of surgery until discharge,
with the total length of stay dependent on postoperative pain control and physical
therapy progress). Patients will receive this surgery and the associated
postoperative inpatient stay as part of standard of care regardless of their
involvement in this study. Research related data collection aside from standard of
care during their perioperative inpatient stay will be approximately 1 hour. (
approximately 1 hour)
4. Postoperative follow-up at 2 weeks +/- 5 days: physical exam, functional mobility
and pain assessment, labs, review of patient-reported daily pain levels, review of
CURES and opioid/medication consumption, review of patient-reported EAA
supplementation or placebo consumption logs (approximately 1 hour)
5. Postoperative follow-up at 6-8 weeks +/- 5 days: physical exam, functional mobility
and pain assessment, labs, review of CURES and opioid/medication consumption
(approximately 30 minutes)
6. Postoperative lumbar MRI without contrast obtained at 8-10 weeks (1 hour)
7. Postoperative follow-up at 12 weeks +/- 5 days: physical exam, review MRI results,
functional mobility and pain assessment, review of CURES and opioid/medication
consumption (approximately 1 hour)
Statistical Plan:
Power analysis: Sample size analysis was performed a priori using data from the
literature evaluating muscle atrophy with and without nutritional supplementation in
patients with total knee arthroplasty, as there is no data assessing paraspinal muscle
volume after lumbar spine surgery, with an expected difference in primary outcome measure
of 4.9% (13.4% +/- 1.9% in control and 8.5% in experimental). Using two independent
groups, a continuous variable primary endpoint, an assumed 2-tailed type-1 error rate of
0.05, and a power value of 80% we require a minimum total of 88 patients with 44 in each
group.
Overall: Baseline characteristics will be compared between the groups using independent t
tests (or the Wilcoxon rank sum test, if the characteristics were not normally
distributed) for continuous measures and the chi-square test for categorical measures.
Continuous variables will be described using the mean and standard deviation. Categorical
variables will be described using absolute frequencies. Pearson's correlation coefficient
(r) will be used to assess relationships between paraspinal muscle CSA, opioid
consumption as morphine milligram equivalents (MME), clinical functional outcome
measures, and postoperative complications. A two-way repeated measured analysis of
variance (ANOVA) will evaluate chronological changes in continuous variables between the
two groups. Significance will be set at p < 0.05.
Specific Aim 1: Axial T2-weighted lumbar spine MRI at the levels of the L1-5
intervertebral discs using a 3 Tesla (3T) MRI with a phased-array surface coil will be
completed within 6 months to 6 weeks (about 1 and a half months) prior to surgery and
prior to treatment intervention and will be compared to the repeat MRI completed at 8-10
weeks postoperatively. Bilateral paraspinal muscle cross-sectional area (CSA) will be
measured by two experienced musculoskeletal radiologists marking the borders of these
muscles. Proton density fat fraction will be used to quantify the proportion of fatty
infiltration and overall atrophy will be qualitatively rated based on visual assessment
using a visual scale modified from the Goutallier grading system. Sagittal spinopelvic
alignment parameters including sagittal vertical axis, pelvic incidence, lumbar lordosis,
and pelvic tilt will be measured on both the pre and postoperative MRIs. The intraclass
correlation coefficient for this measurement will be evaluated and interpreted according
to the predetermined guidelines.
Specific Aim 2: Functional status will be assessed for each treatment arm at baseline, 2
weeks, 6 weeks, and 3 months postoperatively using established, validated clinical
outcome measures completed with a trained member of research staff: the Oswestry
Disability Index 2.1A, 36-Item Short Form Health Survey (SF-36), Patient-Reported
Outcomes Measurement Information System (PROMIS) Physical Function, EuroQol-5 Dimension 5
Levels (EQ-5D-5L), 6-minute walk test, and 5 repetitive sit to stand test. Preoperative
mortality and morbidity risk will be controlled between treatment groups using the
modified Frailty Index. Postoperative adverse events will be recorded throughout the
duration of the study, including but not limited to hospital length of stay, surgical
site infections, unplanned reoperation, mortality, and medical complications requiring
intervention.
Specific Aim 3: Patient-reported pain will be evaluated with a daily pain diary using the
Numerical Pain Rating Scale beginning 1 week prior to surgery for at least 2 weeks
postoperatively or until termination of opioid consumption (for a maximum of 1 month).
Patients will be educated to also record pain levels each time they. Opioid
consumption-including oxycodone, hydrocodone, morphine, codeine, fentanyl, hydromorphone,
and tramadol-will be captured simultaneously through a pain medication diary and compared
between treatment groups as MME.
Safety Monitoring:
A Data Safety Monitoring Board (DSMB) consisting of 7 UCI faculty members from various
relevant disciplines-including orthopaedic surgery, anesthesiology, nutrition,
pharmacology, biostatistics-has been assembled to ensure the safety of all study
participants throughout the duration of the study period. At the first safety meeting
prior to subject enrollment, the DSMB will discuss the protocol and agree upon guidelines
to study monitoring. Subsequently, study data will be evaluated continuously by the study
team and meetings of the DSMB will be held at least two times a year (every 6 months). As
part of the purpose of the study is to evaluate the impact of amino acid supplementation
on functional/clinical outcomes, pain, and opioid use, data ensuring compliance in
supplement ingestion, pain levels, medication use, functional outcomes, and adverse
events will be continuously documented. No adverse outcomes are expected given that the
amino acid supplement is commercially available and has shown to be safe for human
consumption. However, unscheduled emergency meetings may be called at any time by the
DSMB or the study investigators should participant safety questions or other
unanticipated problems or adverse events arise-such as renal failure, severe GI distress,
or melena. Safety updates and reports will be submitted to the UCI Institutional Review
Board with the continuing application each year.
