Anterior Cruciate Ligament Injury
Conditions
Keywords
Knee, ACL, Reconstruction, Rehabilitation, Eccentric Exercise, Electrical Stimulation
Brief summary
This clinical trial evaluates interventions to maximize muscle function and improve cartilage health following anterior cruciate ligament reconstruction. Improving muscle function may improve patient outcomes, improve joint mechanics, and potentially serve as a prevention approach for post-traumatic knee osteoarthritis. Knee osteoarthritis (OA) is a disabling disease that carries a substantial burden to society and to the individual affected.
Detailed description
Restoring quadriceps muscle strength following anterior cruciate ligament reconstruction (ACLR) may help prevent the post-traumatic knee osteoarthritis that affects over 50% of knees 10-20 years after surgical reconstruction. However, a fundamental gap exists in current understanding of how to maximize muscle strength following ACLR, as current rehabilitation fails to restore symmetrical quadriceps strength. The investigators pilot work shows that when patients return to activity, quadriceps strength is \ 70% of the uninjured side, which is far below the recommended 90%. Further, these data suggest that embedding high-intensity neuromuscular electrical stimulation (NMES) and eccentric exercise into standard of care ACL rehabilitation leads to higher quadriceps strength when compared with standard of care alone. However, the true efficacy of these interventions is unknown, as controlled trials with adequate sample sizes are currently lacking. The absence of this information serves as the driving force and focus of the proposed trial. Therefore, the investigators propose a double-blind randomized controlled trial where ACLR patients will be randomized to 1 of 2 arms. Study arms will include: 1) 8 weeks of NMES+8 weeks of eccentric exercise; 2) 8 weeks of NMES placebo+8 weeks of eccentric placebo. All study arms will receive standard of care ACL rehabilitation in addition to the study interventions. The investigators hypothesize that subjects receiving NMES+eccentric exercise (Arm 1) will realize greater improvements in strength and biomechanical function at 6 months following ACLR than patients in the placebo study arm. Further, the investigators anticipate that patients in the NMES+eccentric exercise arm (Arm 1) will best eliminate negative changes in cartilage health at 18 months following ACLR. This study is innovative, because it employs interventions that directly target the primary mechanisms that result in strength loss following ACLR and will also evaluate whether improving muscle strength can minimize early changes in cartilage health, which may be indicative of future osteoarthritis. The proposed research is significant because it will identify evidence-based treatment approaches that can successfully counteract the muscle weakness which plagues ACLR patients for years after injury and contributes to the onset of post-traumatic osteoarthritis.
Interventions
DEVICENeuromuscular Electrical Stimulation (NMES)
The electrical stimulator will deliver a 2500 Hz alternating current, modulated at 75 bursts/s, with a ramp-up time of 2-seconds, followed by a 50-second rest period. Stimulus intensity set to generate a maximum voluntary isometric contraction (MVIC) of at least 40& of the contralateral MVIC.
OTHEREccentric Exercise (ECC)
4 sets of 10 repetitions of an eccentric leg press exercise performed at 70-90% of the 1 repetition maximum
DEVICENeuromuscular Electrical Stimulation (NMES) placebo
The electrical stimulator will deliver a 2500 Hz alternating current, modulated at 75 bursts/s, with a ramp-up time of 2-seconds, followed by a 50-second rest period. Stimulus intensity set to generate a maximum voluntary isometric contraction (MVIC) of 10-20% of the contralateral MVIC.
OTHEREccentric Exercise (ECC) placebo
4 sets of 10 repetitions of an eccentric leg press exercise performed at 10-20% of the 1 repetition maximum
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Connecticut
University of Delaware
University of North Carolina, Chapel Hill
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
14 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Acute, complete ACL rupture * ACL reconstruction with autograft * Scheduled to undergo ACLR at U of Michigan * Willingness to participate in testing and follow-up as outlined
Exclusion criteria
* Previous surgery to either knee * Bony fracture accompanying ACL injury * Patients who experienced a knee dislocation * Female participants who are pregnant or planning pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immediately Post NMES+ECC Intervention Isokinetic Quadriceps Strength Index | Post-NMES+ECC intervention (approximately 16 weeks post-ACL reconstruction) | Bilateral concentric isokinetic muscle strength at 60 degrees per second. Limb symmetry index is calculated as (ACL strength/Non-ACL strength)\*100 |
| 9 Months Isokinetic Quadriceps Strength Limb Symmetry Index | 9 months (9 months post-ACL reconstruction) | Bilateral concentric isokinetic muscle strength at 60 degrees per second. Limb symmetry index is calculated as (ACL strength/Non-ACL strength)\*100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Knee Flexion Moment at 9 Months | 9 months post-ACL reconstruction | Peak knee flexion moment recorded during a single-legged hop (units: Nm/kg\*m) |
| Knee Flexion Angle at 18 Months | 18 months post-ACL reconstruction | Peak knee flexion angle recorded during a single-legged hop (units: degrees) |
| Knee Flexion Moment at 18 Months | 18 months post-ACL reconstruction | Peak knee flexion moment recorded during a single-legged hop (units: Nm/kg\*m) |
| T2 Relaxation Time Symmetry Score for Femoral Knee Joint Cartilage | 18 months post-ACL reconstruction | \[T2 value from MRI at the central weight bearing region of femur for the ACL knee (msec)/T2 value from MRI at the central weight bearing region of femur for the NonACL knee (msec)\] x 100 |
| T1 Rho Relaxation Time Symmetry Score for Femoral Knee Joint Cartilage | 18 months post-ACL reconstruction | \[T1rho value at the weight bearing region of medial femur from MRI for ACL knee (msec)/T1rho value at the weight bearing region of medial femur for NonACL knee (msec)\] x 100 |
| Knee Flexion Angle at 9 Months | 9 months post-ACL reconstruction | Peak knee flexion angle of the ACL leg recorded during a single-legged hop (units: degrees) |
Countries
United States
Participant flow
Recruitment details
Participants were recruited beginning in January of 2019 through July of 2023 from Michigan Medicine.
Pre-assignment details
Participants were not randomized after enrollment for the following reasons: 1. Withdrew Consent 2. Screen fail 3. COVID drops (COVID pandemic prevented testing) 4. Lost to follow-up A baseline testing session occurred prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| NMES+ECC Neuromuscular electrical stimulation (NMES) and Eccentric Exercise (ECC). Patients randomized to the NMES+ECC group will first receive NMES for 2x/week for 8 weeks, beginning at the first post-operative visit. Beginning at 9 weeks after anterior cruciate ligament reconstruction (ACLR) patients will begin to receive eccentric exercise 2x/week for an additional 8 weeks. For NMES, patients will have electrical stimulation delivered to their quadriceps. Fifteen isometric actions lasting 10 seconds each will be elicited during each session. For eccentric exercise, patients will train for 4 sets of 10 repetitions. This group will also receive standard of care ACL rehabilitation alongside the study interventions. | 57 |
| NMES Placebo + ECC Placebo Neuromuscular electrical stimulation (NMES) low intensity/placebo + Eccentric Exercise (ECC) low intensity/placebo arm. Patients randomized to the NMES low intesntiy/placebo + ECC low intensity/placebo group will first receive NMES placebo/low-intensity treatment for 2x/week for 8 weeks, beginning at the first post-operative physical therapy visit. Beginning at 9 weeks after anterior cruciate ligament reconstruction (ACLR) patients will begin to receive an eccentric exercise low-intensity/placebo 2x/week for 8 weeks.
For the NMES low intensity/placebo, patients will have it delivered to their quadriceps 2x/week for 8 weeks beginning at the first post-operative visit. Fifteen isometric actions lasting 10 seconds each will be elicited during each session.
For the eccentric exercise low-intensity/placebo, patients will begin to receive eccentric exercise two times per week for 8 weeks. Patients will train for 4 sets of 10 repetitions. | 56 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 7 |
| Overall Study | Lost to Follow-up | 8 | 8 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | NMES+ECC | NMES Placebo + ECC Placebo | Total |
|---|---|---|---|
| Age, Continuous | 22.9 years STANDARD_DEVIATION 7.1 | 23.0 years STANDARD_DEVIATION 8.1 | 22.9 years STANDARD_DEVIATION 7.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 51 Participants | 105 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 8 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 10 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 40 Participants | 36 Participants | 76 Participants |
| Sex: Female, Male Female | 26 Participants | 26 Participants | 52 Participants |
| Sex: Female, Male Male | 31 Participants | 30 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 56 |
| other Total, other adverse events | 2 / 57 | 3 / 56 |
| serious Total, serious adverse events | 8 / 57 | 6 / 56 |
Outcome results
Primary
9 Months Isokinetic Quadriceps Strength Limb Symmetry Index
Bilateral concentric isokinetic muscle strength at 60 degrees per second. Limb symmetry index is calculated as (ACL strength/Non-ACL strength)\*100
Time frame: 9 months (9 months post-ACL reconstruction)
Population: Active High-Intensity NMES + ECC: 3 subjects withdrawn by investigator, 4 subjects lost to follow up, 1 subject withdrew consent Placebo Low-Intensity NMES + ECC: 4 subjects withdrawn by investigator, 6 subjects lost to follow up, 2 subject withdrew consent
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMES+ECC | 9 Months Isokinetic Quadriceps Strength Limb Symmetry Index | 76.8 Percentage | Standard Deviation 18 |
| NMES placebo + ECC placebo | 9 Months Isokinetic Quadriceps Strength Limb Symmetry Index | 74.5 Percentage | Standard Deviation 19.6 |
p-value: 0.025Mixed Models Analysis
Primary
Immediately Post NMES+ECC Intervention Isokinetic Quadriceps Strength Index
Bilateral concentric isokinetic muscle strength at 60 degrees per second. Limb symmetry index is calculated as (ACL strength/Non-ACL strength)\*100
Time frame: Post-NMES+ECC intervention (approximately 16 weeks post-ACL reconstruction)
Population: Active High-Intensity NMES + ECC: 2 subjects withdrawn by investigator, 0 subjects lost to follow up, 1 subject withdrew consent, 2 people missing strength data Placebo Low-Intensity NMES + ECC: 1 subjects withdrawn by investigator, 2 subjects lost to follow up, 2 subject withdrew consent, 1 person missing strength data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMES+ECC | Immediately Post NMES+ECC Intervention Isokinetic Quadriceps Strength Index | 60.9 Percentage | Standard Deviation 20.5 |
| NMES placebo + ECC placebo | Immediately Post NMES+ECC Intervention Isokinetic Quadriceps Strength Index | 58.4 Percentage | Standard Deviation 19.2 |
p-value: 0.025Mixed Models Analysis
Secondary
Knee Flexion Angle at 18 Months
Peak knee flexion angle recorded during a single-legged hop (units: degrees)
Time frame: 18 months post-ACL reconstruction
Population: Active High-Intensity NMES + ECC: 10 subjects withdrawn by investigator, 8 subjects lost to follow up, 2 subjects withdrew consent, 7 subjects could not complete a single leg hop so data is missing Placebo Low-Intensity NMES + ECC: 7 subjects withdrawn by investigator, 10 subjects lost to follow up, 2 subjects withdrew consent, 6 subjects could not complete a single leg hop so data is missing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMES+ECC | Knee Flexion Angle at 18 Months | 53.4 Degrees | Standard Deviation 14.7 |
| NMES placebo + ECC placebo | Knee Flexion Angle at 18 Months | 48.8 Degrees | Standard Deviation 11.4 |
Secondary
Knee Flexion Angle at 9 Months
Peak knee flexion angle of the ACL leg recorded during a single-legged hop (units: degrees)
Time frame: 9 months post-ACL reconstruction
Population: Active High-Intensity NMES + ECC : 3 subjects withdrawn by investigator, 4 subjects lost to follow up, 1 subject withdrew consent, 16 subjects could not complete a single leg hop so data is missing Placebo Low-Intensity NMES + ECC: 4 subjects withdrawn by investigator, 6 subjects lost to follow up, 2 subject withdrew consent, 10 subjects could not complete a single leg hop so data is missing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMES+ECC | Knee Flexion Angle at 9 Months | 50.9 Degrees | Standard Deviation 14.4 |
| NMES placebo + ECC placebo | Knee Flexion Angle at 9 Months | 44.4 Degrees | Standard Deviation 12.9 |
Secondary
Knee Flexion Moment at 18 Months
Peak knee flexion moment recorded during a single-legged hop (units: Nm/kg\*m)
Time frame: 18 months post-ACL reconstruction
Population: Active High-Intensity NMES + ECC: 10 subjects withdrawn by investigator, 8 subjects lost to follow up, 2 subject withdrew consent, 7 subjects could not complete a single leg hop so data is missing Placebo Low-Intensity NMES + ECC: 7 subjects withdrawn by investigator, 10 subjects lost to follow up, 2 subject withdrew consent, 6 subjects could not complete a single leg hop so data is missing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMES+ECC | Knee Flexion Moment at 18 Months | 1.5 Nm/kg*m | Standard Deviation 0.4 |
| NMES placebo + ECC placebo | Knee Flexion Moment at 18 Months | 1.5 Nm/kg*m | Standard Deviation 0.3 |
Secondary
Knee Flexion Moment at 9 Months
Peak knee flexion moment recorded during a single-legged hop (units: Nm/kg\*m)
Time frame: 9 months post-ACL reconstruction
Population: Active High-Intensity NMES + ECC: 3 subjects withdrawn by investigator, 4 subjects lost to follow up, 1 subject withdrew consent, 16 subjects could not complete a single leg hop so data is missing Placebo Low-Intensity NMES + ECC: 4 subjects withdrawn by investigator, 6 subjects lost to follow up, 2 subject withdrew consent, 10 subjects could not complete a single leg hop so data is missing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMES+ECC | Knee Flexion Moment at 9 Months | 1.4 Nm/kg*m | Standard Deviation 0.3 |
| NMES placebo + ECC placebo | Knee Flexion Moment at 9 Months | 1.3 Nm/kg*m | Standard Deviation 0.3 |
Secondary
T1 Rho Relaxation Time Symmetry Score for Femoral Knee Joint Cartilage
\[T1rho value at the weight bearing region of medial femur from MRI for ACL knee (msec)/T1rho value at the weight bearing region of medial femur for NonACL knee (msec)\] x 100
Time frame: 18 months post-ACL reconstruction
Population: Active High-Intensity NMES + ECC: 10 subjects withdrawn by investigator, 8 subjects lost to follow up, 2 subject withdrew consent, 1 person with MRI scan error so data is missing Placebo Low-Intensity NMES + ECC: 7 subjects withdrawn by investigator, 11 subjects lost to follow up, 2 subject withdrew consent
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMES+ECC | T1 Rho Relaxation Time Symmetry Score for Femoral Knee Joint Cartilage | 103.0 Percentage | Standard Deviation 15.9 |
| NMES placebo + ECC placebo | T1 Rho Relaxation Time Symmetry Score for Femoral Knee Joint Cartilage | 106.1 Percentage | Standard Deviation 21.9 |
Secondary
T2 Relaxation Time Symmetry Score for Femoral Knee Joint Cartilage
\[T2 value from MRI at the central weight bearing region of femur for the ACL knee (msec)/T2 value from MRI at the central weight bearing region of femur for the NonACL knee (msec)\] x 100
Time frame: 18 months post-ACL reconstruction
Population: NMES+ECC arm: 10 subjects withdrawn by investigator, 8 subjects lost to follow up, 2 subject withdrew consent, 1 person with MRI scan error so data is missing NMES placebo + ECC placebo arm: 7 subjects withdrawn by investigator, 11 subjects lost to follow up, 2 subject withdrew consent
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMES+ECC | T2 Relaxation Time Symmetry Score for Femoral Knee Joint Cartilage | 101.3 Percentage | Standard Deviation 8.7 |
| NMES placebo + ECC placebo | T2 Relaxation Time Symmetry Score for Femoral Knee Joint Cartilage | 104.4 Percentage | Standard Deviation 9.8 |