Bregenhof et al.

Trials (2018) 19:75

DOI 10.1186/s13063-018-2448-3

STUDY PROTOCOL Open Access

The effect of targeted exercise on knee-

muscle function in patients with persistent
hamstring deficiency following ACL
reconstruction – study protocol for a
randomized controlled trial
Bo Bregenhof1,3* , Uffe Jørgensen1, Per Aagaard2, Nis Nissen3, Mark W. Creaby4, Jonas Bloch Thorlund2,
Carsten Jensen3, Trine Torfing5 and Anders Holsgaard-Larsen1

Abstract
Background: Anterior cruciate ligament (ACL) reconstruction, using hamstring auto-graft is a common surgical
procedure, which often leads to persistent hamstring muscle-strength deficiency and reduced function. The purpose of
this randomized controlled trial (RCT) is to investigate the effect of a combined, progressive, strength and neuromuscular
exercise intervention on knee muscle strength, functional capacity and hamstring muscle-tendon morphology in
ACL-reconstructed patients with persistent hamstring muscle-strength deficiency compared with controls.
Methods/design: The study is designed as a multicenter, parallel-group RCT with balanced randomization (1:1) and
blinded outcome assessments (level of evidence: II) and will be reported in accordance with the CONSORT Statement.
Fifty ACL-reconstructed patients (hamstring auto-graft) with persistent limb-to-limb knee-flexor muscle-strength
asymmetry at 12–24 months’ post surgery, will be recruited through outpatient clinics and advertisements. Patients will
be randomized to a 12-week progressive, strength and neuromuscular exercise group (SNG) with supervised training
twice weekly or a control intervention (CON) consisting of a home-based, low-intensity exercise program. Outcome
measures include between-group change in maximal isometric knee-flexor strength (primary outcome) and knee-extensor
muscle strength, hamstring-to-quadriceps strength ratios of the leg that has been operated on and Knee injury and
Osteoarthritis Outcome Score (KOOS) (secondary outcomes).
In addition, several explorative outcomes will be investigated: The International Knee Documentation Committee Subjective
Knee Form (IKDC), the Tegner Activity Score, rate of force development (RFD) for the knee flexors and extensors, tendon
regeneration and potential muscle hypertrophy at graft harvest site evaluated by magnetic resonance imaging (MRI),
postural control, kinetic/kinematic gait characteristics and knee-related functional capacity.
(Continued on next page)

* Correspondence: [email protected]
1
Orthopaedic Research Unit, Department of Orthopaedics and Traumatology,
Odense University Hospital, Institute of Clinical Research, University of
Southern Denmark, Sdr. Boulevard 29, 5000 Odense C, Denmark
3
Department of Orthopaedics, Lillebaelt Hospital, Kolding, Skovvangen 2-8,
6000 Kolding, Denmark
Full list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Bregenhof et al. Trials (2018) 19:75 Page 2 of 13

(Continued from previous page)

Discussion: This RCT is designed to investigate the effect of combined, progressive-resistance and neuromuscular exercises
on knee-flexor/extensor strength, in the late rehabilitation phase following ACL reconstruction. Reduced hamstring strength
represents a potential risk factor for secondary ACL rupture and accelerated progression of osteoarthritis. If deemed
effective, the intervention paradigm introduced in this study may help to improve current treatment strategies in ACL-
reconstructed patients.
Trial registration: ClinicalTrials.gov, ID: NCT02939677 (recruiting). Registered on 20 October 2016.
Keywords: ACL reconstruction, Rehabilitation, Muscle strength, Physical function, Exercise,

Background examined the regenerative capacity of the semitendinosus

Anterior cruciate ligament (ACL) reconstruction is a com- and gracilis tendons [20–22] demonstrating substantial
mon arthroscopic procedure, with approximately 300,000 tendon regeneration at 6 months after time of harvesting.
reconstructions performed annually in the United States However, regeneration is slow and may continue up to
[1]. ACL reconstruction aims to restore functional stability approximately 12–24 months after ACL reconstruction,
of the knee, and can be performed using a variety of differ- without guarantee of full muscle-tendon regeneration
ent surgical techniques and graft sites [2]. The hamstring [20, 22], and thus it may have impact on the effect of
tendon is one of the most commonly used graft donor sites muscle-strength interventions.
used for ACL reconstruction [1, 3]. Although current ACL The objective of this study is, therefore, to investigate the
reconstruction procedures intend to restore internal knee effect of targeted exercise on knee-muscle strength and
biomechanics, function of the ACL-reconstructed knee re- joint function in ACL-reconstructed patients with persist-
mains different from that of healthy knees [4, 5] and is ent hamstring muscle deficiency 12–24 months post sur-
associated with early development of osteoarthritis [6–8]. gery compared with controls. Furthermore, an explorative
Therefore, information about factors associated with part of the study will evaluate the extent of tissue regener-
increased risk of osteoarthritis, such as lower-limb muscle- ation at the graft harvest site by MRI, and kinematic and
strength deficits, should be part of the risk management kinetic analyses on functional gait performances.
with ACL reconstruction [6]. In a recent study, maximal As such, this study is expected to provide important
isometric hamstring-muscle strength was reported to be clinical evidence on late-phase rehabilitation in ACL-
22% lower in the ACL-reconstructed limb at 18 months reconstructed patients. If deemed effective, these study
post surgery, and reduced knee-joint function was also findings may help identify and refine optimal rehabilita-
observed compared with healthy controls [9]. Notably, tion paradigms for ACL-reconstructed patients and help
hamstring muscles are considered important protagonists to describe and/or develop optimal exercise-based ther-
to the ACL [10] and reduced knee-flexor strength repre- apy to improve donor-site tendon regeneration.
sents a potential risk factor for secondary ACL rupture
[11]. According to international standards and consensus, Methods/design
ACL postoperative rehabilitation is generally limited to the Study design
first 9–12 months post surgery. Furthermore, the effect of The study is designed as a prospective, superiority,
early (first 12 months post surgery) rehabilitation has pre- parallel-group randomized controlled trial (RCT) with
viously been studied [12, 13] .Thus, long-term rehabilita- balanced and blinded randomization (1:1) with blinded
tion protocols of ACL-reconstructed patients, especially outcome assessment (level of evidence: II). The study
when using semitendinosus auto-grafts, are strongly protocol adheres to the SPIRIT Statement (Standard
advised [14]. Due to well-documented positive effects, Protocol Items: Recommendations for Interventional
neuromuscular training has become an integral part of Trials) (see Additional file 1 for the SPIRIT Checklist
most early post-operative ACL reconstruction rehabilita- and Fig. 1 for the SPIRIT Figure) as well as to the CON-
tion programs [12, 15–17]. However, there is limited evi- SORT Statement (Consolidated Standards of Reporting
dence on studies performing muscle-strength interventions Trials) [23, 24].
during the late rehabilitation phase (12 months post sur-
gery) following ACL reconstruction [12, 14]. Participants, randomization and blinding
Tissue regeneration by means of magnetic resonance A sample of 50 elective, ACL-reconstructed patients are
imaging (MRI)-verified muscle volume and tendon-graft- planned to be recruited at 12–24 months’ post-operative
site regrowth is generally considered to be one of the piv- outpatient clinic follow-up from the Department of Or-
otal preconditions for postoperative recovery in terms of thopaedics and Traumatology, Odense University Hos-
improved knee-joint function [18, 19]. Several studies have pital, Denmark and the Department of Orthopaedics,
Bregenhof et al. Trials (2018) 19:75 Page 3 of 13

Fig. 1 SPIRIT Figure. Template of content for the schedule of enrollment, interventions and assessments

Lillebaelt Hospital, Kolding, Denmark, and from poster orally introduce the trial to eligible participants. Follow-
advertisement at local sports clubs, education facilities, ing this, interested patients will receive written informa-
etc. tion and an invitation to be screened using handheld
Eligible patients (inclusion and exclusion criteria are dynamometry for final evaluation of eligibility. Inclusion
listed in Table 1) will receive verbal and written informa- criteria will be confirmed from the patient’s written
tion about the conditions of the trial and sign a stan- medical history, obtained from the surgeon, as well as
dardized consent form. The primary investigator will during conversation with the patient. Handheld dyna-
mometry will be used to determine objective eligibility
Table 1 Inclusion and exclusion criteria for participants in the with respect to between-limb strength asymmetry.
study Height and weight will be measured to determine Body
Inclusion Exclusion Mass Index (BMI). If participants meet the inclusion
• ACL reconstruction using • Other known joint pathology criteria, they will be invited to participate in the study.
hamstring tendon auto-graft that will affect participation in Written informed consent will be given prior to, or at,
the intervention baseline testing and collected by the primary investigator or
• Age between 18 and 40 years • BMI > 35 the study coordinator/study nurse. Finally, participants will
• A pathologically defined • Decline to participate have the option of supplementary informed discussion with
between-limb asymmetry ratio • Not understanding written the primary investigator at any time point prior to baseline
(> 10% leg-to-leg difference) for Danish language
maximal isometric strength of • Other known medical conditions
testing. Patients declining to participate in the trial will
the knee flexors at 12–24 months’ that will affect participation in the receive standard healthcare instructions (specified below).
follow-up intervention After baseline measurements, participants will be ran-
ACL anterior cruciate ligament, BMI Body Mass Index domly allocated (permuted blocks of four to six persons)
Bregenhof et al. Trials (2018) 19:75 Page 4 of 13

to either the targeted exercise or the control group. The exercise program has been developed. Implementation in
randomization sequence will be computer generated using accordance with “best practice” has been undertaken.
Stata 13.0 (StataCorp, College Station, TX, USA) statistical The SNG intervention will be performed twice weekly
software with a 1:1 allocation ratio using sequentially for 12 weeks with each session lasting 60–70 min.
numbered opaque, sealed envelopes. The allocation Patients will be admitted continuously into class-based
sequence and preparation of the concealed envelopes will groups of both novice and experienced participants.
be completed by a central study coordinator (JL) not in- Group-based exercises will have a maximum of six par-
volved in the conduct of the trial. To prevent bias during ticipants, and will be performed at the hospital rehabili-
the allocation sequence, the name and date of birth of the tation facility (Kolding) as well as in a local commercial
participant will be written on the envelope immediately fitness centre (Odense). The physiotherapists involved in
after randomization by the research nurse. The primary the training are experienced in the rehabilitation of
investigator will be blinded to allocation and will not par- knee-related injuries, will participate in scientific semi-
ticipate in testing, randomization or in the training of nars on ACL-rehabilitation and exercise, and will be
study participants. The statistical analysis will be per- instructed and trained in the specific intervention proto-
formed on allocation codes only and thus the data analysts col by the principal investigator prior to the initiation of
will be blinded in relation to intervention allocation. participant recruitment.
Blinding to treatment allocation of patients, physio- After 2 weeks of familiarization with emphasis on correct
therapists and nurses (healthcare providers) will not be technique, the strengthening part of the intervention will
possible due to the nature of the interventions. However, commence consisting of eight exercises (Additional file 2)
blinded, independent data collectors will be responsible for the lower extremities performed in three sets of 10 rep-
for baseline and follow-up assessments, and responses etitions with an intensity of 12 repetitions maximum with
entered in databases identified by identification numbers the time for rest (between sets). To apply with the princi-
only. The principal investigator and data analyst (BB) ples of explosive-type resistance training (RFD-training)
will be blinded to treatment allocation as data will be the participants will be instructed to complete the concen-
analyzed using coded identification numbers. The coding tric phase of the movement “as fast as possible,” then pause
and re-coding of the identification numbers will be briefly, and complete the eccentric phase of the movement
performed by the central study coordinator. in approximately 2–3 s. Measurements of the velocity
To maintain the overall quality and legitimacy of this during the concentric phase are not applicable; however,
clinical trial, un-blinding in terms of allocation, will only the quality of the explosive component of the exercise is
occur in exceptional circumstances (e.g., harm) when supervised by an experienced physiotherapist throughout
knowledge of the actual treatment is essential for further the entire intervention period. The participants are encour-
management of the participant. Investigators will before aged to perform the maximum number of repetitions
un-blinding, discuss with the members of the projects possible within each set. If the number of repetitions is
advisory group whether un-blinding is necessary and, to below 8 or exceeds 12, the loading will be adjusted for the
which extent, the un-blinding unfolds. The primary next set. The physiotherapists will supervise the individual
investigator will maintain the blind as far as possible. progression for each participant.
Allocation will not be disclosed to other study personnel The neuromuscular aspects of the training program will
including other site personnel, monitors, corporate focus on proprioception and postural function with the key
sponsors or project office staff. The investigator will elements being balance and functional stability [29]. To
report all code breaks (with reason) as they occur. allow for progression of the neuromuscular exercises, two
or three levels of difficulty are given (Additional file 2).
Combined strength and neuromuscular exercise Progress is made when a given exercise is performed with
intervention (SNG) good sensorimotor control and a high quality of perform-
Participants allocated to combined muscle strengthening ance (based upon visual inspection by the physiotherapist).
and neuromuscular exercise (SNG) will be engaged in an Number of sets, reps and weight will be recorded to deter-
exercise regimen based on progressive strength training, mine whether the patient is ready to progress after each
including elements of neuromuscular exercise. The train- session. Acceptable compliance is defined as participation
ing program is based on exercises described in the current in 75% or more of all training sessions (i.e., 18 sessions).
academic literature which have been applied to ACL-
reconstructed patients [16, 25–28] (Additional file 2). Control group (CON)
Furthermore, advice on exercises from professional ex- Controls (CON) will receive instructions (a pamphlet)
perts in physiotherapy, ACL-reconstruction rehabilitation regarding a training regimen of home-based, weight-
and knee-joint biomechanics, have been implemented. No bearing, low-intensity exercises (Additional file 3). CON
isolated development or feasibility work of the present participants will be instructed and advised to perform
Bregenhof et al. Trials (2018) 19:75 Page 5 of 13

the home-based exercises twice weekly. Specific exercise increase over time. “Pain as usual” is defined as the pain
instructions using body weight (gravity) and resistance level prior to exercise. If this does not occur, the level of
bands, will be provided by the physiotherapists upon exercise progression will be reduced [25].
randomization (Additional file 3). The home-based Participants in the CON group will have access
training regimen of the control group (CON) is based (phone) to the involved staff for advice throughout the
upon the fact that persistent asymmetry of hamstring duration of the trial.
muscle strength has been evaluated by hand-held dyna- All loads (kg) lifted during all exercises will be re-
mometry, before enrollment. There is currently, no corded in an exercise diary, comprising the date of each
established national guideline, concerning late rehabilita- session (to determine the number of sessions), exercises
tion programs, to ACL patients with muscle asymmetry performed (including loads lifted, number of repetitions
and/or knee-instability symptoms. However, since the and sets), perceived exertion (Borg RPE CR-10) [30].
referring surgeon has observed pathological asymmetry of Furthermore, SNG participants will be instructed to note
the knee-extensors at inclusion and for ethical reasons, the individual resistance and level of difficulty for the
patients in the current trial are offered a low-resistance neuromuscular exercises (to determine progression).
exercise regimen to mimic realistic clinical guidelines for During the study, no concomitant care or interventions
the current patient group (Additional file 3). are prohibited.

Pain monitoring during exercise intervention Timing of assessments

The intervention procedures may provoke musculoskel- Assessments will be performed at baseline (prior to
etal pain and participants will, therefore, be asked to rate randomization), following the intervention (12 weeks
perceived pain intensity in their training diary before post baseline) (the primary endpoint) and 6 months post
and after training and test sessions using a Visual intervention (Fig. 2; Table 2: Outcome measurements).
Analogue Scale (VAS, 0 mm = no pain, 100 mm = worst Subjects will be evaluated in terms of full range of
possible pain). Pain (muscle or joint) up to a level of motion, and knee laxity, though proprioceptive status is
50 mm will be considered “acceptable” in the period not evaluated before inclusion. Although testing for
immediately after each training session. The day after quadriceps-muscle-strength deficit is part of the study,
training, pain should subside to “pain as usual” and not eligible participants having only quadriceps muscle-

Table 2 Outcome measurements

Data collection instrument Collection time point
Baseline Post (12 weeks) Post (6 months)
Primary endpoint
Primary outcome
Maximal isometric knee flexor strength Maximal isometric dynamometry x x x
(of the ACL-reconstructed leg)
Secondary outcomes
KOOS – 5 subscales PROM x x x
Maximal isometric knee-extensor strength Maximal isometric dynamometry x x x
Hamstring-to-quadriceps ratio Maximal isometric dynamometry x x x
Explorative outcomes
Counter movement jump 3-dimensional motion analysis x x
Gait analysis 3-dimensional motion analysis x x
One-legged jump for distance Simple functional test x x
Postural sway Simple functional test x x
Rate of force development Maximal isometric dynamometry x x x
Quadriceps and hamstring morphologies MRI x x
Volume
Peak cross-sectional area
Length
IKDC PROM x x x
Patient characteristics (age, BMI, time since operation, Tegner Activity Level Scale score) will be obtained at baseline
KOOS Knee injury and Osteoarthritis Outcome Score, IKDC International Knee Documentation Committee Subjective Knee Form, MRI magnetic resonance imaging,
PROM Patient-reported Outcome Measure
Bregenhof et al. Trials (2018) 19:75 Page 6 of 13

Fig. 2 Study flowchart. Participant flow through intervention period

strength deficits will not be included. After the interven- general, excellent test-retest reliability in lower-limb
tion period, all participants will be encouraged to muscle strength has been reported in both healthy
continue the exercise program unsupervised at home or people and patients [32, 33].
in their local fitness center.
Secondary outcome measures
Patient characteristics Between-group changes in maximal unilateral isometric
At baseline (prior to randomization), height and weight extensor strength (quadriceps) and hamstring-to-
will be measured, and age will be recorded. Time since quadriceps-muscle-strength ratio will be obtained using
surgery will be obtained from the Danish National ACL the same type of stabilized dynamometry as used for the
Reconstruction Registry and the Tegner Activity Level primary outcome variable [9, 32, 34, 35]. Furthermore,
Scale will be completed. the Knee injury and Osteoarthritis Outcome Score
(KOOS) questionnaire will be administered to all trial
Primary outcome measure participants to assess their perception of daily knee func-
The primary outcome is the between-group change in tion and related symptoms [36, 37]. KOOS is a 42-item,
maximal unilateral isometric knee-flexor strength (ham- self-administered, self-explanatory questionnaire that
string) recorded in the leg that has been operated on covers five patient-relevant categories: Pain, Other
using stabilized dynamometry at a 90° angle (0° = full Disease-Specific Symptoms, Activity of Daily Living
anatomical extension), according to methods described Function, Sport and Recreation Function and Knee-
by Jensen et al. [31] and Holsgaard-Larsen et al. [9]. In related quality of life. It has been developed and
Bregenhof et al. Trials (2018) 19:75 Page 7 of 13

validated for several cohorts of young and/or active subsequently analyzed [47]. The test will be performed
patients with knee injury and/or knee osteoarthritis for both legs, with eyes open and closed.
[36–39]. The one-legged hop for distance mimics ambulant
sporting activities and demands explosive muscle function,
Explorative outcome measures postural balance ability, and functional stability of the
The International Knee Documentation Committee Sub- knee. This test has previously been used as a sensitive and
jective Knee Form (IKDC) will be used. The IKDC is a responsive measure in ACL research [9, 48, 49] and previ-
site-specific instrument that has been designed to assess ous studies have reported high test-retest reliability in tri-
symptoms, function, and sports activity levels in patients als with patients suffering from ACL deficiency [9, 50–52].
who have one or more of a variety of knee conditions in- The participant stands on the leg to be tested, then
cluding ligamentous, meniscal, articular cartilage, arth- takes off to cover a maximal horizontal distance, and
ritic and patello-femoral pathologies [38, 40]. lands on the same limb with hands placed behind the
The Tegner Activity Score will also be employed, as it back. The participant is carefully instructed to perform a
aims to provide a standardized method of grading work maximal horizontal hop with a controlled and balanced
ability of the lower limb, performance of activities of landing and to keep the landing foot in place for 2 to
daily living and magnitude of competitive sport partici- 3 s, until the landing position has been recorded by the
pation, in patients with orthopedic knee injuries and tester. Failure to maintain one-legged standing balance
knee osteoarthritis. The scale score ranges from 0 (knee- for 3 s results in a disqualified hop. The distance hopped
related sick leave or disability) to 10 (engaged in com- is measured in centimeters (±0.5 cm) from the toe at
petitive sports). The Tegner Activity-level Scale has push-off to the heel where the participant lands. Partici-
shown acceptable test-retest reliability in knee patients pants will perform one practice trial and at least three
[41], and been shown to be valid and reliable for asses- test trials or until no further improvement is observed.
sing activity level in individuals with ACL injury [38, 41]. The best trial will be used, and a symmetry index will be
Rapid muscle force capacity (rate of force develop- calculated (reconstructed side/non-affected side).
ment: RFD200), representing the rate of force change Tendon regeneration (semitendinosus tendon) and
during the very early phase of muscle contraction changes in macroscopic hamstring and quadriceps
(0–200 millisecond (ms) relative to force onset), will muscle morphology (hypertrophy) will be assessed by
be determined for the knee flexors and extensors MRI. Evaluation will be performed for all participants
[32, 42, 43]. from both groups prior to, and after, the 12-week inter-
Three-dimensional kinematic/kinetic analysis of hori- vention period.
zontal gait at self-selected velocity and standardized MRI scans will range from the iliac crest orthogonal
one- and two-legged (dual-force-plate methodology) axial plane to the transition between the proximal tibial
counter-movement jumping (CMJ) will be performed metaphysis and diaphysis, while participants lie supine
using an eight-camera motion capture system (100 Hz; in the scanner (Philips Inginia 1.5 T system with soft-
Vicon Motion Systems, Oxford, UK), in synchrony with ware release R5.1.17). MRI sequence details will be the
two force plates (1000 Hz; AMTI, 0R6-7 Series Inc., following: Coil = Integrated posterior/anterior coil; se-
Watertown, MA, US) embedded in the floor. Bilateral quence, transverse T1-weighted mDIXON TSE, TR
CMJ will be performed with each leg positioned on a (repetition time) 550 ms; TE (echo time) 20 ms; 1 NSA
separate force plate, while unilateral CMJ analysis on a (number of signals averaged); FOV (field of view) 340 ×
single force plate will be undertaken in accordance with 467 mm., ST (slice thickness) 10 mm; gap 3 mm; num-
the procedures described previously [44]. Using the ber of slices 60. Post-processed images will be In Phase
standard plug-in-gait marker model and inverse dynam- (IP) and Water Only (W). Both the radiologist and
ics analysis [44, 45], angle and moments of the lower- primary investigator will, prior to analysis, measure a
limb joints and be calculated [9, 46]. subgroup of MRIs to achieve data on inter-observer reli-
Postural control is evaluated by assessment of the ability. All evaluations will be blinded to the participant’s
movement of the center of pressure (CoP) of the vertical randomization. In case of disagreement on the radio-
ground reaction force within the base of support of the graphic findings, a consensus opinion will be obtained.
feet to maintain postural equilibrium during the static All MRI evaluations will be performed in collaboration
stance. Deficits in postural sway have been reported after with the Section of Musculoskeletal MRI, at the Depart-
ACL injury and reconstruction [29]. Patients will be ment of Radiology, Odense University Hospital. Ham-
instructed to stand one-legged, on the test limb with the string and quadriceps volume, selected single-site, axial,
contralateral limb flexed and both arms on the hips and cross-sectional area (CSA) values, and hamstring length
maintain a stable posture on the platform during which will be evaluated by MRI analysis as described by Eriks-
the range of CoP excursion (30 s) is recorded and son et al. [20] and Tadokoro et al. [21]. The
Bregenhof et al. Trials (2018) 19:75 Page 8 of 13

morphological characteristics (volume, peak CSA and email, about consecutive clinical visits. All withdrawals
length) of the quadriceps and hamstring muscles will be concerning study participation, will be reported in future
evaluated for both limbs using manual segmentation by publications, including incomplete outcome datasets,
tracing the margin of the respective muscle and tendon due to incomplete follow-up, participant discontinue or
in successive axial slices. Furthermore, length of tendon deviation from intervention.
and muscle will be determined by transversal slice. Mea- No provision of care beyond that immediately required
surements will be made of the hamstring muscles, in- for the proper and safe conduct of the trial, and the
cluding semitendinosus, gracilis, semimembranosus and treatment of immediate adverse events related to trial
the long head of the biceps femoris. Quadriceps muscles procedures is provided. Participants’ healthcare needs
will include rectus femoris, vastus intermedius, lateralis that arise as a direct consequence of trial participation
and medialis. Cross-sectional area will be determined by (e.g., intervention-related harms), will be covered and
locating the 10-mm slice with the greatest CSA and treated accordingly, by the Danish public healthcare sys-
averaging this along with five additional slices immedi- tem. No plans are made to provide or pay for ancillary
ately cranial and caudal (in total, 11 slices). Tendon care during the trial.
regeneration will be defined as having occurred if the All tests described in the protocol have been performed
tendon is visible below the musculotendinous junction. previously in a similar patient group without causing any
The semitendinosus and gracilis tendons will be identi- issues and/or undesired side-effects [9]. As described
fied, and evaluated in terms of volume, peak CSA and above, study participants will report pain on a VAS, before
length, from the distance between the joint line and the and after each training session. Pain up to 2 on the scale is
distal muscle-tendon junction. Tendon regeneration will considered “safe,” up to 5 is considered “acceptable,” while
be evaluated as being full, partial or non-regenerated, in pain scores above 5 are considered “high risk.” Post-
comparison with the ipsilateral leg [19, 22]. training/-testing pain is accepted as long it does not last
for more than 24 h after the previous training/test session
Adverse events and participants judge the pain to be acceptable.
Adverse events will be monitored with a non-leading The study will adhere to Recommendations for the
questionnaire during the entire phase of intervention, as Conduct, Reporting, Editing and Publication of Scholarly
a part of participant’s training diary. All events will be Work in Medical Journals (the Vancouver Convention)
coded in accordance with the Medical Dictionary for [53]. The authors of the current protocol article will also
Regulatory Activities, as currently required by all regula- be co-authors on publications derived from this study
tory authorities, including the US Food and Drug relative to their specific contributions. Irrespective of
Administration and the European Agency for the Evalu- positive or negative results, the data will be published in
ation of Medicinal Products. All participants will have international peer-reviewed journals and presented as
the opportunity to contact the primary investigator (BB) lectures at scientific conferences, nationally and inter-
and the engaged physiotherapist(s) at any time during nationally, in accordance with CONSORT guidelines for
the trial. Adverse events or harm to participants during the reporting of clinical trials [23, 24]. The need for a
the intervention will be reported to the primary investi- Data Monitoring Committee (DMC) was deselected due
gator (BB) daily. There are no stopping criteria based on to known minimal risks of the planned intervention pro-
the collected data. We intend to report/publish, inde- cedures. Consecutive modifications to trials will be eval-
pendently of the direction of the results. uated and performed by the Trial Steering Committee
(TSC). Protocol modifications will be reported to, and
Ethical considerations approved by, the Steering Committee while also reported
All participants will be informed about the nature, scope to the Regional Ethical Committee. All modifications
and risks of the study, and will be asked to give their writ- will be communicated to all study members by the pri-
ten consent to participate. The trial has been registered mary investigator (BB) and all modifications to the test
with The Regional Committees on Health Research Ethics and exercise protocols will be reported at ClinicalTrials.-
for Southern Denmark with registration ID S-20160034. gov. No plans are made for ancillary studies involving
The study will be performed in accordance with the the collection or derivation of data for purposes that are
ethical standards in the 1964 Declaration of Helsinki. separate from the main trial or for ancillary studies.
Participants may withdraw from the study for any rea-
son at any time. The primary investigator may also with- Sample size calculation and statistical procedures
draw participants from the study to protect their safety Sample size estimation was performed using maximal
and/or if they are unwilling or unable to comply with unilateral isometric knee-flexor strength of the operated
required study procedures. Throughout the intervention leg (primary outcome) from a previously published pilot
and follow-up period, participants are reminded, by study on the present test protocol and reliability data
Bregenhof et al. Trials (2018) 19:75 Page 9 of 13

from our laboratory [5]. The statistical model contains will be considered the preferred treatment of choice; (2)
one baseline and one follow-up assessment. If gains in knee-flexor strength are superior in CON
Between-group difference in change score of 0.31 Nm compared with SNG, home-based exercises will be con-
bw-1 in knee-flexor strength in the ACL-reconstructed limb sidered the preferred treatment of choice; and (3) if
resulting in a less than 2.5% deficit of the healthy leg prior knee-flexor strength improvement does not differ
to intervention is considered of clinical relevance [5]. To between the two treatment groups, the intervention
achieve a statistical power of 80% (β = 0.80), using a SD of associated with the greatest functional improvement and
0.37 Nm bw-1 pre and post intervention, and allowing the pain relief, and the least adverse events, will be favored.
detection of statistically significant differences at an α =
0.05 level (two-tailed testing), a sample size of n = 23 was Discussion
calculated for each group; the estimated recruitment of 50 This randomized clinical trial will evaluate the effect of a
participants (in total) allows for possible dropouts. targeted resistance-exercise intervention on neuromus-
All study data will be obtained electronically on site by cular knee-joint function and muscle-tendon morph-
the research physiotherapist in the laboratory where the ology in ACL-reconstructed patients with persistent
data will originate. Original study forms will be col- hamstring-muscle-strength deficiency. As a prospective
lected, stored and entered on file at the participating site RCT, the results of this study are expected to provide
by the research nurse. Participant files are stored in high-level evidence of the potential clinical and func-
numerical order in a secure and accessible place. Partici- tional benefits of performing an exercise-based interven-
pant files will be maintained in storage for a period of tion in the late rehabilitation phase following ACL
5 years after completion of the study. The research nurse reconstruction, using hamstring auto-grafts. So far, no
will, weekly, send email reports with information on RCTs have evaluated the effect of combined,
missing data, missing forms and missing visits. A progressive-resistance training and neuromuscular exer-
complete back up of the primary database will be per- cise in the late rehabilitation phase in patients demon-
formed twice a month, to an external back-up hard drive strating persistent hamstring deficiency following ACL
and subsequently to a secure Share-Point location reconstruction. If deemed effective, the intervention
administrated by the university hospital. paradigm introduced in this study may help improve
All outcome measures will be checked for Gaussian current treatment strategies for patients undergoing
distribution by use of QQ-plots and parametric statis- ACL reconstruction.
tical and/or non-parametric analyses will be used when
deemed appropriate. All statistical tests will use an α- Outcome variables
level of 0.05 and data will be presented as means and Comprising the primary outcome variable, maximal
95% confidence interval unless otherwise stated. hamstring-muscle strength, immediately following inter-
Between-group mean differences in outcome measures vention (12 weeks) is chosen to examine if persistent
and 95% confidence intervals will be evaluated using a hamstring-strength deficiency can be reduced by targeted
general mixed linear model in which the participant’s exercise-based intervention. Furthermore, patient-reported
baseline score is entered as a covariate [54]. All analyses perceived knee-joint function is evaluated at 6-month
will follow the “intention-to-treat principle” [55]. follow-up to evaluate the long-term effect of the interven-
Furthermore, subsequent “per-protocol” analysis for tion on knee function and knee-related quality of life.
patients demonstrating the a-priori-defined acceptable Patient-reported outcome variables are obtained
compliance to exercise will be performed. The “last-ob- (secondary/explorative outcomes) to investigate potential
servation-carried-forward” method will be used for data effects on self-perceived function in daily living, knee
imputation in cases of missing outcome measures. All pain, symptoms, sports and recreation and knee-related
statistical analyses will be blinded to the analyst (BB) quality of life. A recent cross-sectional study from our
and will be performed using Stata 13 software (Stata- laboratory demonstrated strong associations between
Corp, College Station, TX, USA). No plans for additional patient-reported outcomes and the objective outcomes
analyses is made. listed in the current trial [9]. Such potential associations,
if also detected in the current prospective RCT, may
Data interpretation provide further understanding of the underlying impair-
To minimize bias, we have a-priori decided how to ments in neuro-mechanical muscle function associated
interpret different result scenarios: (1) If knee-flexor with ACL surgery.
strength improvement is superior (statistically significant In accordance with the International Classification of
and clinically relevant (≥0.31 Nm bw-1 in knee-flexor Function, Disability and Health [56] the current test
strength)) in SNG compared with CON, the combined battery is composed of different test types that cover dif-
intervention of strength and neuromuscular exercises ferent domains. Maximal isometric muscle strength is
Bregenhof et al. Trials (2018) 19:75 Page 10 of 13

related to body structure and function whereas the ACL reconstruction, will not be excluded even though
remaining test types (one-legged jump for distance, kine- their functional limitations may be slightly different from
matic/kinetic outcomes of gait and counter movement the remaining sample.
jumping) mainly serve to evaluate neuromuscular Since the trial is based upon patients volunteering for
impairments, which are primarily related to activity. a physical intervention, the study may potentially be
Impairments in body structure and function (i.e., Max- affected by selection bias. However, it will be possible to
imum Voluntary Contraction (MVC)) are linked to limi- compare the KOOS scores of the current sample with all
tations in activity [56], which have been proposed to patients registered in the Danish National ACL Recon-
affect health-related quality of life [57]. Thus, interven- struction Registry and consequently assess potential
tion paradigms aimed at improving maximal knee- discrepancies.
extensor and flexor strength (MVC) might be expected Acceptable compliance with exercise will be defined as
to improve activity outcomes and thereby positively participation in 75% or more of all training sessions con-
affect quality of life. In support of this notion, we have ducted (i.e., 18 sessions). The current study will be based
previously demonstrated that hamstring and quadriceps upon the “intention-to-treat” analysis including all pa-
MVC are central outcome variables to explain the inter- tients allocated for training irrespective of the number of
individual variation in KOOS profile (subjectively per- training sessions. A “per-protocol” analysis will also be
ceived knee-joint function) in ACL-reconstructed performed to explore whether compliance to training
patients [9]. Thus, it may be reasonable to assume that will have any effect on the observed results.
the expected improvements in hamstring and/or
quadriceps-muscle strength elicited by the intervention
Limitations
regimen will result in improvements in the remaining
Analysis of cost-effectiveness is not planned for this inter-
three test types evaluating activity and patient-reported
vention. Furthermore, despite the interesting perspective
outcomes. The present choice of relevant test parame-
of qualitative analysis concerning patient experience that
ters is based on previous study reports [9, 31, 48–51,
could have been added to the protocol, no priority on this
58–64] and is commonly used in the local department of
perspective has been obtained and is thus omitted.
orthopedics and orthopedic/biomechanical science.
Due to the non-invasive/non-pharmacological interven-
tion, no auditing is planned during the trial. Due to a rela-
Study design
tively low sample-size of the present mechanistic trial no
To ensure a high internal validity and to avoid subgroup
analysis of cost-effectiveness is planned for this study.
analysis due to potential differences in rehabilitation
protocol(s), all participants allocated to CON interven-
tion will be advised to perform home-based exercises of Summary
low intensity (for details, see Additional file 3). Conse- This study will use a randomized controlled design to
quently, this may affect the generalizability, especially in investigate the effect of a targeted exercise intervention
the conventional clinical settings where late-phase compared with controls, on knee-joint function in
(12 months post surgery) rehabilitation generally is not patients with persistent hamstring-muscle-strength defi-
offered to patients, besides brief recommendations ciency 1 year after ACL reconstruction surgery using
regarding engaging in training and/or referencing to hamstring tendon auto-graft. The trial results should
web-based rehabilitation programs. help to determine whether targeted exercise interven-
To improve external validity and generalizability, only tions can increase hamstring strength, and thereby be
a few exclusion criteria will be employed. An exclusion employed in the late rehabilitation phase for ACL-
criterion of BMI above 35 will be used since obesity reconstructed patients demonstrating persistent ham-
causes soft skin tissue artifacts that will affect the valid- string muscle-strength deficiency. If deemed effective,
ity of 3-dimensional motion analysis. Mechanical stabil- the intervention paradigm introduced in this study may
ity in the reconstructed knee, will be evaluated by the help to improve current treatment strategies and their
surgeon at the standard 1-year outpatient clinic follow- timing for patients undergoing hamstring auto-graft
up. In case of an insufficiently healed graft, poor mech- ACL reconstruction. Furthermore, the explorative part
anical knee-joint stability or reduced range of motion, of the trial will provide understanding of the underlying
the surgeon will evaluate the need for re-surgery. In impairment in mechanical muscle function associated
such cases participants will be excluded due to the with ACL reconstruction. The results will be submitted
potential occurrence of other known joint pathologies to a peer-reviewed international journal for publication
that may affect adherence to the intervention protocol. irrespectively of the outcome obtained, in accordance
Patients who demonstrate associated meniscal and/or with the CONSORT guidelines for the reporting of
cartilage procedures, which are commonly related to clinical trials.
Bregenhof et al. Trials (2018) 19:75 Page 11 of 13

Additional files Lead investigators (Kolding hospital)

Orthopedic surgeon, NN, is responsible for identification and recruitment at
Kolding Hospital facility. Furthermore, a part of the Steering Committee.
Additional file 1: SPIRIT Checklist. SPIRIT 2013 Checklist: recommended
items to address in a clinical trial protocol and related documents.
(DOC 123 kb) Authors’ contributions
AHL conceived the project. BB is leading the coordination of the trial. AHL
Additional file 2: Exercise protocol. Exercise protocol for supervised
wrote the protocol manual, whereas NN, UJ, MWC, JBT and CJ assisted with
intervention group. (PDF 1193 kb)
the study design and protocol preparation. BB and AHL procured the project
Additional file 3: Exercise protocol. Exercise protocol for home-based funding. AHL and PA designed the biomechanical and physical impairment
intervention group. (PDF 286 kb) measures. BB, AHL, CJ and PA designed the neuromuscular and strength
exercise program in collaboration with the physiotherapists, involved with
the training in this project. TT, BB and AHL designed the MRI protocol in
Acknowledgements correspondence with the Radiology Department at Odense University Hospital.
Not applicable
AHL and BB performed the sample size calculation and designed the statistical
analysis plan. BB will be the blinded analysts on the project, while BB and NN
Funding will recruit and screen the participants and manage the project. BB and AHL
This project was funded by: The Region of Southern Denmark PhD fund; The wrote the first draft of this manuscript. All authors provided feedback on drafts
Region of Southern Denmark research fund; The Danish Rheumatism of this article and read and approved the final manuscript.
Association; University of Southern Denmark health faculty scholarship;
Odense University Hospital research grant; Orthopedics Department of
Ethics approval and consent to participate
Kolding Hospital. None of the funding bodies play any role in the study
Ethics Committee of the Region of Southern Denmark (ID: S-20160034).
other than to provide funding.
All participants have been given written and oral information before entering
enrollment. Written consent to participation and publication, have been, and
Availability of data and materials will be, obtained from all participants, in this study (enrollment is currently still
The datasets used and/or analyzed during the current study will be available from in progress). The consent form is held by the corresponding authors’ institution
the corresponding author upon relevant request. Project datasets will be housed and is available for review by the Editor-in-Chief upon request.
on the project’s Share-point website, and all datasets will be password protected
and available to the trial manager. The principal investigator will be given access
to the cleaned datasets on request. To ensure confidentiality, data dispersed to Consent for publication
project team members will be blinded of any identifying participant information. The corresponding authors confirm that informed written and oral consent
Substantive contributions to the design, conduct, interpretation and has been received for publication of the manuscript, additional files and
reporting of this clinical trial are recognised through the granting of supplementary figures. Written informed consent has been obtained from
authorship on the final protocol article. No additional writers have been the participants and authors, for publication of their individual details in this
hired to improve clarity and structure in the protocol article. manuscript, although no individual participant details will be published in
Access to the full protocol is granted through the departments public this study protocol article. The consent form is held by the corresponding
website. Participant-level dataset and statistical coding will be available on authors’ institution and is available for review by the Editor-in-Chief upon
reasonable demand. request. The study results will be released to the participating physicians,
referring physicians, participants and the general medical community,
Furthermore, all participants will be invited to participate in a presentation,
Trial status
reviewing the process and results produced throughout the study period.
Protocol version 5, 21 July 2017
Date of witch recruitment was initiated: 4 January 2017
Approximate date when recruitment will be completed: 1 January 2019 Competing interests
All the authors declare that they have no competing interests, in accordance
Trial organization with BioMed Central’s guidance on competing interests.
Principal investigator and trial manager (BB, AHL)
Advice for lead investigators
Evaluation of need to audit trial completion. Publisher’s Note
Ethics Committee and data applications Springer Nature remains neutral with regard to jurisdictional claims in
Data verification published maps and institutional affiliations.
Budget administration and contractual issues with individual centers
Preparation of protocol and revisions Author details
1
Organizing Steering Committee meetings Orthopaedic Research Unit, Department of Orthopaedics and Traumatology,
Publication of study reports Odense University Hospital, Institute of Clinical Research, University of
Principle investigator and administrator Southern Denmark, Sdr. Boulevard 29, 5000 Odense C, Denmark.
2
Study planning Department of Sports Science and Clinical Biomechanics, University of
Organization of Steering Committee meetings Southern Denmark, Campusvej 55, 5230 Odense M, Denmark. 3Department
Research physiotherapist of Orthopaedics, Lillebaelt Hospital, Kolding, Skovvangen 2-8, 6000 Kolding,
Preparation of protocol and revisions Denmark. 4School of Exercise Science, Australian Catholic University, PO Box
Conduct of baseline and follow-up tests, except MRI 456, Virginia, Queensland 4014, Australia. 5Department of Radiology, Odense
Physiotherapist University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark.
Overseeing and conducting interventions
Reporting adverse events to lead investigator/trial manager Received: 11 September 2017 Accepted: 3 January 2018
Data collection
Steering Committee (PAA, UJ, NN, AHL)
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