Is radial extracorporeal shock wave therapy combined with a specific rehabilitation program (rESWT + RP) more effective than sham-rESWT + RP for acute hamstring muscle complex injury type 3b in athletes? Study protocol for a prospective, randomized, double-blind, sham-controlled single centre trial

This is a randomized controlled trial (RCT) on rESWT + RP vs. sham-rESWT + RP, with blinding of patients and evaluators/assessors, but without blinding of the therapist who will perform the rESWT. All the patients will be recruited from the Club Deportivo UAI Urquiza (Villa Lynch, Province Buenos Aires, Argentina). Officials of the Club Deportivo UAI Urquiza will be instructed that athletes who experience sudden, sharp pain in the posterior aspect of the thigh during training or competition shall immediately stop activity. These athletes will then be evaluated regarding the presence of the inclusion criteria of this study on the day of injury.

Figure 3 shows the flow of patients through the present study according to the CONSORT statement [39], and Table 3 the schedule of enrollment, interventions, and assessments according to SPIRIT [40].

This study has received approval from the local institutional ethics board of the Universidad Abierta Interamericana, Buenos Aires, Argentina (Nr. 0-1027).

Adults aged 18–35 years (both female and male) with clinical and ultrasonographic diagnosis of acute HMC injury type 3b are eligible for inclusion.

The inclusion criteria are physical conditions for rehabilitation (i.e., no surgery required), willingness of the patient to participate in the study, written informed consent signed and personally dated by the patient, and no contraindications for rESWT.

The exclusion criteria are children and teenagers below the age of 18, adults aged > 35 years old, patients with clinical and ultrasonographic diagnosis of acute HMC injury type 3b who got injured more than 7 days before potential enrollment into this study, patients with clinical and ultrasonographic diagnosis of acute HMC injury type 3A or type 4, bilateral acute HMC injury (types 3A, 3B, or 4), proven or suspected HMC injury (types 3A, 3B, or 4) of the same lower limb in the time period of 6 months before potential enrollment into this study, muscle injury caused by external impact on the back of the affected thigh (category B according to [1]), surgery on the affected lower limb in the time period of 1 year before potential enrollment into this study, acute or chronic lumbar pathology (because some cases of thigh pain may relate to spinal pathology; c.f. [8]), no willingness of the patient to participate in this study, and/or written informed consent not signed and not personally dated by the patient, and contraindications of rESWT (including treatment of pregnant patients, patients with blood-clotting disorders (including local thrombosis), patients treated with oral anticoagulants, patients with local bacterial and/or viral infections/inflammations, patients with local tumors, and patients treated with local corticosteroid applications in the time period of 6 weeks before the first rESWT session (if applicable)).

The patients that fulfill the inclusion criteria and do not fulfill any of the exclusion criteria will be randomly allocated to either rESWT + RP (n = 20) or sham-rESWT + RP (n = 20). Randomization will be performed as described in [41] in a randomized, controlled study on rESWT for Achilles tendinopathy. Specifically, a computerized random-number generator will be used to formulate an allocation schedule. Patients will be randomized to either treatment (rESWT + RP or sham-rESWT + RP), with use of the method of randomly permuted blocks. The randomization scheme will be generated with the use of the website, www.​randomization.​com. Forty patients will be randomized into five blocks. A medical assistant at the clinic of the Principal Investigator (J.C.) will allocate interventions by means of opaque sealed envelopes that will be marked according to the allocation schedule. The medical assistant will be unaware of the size of the blocks. The randomized intervention assignment as outlined above will be concealed from both patients and health care staff until recruitment will be complete and irrevocable.

Patients and the assessor will be blinded in this study. The assessor is the person who will assess the outcome of treatment during follow up. In this study, the assessor will be a medical doctor affiliated with IMAXE Diagnostico X Images, Ciudad Autónoma de Buenos Aires, Argentina (AR). IMAXE itself is affiliated with the Faculty of Medicine at the Universidad de Buenos Aires, Argentina.

The therapist will not be blinded in this study. This will be done because even when using coded “active” and “sham” handpieces in a study on rESWT, blinding of therapists can only be achieved when another person prepares the device before rESWT or sham-rESWT. This, however, is almost impracticable and has not been done in any of the more than 100 studies on radial and focused ESWT listed in the PEDro database [34]. The solution to this issue is a strict, standardized way of interaction between the therapist and the patients, irrespective of treatment allocation (as mentioned in [42]; c.f. also [43]). This approach will also be applied in the present study. The therapist is the person who will administer either rESWT or sham-rESWT to the patient. In this study, the therapist will be the principal investigator.

All patients will perform a specific rehabilitation program (RP) that will last for 8 weeks, independent of the individual time interval to return to play (in line with [27]). This RP was developed based on recommendations in the literature [44‐46]. The key objective of this RP is that after injury, the patient will develop functional, neuromuscular, and biomechanical skills according to the demands of the sport she/he performs, while minimizing the risk of reinjury. Therefore, the proposed RP will take the patient through a combination of low-risk and high-demand movements, based on a systematic process. This process will consist of an orderly sequence of steps or phases—acute phase, subacute/regeneration phase, and functional phase. Each phase will depend on the outcome of the previous phase and will use the individualized response as criterion of progression. The RP will be controlled by the same physiotherapist who will not participate in the inclusion/exclusion process or any subsequent evaluation of the patient.

The goals of the acute phase include to (i) prevent re-rupture at the injured site; (ii) prevent excessive inflammation and formation of scar tissue; (iii) increase tensile strength, adhesion, and elasticity of new granulation tissue; (iv) reduce build-up of interstitial fluid; and (v) detect and treat any lumbopelvic dysfunction. Once a patient will be included in the proposed study, she/he will be instructed to avoid the use of medication and apply the RICE principle (rest, ice, compression, and elevation) three times per day in order to stop the injury-induced bleeding into the muscle tissue and thereby minimize the extent of the injury (see, e.g., [47]).

With regard to the optimum time interval for starting active rehabilitation after acute HMC injury type 3b, some authors recommended immobilization for 3 to 5 days, followed by active mobilization [47]. Other authors pointed out that starting rehabilitation 2 days after injury rather than waiting for 9 days shortened the interval from injury to pain-free recovery and the time to return to play by approximately 3 weeks without any significant increase in the risk of reinjury [27]. However, it is not known whether starting rehabilitation already 2 days after injury has any benefit over starting rehabilitation 5 days after injury. We will therefore follow the recommendation in [47] and progress to the subacute phase after 5 days.

The criterion for progression to the subacute/regeneration phase will be absence of pain 5 days after injury. If the symptoms caused by the injured muscle persist for more than 5 days, we will reconsider the existence of more extensive tissue damage and/or intramuscular hematoma that might require special attention and treatment by an orthopedic surgeon.

The goals of the subacute/regeneration phase include to (i) improve overall core stability; (ii) improve strength and symmetry; (iii) reduce pain during prone isometric, isolated hamstring contractions at 15° knee flexion; (iv) improve hamstring flexibility of both legs; (v) improve hip flexor flexibility of both legs; and (vi) improve neuromuscular control. During the subacute/regeneration phase, the patient will work on both legs daily during a single session. Exercises will be conducted to correct the different risk factors and mechanisms related to the lesion of the hamstring musculature. The exercises will be divided into four groups: core stability and lumbopelvic control, flexibility and neural mobilization, hamstring and gluteal strength, and running technique. In addition, basic aerobic conditioning will start when the patient will be able to perform at least three sessions of the running technique without any discomfort or pain. Three running sessions per week will be performed at the clinic of the principal investigator and will include four sets of 5 min at a low to moderate intensity (individually rated by the patient). Suspension of running sessions will be permitted in the event of discomfort or pain.

The criteria for progression to the functional phase will be no pain in prone position with knee flexed to 15°, no pain during slump test, <  10% asymmetry when in prone position with knee flexed to 15°, <  10% asymmetry during active knee extension test, and < 5° asymmetry in the modified Thomas test.

The goals of the functional phase include to (i) increase the optimum length of the hamstrings, (ii) decrease leg asymmetries in optimum length, (iii) decrease leg asymmetries in concentric hip extension, (iv) decrease leg asymmetries in horizontal force production during running, and (v) improve torsional capabilities. The functional phase will comprise daily exercises, with three sessions per week at the clinic of the principal investigator (every other day) and the remaining sessions at the club or at home. The exercises will comprise the following: core stability and lumbopelvic control, flexibility and neural mobilization, hamstring and gluteal strength, plyometric training, and running technique. During the functional phase, the running session will consist of two sets of 10 min at moderate to high intensity (individually rated by the patient). Suspension of running sessions will be permitted in the event of discomfort or pain.

The criteria for return to play will be (according to [48]) absence of pain on palpation, absence of pain during flexibility testing (active knee extension test and passive straight leg raise test), absence of pain during strength testing (isometric force test), absence of pain during and after functional testing (repeated sprint ability test and single leg bridge), similar hamstring flexibility, psychological readiness/athlete confidence, and clearance by the medical staff. The quantity and quality of the supervised rehabilitation sessions at home or the sports club will be documented.

Patients in the rESWT group will receive the specific rehabilitation program as outlined above, and rESWT as follows: nine rESWT sessions; three sessions per week (interval between sessions: two or three days); rESWT device: Swiss DolorClast (Electro Medical Systems, Nyon Switzerland), EvoBlue handpiece, 15 mm applicator; 2500 rESWs per session, with energy density between 0.12 and 0.16 mJ/mm² (achieved by operating the Swiss DolorClast at air pressure between three and four bar), depending on what the patient tolerates; 15 rESWs per second, resulting in treatment time between 3 and 5 min per session; application of rESWs in prone position, with the patient lying on an examination table; exact location of the application of rESWs determined by clinical and ultrasonographic examinations; treatment of both the side of injury and the entire affected muscle (from distal to proximal in order to relax the affected muscle); application of rESWs in sagittal (dorsal—ventral) direction; and no use of local anesthesia.

Patients in the sham-rESWT group will receive the specific rehabilitation program as outlined above, and sham-rESWT as outlined above, with a specially designed sham EvoBlue handpiece that looks and sounds like the EvoBlue handpiece of the Swiss DolorClast, but does not generate radial shock waves. This is achieved by blocking the projectile (“15” in Fig. 1) shortly before it strikes the metal applicator (“17” in Fig. 2). The sham EvoBlue handpiece will not emit any radial shock wave energy.

All patients will perform RP that will last for 8 weeks, independent of the individual time interval to return to play. The RP will start with a first visit to the clinic of the principal investigator during which clinical and ultrasonographic diagnosis will be performed. This first visit may take place on the day of injury (D0) or the first day (D1) or second day (D2) after injury (the sooner the better).

After the first visit, an individual number of days will follow until the fifth day after injury (D5) will be reached (acute phase). During this time, the patient will apply the RICE principle (rest, ice, compression, and elevation). Visits to the clinic of the principal investigator may be scheduled during this time but are not mandatory.

On D5, the subacute/regeneration phase of the RP will start, with three visits per week to the clinic of the principal investigator. The exact time for progression from the subacute/regeneration phase to the functional phase of the RP will be individually determined, depending on whether the criteria for progression will be fulfilled. During the functional phase, there will also be three visits per week to the clinic of the principal investigator.

Study treatments (rESWT or sham-rESWT) will start on D5. Each patient will be treated with nine sessions of rESWT or sham-rESWT, with three sessions per week. Accordingly, study treatments may take place at D5, D7, D9, D12, D14, D16, D19, D21, and D23.

Six months after inclusion into the study, there will be a separate visit for evaluating patient’s satisfaction with the treatment outcome.

The time interval necessary for reaching return to play will be as follows: based on our experience, we expect that approximately 75% of the patients treated with rESWT + RP will reach return to play within 5 weeks after D0. Furthermore, we expect that only approximately 25% of the patients treated with sham-rESWT + RP will reach return to play within 5 weeks after D0.

The primary clinical outcome will be the individual time (days) necessary to return to play. Individual treatment success is defined as the possibility to return to play with the following criteria fulfilled (according to [48]): absence of pain on palpation, absence of pain during flexibility testing (active knee extension test and passive straight leg raise test), absence of pain during strength testing (isometric force test), absence of pain during and after functional testing (repeated sprint ability test and single leg bridge), similar hamstring flexibility, psychological readiness/athlete confidence, and medical staff clearance.

Secondary clinical outcomes will be individual patient’s satisfaction at 6 months after inclusion into the study (using a scale ranging from 0 (maximum dissatisfaction) to 10 (maximum satisfaction)), and presence or absence of reinjury during a time period of 6 months after inclusion into the study (defined as sudden, sharp pain in the posterior aspect of the thigh that was initially injured, accompanied by the same objective criteria initially used for the diagnosis of acute HMC injury type 3b).

In addition to primary and secondary clinical outcomes, the following parameters will be evaluated and reported: patient’s sex, age, weight, height, and body mass index; the interval between injury and the first treatment (in days); and patient’s individual training load (number of training sessions per week; duration of training sessions).

Note that we will document the anatomical location of the injury. However, in line with the literature [26‐28], we will not perform a sub-analysis with respect to a possible correlation between the results of clinical intervention and the anatomical location of the injury.

In the aforementioned studies [26, 27]), the cumulative probability of resumptions of sports activity on day 35 after acute HMC injury type 3b in professional soccer players [26] or recreational athletes [27] was only respectively 20% [26] or 5% [27] after treatment with a rehabilitation program.

On this basis, we performed a power analysis for a percentage of 25% as well as for various other percentages (ranging between 10 and 99.9%) of patients with treatment success when treated with sham-rESWT + RP (n = 20), accounting for a two-sided confidence interval of 95% (and, thus, a type-1 error rate of 5%) and a percentage of patients with treatment success when treated with rESWT + RP (n = 20) of 75%. Calculations were performed using the software, Open Source Epidemiologic Statistics for Public Health (www.​openepi.​com). Furthermore, we calculated the minimum sample size in both groups (rESWT + RP, sham-rESWT + RP) that would be necessary for detecting a difference in treatment success between the patients treated with rESWT + RP and the patients treated with sham-rESWT + RP accounting for a two-sided confidence interval of 95% and a power of 0.8. Calculations were also performed using the software, Open Source Epidemiologic Statistics for Public Health (www.​openepi.​com). The results are summarized in Tables 4 and 5.

In summary, the proposed study would have a power of less than 0.8 in finding a difference in treatment success (possibility to return to play with the criteria established in [48] fulfilled) between rESWT + RP and sham-rESWT + RP for treating acute HMC injury type 3b if the percentage of patients with treatment success when treated with sham-rESWT + RP would be higher than 30%. This, however, is not to be expected considering the aforementioned data published in [26, 27]. This reinforces the validity of the protocol of this study for testing efficacy and safety of rESWT + RP using the Swiss DolorClast for acute HMC injury type 3b.

Follow-up will be the same for all study patients. The design of this study guarantees that there will be full compliance with the allocated treatment and, thus, no contamination of one group.

The primary clinical outcome will be the individual time (days) necessary to return to play. The primary clinical outcome will return a single data point (number of days) for each patient. Time of return to play is not normally distributed data. Accordingly, we will report inter-quartile ranges of this variable. Comparison between groups will be performed using the nonparametric Mann-Whitney test.

One secondary clinical outcome will be assessment of patient’s satisfaction at 6 months after inclusion into this study (using a scale ranging from 0 (maximum dissatisfaction) to 10 (maximum satisfaction)). This secondary clinical outcome will return a single data point (on a scale ranging from 0 to 10) for each patient, which is not normally distributed data. Accordingly, we will report inter-quartile ranges of this variable. Comparison between groups will be performed using the nonparametric Mann-Whitney test.

Another secondary clinical outcome will be presence or absence of reinjury during a time period of 6 months after inclusion into the study. This secondary clinical outcome will return a single data point (“yes” or “no”) for each patient, which is not normally distributed data. Accordingly, we will report absolute and relative numbers of “yes” and “no” of this variable. Comparison between groups will be performed using Fisher’s exact test.

The probability value of less than 0.05 (p value < 0.05) will be considered as statistically significant [51]. All calculations will be performed using GraphPad Prism (version 5.00 for Windows, GraphPad Software, San Diego, CA, USA).

All main conclusions of the study will be based on analyses of intention to treat rather than analyses of treatment. Note that there are various available methods for handling missing data in clinical trials [52]. In case of missing data (i.e., in case a patient will withdraw or will be lost during the treatment or the follow-up periods), we will determine the most appropriate method for performing analyses of intention to treat. After randomization and the first rESWT or sham-rESWT, no patient will be replaced.

All efforts will be made to keep the proportion of patients lost to follow-up too small to affect the main findings of this study. Patient-centered care throughout this study will ensure that no patients will be lost to follow-up, or the number of patients lost to follow-up will be so small that findings would be unaffected by their inclusion. We will report actual probability values for all outcomes except where probability values less than 0.001 are found. We will avoid any retrospective unplanned subgroup analysis and, thus, “data dredging.”