Clinical trial NCT05342441: Optimizing Graft Selection for ACL Reconstruction
Official title: Optimizing GRAft SElection for ACL Reconstruction (GRASE-ACL Trial) - a Three-armed Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: ACL - Anterior Cruciate Ligament Rupture
Keywords: ACL reconstruction
Graft choice
Quadriceps graft
Semitendinosus/gracilis graft
Muscle morphology
Neuromuscular control
BPTB graft
Patient reported function
Lead sponsor: Hvidovre University Hospital
Sponsor class: OTHER
Collaborators: name: University College Copenhagen
name: National Research Centre for the Working Environment, Denmark
First posted: 2022-04-22
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, assesor blinded randomized controlled study
Primary purpose: TREATMENT

Brief summary: Purpose:

To investigate the differences between the three most common methods for reconstruction of the anterior cruciate ligament (ACL), to support the development of the best method for the individual patient.

Main research area: ¨ Sports Orthopedic Surgical research.

State of the art:

Every year in Denmark 2500 patients receive surgical reconstruction surgery to replace a ruptured ACL. Many patients experience a decline in knee function and 4-12% suffer a new ACL rupture within 5 years. According to data from the Danish ACL register, three methods of reconstruction are most prevalent, but with large variation between hospitals. This indicates lack of consensus on optimal surgical procedure.

Design:

Assessor-blinded randomized controlled study. 150 patients aged 18-40 with ruptured ACL are allocated to reconstruction with tendon(s) harvested from either the semitendinosus and gracilis, or the patella tendon, or the quadriceps tendon. Patient follow-up will be conducted preoperatively and 1, 6, 12, 24 months postoperatively.

Primary technologies and outcomes:

* Patient-reported knee-joint function, quality of life and donor-site morbidity is obtained with standardized questionnaires. Primary outcome is subjective knee function with the International Knee Documentation Committee evaluation form (IKDC)
* Instrumented analysis of knee-joint coordination and neuromuscular control including 3-D motion capture and electromyography (EMG) during single leg jumps, landings and change-of-direction. Measurement of maximal explosive muscle power in knee extension and flexion. Primary outcome is relative difference between injured and healthy leg in rate of force development (RFD-LSI).
* Standard clinical knee examination of range of motion and instrumented examination of knee-joint stability.
* Magnetic Resonance Imaging (MRI) of the thigh muscles for examination of muscle morphology.

The trial is designed for publication in three primary publications

1. - Patient reported effect of graft choice in ACL reconstruction
2. - Biomechanical effect of graft choice in ACL reconstruction
3. - Clinical effect of graft choice in ACL reconstruction

Additional secondary publications are in the pipeline. Reference to primary protocol and results will always be emphasized in secondary publication to ensure methodological transparency.

Detailed description: Purpose:

The aim of this randomized controlled trial is to investigate the effect of graft choice in anterior cruciate ligament (ACL) reconstruction surgery, primarily from a patient-centered as well as a novel biomechanical perspective; and secondly from a clinical and muscle morphological perspective.

The study compares the three most common methods for ACL reconstruction: autograft harvested from the m. quadriceps tendon (QT), the hamstring tendons (ST/Gr), and the patella tendon (BPTB).

By applying this 360° scientific approach, it is the hope to improve the possibilities for a much-needed evidence-based and individualized treatment of ACL ruptures.

Objectives and hypotheses:

• Objective no. 1: The patient-centered perspective To investigate the effect of graft choice on patient-reported questionnaire scores, primarily on the International Knee Documentation Committee Evaluation Form (IKDC).

The investigators hypothesize that of all three grafts, the QT graft will result in non-inferior patient reported knee function.

* Objective no. 2: The biomechanical perspective To investigate the effect of graft choice on muscle strength and knee joint control. The investigators hypothesize that of all three grafts, the ST/Gr graft will show largest negative effect on explosive muscle strength.
* Objective no. 3: The clinical perspective To explore the effect of graft choice on knee stability and surgery complications.
* Objective no. 4: The muscle morphological perspective To explore the effect of graft choice on length and cross section area of the hamstring tendons.

State-of-the-art:

The most common method for ACL reconstruction in Denmark is the use of an autograft to replace the ruptured ACL. The autograft is harvested from either the m. quadriceps tendon (QT), the m. semitendinosus and m. gracilis tendons (hamstrings) (ST/Gr), or the patella tendon with bone plugs (BPTB).

The BPTB graft was initially used as standard method. It has the advantages of faster graft incorporation (bone to bone healing), reliable graft size and low risk of graft rupture and knee laxity. It is widely used around the world. In Denmark it accounts for app. 10% of all reconstructions. A number of disadvantages of the BPTB graft have been described in the literature: anterior knee pain, pain from the donor site, extension strength deficits, and decreased knee joint flexion range of motion.

Due to these potential morbidity problems of the BPTB graft, there was a shift towards the ST/Gr graft as the preferred choice. Today, the ST/Gr graft is harvested in more than 52% of all ACL reconstructions in Denmark. From a surgeon's perspective, the graft is easy to harvest, time efficient, and leaves smaller scars. The ST/Gr graft is however associated with increased laxity of the knee joint compared to the BPTB graft, and the size of the graft can be a challenge. Also, harvest of the ST/Gr graft is associated with sustained loss of strength, length, and volume of the harvested muscles. This is of concern, as biomechanical research has shown that semitendinosus is essential to stabilize the knee joint and protect the ACL during cutting movements. Finally, recent research indicates higher risk of revision surgery using the ST/Gr graft compared to the BPTB graft.

Currently, particularly in Scandinavia, surgeons are reintroducing a third graft, the QT graft. The advantages of the QT graft are large and predictable graft size and acceptable clinical outcomes. A recent study from the Sports Orthopedic Research Center - Copenhagen (SORC-C) at Hvidovre Hospital found no difference in revision rates between the ST/Gr graft and the QT graft in a cohort of more than 400 patients. The QT graft now accounts for app. 10% of all ACL reconstructions in Denmark, but the graft remains a relatively untested method.

Methods:

Study design and approvals:

This is an assessor-blinded randomized controlled trial with a three-group parallel design. Patients will be randomized to ACL reconstruction with either BPTB, ST/Gr, or QT graft with a 1:1:1 allocation. Follow-up will be performed 1, 6, 12, and 24 months after reconstruction.

The study will adhere to the CONSORT guidelines for reporting of Multi-Arm Parallel-Group Randomized Trials (http://www.consort-statement.org) and is pre-registered at http://www.clinicaltrials.gov.

The study is approved by the Scientific Ethics Committee for the Capital Region (Journal-no.: H-19001194) and by the Danish Data Protection Agency (Jr. no. VD-2018-524)

Randomization and blinding:

Patients will be randomly assigned to a treatment group using a 1:1:1 allocation ratio using a randomization schedule of permuted blocks of random sizes. The randomization will be stratified by biological sex and age. The final randomization will be made after arthroscopic assessment of the knee and evaluation according to the in- and exclusion criteria.

Outcome assessors are blinded to group allocation. Before each patient visit, tape will be placed on possible scars to hide donor graft site. Given the nature of the intervention, blinding of patients and surgeons is not feasible.

Treatment:

The procedure is initiated with knee arthroscopy. Ligament lesions, meniscus tear, and cartilage damage are inspected and treated if indicated, and ACL remnants are removed.

The BPTB graft is harvested through two 4-5 cm incisions, one on the tibial tuberosity and one on the patella. The middle 10 mm of the patella tendon plus 20-30 mm bone plugs at each end from corresponding tibia and patella is harvested.

The ST/Gr graft is harvested through a 4-5 cm incision at the pes anserinus. Both the semitendinosus and the gracilis tendon is identified and harvested. The tendons are prepared and folded to a four-stranded graft with a total diameter of 7-10 mm.

The QT graft is harvested through a 4-5 cm incision at the upper pole of the patella. A graft sized 10-12 mm in with and app. 6 mm in depth is harvested from the middle part of the tendon.

The femoral tunnel is placed anatomically central in the native footprint of the ACL. The tibia tunnel is also placed anatomically; the center of the tunnel being medially between the eminential spines at the level of the posterior margin of the anterior horn of the lateral meniscus. The BPTB graft is fixed both proximally and distally with a Milagro screw (DePuy Synthes) or similar . The ST/Gr and QT grafts are fixed proximally with the RIGIDFIX® Curve Cross Pin System (DePuy Synthes) and distally with a Milagro screw (DePuy Synthes) or similar.

The patients are referred to rehabilitation according to Danish rehabilitation guidelines following ACL reconstruction.

¨

Statistics:

Analysis will be performed with a linear mixed-effects model of the relationships between outcomes and treatment group (BPTB, ST/Gr, and QT graft) and time points (pre-operative, 1-month, 6-month, 12-month, and 24-month follow-up). Fixed effects are time and treatment group, and random effects are patient ID.

Sample size:

The study includes two primary outcomes, the IKDC score change between treatment groups from pre-operative to 12-months follow-up, and the LSI-RFD between treatment groups at 12-months follow-up. The two outcomes are of different hypotheses and independent.

Based on literature, the minimal clinically important difference in IKDC score is approximately 10 points, and the standard deviation on the change in IKDC score from baseline to after ACL reconstruction is approximately 13 points. Based on these assumptions, 37 patients are needed per group (α = 0.05, β = 0.80).

A local unpublished pilot study of 10 healthy individuals showed a minimal detectable difference in LSI-RFD of 12% and a standard deviation in the group of 17%. Based on these assumptions, 40 patients are needed per group (α = 0.05, β = 0.80).

A total inclusion number of 150 is decided to account for a patient dropout of app. 10%.

Eligibility criteria: List of Inclusion criteria

* clinically confirmed first-time ACL rupture
* Current injury sustai´ned within 2 years
* high activity level prior to ACL rupture (Tegner score ≥ 3) and personal goal of returning to physical activity.

List of preoperative exclusion criteria

* Inadequate Danish language skills to answer questionnaires.
* Prior ligament surgery in the injured knee
* Prior ligament surgery in the non-injured knee
* Instability of the non-injured knee
* Known osteoarthritis (Kelgren Lawrence score ≥ 2)
* Prior open surgery to either knee
* Prior severe fracture involving knee joint surfaces
* Prior severe injury to thigh muscles in either leg (e.g. tear or compartment)
* Prior severe injury to the patella tendon of either knee (e.g. subluxation)
* Medical condition preventing full participation (e.g. active cancer, - rheumatoid arthritis)
* Psychiatric condition preventing full participation
* Pregnancy
* Obesity (BMI \> 30)

List of Perioperative exclusion criteria (Arthroscopy)

* Medial meniscus lesion \> 50%
* Lateral meniscus lesion \> 50%
* Treated Meniscal root lesion or radial meniscal tear that require restrictive regimen
* Cartilage lesion \>2cm2, Articular cartilage injury classification (ICRS) grade 3
* Concurrent ligament injury (except medial collateral ligament (MCL) lesion grade 1-2)

Primary outcomes:
measure: International Knee Documentation Committee score (IKDC).
timeFrame: 12 months follow up.
measure: Rate of Torque Development - Limb Symmetry Index (RFD-LSI).
timeFrame: 12 months follow up
Secondary outcomes:
measure: International Knee Documentation Committee score (IKDC).
timeFrame: Baseline, 1, 6, and 24 months follow up.
measure: Donor site discomfort.
timeFrame: Baseline, 6, 12, and 24 months follow up.
measure: Return to sport questionnaire.
timeFrame: Baseline, 6, 12 and 24 months follow up.
measure: Workability questionnaire
timeFrame: Baseline, 1, 6, 12, and 24 months follow up.
measure: Patient Acceptable Symptom State questionnaire (PASS)
timeFrame: Baseline, 12, and 24 months.
measure: Rate of torque Development - Limb Symmetry Index (RFD-LSI).
timeFrame: Baseline, 1, 6, and 24 months follow up.
measure: Knee and hip angles.
timeFrame: Baseline, 6, and 12 months follow up.
measure: Knee and hip moments.
timeFrame: Baseline, 6, and 12 months follow up.
measure: Neuromuscular control.
timeFrame: Baseline, 6, and 12 months follow up.
measure: Knee laxity
timeFrame: Baseline, 6, and 12 months.
measure: Number of patients undergoing revision surgery due to graft failure.
timeFrame: Baseline, 12, and 24 months follow up.
measure: Number of patients experiencing re-rupture of the operated ACL.
timeFrame: Baseline, 12, and 24 months follow up.
measure: Muscle cross sectional area
timeFrame: At 12 months follow up.
measure: Hamstring muscles retraction
timeFrame: At 12 months follow up.
measure: Number of patients experiencing rupture of the contralateral ACL.
timeFrame: Baseline, 12, and 24 months follow up.
Other outcomes:
measure: Psychological consequences
timeFrame: 1, 6, 12, and 24 months follow up.
measure: Clinical knee range of motion
timeFrame: 6 and 12 months follow up.
measure: One-leg jump performance
timeFrame: 6 and 12 months follow up
measure: Postoperative progress
timeFrame: Every second week through first year following ACL reconstruction.
measure: Postoperative rehabilitation
timeFrame: Every second week through first year following ACL reconstruction
Locations:
city: Hvidovre
country: Denmark
facility: Copenhagen University Hospital - Amger/Hvidovre
Study officials:
affiliation: Hvidovre UH
name: Per Hölmich, D.M.Sc/D.Sc
role: STUDY_DIRECTOR
affiliation: University College Copenhagen
name: Mette K Zebis, MSc, PhD
role: STUDY_DIRECTOR
References: