Clinical trial NCT05450458
Conditions: Overuse Injury Body Mass Index in Athletes
Keywords: KNEE PAIN SPORTSMEN HYALURONIC ACID
Sponsor: Hospital Regional Tlalnepantla
Start date: 2023-02-01; Completion date: 2025-04-30
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Sports activity represents part of day living people, a knee pain originated by high demand joint activity could represent a limitation to continue sports. The aim of this clinical trial is demonstrate the effects of hyaluronic acid in sportsmen with knee pain.

Detailed description:
Sports activities have become a fundamental part of our daily life, this has led to an overuse of load joints, being the knee the most relevant. Overuse injuries of the knee result from microtrauma associated with physical activity and exercise that exceeds the strength of the cartilage tissue.

The purpose of this study is to evaluate the usefulness and safety of hyaluronic acid in athlete patients with knee overuse syndrome. Investigators hypothesis is that hyaluronic acid y safe and can improve symptoms of knee pain in sports patients. . Scores recorder data will be made at 15 days, then at 3 and 6 months after two knee injections of hyaluronic acid with sorbitol (Synolis VA).

Synolis VA is a viscoelastic, sterile, non-pyrogenic, isotonic, buffered solution of 2% hyaluronic acid. The hyaluronic acid used in synolis VA is obtained from bacterial fermentation and has a high molecular weight of 2 mdaltons, it has a neutral pH of 6.8 - 7.4 like synovial fluid. High concentration and high molecular weight of hyaluronic acid combined with sorbitol limits its degradation and confers the capacity of viscoelastic solution to restore joint lubrication and shock absorption properties.

This research protocol has been approve by the ethics and research Institutional committee in ISSEMyM Tlalnepantla Estado de Mexico number: CEI/0504/PI./2022. All participants must sign a informed consent to confirm be part fo this study.

Arms: arm 1: All overuse knee syndrome participants after both knee joint infiltration with two doses each of Synolis VA (2ml = 40 milligrams of hyaluronic acid with 80 milligrams of sorbitol).
Interventions: intervention 1: KNEE JOINT INFILTRATION WITH HYALURONIC ACID WITH SORBITOL SYNOLIS VA
Intervention descriptions: intervention 1: KNEE INFILTRATION WITH HYALURONIC ACID WITH SORBITOL IN SPORTSMEN

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
RESEARCH PROTOCOL 
Study title: Safety and effectiveness of hyaluronic acid and sorbitol with overuse knee pain 
in sportsmen 
Protocol Reference ethics commitee number: CEI/0504/PI./2022 
ClinicalTrials.gov: NCT05450458 
 
DATE: 01/12/2023 
 
 


 
ABSTRACT 
INTRODUCTION 
KNEE OVERUSE KNEE SYNDROME 
 
ETIOLOGY 
 
DIAGNOSIS 
 
 
IMAGE DIAGNOSIS 
 
CLASSIFICATIONS 
OVERUSE KNEE SYNDROME TREATMENT 
 
NON SURGICAL 
ANTIINFLAMATORY NON STEROIDEAL TRATMENT 
 
INFILTRATIONS 
PHYSIOTHERAPY 
HIALURONIC ACID TYPES: 
HYALURONIC ACID PLUS SORBITOL 
EVALUATION 
RESEARCH QUESTION 
PROTOCOL JUSTIFICATION 
HYPOTHESYS 
 
HYPOTHESIS 
 
NULE HYPOTHESIS 
OBJECTIVES 
 
MAIN OBJECTIVE 
 
SPECIFICT OBJETIVES 
MATERIALS 


 
STUDY DESIGN 
 
SELECTION CRITERIA 
 
 
INCLUSION CRITERIA 
 
EXCLUSION CRITERIA 
 
ELIMINATION CRITERIA 
 
VARIABLES 
 
POPULATION UNIVERSE 
 
POPULATION SIZE 
 
STUDY DESIGN 
STATISTICAL ANALYSIS 
ETHICAL IMPLICATION 
ORGANIZATION 
 
APPENDIX 1 
APPENDIX 2 
APPENDIX 3 
REFERENCES 
 
 
 
 
 
 
 
 
 
 


Abstract: 
Introduction:  The presence of overuse syndrome has been found with increasing frequency 
in patients who perform impact sports activities. Repetitive micro-trauma as a result of 
intense sport will cause the onset of joint degeneration that will generate pain, functional 
disability and in some cases limitation to continue carrying out sports activities.  
Aims: the aims of this prospective and longitudinal intervention cohort study  is to evaluate 
the safety and efficacy of hyaluronic acid plus sorbitol through clinical and functional 
analysis of sports patients undergoing overuse knee syndrome. 
Patients and Methods:  
According to the inclusion criteria, the participants who agree to part of the study will be 
enrolled, two dose of hyaluronic acid plus sorbitol will be applied in each knee, then 
strategies techniques for continue with sports activities.  The KOOS and IKDC scores will 
be evaluated at 15 days 3 and 6 months. Once we obtain all data results a statistical analysis 
will be made. 
Introduction: 
It is increasingly common to find patients who refer knee pain after any kind of sports, 
overuse syndrome of the knee has been the most common cause. This entity can be 
conditioned by repetition microtrauma which are in direct relation with the repenting rise of 
the intensity, duration and volume in sports activity, and also we could find incorrect 
training techniques or also do not count with appropriate equipment during training. 
Knee Overuse Syndrome 
Musculoskeletal conditions are common during competitive practices and correspond to 80% 
of sports injuries. Of these, joint pathologies, especially of the knee, have increased 
significantly due to the large number of people who practice activities, both professionally 
and recreationally. Athletes who push their physical capacity to the limit, will present a 
type of joint injury that has been classified as excessive use of a joint, representing up to 42% 
of all sport-related musculoskeletal conditions. An overuse injury could be defined as one 
of gradual origin, caused by repetitive micro-traumas without an identifiable injury 
mechanism that triggered it. Therefore, the overuse syndrome is related to chronic 
repetitive injuries caused by sports activities, where one of its characteristics is that they 
occur when there is not enough time for small injuries to heal properly, these being the 
result of microtraumas associated with physical activity and exercise that exceed the tissue 
tolerance of the affected structure. There are distinct types of overuse injuries, which 
depend on the affected anatomical area: tendinitis, bursitis, stress fractures, osteoarthritis 
among others. The presence of these micro-traumas related to the increased intensity and 
frequency in the use of a joint Will eventually cause inflammation and wear of the cartilage, 


resulting in an overuse injury. The lower extremity is most affected, due to the overload 
imposed in sports involving running and jumping, in which the force of the knees can reach 
up to 10 times body weight. 
 
Etiology 
It has been observed that between 35 and 45% of all injuries related to sports activity are 
due to people with overuse syndrome and that approximately one third of these are related 
to the knee joint. The overall prevalence of knee overuse injuries varies between sports 
activities: For example, patellofemoral pain syndrome constitutes 25% of knee injuries in 
runners, patellar tendinopathy has a prevalence of 40 % to 50% in elite volleyball players 
and 2.8 to 4.8 in runners. It is common for patients with a history of knee overuse and who 
practice professional sports to develop degenerative cartilage injuries, causing knee 
osteoarthritis. It has been observed that knee osteoarthritis affects more frequently patients 
who practice sports activities on a regular basis. Despite the great benefits obtained from 
sports practice, an increase in pain and joint damage caused during training has been 
observed. This Will later lead to functional limitation, conditioning a decrease in physical 
performance or even premature withdrawal from the sport. 
Diagnosis 
The diagnosis of overuse injuries and early osteoarthritis in sports patients is carried out 
through physical examination, obtaining information related to the type of sport, weekly 
practice time and time spent practicing it, this can offer us a clear idea of what whether it is 
an injury caused by micro-traumas, in addition, to the fact that there is already an evidence 
limitation to complete the sports activity or even withdraw from it, can confirm the 
diagnosis. Adequate inspection for the identification of biomechanical factors that 
predispose to specific conditions are femoral anteversion, valgus or varus of the knee, 
patellar malposition, excessive lateral insertion of the patellar tendon, foot pronation, 
decreased muscle mass vastus medialis and abnormal trajectory of the patella. This i show 
the clinical recurrence of pain, discomfort, intermittent periods of inflammation or edema 
followed by long periods with minimal symptoms and anterior knee pain caused during the 
squat, Will lead us to the clinical diagnosis of overuse. As for radiographic studies, by 
ultrasound, magnetic resonance, or arthroscopy, these will allow us to stage the degrees of 
joint injury. 
Radiologic diagnosis: 
- 
Simple X rays help to detect causes of knee pain, such as bipartite patella, 
osteoarthritis, loose bodies, occult fractures, and tumors. Several risk factors have 


even been identified, such as patella alta or lateralization of the patella in the 
femoral Groove. A radiographic study is required that allows us to identify specific 
injuries where degrees of joint injury in the knee can be stratified. Therefore, the 
diagnosis could be confirmed, by visualizing osteophytes, joint space narrowing, 
subcondral sclerosis, bone cysts, and grading these changes according to the 
Kellgren and Lawrence II to IV scale.  
- 
MRI can provide information on degenerative changes, such as fissures or thinning 
of cartilage, subchondral bone marrow edema and cysts. 
- 
Musculoskeletal ultrasound can be a useful tool to identify focal changes in tendon 
and subtle changes in vascularity (by mean of color / Doppler), one of its benefits, 
although it’s low cost, Will be the absence of radiation and patient comfort, 
compared with another image modalities. 
CLASSIFICACION 
Overuse injuries of the knee in adults include patello femoral Paint syndrome, quadriceps-
patellar tendinopathy, and iliotibial band syndrome. As an addition to the classification 
criterion described for osteoarthritis, a classification has been proposed to identify the 
subpopulation of patients in the early stage who have a high risk of presenting Frank 
osteoarthritis of the knee. This type of classification for early osteoarthritis, a classification 
has been proposed to identify the subpopulation of patients in the early stage who have 
an elevated risk of presenting Frank osteoarthritis of the knee. This type of classification 
for early osteoarthritis is focused not as an individual diagnostic method but allows 
comparison of groups or subgroups of populations with similar characteristics, allowing 
standardization in clinical studies. Classifying osteoarthritis in initial stages is complex 
since conventional imaging criterion as well as signs and symptoms appear more 
sporadically, manifesting when there is heavy physical activity or repetitive sports. 
Therefore, a patient can be classified as having early osteoarthritis based on clinical and 
radiographic findings that must be integrated into the following 3 criteria: 
1.- Knee pain (at least 2 episodes in les tan 10 days) 
2.- Simple X-rays with Kellgren-Lawernce grade 0 or I or II osteoarthritis (osteophytes only) 
3.- At least one for the following criterion: 
- Arthroscopic findings of condral injury 
- Findings of joint or meniscal degeneration by magnetic resonance imaging 


 
The U-s National Athletic Injury Reporting System (NAIRS) divides overuse injuries into the 
following categories:  
a) Undetectable – where the athlete does not stop their athletic activities, 
b) Minor leaving1-7 days of sports activity  
c) Moderate: from 8 to 21 days of abandonment of activities and 
d) Major: more than 21 days of loss of activities and serious injuries, resulting in 
permanent disability. 
TREATMENT OF KNEE OVERUSE SYNDROME: 
There is no specific treatment guideline for most conditions caused by knee overuse. It is 
essential to have an adequate diagnosis of osteoarthritis at an early stage to incorporate 
the most appropriate treatment. The most recommended treatment for early 
osteoarthritis, includes weight loss, physical therapy, non-steroidal anti-inflammatory 
drugs, nutraceutical supplements, topical treatments, and steroid injections. In knee 
overuse syndrome, starting with a decrease in overload, correcting gait abnormalities, 
improving training techniques, adding strengthening and stretching exercises, as well as 
adapting the use of footwear and adding physical therapies with ice, have resulted 
effective methods as first line treatment. 
NON-SURGICAL  
The first line of treatment in early osteoarthritis of the knee caused by overuse in sports 
should be given conservatively and without surgery. The main objective of this treatment 
is to delay arthroplasty through a protocol that includes non-steroidal anti-inflammatory 
drugs, joint injections, as well as general measures of weight loss following a series of low-
impact exercises. Physical therapy has an important role in the treatment of early 
osteoarthritis in athletes, stretching the extensor and abductor muscles of the knee can 
reduce pain and improve function. Cold therapy can also decrease the level of 
prostaglandins in synovial tissue resulting in decreased inflammation, reducing 
atherogenic muscle inhibition and facilitating vastus medialis motor neuron activity. 
Cryotherapy may allow more effective strengthening of the quadriceps in patients with 
knee joint abnormality; therefore, despite the current lack of clear research evidence, 
cryotherapy is recommended as a mainstay of conservative treatment in physiotherapy. 
NON-STEROID ANTI-INFLAMMATORY AGENTS 


Drug treatments commonly include the use of pain relievers such as aspirin or 
acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs); The use of NSAIDs is 
controversial due to the absence of histological inflammatory response in knee overuse 
syndrome. There is also concern that NSAIDs may interfere with the normal healing 
response of muscles and tendons.  
INFILTRATIONS  
- 
Platelet Rich Plasma (PRP) injections have been studied for the treatment of 
tendinopathy and osteoarthritis, obtaining Good medium-term results in the 
treatment of recalcitrant patellar tendinopathy by applying multiple injections. The 
use of PRP has been qualified by the Clinical Practice Guidelines of the American 
Academy of Orthopedic Surgeons (AAOS) for the treatment of knee osteoarthritis, 
however their decision was that it’s use cannot be recommended for or against 
treatment of knee osteoarthritis. 
INFILTRATION WITH HIALURONIC ACID 
Visco-supplementation with hyaluronic acid is one of the most recommended 
treatments for the non-surgical management of osteoarthritis, it can be 
recommended as first-line therapy, or when corticosteroids and non-steroidal anti-
inflammatory drugs are inefficient, contraindicated or poorly tolerated; 
viscosupplementation is a safe procedure, without any systemic or local side 
effects,  excluding possible injection pain and a feeling of heaviness for a few hours 
or days after treatment. Hyaluronic acid is one of the most used methods to 
preserve the cartilage and intra-articular structures of the knee. It protects the 
chondrocytes and lubricates the joint to stabilize the cartilage and the synovial 
membrane, benefits have also been described in its analgesic and intra-articular 
structures of the knee. It protects the chondrocytes and lubricates the joint to 
stabilize the cartilage and the synovial membrane, benefits have also been 
described in its analgesic and anti-inflammatory effects. Viscosupplementation 
significantly reduces knee pain during the first months, after which the effect is 
maintained for another 12 to 18 months. During this time joint function can 
improve and therefore patients can quickly return to sports activities.  
 
Physiotherapy  
 
A fundamental part of the overuse syndrome treatment is to know that mistakes in 
techniques of training could be avoided by guidelines of different type of exercises. 
Physical therapy should focus on stretching inflexible muscles and tendons (for 


example: iliotibial band and hip external rotators in ITBS, hamstrings in patellar 
tendinopathy) and strengthening weak / core muscles (quadriceps and hip external 
rotators in PFPS/patella tendinopathy), in addition to the eccentric muscles. 
Specific training should be instituted for some conditions, such as quadriceps and 
patella tendinopathies. It has been found that physical therapy as a treatment for 
osteoarthritis in early stages has symptomatic benefits, and in sports patients it 
Will allow them to adapt a specific toning program that limits joint impact.  
 
TYPES OF HYALURONIC ACID  
 
Native HA. Has a molecular weight of 4-10 million Daltons and is present in joint 
fluids at a concentration of approximately 0.35 g/100 ml; Hyaluronic Acid is a 
glycosaminoglycan, linear polysaccharide, composed of repeating units (D-
glucuronic acid and N-acetyl-glucosamine), is one of the main components of the 
extracellular matrix. It is part of the connective, epithelial and neuronal tissues. 
Infiltrations with hyaluronic acid are a viable option for athletes diagnosed with 
early osteoarthritis by reducing the absorption of loads in the knee, improving 
lubrication as well as having a certain degree of chondroprotection. Its principal 
biological effects are the regulation of anti-inflammatory mechanisms with 
antioxidants, reduction in the induction of cytokines, anabolic effect on cartilage 
and blockade of joint nociceptors that reduce pain.  
 
Hyaluronic Acid with Sorbitol 
Trade Name: Synolis VA 
Approved chemical or generic name: hyaluronic acid (NaHa), sorbitol (C3H8O3), 
sodium chloride (NaCl), phosphate salts (Na2HPO4 + NaH2PO4) and sterile water 
for injection (SWFI).  
 
Synolis VA is a viscoelastic, sterile, non-pyrogenic, isotonic, buffered solution of 2% 
hyaluronic acid. The hyaluronic acid used in synolis VA is obtained from bacterial 
fermentation and has a high molecular weight of 2 Mdaltons, it has a neutral pH of 
6.8 - 7.4 like synovial fluid. High concentration and high molecular weight of 
hyaluronic acid combined with sorbitol limits its degradation and confers the 
capacity of viscoelastic solution to restore joint lubrication and shock absorption 
properties. Synolis VA work by restoring physiological and viscoelastic properties 
of synovial fluid that have been progressively lost during the development of 
osteoarthritis. Synolis VA therefore reduces pain and discomfort caused by 
symptomatic OA and improves joint mobility. 
 


Composition: Each 1 ml contains: hyaluronic acid 20 mg, Sorbitol 40 mg, phosphate 
buffered solution 1ml. Synolis VA contains a 2 ml siringe of viscoelastic solution.  
 
Contraindications. 
 
 Synolis VA should not be used in: 
- 
Patients known to be hypersensitive to hyaluronic acid or sorbitol. 
- 
Pregnant lactating patients 
- 
Minors 
- 
Skin disease or infection at the level of the application site. 
CLINICAL EVALUATION  
The knee injury and Osteoarthritis Outcome Score (KOOS) is a new, well-designed, 
and simple self-administered instrument developed to assess short, and long-term 
symptoms and function in patients with knee injuries and osteoarthritis. It has 
good evidence of reliability, validity, and responsiveness in different populations 
with different pathologies, injury duration, ages, and activity levels. The KOOS 
scale has been shown to be very effective in Young and active patients; it is 
intended to be used in short and long-time intervals; to assess week-to-week 
changes induced by treatment (medication, surgery, physical therapy). All items 
were scored from 0 to 4, and each of the five scores was calculated as the sum of 
the included items; scores are then converted to a scale of 0-100, where zero 
represented extreme knee problems and 100 represented no knee injury, this can 
be represented as a percentage.  
 
The INTERNATIONAL KNEE DOCUMENTATION COMMITTEE IKDC, is a patient. 
oriented score to qualify symptoms and functions related to the activity of daily 
living; evaluates knee injuries and categorizes them into subjective variables, 
symptoms, ranges of motion and ligamentous exploration, which is subcategorized 
into normal, almost normal, abnormal and severely abnormal, the objective of this 
scale is to provide the physician with information on patient satisfaction and their 
knee. Point son the Subjective Knee Assessment Form are calculated by adding the 
points for the individual items, and then transforming the points on a scale from 0 
to 100. The transformed points are interpreted as a measure of the ability to 
function, with higher points representing higher levels of functioning and lower 
levels of symptoms. One hundred points are interpreted to mean that there is no 
limitation in activities of daily living or sports activities, and the absence of 
symptoms.  


Justification and Statement of the Problem 
 
Currently there is a major influence to promote sport in the population, however, 
despite its great benefits, the development of early osteoarthritis secondary to 
micro-trauma due to overuse must be taken into consideration. In fact, the 
presence of early osteoarthritis following a prolonged or intense period of physical 
activity, or in those who practice impact sports regularly, is well described. 
Athletes who have initial stages of osteoarthritis require a treatment that improves 
their clinical symptoms and improves functional functions for as long as possible. 
Another objective of treatment is for their daily sports activities; sports activities; 
intraarticular HA injections are more effective in young patients, especially in the 
long term, while the results are les promising in athletes with advanced 
osteoarthritis. Reducing the viscoelasticity of synovial fluid, the transmission of 
mechanical force to the cartilage increases susceptibility to mechanical damage. 
Therefore the restoration of normal joint homeostasis is the reason for the 
administration of hyaluronic acid in the joints , in addition to seeking a 
physiological healing process and, if possible, complete; secondly, to shorten the 
recovery time, especially in athletes who are not going to limit their activity. The 
currently 
evidence 
that 
exists 
regarding 
the 
efficacy 
and 
safety 
of 
viscosupplementation in athletes is limited, hence the present investigation arises 
from the understanding that there are no protocols that demonstrate the benefits 
of knee joint infiltration using hyaluronic acid plus sorbitol in athlete patients, so in 
order to determine the safety and efficacy of this treatment, the following 
research question is proposed: 
 
 
RESEARCH QUESTION 
 
Is there a clinical and functional difference in the short and medium term in 
patients with knee pain due to overuse associated with sports treated by 
infiltration with hyaluronic acid with sorbitol? 
 
Hypothesis 
 
Athletes with sports-related overuse knee pain have Good clinical and functional 
results in the short and medium term through joint infiltration of hyaluronic acid 
with sorbitol. 
 
Null Hypothesis 


 
Athletes with knee pain due to sports-related overuse do not have Good clinical 
and functional results in the short and medium term through joint infiltration of 
hyaluronic acid with sorbitol.  
 
Objectives 
 
General Objective 
 
To evaluate safety and efficacy of hyaluronic acid with sorbitol in athletes with 
overuse knee pain by comparing functional outcomes at short, medium and long 
term after treatment.  
 
Specific Objectives 
 
- 
To assess the safety and efficacy of hyaluronic acid with sorbitol in patients with 
sports-associated knee pain. 
- 
To compare the clinical and functional results of patients with sport-associated 
knee pain after before and after treatment. 
METHODS 
Study Design  
This research will be a cohort study, prospective and unidirectional direction. 
 
Selection Criteria 
- 
Patients with knee pain for more than 3 months 
- 
Patients between 30 and 55 years old 
- 
Patients without a history of previous knee joint surgery. 
- 
Patients without chronic-degenerative diseases such as diabetes, hypertension, 
rheumatoid arthritis or other autoimmune diseases. 
- 
Patients who perform impact social sports at least 3 times a week for more than 1 
hour in the last 3 months prior to treatment. 
- 
Patients without a history of allergies to non-steroidal anti-inflammatory drugs. 
- 
Patients with no history of infection in or around the knee. 


EXCLUSION CRITERIA 
- 
Patients who cannot be categorized as social athletes. 
- 
Patients with an associated sports injury that limits their sports practice. 
- 
Patients who have a treatment associated with knee pain independent of that 
established in the study protocol. 
ELIMITATION CRITERIA 
- 
Patients who suffer from an injury or illness during the study that may limit their 
sports activity or who require an analgesic or anti-inflammatory treatment other 
than that established in the protocol.  
- 
Patients who personally want to leave the study. 
- 
Patients who did not have complete follow-up during the study. 
- 
Patients who present an allergic or infectious reaction related to hyaluronic acid or 
prolotherapy or sepsis and antisepsis methods for infiltration. 
- 
Patient with an allergic reaction to non-steroidal anti-inflammatory drugs.  
 
VARIABLES 
Variable 
Operational 
Definition 
Dimension  
Variable 
type 
Instrument 
Indicator 
Age 
Time of life of 
any person 
Without 
categories 
Quantitative 
Discrete 
Interview 
Years 
Gender 
Biological and 
physiological 
characteristics 
that 
differentiate a 
man from a 
woman 
Female 
 
Male 
Qualitative 
Nominal 
Interview 
Gender 
Body 
Mass 
Index 
Score 
calculated 
by 
weight 
and 
height 
of 
a 
person.  
Normal 
Overweight  
Obesity 
Quantitative 
Discrete 
Measuring 
tape 
Weighing 
machine 
Weight 
in 
kg 
/ 
Height 
in 
square 
meters  
Affected 
Knee 
Anatomic 
Knee side 
Left 
Qualitative 
Physical 
Exploration  
Left 


Right 
Nominal 
Right 
Athlete 
 
Person 
who 
practice 
any 
type of sport  
Social 
Amateur 
Professional 
Qualitative 
Nominal 
Interview 
Have 
a 
sports 
activity 
for 
more 
than 3 months, 3 
times a week over 60 
minutes per session 
Score KOOS 
Scores 
that 
evaluate 
functional and 
osteoarthrosis 
around 
the 
knee 
Symptoms 
Joint 
Stiffness 
Pain 
Regular 
activities 
Sports 
activities 
Quality 
of 
life 
 
Quantitative  
Discrete 
Interview 
Physical 
Exam  
Percentage 0-100% 
Score IKDC 
International 
Knee 
Documentation 
Committee 
Symptoms 
Regular 
Activities 
Sports 
Activities 
Quantitative 
Discrete 
Interview 
Physical 
exam 
Percentage  
0-100% 
Visco 
supplementat
ion  
Intraarticular 
joint injection 
of high weight 
molecular 
hyaluronic 
acid 
with 
sorbitol 
Mono dose 
Multi dose  
Qualitative 
Nominal 
Hyaluronic 
acid 2ml plus 
sorbitol 
2 
dose per knee 
Yes = Knee joint 
infiltration 
No= Did not apply 
Training 
sports 
technique 
Coaching 
for 
adequate 
techniques 
of 
certain 
sports 
Manual 
technique 
Instrumented 
Qualitative 
Nominal 
Personalized 
coaching 
techniques 
Achievement survey  


activities 
 
Or 
Information 
brochure 
 
Research Universe 
General Population who does sports activities and have knee overuse syndrome between 
June of 2022 and October 2022. 
 
Sample Size 
It will be a non-probability sampling where will be chosen participants who meet selection 
criteria over the enrolling time which will be for 5 months. The lower limit will be 60 
participants and the higher limit will be 120 participants. 
 
Sample size formula: n(sample), z (confidence level), p (probability to occur the studied 
event), q (probability to didn’t occur the studied event) and e (maximum accepted estimated 
error) 
        Z2 * p*q 
n = ————— 
             e2 
 
Study Design 
Research enrolling and diffusion will be initiated after authorization of the ethics and 
investigation committee. All participants with knee pain related to sports will be accepted 
for a physical evaluation. All participants will be interviewed about physical activities, 
sports, injuries, and knee pain. Once they have been categorized as athletes with knee 
overuse pain syndrome and have met the selection criteria, then will be invited to the 
research. For this, the participants must be agreed and sign the informed consent Appendix 
1 and 2. 
 
Before treatment Group 
To participants who initiate the study research will be applied the KOOS and IKDC scores, 
the results will be recorder in the collection data sheet. Appendix 2. Participants will be 
explored by physical exam focus on knee pathology, and also an echography knee scan 


looking for non-overuse pain injuries.  Coaching for sports activities will be explain for 
each patient in order to improve its own training techniques adding stretching exercises for 
previous and after training. 
 
After treatment Group 
After KOOS and IKDC scores were recorder two dose of Hyaluronic Acid plus sorbitol 
will applied. Technique: On the examination table, the patient will lie down at supine 
position and the area of  the knees to be infiltrated will be discovered.  Asepsis of the knee 
region will be performed using an iodine and alcohol solution, the remaining synovial fluid 
in the joint will be extracted with a 10cc syringe then 4 milliliters of 80 mg of hyaluronic 
acid plus 160 mg of sorbitol will be applied (Synolis VA Aptissen S. A.) at the sub 
quadricipital level with a 22G x 32mm sterile needle.  At the end of the infiltration, the 
needle will be removed, and the injection site will be covered with a small sticky-band, 
which can be thrown away after 20 minutes. It will be recommended do not made any kind 
of sports activity following the next 72 hours and applied ice therapy 3 times per day for 
over 20 minutes. Scores recorder data will be made at 15 days, then at 3 and 6 months. 
 
Once the enrolling phase of the trial be concluded, statistical analysis will be made with 
Excel Office software for Windows, IBM SPSS and Prisma. 
 
Statistical analysis 
Recorder data of the functional scores will be evaluated before and after treatment, also at 
15 days, 3 and 6 months after hyaluronic acid supplementation.  
Data analysis will be made by means standard deviation for numeric variables, also t-
test for parametric and Wilcoxon Mann Whitney for non-parametric variables, a standard 
error of 95% is allowed. Differences in time will be calculated and group compared by 
Anova test. Variable correlation and association measures with relative risk and attributable 
risk with Fisher’s test will be made with an confidence interval of 95%. 
 
Ethical Implications 
This research project will be developed after approvement of the ethics and research 
Institutional committee. 
This research study will be according to principles of ethics by the Helsinki Declaration 
(2000) following three principles of ethics: beneficence, justice and respect for people. 
All the declared principles will be followed in relation to the guide of good clinical practice. 


 
This study research will follow the ethical codes established by the 18ª worldwide medical 
assembly, protection principle of the participants in the Nuremberg Code (1947), Belmont 
inform (1979), OMS guidelines and CIOMS (2002) guides for human biomedical research. 
Also following the NOM 012 of biomedical research health department. 
 
Organization 
Human Resources: Principal Research, co-author, medical assistant. Statesian 
Economic burden: Noneconomic profit will be obtained by the principal author and 
coauthor. It will be no economic benefit will be for any participant. 
Physical Resources: 
Medical office: In this area medical assistant will collect the score records, physical 
examination, sonographic evaluation, coaching sports hygiene techniques, and stretching 
exercises. 
Request Funds: This Study research will be sponsored by Aptissen  
 
 


 
 
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Tiu T, Craig Van Dien MD. Knee overuse disorders.  
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APPENDIX 1 
 
 
 


 
 
 


APPENDIX 2 
 


 


 
 
 


Appendix 3 
APENDIX 3: Data collection sheet  
Date sheet colection 
Safety and efficacy of hyaluronic acid plus sorbitol in sports man with overuse knee pain. 
1.- Participant indetification cardex 
Date:________________________ 
Participant ID:______________________________  Age_____________________ 
Gender: Male_____  
Female______ 
Afected Side____________Right___   Left______ Both______ 
Weight___________Kgs     High_________________cms   BMI:______________ 
2.- Sports Activities: 
Activity:____________________________ Elapsed Time since begin this sport_________ 
Frecuency 
_________________days per week    ________________minutes per day 
3.- Treatment: 
 
 
 


INFORMED CONSENT FORM 
Research title: Safety and efficacy of sodium hyaluronate plus sorbitol in athlete patients 
with knee pain due to overuse. 
ClinicalTrials.gov: NCT05450458 
Date: 01/12/2023 
 
 


 
 
Informed Consent Letter for Knee Joint Infiltration and Inclusion in Research Protocol: 
Safety and efficacy of sodium hyaluronate plus sorbitol in athlete patients with knee 
pain due to overuse. 
ClinicalTrials.gov: NCT05450458 
This letter constitutes the free and voluntary decision made by a patient, where they 
accept the diagnostic and/or therapeutic actions suggested by their doctor. 
Date 
of 
Issuance:______________________________________________________________ 
Institution: Instituto de Seguridad Social del Estado de México y Municipios. 
Location: Hospital Regional Tlalnepantla 
Diagnosis__________________________________________________________________
____ 
Under this letter, I authorize that I:________________________________________ be 
included in the medical research protocol called: Hyaluronic Acid in Overuse Knee Pain, in 
which I will undergo: JOINT INFILTRATION OF ONE OR BOTH KNEES IN 2 DOSES USING 
HIGH MOLECULAR WEIGHT SODIUM HYALURONATE SOLUTION (2 MDALTONS) PLUS 
POLYOL (SORBITOL) SYNOLIS. 
This biological implant consists of a sterile viscoelastic isotonic solution of sodium 
hyaluronate indicated to improve the symptoms of knee pain and mobility in patients with 
osteoarthritis. This product is indicated as a non-surgical treatment option for knee 
injuries. 
Treatment risks: Infrequent risks have been reported, including the presence of knee 
edema, increased synovial fluid, skin redness, and temporary local pain. Other adverse 
effects may include an immunological allergic reaction to the components, triggering 
anaphylactic shock, septic arthritis, and even death. 
Benefits: The expected benefits of this treatment are to temporarily improve knee pain 
and function during medium and high-impact sports activities, even with elevated BMI. 


Contraindications: This synthetic implant cannot be applied to pregnant patients, 
breastfeeding individuals, persons under 18 years old, or patients with a history of knee or 
peripheral tissue infection. 
The procedure will be carried out using sterile technique, consisting of cleaning the area 
to be infiltrated with alcohol antiseptic solution. Infiltration with a 22G x 32mm needle at 
the lateral infra-patellar level of the patella. Placement of a sterile dressing with adhesive 
bandage which can be removed 20 minutes after application. It is recommended not to 
perform physical or high-impact sports activities for the following 48 hours. 
I will undergo an evaluation with two questionnaires (IKDC and KOOS scores) that I should 
fill out with the utmost accuracy on the day of the infiltration, at 15 days, 3 months, and 6 
months. 
With prior authorization and understanding that the procedure and all related details 
have been explained to me, I give my explicit consent authorizing the use of my results for 
the research protocol. 
 
_______________________________                _______________________________ 
Full Name and Signature of Patient                Name and Signature of Treating Physician 
 
_______________________________                _______________________________ 
                          WITNESS 1                              WITNESS 2 
 
Appendix: Informed Assent to participate in the Research Protocol. 
Research Name: Safety and efficacy of sodium hyaluronate plus sorbitol in athlete 
patients with knee pain due to overuse. 
Principal Investigator: xxxxxxxxxxxxxxxxxxxxx 
Co-Investigator: xxxxxxxxxxxxxxxxxxxxxxxxxx 


Institutional Site: xxxxxxxxxxxxxxxxxxxxxxxxxx 
The objective of this research is to understand the efficacy, safety, and clinical benefits of 
Sodium Hyaluronate plus Sorbitol, in patients with early osteoarthritis secondary to knee 
overuse syndrome in athletes. 
This research project has the following characteristics: 
1. Description of the research: It intends to compare a control group against the study 
group where participants for each group will be randomly (by chance) selected. 
Study Group: This group will receive 2doses of sodium hyaluronate plus sorbitol in the 
affected knee. 
2. Risks and discomforts: There may be no clinical difference in their symptoms and they 
may continue with pain or functional limitation that partially or totally impedes sports 
activity. In the study group: anaphylaxis to sodium hyaluronate components may occur, 
knee redness, edema, and temporary residual pain. 
3. Expected benefits: No benefit will be obtained by integrating into this study; however, 
their results will be useful for international medical scientific development. 
4. Compensation in case of damage: If any adverse effect related to the applied treatment 
is presented, follow-up and treatment will be provided for the effects caused by the 
infiltration. 
5. Economic Compensation: No economic remuneration exists for integrating into this 
study. The decision to integrate into this research is entirely voluntary and there is the 
possibility of withdrawing from it at any time without losing any benefits that might be 
obtained. Medical evaluations, visco-supplementation therapy, or physiotherapy will be at 
no cost. 
6. Protection of personal data: The researchers will have access to medical history and 
clinical records while safeguarding the protection and confidentiality of personal data. The 
patient’s identity will not be exposed in any results publication. 
7. Information update: During the study, participants will be informed of new information 
that might be relevant to their decision to continue being part of the study. 


8. Research duration and data collection: Information related to symptoms and lifestyle 
will be requested for a period of 6 months after participating in this research. Contact can 
be in a medical consultation area, by video call, phone call, or email. An emergency phone 
number will be provided in case additional information or evaluation is needed beyond 
the scheduled. 
9. Number of patients: This research intends to involve approximately 70 participants. 
 
I voluntarily accept to participate in this clinical research trial. 
 
Yes                          No 
 
Participant Name:________________ Signature:________________ Date: _________ 
 
Witness:____________________________ 
Signature:________________ 
Date: 
__________ 
 
Person obtaining consent:__________________ Signature: __________________