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. 2020 Sep 16;100(12):2154–2164. doi: 10.1093/ptj/pzaa169

Michigan Initiative for Anterior Cruciate Ligament Rehabilitation (MiACLR): A Protocol for a Randomized Clinical Trial

Kazandra Rodriguez 1, Steven A Garcia 2, Cathie Spino 3, Lindsey K Lepley 4, Yuxi Pang 5, Edward Wojtys 6, Asheesh Bedi 7, Mike Angelini 8, Bethany Ruffino 9, Tyler Bolley 10, Corey Block 11, Jessica Kellum 12, Andrew Swartout 13, Riann M Palmieri-Smith 14,✉
PMCID: PMC7720639  PMID: 32939539

Abstract

Objective

Restoring quadriceps muscle strength following anterior cruciate ligament reconstruction (ACLR) may prevent the posttraumatic osteoarthritis that affects over 50% of knees with ACLR. However, a fundamental gap exists in our understanding of how to maximize muscle strength through rehabilitation. Neurological deficits and muscle atrophy are 2 of the leading mechanisms of muscle weakness after ACLR. High-intensity neuromuscular electrical stimulation (NMES) and eccentric exercise (ECC) have been shown to independently target these mechanisms. If delivered in succession, NMES and then ECC may be able to significantly improve strength recovery. The objectives of this study were to evaluate the ability of NMES combined with ECC to restore quadriceps strength and biomechanical symmetry and maintain cartilage health at 9 and 18 months after ACLR.

Methods

This study is a randomized, double-blind, placebo-controlled, single-center clinical trial conducted at the University of Michigan. A total of 112 participants between the ages of 14 and 45 years and with an anterior cruciate ligament rupture will be included. Participants will be randomly assigned 1:1 to NMES combined with ECC or NMES placebo combined with ECC placebo. NMES or NMES placebo will be delivered 2 times per week for 8 weeks beginning 10 to 14 days postoperatively and will be directly followed by 8 weeks of ECC or ECC placebo delivered 2 times per week. The co-primary endpoints are change from baseline to 9 months and change from baseline to 18 months after ACLR in isokinetic quadriceps strength symmetry. Secondary outcome measures include isometric quadriceps strength, quadriceps activation, quadriceps muscle morphology (cross-sectional area), knee biomechanics (sagittal plane knee angles and moments), indexes of patient-reported function, and cartilage health (T1ρ and T2 relaxation time mapping on magnetic resonance imaging).

Impact

The findings from this study might identify an intervention capable of targeting the lingering quadriceps weakness after ACLR and in turn prevent deterioration in cartilage health after ACLR, thereby potentially improving function in this patient population.

Anterior cruciate ligament (ACL) reconstruction (ACLR) leads to significant reductions in quadriceps strength,1–3 and this decreased strength is related to a decreased quality of life,4 higher risk of secondary ACL injury,5 abnormal sagittal plane knee biomechanics during walking and single-leg hopping,6–8 and the development of posttraumatic osteoarthritis (PTOA) (ie, degeneration of knee articular cartilage and subchondral bone) in 50% of reconstructed limbs9 between 10 and 20 years after injury.9–11 Quadriceps weakness persists for years after ACLR1–3 in spite of rehabilitation programs focused on restoring quadriceps strength. This suggests that current ACL rehabilitation is inadequate, and interventions capable of improving quadriceps strength are crucial to improve ACLR outcomes.

Quadriceps activation failure leads to a diminished ability to voluntarily contract the muscle and is considered a source of the muscle weakness that persists after ACLR.12 Early after ACLR, the magnitude of activation failure is large (approximately 25%) and can prevent effective strengthening, thus hindering rehabilitation.13

Neuromuscular electrical stimulation (NMES) can directly depolarize motor axons leading to involuntary contraction.14 Therefore, the use of NMES is an attractive therapy to override activation failure as it can activate the quadriceps exogenously. Previous work has shown that NMES and exercise is superior to exercise alone at improving muscle strength.15–17 To target muscle atrophy, emerging evidence suggests that the higher mechanical stress achieved via eccentric exercise (ECC) is critical to initiate strain-sensing molecules that mediate tissue growth.18 Given the unique capability of ECC to mechanically promote protein synthesis, the incorporation of ECC into ACLR rehabilitation after targeting quadriceps activation failure via NMES is likely an effective therapeutic prescription to promote the optimal recovery of quadriceps strength.

The overall purpose of this study is to examine the ability of NMES combined with ECC (NMES + ECC) to restore quadriceps function and sagittal plane knee biomechanical symmetry as well as to minimize cartilage degeneration after ACLR. The primary objective is to establish if NMES + ECC will maximize quadriceps strength symmetry at 9 and 18 months after ACLR. Secondary objectives include establishing if NMES + ECC will improve quadriceps cross-sectional area, sagittal plane knee biomechanics symmetry during hopping, physical function, quadriceps activation, and cartilage health more effectively than placebo. Our hypothesis is that NMES + ECC will improve quadriceps strength symmetry, knee flexion angle and moment symmetry, and physical function at 9 and 18 months after ACLR compared with placebo. In addition, we hypothesize that NMES + ECC will lead to fewer signs of early cartilage degeneration in the ACLR limb, as demonstrated by greater T1ρ and T2 relaxation time ratios, at 18 months after ACLR.

Methods

Trial Design

This is a randomized, double-blind, placebo-controlled clinical trial that began in spring 2019 and will continue for 5 years. This is a single-center study occurring at the University of Michigan. A trial schematic is shown in Figure 1.

Figure 1.

Figure 1

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Schematic timeline of the clinical trial. ACLR = anterior cruciate ligament reconstruction; ECC = eccentric exercise; MRI = magnetic resonance imaging; MVIC = maximum voluntary isometric contraction; NMES = neuromuscular electrical stimulation.

Participants

Participants will be recruited from Michigan Medicine via search of electronic medical records. A total of 112 patients will be enrolled in this study, which includes a 20% attrition rate. Thus, we expect that at least 90 participants will complete the study (ie, 45 participants in each group). Inclusion and exclusion criteria are outlined in the Table.

Table.

Trial Inclusion and Exclusion Criteriaa

Inclusion Criteria (Must Meet All) Exclusion Criteria (Cannot Meet Any)
• 14–45 years of age

• First-time, initial ACL tear

 

• ACLR graft with bone patellar tendon bone autograft or semitendinosus gracilis autograft

 

• Willingness to participate in testing and follow-up as outlined

 • Previous surgery to either knee

• Bony fracture accompanying ACL injury

 

• Patients who experienced a knee dislocation

 

• Female participants who are pregnant or planning pregnancy

 

• Participation in concomitant interventions
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a ACL = anterior cruciate ligament; ACLR = anterior cruciate ligament reconstruction.

The sample size of 112 participants (56 per group) provides sufficient power to test the primary hypotheses regarding 2 separate comparisons (each coprimary endpoint, quadriceps strength symmetry at 9 and 18 months after ACLR) of NMES + ECC vs NMES placebo combined with ECC placebo. Because there are 2 coprimary endpoints, each test will be conducted at the 1-sided 0.025 type I error level (0.05/2; Bonferroni adjustment for 2 comparisons). We hypothesize that the effect size (treatment difference/SD) will be at least 0.60 for the tests of NMES + ECC vs NMES placebo combined with ECC placebo. Assuming a 20% dropout (resulting in an effective sample size of 45 per group), we have at least 80% power to detect this effect size. The effect size chosen (0.6) is conservative as our pilot data revealed an effect of 1.13 when comparing standard-of-care ACL rehabilitation group with our NMES + ECC intervention.19 The sample size in our pilot work is rather small (the NMES + ECC group had 8 participants, and the standard-of-care group had 10 participants), and as such we felt it prudent to be conservative and chose an effect smaller than that estimated to ensure we had a more than adequate sample to detect differences in our primary outcomes.

Randomization

After ACLR, eligible participants will be allocated to 1 of 2 treatment groups, NMES + ECC or NMES placebo + ECC placebo, via minimization.20,21 This approach allows for control of known confounders (meniscal injury and treatment, articular cartilage injury, sex, and graft type) when some of these combinations are relatively rare. The potential imbalance (and subsequent loss of power) between the study arms when there are many important confounders is mitigated using minimization. Allocation is concealed via a secure web-based application used by the research coordinator to enter participant information and to obtain the assigned study arm. The assigned study arm is sent directly to the physical therapists and can be checked via the study website by unmasked study team members only (ie, masked members do not have access to this website).

Masking

The participants and outcome assessors are masked with regard to patient treatment assignment. The principal investigator, coinvestigators, medical monitor, and data coordinating center project managers are also masked with regard to group assignment.

Interventions

Physical therapy

Participants for both study arms, regardless of randomization assignment, will undergo ACL rehabilitation (Fig. 2). All study interventions are being delivered by a team of 4 physical therapists. While an attempt is made to achieve continuity of intervention delivery (ie, the same physical therapist delivering all treatments to a single patient), this does not often occur because of patient and physical therapists’ schedules. As such, usually 2 physical therapists are involved in the intervention delivery for a single patient.

Figure 2.

Figure 2

Figure 2

Figure 2

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Post-surgery physical therapy protocol.

High-intensity NMES and NMES placebo

NMES is delivered 2 times per week for 8 weeks after ACLR. Treatment will begin approximately 7 to 14 days postoperatively as participants need to be able to achieve approximately 60 degrees of knee flexion prior to NMES treatment. At the beginning of each week of treatment, patients will have their maximum voluntary isometric contraction measured (Humac Norm Dynamometer; CSMI Solutions, Stoughton, MA) in their non-ACLR limb to determine NMES dosage for the week. To deliver NMES, stimulating electrodes will be placed over the vastus lateralis proximally and the vastus medialis distally. A VectraNeo stimulator (Chattanooga, Lewisville, TX, USA) will be set to deliver a variable muscle stimulation waveform, with a 200-microsecond phase duration, modulated at 75 bursts per second, with a ramp-up time of 2 seconds followed by a 50-second rest period. The treatment intensity will be set at the beginning of each week to an intensity that elicits a contraction in the ACLR limb that is equivalent to a 40% maximum voluntary isometric contraction of the contralateral side.22 Fifteen isometric contractions lasting 12 seconds (including ramp-up time) each will be delivered for all sessions.

NMES placebo intervention will follow the same protocol as the actual NMES intervention, with the exception of the current intensity. The current intensity will be set to achieve a 15% maximum voluntary isometric contraction of the contralateral side. This placebo intensity was chosen as our pilot work showed no effect with this treatment intensity on muscle strength.

ECC and ECC placebo

ECC study therapy is also delivered 2 times per week for 8 weeks but begins after NMES treatment ends 9 to 10 weeks after ACLR. Participants will be positioned in a BLAST! Leg Press (BioLogic Engineering Inc, Dexter, MI) with their ACLR knee range of motion limited to 20 to 60 degrees of knee flexion. Participants will perform 10 warm-up trials consisting of the concentric and eccentric phases of a leg press with the ACLR limb at 10% of their 1-repetition maximum (1-RM). Following warm-up, each participant will perform 10 isokinetic leg press actions with the ACLR limb. In total, participants will complete 4 sets of 10 repetitions with 2 minutes of rest between.19,23 All repetitions will be performed at a speed of 3 units. The intensity of the training will be set at the beginning of each week when participants are asked to perform a single-leg (ACLR limb only) 1-RM on the device. During the eccentric actions, participants will train at intensity equal to 70% of their 1-RM in the first 2 weeks of the intervention and at 90% of their 1-RM for the remaining 6 weeks. Concentric intensity will be set at 40% of the 1-RM. The intensity of the eccentric actions was chosen based on our pilot work.19

The ECC placebo will follow the same protocol as the actual ECC intervention with the exception of the training intensity. The eccentric training intensity will be set to 10% of the 1-RM, but the concentric intensity will be set to match that of the active ECC intervention at 40% of the 1-RM. The 40% concentric intensity was chosen as patients in our clinic are typically performing leg presses at this intensity and thus does not differ from the standard of care.

Treatment Adherence

To directly monitor treatment adherence, treatments will be delivered in person. Session adherence will be calculated as the total number of sessions completed relative to the number of sessions prescribed (32 total sessions: 16 each of NMES and ECC).

Physical Therapist Training and Treatment Fidelity

In-person training is provided to physical therapists prior to study initiation to maximize fidelity of interventions. This training provides instruction on the standard-of-care rehabilitation program, instruction on the protocol for each study arm, and practice trials of the NMES+ECC protocol with people who are healthy to ensure consistency.

Adverse Events

Adverse events will be reported within 72 hours in the study database. The data coordinating center will distribute narrative reports for serious adverse events to the Data Safety Monitoring Board using a web-based application. All adverse events will be monitored and followed until adequately resolved.

Outcome Measures

The primary outcome measures are peak isokinetic quadriceps muscle strength symmetry at 9 and 18 months after ACLR. Isokinetic quadriceps strength will be assessed using an isokinetic dynamometer (Humac Norm; CSMi) and will be measured concentrically at 60 degrees per second for both limbs with testing order counterbalanced. Three trials will be recorded, and the trial with the largest peak torque in each limb will be extracted to calculate the quadriceps index: (ACLR limb/contralateral limb) × 100. Intersession reliability using this protocol in our laboratory is high (intraclass correlation coefficient [ICC] = 0.92).

Isometric quadriceps strength and quadriceps activation will be assessed on the same dynamometer used for isokinetic testing. Quadriceps activation will be assessed as we have done previously using the interpolated twitch technique24 and the percent activation equation: (1 – [superimposed twitch torque/resting twitch torque]) × 100. Protocols similar to ours have shown moderate between-day reliability (ICC = 0.89).25

Quadriceps atrophy will be assessed by quantifying cross-sectional area of the vastus lateralis, vastus medialis, and rectus femoris using an ultrasound machine (ArtUs; Telemed, Vilnius, Lithuania) (gain = 45%; depth = 4.5 cm) while participants lie supine with their legs in complete extension. Three panoramic images of each muscle are being assessed. The vastus lateralis and rectus femoris images are obtained at 50% of the distance from the anterior superior iliac spine to the lateral border of the patella and the superior border of the patella, respectively.26 Vastus medialis images are collected at 80% of the distance from the anterior superior iliac spine to the medial border of the patella. Intersession reliability of cross-sectional area for these quadriceps muscles in our laboratory is moderate to high (ICCs = 0.85–0.95) (unpublished data).

Bilateral knee biomechanics, including knee flexion angle and knee extensor moment, will be assessed using 3-dimensional motion analysis.27,28 Joint moments will be normalized to participant height and mass. Participants will perform 5 successful single-leg forward hops onto a force platform (Model 0R6–7, Advanced Medical Technologies, Inc. Watertown, MA, USA). Biomechanical data will be time normalized to 100% of stance phase for graphical purposes, with initial contact equating to the time when the vertical ground reaction force first exceeds and falls below 10 N and the end of the landing equates to 250 milliseconds after initial contact.29 Bilateral data will be ensemble averaged across stance, and the area under the curve will be calculated for each limb, as we have done previously.23,27 The area under the curve integrals will then be used to calculate a limb symmetry index: (ACLR/contralateral) × 100.23,27 Additionally, peak angles and moments will be extracted, and their limb symmetry indexes will be calculated.

Bilateral knee magnetic resonance images will be obtained on a 3-T research unit (Philips MRI Ingenia, Andover, MA, USA) using a commercially available 16-channel transmit receive knee coil at 18 months after ACLR. A variety of pulse sequences will be utilized to perform T2 and T1ρ mapping. The intra- and inter-multiple 3-dimensional volumetric images acquired with different relaxation (eg, T2 or T1ρ) time weightings will be co-registered with Elastix,30 and then manual segmentation of the femur, tibia, and patella articular cartilage will be completed using ITK-SNAP software.31 Detailed angular-radial segmentation32 will be performed on femoral cartilage, while a simple depth-specific segmentation33 will be applied to other cartilage. Both T2 and T1ρ relaxation rates will be calculated bilaterally and expressed as symmetry scores: (ACLR/contralateral) × 100.

The following 5 patient-reported outcomes will also be recorded: Knee Osteoarthritis and Outcome Scale,34 PROMIS Physical Function,35 Tegner Activity Scale,36 Marx Activity Scale,37 and Tampa Scale of Kinesiophobia.38

Data Analysis

Statistical analysis

The primary outcomes will be tested at the 1-sided 0.025 level, adjusting for the multiple comparisons of 2 co-primary endpoints. Separate linear models will be fit for each of the 2 co-primary endpoints, 1 for the 9-month change from baseline and 1 for the 18-month change from baseline in isokinetic quadriceps muscle strength symmetry. The models will include treatment group, type of graft, surgeon, age, sex, and baseline isokinetic quadriceps strength symmetry index. Least-squares mean change from baseline, along with standard errors, will be presented for each group. For the comparisons of combination NMES + ECC with the placebo group, least-squares mean group differences in the change from baseline will be presented along with associated 97.5% upper confidence bounds and P values. The analysis of the primary endpoints will use the intention-to-treat analysis set, defined as all randomized participants. A secondary analysis of the primary endpoints will use the per-protocol analysis set (the intention-to-treat set excluding participants who have not received at least 1 study intervention and who have major protocol deviations). Multiple imputation will be used to handle missing data. This approach is consistent with the recently published ICH E9 (R1) addendum on estimands and sensitivity analysis,39 which provides a framework for defining the target population, an endpoint of interest to answer the scientific question, strategies for addressing inter-current events (eg, non-compliance with study treatment, dropouts), and population summaries used to compare treatments. Appropriate nonlinear parametric or nonparametric tests may be applied if necessary.

All tests of secondary endpoints will be conducted at the 2-sided .05 level, without adjustment for multiplicity, using comparable models as for the primary endpoints. The intention-to-treat analysis set will be used. In addition, for magnetic resonance imaging–related endpoints, we will include articular cartilage injury and meniscus injury and treatment as covariates in the linear model.

Descriptive statistics for safety outcomes will be summarized overall and by treatment group.

Ethics

Participants will be informed about the study and will sign an informed consent form before participating in the trial. This study was approved by the University of Michigan Medical Institutional Review Board (HUM0014492). Protocol modifications will be reported to the institutional review board and to the trial registry.

Participants are assigned an identification code for all documentation. All electronic data will be password-protected and stored on password-protected computers and servers.

Role of the Funding Source

The funder (National Institutes of Health, ref. no. 1R01HD093626-01A1) played no role in the design, implementation, analysis, or interpretation of results or the decision as to whether and where to publish papers.

Discussion

Current ACL rehabilitation approaches fail to consider the primary mechanisms, activation failure and muscle atrophy, which result in the lingering quadriceps weakness plaguing patients after ACLR. The failure to directly target these mechanisms likely explains why ACL rehabilitation is inadequate. In this study, we employ NMES to target the quadriceps activation failure present early after ACLR and subsequently utilize ECC to mechanically engage protein synthesis pathways, thereby improving muscle growth. The findings from this study could significantly improve existing ACL rehabilitation approaches and may assist in preventing the early development of PTOA.

NMES delivered along with isometric/concentric exercise has been studied and has mostly shown positive results. Quadriceps strength has been improved in studies where NMES was used on top of muscle contractions or alongside standard-of-care ACL rehabilitation. Further, these improvements in strength were greater than those of controls who were not exposed to NMES.6,31,40,41 These results suggest that the use of NMES alongside exercise leads to improvements in muscle strength. However, it is important to note that while strength was improved in these studies, patients did not achieve symmetrical strength as limb symmetry indices range from 37.9% to 83.1%.15,17,41,42 This persistent asymmetry suggests the combination of NMES and concentric/isometric exercise is not adequate to restore quadriceps function after ACLR.

ECC has been shown to safely improve muscle strength and size in young43 and older adults.44 When ECC alone is used in patients following ACLR, recovery of quadriceps strength is achieved earlier after surgery compared with NMES only and standard of care.19 Notably, ECC restores quadriceps strength to postoperative/pre-intervention levels and may even improve quadriceps strength to values similar to adults who are uninjured and healthy.1 However, it is critical to note that while ECC is an effective method to addressing the quadriceps weakness observed following ACLR, it still falls short of fully restoring symmetrical strength (eg, >90%), with an average limb symmetry index of 84.8%.23 We contend that the use of NMES prior to ECC may enhance the effectiveness of ECC given that quadriceps activation failure should be minimized or eliminated.

Our preliminary work shows NMES + ECC may result in superior improvements in quadriceps strength and function compared with current standard of care after ACLR.19 In fact, NMES + ECC improved quadriceps strength by 26% compared with the results for patients who had ACLR and received the standard of care.19 Despite the promising findings of NMES + ECC, 1 limitation of this work is the inability to evaluate the true clinical effect of the intervention due to small sample sizes.19,19,45,46 In addition, studies have typically administered NMES using a maximum tolerated intensity19,22,45 rather than selecting an intensity that generates a similar quadriceps contraction among all patients. These likely result in substantial variability in the delivered dosage and, in turn, may limit accurate conclusions from being drawn. The current study will address the limitations of previous NMES research and allow for the true effect of high-intensity NMES to be better understood.

Given the hypothesized ability of NMES + ECC to improve muscle strength more than placebo, this study also provides us a unique opportunity to determine if an intervention better capable of restoring muscle strength is effective at reducing negative changes in cartilage health, which could reduce the risk of PTOA. Quadriceps weakness has been shown to increase the risk of PTOA.47,48 However, it remains unknown if effective quadriceps strengthening can prevent PTOA development. By using techniques (cartilage-sensitive magnetic resonance imaging) and metrics (T1ρ and T2 relaxation times), we can determine for the first time if strengthening interventions can minimize cartilage degeneration.

We acknowledge several limitations to the approach and research design of the current study. First, the study team members delivering the intervention are not masked with regard to patient group assignment and may introduce bias. This limitation is unavoidable. Second, ideally we would have included 2 additional groups in our design (NMES placebo combined with ECC and NMES combined with ECC placebo) to allow us to understand if 1 of the therapies alone were driving the changes we may see in quadriceps strength. The number of participants required for this factorial study design prevented this approach. By assessing strength after NMES and after ECC application, we hope to begin to differentiate the effects of the interventions alone. Lastly, we acknowledge that examining cartilage metrics at 18 months after ACLR will not be a time point where PTOA is present in our sample. However, T1 and T2 relaxation times have shown changes in the cartilage of ACLR patients as early as 6 months postoperatively.49

To promote the dissemination of results from our study to clinical rehabilitation, the results will be presented at conferences and published in peer-reviewed journals.

Contributor Information

Kazandra Rodriguez, School of Kinesiology, University of Michigan, Ann Arbor, Michigan; and Orthopaedic Rehabilitation and Biomechanics Laboratory, University of Michigan.

Steven A Garcia, School of Kinesiology, University of Michigan; and Orthopaedic Rehabilitation and Biomechanics Laboratory, University of Michigan.

Cathie Spino, School of Public Health, University of Michigan.

Lindsey K Lepley, School of Kinesiology, University of Michigan; and Orthopaedic Rehabilitation and Biomechanics Laboratory, University of Michigan.

Yuxi Pang, Department of Radiology, Michigan Medicine, Ann Arbor, Michigan.

Edward Wojtys, Michigan Medicine; and Department of Orthopaedic Surgery, Michigan Medicine.

Asheesh Bedi, Michigan Medicine; and Department of Orthopaedic Surgery, Michigan Medicine.

Mike Angelini, School of Kinesiology, University of Michigan; and Orthopaedic Rehabilitation and Biomechanics Laboratory, University of Michigan.

Bethany Ruffino, Department of Orthopaedic Surgery, Michigan Medicine.

Tyler Bolley, Michigan Medicine.

Corey Block, Michigan Medicine.

Jessica Kellum, Michigan Medicine.

Andrew Swartout, Michigan Medicine.

Riann M Palmieri-Smith, School of Kinesiology, University of Michigan, 401 Washtenaw Avenue, Ann Arbor, MI 48109 (USA); Orthopaedic Rehabilitation and Biomechanics Laboratory, University of Michigan; and Department of Orthopaedic Surgery, Michigan Medicine.

Author Contributions

Concept/idea/research design: K. Rodriguez, C. Spino, L.K. Lepley, A. Bedi, R.M. Palmieri-Smith

Writing: K. Rodriguez, C. Spino, L.K. Lepley, R.M. Palmieri-Smith

Data collection: S.A. Garcia, Y. Pang, M. Angelini, T. Bolley, C. Block, J. Kellum, A. Swartout, R.M. Palmieri-Smith

Data analysis: S.A. Garcia, Y. Pang, M. Angelini, R.M. Palmieri-Smith

Project management: S.A. Garcia, M. Angelini, T. Bolley, C. Block, J. Kellum, A. Swartout, R.M. Palmieri-Smith

Fund procurement: C. Spino, A. Bedi, R.M. Palmieri-Smith

Providing participants: E. Wojtys, A. Bedi, T. Bolley, C. Block, J. Kellum, A. Swartout, R.M. Palmieri-Smith

Providing facilities/equipment: R.M. Palmieri-Smith

Providing institutional liaisons: R.M. Palmieri-Smith

Clerical/secretarial support: B. Ruffino

Consultation (including review of manuscript before submitting): Y. Pang, E. Wojtys

Funding

This study was supported in part by the National Institutes of Health (No. 5-R01-HD-093626-02). Any opinions, findings, and conclusions or recommendations expressed in this study are those of the authors and do not necessarily reflect the views of funding sources.

Clinical Trial Registration

This study was registered at ClinicalTrials.gov (NCT03626857).

Disclosures

The authors completed the ICMJ Form for Disclosure of Potential Conflicts of Interest and reported no conflicts of interest.

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