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2: Materials and methods

25
2
material and methods
2.1 Patient Collective
2.1.1 Selection of sample scope
The null hypothesis (H of this study is: The effect of non-animal, stable
0)

lated hyaluronic acid is no better than that of placebo or the two

Products are equally good. The alternative hypothesis (H indicates that the hyaluronic acid
1)

is superior to placebo.
The selection of the sample size has a decisive influence on the
nis. If the sample size is too small, the null hypothesis is retained
it is rather rejected. To calculate the statistically necessary size of the
comparative patient groups, the optimal sample size was calculated.
net. Should a difference be found in the mean values of the two treatment groups of
30 mm on the visual analog scale with an error probability of = 0.05
and = 0.2 (corresponding to a power of 0.8) is a sample circum-
of 11 patients per group (22 in total). The -error means,
that the risk of a false positive result is a maximum of 5%, the error
on the other hand, the risk of a false negative result is a maximum of 20%. The
Power or separation, thus the likelihood of an actual difference
is equivalent to 1 - , ie 80%. The assumed standard deviation is
at 24 mm. With an anticipated drop-out rate of 20%, a
of 14 patients per group. The calculation of the
(s) was made according to the following formula:
(
)
2
2
1 96 0 84
2
.
.
n
d
s
+
=
As shown in Fig
As shown in Fig
As shown in Fig
The factor 2 represents a constant; 1.96 is the z value for = 0.05 and 0.84 as
z value for = 0.2; d corresponds to the difference to be recognized in the mean values
the treatment group; s is the standard deviation.
The incidence of 30 persons randomized to the verum and placebo groups was
, thus satisfies the above conditions.

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26
2.1.2 Patient recruitment
The present study corresponds to the criteria of a clinical, randomized dop-
blind study. It was founded by the ethics committee of the medical chamber Westfalen-Lippe
under the registration number 4IISkwara1.
A total of 30 patients with radiologically confirmed knee joint arthrosis (Kell-
gren II or III) in this study. The patients were informed about the
hour of the Orthopedic Clinic of the University Hospital Mnster and from
recruited orthopaedists. At first only unsatisfactory participation was possible
other patients will be won over a newspaper for the study.
In the consultation, patients were given information on the
the course of the disease, the previous treatment regimens, and
on the state of research. In particular, the conservative treatment
with intra-articular injections (eg with hyaluronic acid). Furthermore
patients were informed about the background of the study, the student's
intra-articular injection and the specific side-effects of both preparations.
enlightened. After extensive medical examinations and physical examinations
an explanation was made regarding the use of the permitted accompanying medication
(no non-steroidal anti-inflammatory drugs, if applicable, paracetamol up to a maximum of 2 grams /
day).
If patients were able to follow the strictly tested inclusion and exclusion criteria,
(see below), they were informed about compu-
tered random counters are assigned to one of the two treatment groups.
A preliminary examination with a survey of all patients was carried out
As well as a clinical examination and a gait analysis including EMG
immediately prior to injection therapy.
Since so far no studies with ganganalytic studies for NASHA preparations
, a placebo (physiological saline solution)
which has no influence on the inflammatory processes in gonarthrosis and
has no analgesic effect. An overview of effectiveness
and compatibility of the active ingredient was thus possible.

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27
The patients of the verum group received a single injection with non-
stabilized hyaluronic acid (Durolane) from Q-Med (currently: distribution)
by Smith & Nephew). Patients in the placebo group received a one-
(NaCl 0.9%) from B. Braun, Melsun-
Prior to the injection, possible joint effusions were removed.
In order to ensure close monitoring of success, patients received the question-
the WOMAC, the visual analogue scale and the SF-36
Filling in bi-weekly intervals. After twelve weeks a new one was made
Visits with all surveys and scores, as well as a
trolled gait analysis and electromyography (EMG) by means of the same,
blinds. Furthermore,
effects.
In a study by Krocker et al. there is no improvement after two weeks
Life quality, but after 24 weeks a significant improvement in pain,
the quality of life and the extent of the movement, so that the presumption was expressed
, the effect of stabilized hyaluronic acid may be delayed, but last longer
(78). Since NASHA has an intraarticular half-life of four weeks (7),
in this study, similar to other studies with hyaluronic injections (82, 95, 104,
114), a follow-up period of three months.
2.1.3 Inclusion Criteria
The inclusion criteria are listed below:
o Men and women between 35 and 80 years
o Radiological secured knee osteoarthritis (Kellgren II - III)
o pain after the VAS scale of 40 mm
o Chronic pain for at least 6 months
o Lequesne index of at least 10 at baseline
o patients with otherwise well nourished / general condition
ensuring patient compliance o

o Signed informed consent

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28
2.1.4 Exclusion Criteria
The exclusion criteria include:
o alcoholics, drug or drug addicts
o patients with mental illness, epilepsy or suicide risk
o women of childbearing age
o people, not the auditor's opinion the patient consent form
or have a high non-compliance
o Participation in a clinical trial within the last 3 months, or at the same
timely participation in another clinical trial
o Known intolerance to an ingredient of the test product
o Acute hemarthrosis or acute joint effusion, which makes a puncture required
o patients with non-osteoarthrotic joint disease (inflammatory Gelenker-
(polyarthritis), lesions of the ligaments, complete resection of the meniscus,
Chondrocalcinosis, Sudek's atrophy)
o Permitted previous surgery less than three months
o coxarthrosis with a severity, which affect the functionality of the knee
enced
o Axial deviation of more than 15 degrees in valgus or varus position (X)
o clinically significant medio-lateral or anterior-posterior instability
o evidence of Retropatellar arthrosis
o Other diseases that a contraindication to corticosteroids or hyaluronic acid
songabe (cancer, infections)
o presence of a contraindication for intra-articular treatment (Infektio-
skin damage and skin diseases in the vicinity of the injection site)
o Intra-articular joint treatment within the last 6 months using
of hyaluronic acid or glycosaminoglycan-containing substances
o Intra-articular joint treatment within the last 3 months using
of corticoid-containing substances
o Severe systemic diseases (eg., tumor diseases)

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29
o Uncontrolled diabetes mellitus or uncontrolled thyroid disease
o use of anticoagulants
o presence of a concurrent disease or taking concomitant medication
(non-steroidal antiphlogistics, antidepressants, neuroleptics, and the like), during the
Duration of the study, which would influence the evaluation of the study
o Peripheral neuropathy
o Existing or suspected infections arthrogenic
2.1.5 "Wash-out" phase
Before the intra-articular injection, a one-week "wash-out" phase was performed while
(NSAIDs) who did not receive any non-steroidal anti-inflammatory drugs (NSAIDs)
were allowed. An exception was the daily intake of 100 mg acetylsali-
cylic acid for the prophylaxis or therapy of cardiovascular diseases. Of this
only in one patient of the hyaluronic acid group.
With this measure, the pain status before injection therapy should be as much as possible
accurate and unadulterated. As "emergency medication", patients received
a daily intake of 4 x 500 mg over the entire study period
Paracetamol is allowed. Of the patients who completed the study, however, needed
none this pain medication.
2.2 Studiendesign
2.2.1 Study structure
A prospective, controlled and randomized, double-blind study was
(GCP) guidelines (29), in which a hyaluronic acid-
was compared with a placebo. Both studies were conducted in parallel
controlled conditions ambulatory at the university hospital Mnster of two
Doctors of the Department of General Orthopedics. The doctors were
of the double-blind conditions Patients was injected.
The allocation to the treatment groups was carried out by computer-generated random-
counter. Each group included 15 patients. Study breakers were not affected by new ones

Page 6
2: Materials and methods
30
Patients. Only after the end of the study did the patients receive the in-
to which treatment group they had been assigned.
Twelve weeks after the injection, a final examination with
tion of all relevant parameters.
2.2.2 Principle and timing of data collection
The duration of the study was 12 weeks for each patient. During this period
seven visits were foreseen. The first visit was followed by a screening with
management of injection therapy. At the visits two to six the patients filled
independent questionnaires from which the visual analogue scale, the WOMAC and the SF-
36; a physical examination did not take place. After twelve weeks
the seventh visit took place, in which a follow-up was carried out.
The visits one and seven included the following investigations:
Visite 1:
o Information / informing the patient about the basics and the course of studies
o Clinical examination focusing on the orthopedic examination
o check of inclusion and exclusion criteria
o clarification on allowed concomitant medication
o signing the informed consent
o collecting the visual analog scale of the SF-36, the Lequesne scores and the
Knee Society scores and the WOMAC score
o carrying out the computer-assisted gait analysis and electromyography
o patients numbering (ascending and continuous)
o allocation to a treatment group (hyaluronic acid or placebo) in accordance with
of randomization
o carrying out the intra-articular injection
Visite 7:
o the end of the treatment period
o Where appropriate documentation of adverse events (AEs)

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31
o Review and documentation of concomitant medication
o collecting the visual analog scale of the SF-36, the Lequesne scores and the
Knee Society scores and the WOMAC score
o carrying out the computer-assisted gait analysis and electromyography
2.2.3 Discontinuation of Studies
The study could be interrupted at any time on the patient's request,
on the other hand, if desired by the sponsor or the head of the clinical trial
has been. Similarly, the investigator was able to terminate the study on patient well prematurely. On
serious, undesirable event or a subsequent acquaintance of a
Exclusion criteria were also reasons for a premature termination of studies.
Unacceptable events (UE) included all studies carried out during the studies
disorders, all subjective and objective symptoms (one-
finally changes of laboratory parameters) and all additional diseases
or accidents, regardless of a possible, causal link to the gift
of study medication. In the clinical trial in the medi-
free pre-and post-period, both placebo and hyaluronic acid
and are not yet listed in the test information, were also considered
adverse events.
Severe adverse events (SUE) were events where certainty or
justified suspicion exists that through it life threatened or health
severe or permanent damage. These include death, life-threatening
malignant diseases and diseases that leave permanent damage.
2.3 Questionnaires / Scores
In order to assess the success of therapy in terms of quality of life and functional
in addition to the course analysis, five common questionnaires and scores were used.
o The Knee Society Score (KSS)
o The visual analog scale (VAS according to Huskisson)
o The Lequesne score (ISK = index of severity for osteoarthritis knee)

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32
o The Western Ontario and McMaster Universities Osteoarthritis score index
(WOMAC)
o The Medical Outcomes Study Short Form-36 (SF-36)
Of these scores, the visual analog scale represents the primary efficacy parameter
The goal was an improvement of the VAS by at least 30 mm.
2.3.1 The visual analog scale according to Huskisson
With the help of the visual analog scale according to Huskisson, a quantitative, subjective
Assessment of pain by the patient (46, 64). The patients are
calls for a 100 mm long distance to be felt.
This corresponds to 0 mm of absolute pain-freeness. 100 mm correspond to an un-
bearable pain.
The assessment of the pain by the patient took place both during screening as
also at all visits (1 - 7). An inclusion criterion for this study was a mini-
painter output value of 40 mm.
2.3.2 The Medical Outcomes Study Shortform 36 (SF-36) questionnaire
The SF-36 is used for the standardized recording of health-
without addressing individual diseases (27). 1991 created an international
The International Quality of Life Assessment Group (IQOLA), an in-
internationally available questionnaire. By means of 36 questions on health and the
physical and mental well - being, eight parameters are defined as valid and objective
Assessment of the quality of life.
The SF-36 is suitable for patients from the age of fourteen and allows this
Completed by the patient himself or by an interviewer in direct conversation
or by telephone, whereby in this study the patients completed the questionnaires.
The evaluation of the SF-36 was carried out according to the manual for the German-
curved version of Bullinger and Kirchberger (28). It contains the complete
of the "SF-36 Health Survey Manual and Interpretation Guide."
The parameters are calculated in such a way that a higher value is given to a better health-
state. Accordingly, a high value in the range of the function-

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33
to a better function and a high value in the pain scale
Painlessness.
Table 2-1: Parameters of the SF-36
Parameters (abbreviation)
ask
(Number)
description
Physical function (PF) 10
The extent to which the state of health
perennial activities such as self-care,
Walking and lifting
Physical role (RP)
4
The extent to which the health status
activities and work
Physical pain (BP)
2
Extent of pain and impact
the work
General Health (GH)
5
Personal assessment of health (against
future, resistance)
Vitality (VT)
4
Feeling to be energized, full swing
or tired and exhausted
Social Functionality (SF)
2
Extent in which physical health
or emotional problems normal social ac-
activities
Emotional role function (RE)
3
The extent to which emotional problems affect the
and daily activities
Psychological well-being (MH)
5
General mental health, including
depression, anxiety, emotional and behavioral dis-
control, general agreement on the
Ness
Change of health
1
Assessment of the current state of health
compared to last year
2.3.3 The Western Ontario and McMaster Universities Osteoarthritis Index
The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) is a
Questionnaire for recording the everyday problems of patients with gonarthrosis
(115). In combination with the SF-36,
as well as disease-specific complaints. Based on
24 questions are the three parameters "pain" (5 questions), "stiffness" (2 questions)
and "physical functioning" (17 questions). On a scale of 0 - 10
the patient can self - reliantly and with only a little time - consuming problems
The ability to objectify these parameters.

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34
The WOMAC score is suitable in the daily routine for recording clinically relevant
vanter changes after pharmacological, physiotherapeutic and surgical
intervention. Together with the SF-36, a comprehensive picture of the Le-
quality of the subjects.
2.3.4 The Lequesne function score (ISK score)
The European League against Rheumatism (EULAR) has, in addition to treatment guidelines
for the treatment of osteoarthritis, a patient questionnaire recommended for drug studies,
for evaluation of the knee joint (11). With this questionnaire
information on the areas of pain and discomfort, maximum
distance and on activities in everyday life. The points of these single-
scores are added to a total value at the end.
An inclusion criterion for this study was a minimum score of 10 points. Of the
Lequesne function score was collected again at the last visit.
2.3.5 The Knee Society Score (KSS)
In 1989, the Knee Society Score (KSS) was prepared by the American Knee Society (65).
With its help, the pain, the joint stability and the functionality of a
Joint on an ordinal point scale. A value of 200 corresponds to absolute
freedom of complaint. The lowest possible score is -70. The Knee Society
Score consists of two subareas. The Kniescore summarizes the score of pain-
and the data of a physical examination concerning stability,
constraints and joint deformities. In the function
Point values for the possible walking distance, restrictions when climbing the stairs and
required walking aids.
Although the Knee Society Score has very different aspects regarding the
damaged knee, it is suitable for its reliable and comparable Wi-
of the current state of health was good for longitudinal studies and became
therefore included in this study.
2.4 Computer-assisted gait analysis
The movements and forces occurring during the gait can be combined with the com-
based gait analysis. To assess the

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35
In the case of gonarthrosis patients, movement sequences and the acting forces are the
the lower extremities are of particular importance. In the before-after-
Comparison can lead to pain-induced changes in the gait, Legs
Preservation or already occurring contractures are objectively represented and analyzed
become.
For computer-assisted gait analysis, a computer system is created using
ned body points, a three-dimensional image of the
wegungsablaufs. This figure allows an accurate analysis of the movements in the
large joints.
The computer-based motion analysis can be carried out either with active markers such as Dio-
those which emit light themselves for registration, or with passive, light-
the markers. The data acquisition of the ganglabors of the functional area
Movement analysis in the Mnster University Hospital is performed with passive markers
(Reflector balls with Scotch-Lite foil [ small ball 20 mm; large ball
26 mm]; Helen Hayes Marker Set and Spacer 65 mm, Bright Glue
30 mm x 10 mm). These are adapted according to the Helen-Hayes model to the Acro-
mia, the epicondyli lateral humeri, dorsally between the radius of the wrist
and the ulna, the iliac spine, superiores anteriores, the spinal process of the five-
2 cm above the joint gap of the knee joints
medial as well as lateral, to the lateral lateral and medial artery, the distal Osme-
tatarsale II as well as over the calcaneus. The markers over the calcaneus should be
in standing the same distance from the ground as the balls above the Os Me-
tatarsale II. The imaginary connecting line of both markers corresponds to the longitudinal-
axis of the foot and thus reproduces an image of the foot movement. To calculate the
Articulations are also continued on ball bearings on 65 mm long spacers
lateral to the upper and lower limbs.
The position of the balls in the room is recorded over a seven-meter-long walking distance.
At six points is a permanently installed unit of a light-emitting diode ring
and filtered optoelectrical cameras (Motion Analysis Corporation,
Santa Rosa, USA: 1. Camera Motion Analysis Mac Lite, 2. - 6. Camera: COHU High
Performance CCD Camera 4910 Series, 60 Hz). These direct the captured images directly

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36
to two computers. (1st computer: processor Pentium II-300 MHz, operating system
Windows NT 4.0; 2. Computer processor 80486-60 MHz, operating system DOS 6.22).
These process the data using the software Expert Vision 5.35 and Ortho-
trak 4.2. This results in a three-dimensional point cloud which leads to a simpler Vi-
sualisation, corresponding to the Helen-Hayes model, with lines to a "
male "can be connected. On the movement of the point clouds a
Analysis of the gait cycle.
The measured steps are averaged to an average step cycle
and divided into 100 time units. For each time unit, all the
parameter. Of particular interest are the respective extreme values as well as
the amount of movement in the individual joints.
During the course of the examinations the patients walk over two force measuring plates
Advanced Mechanical Technology, Inc. (& quot; AMTI BP 2416-2000 & quot; and & quot; ORG-5
v. AMTI - 1000 "each with MCA-6 amplifier), which can be used to generate the resulting ground-
forces in three dimensions. The simultaneous recording of the soil reaction forces
by the force measuring plates with 600 Hertz either manually or after triggering
a contact measuring mat concealed on the ground in front of the two force measuring plates
.
In this study, changes of the gait through a knee-
can be recorded. Therefore, in the evaluation of the gait analysis the movements in
the joints of the lower limb in the sagittal, frontal and transverse plane of
interest. Together with the regulations of soil reactors and
the information about the joint positions can be the one effective at the joints
Torques can be determined. As these are absorbed by muscular
must be able to make conclusions about the stress on the respective joints
pull.
2.4.1 Performance of the gait analysis
The evaluation of the gait analysis was based on the study pro-
one study before injection therapy and one control after twelve weeks of

Page 13
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37
chen. At the beginning of the study, the current body-
(in kg), body height (cm) and foot length (cm).
The reflector balls were then placed on the skin. Spacer and
Reflector balls were fixed with non-reflective adhesive strip (Leukofix)
in order to minimize the risk of balls being released during the examination.
In order to perform a stand - up, the patient presented himself at the level of the two
Force measuring plates in the direction of rotation. The goal was to get all the markers from the
cameras over the
Computer. For this purpose, the patient took a slightly spread-out step
10 - 20 externally rotated feet, and abducted both arms to 90 . Could the Com-
the position of the patient was slight
and the recording is repeated.
Subsequently, the medial markers on the malleolus and the femoral condyle were
because these would be a hindrance in free walking and would have influenced the gait.
These measuring points were used to determine the centers of the knee and ankle joint
however, can be dispensed with during the recording of the gait image. For the
In the course of the gait analysis, the patients proceeded from a starting marking in the usual
Speed up to the end of the lab. The return path could also be used as a measuring
be used. As the patient was not informed, a
influenced gait. The execution of some trials, in which none
Measurement, served to acclimatise. For normal step length and gait,
speed with the entire plantar surface of a foot, centered on the force-
the starting position has been adjusted accordingly. All Pa-
served without walking aids.
At least three passages with an optimum impact on the force-
and then the data using the above software
averaged and evaluated. Here the measured data on body weight
and size as well as foot length of the patient normalized to them later independently of these
Variables. A copy of the evaluation can be found in the
Patient records, one in digital memory.

Page 14
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38
2.5 Electromyography
During the performance of electromyography, single-
an electromyogram of the maximum activity. In connection with
followed by a recording of the EMG when walking freely. The EMG was derived from the
M. rectus femoris, the Mm. vasti medialis and lateralis, the semitendinosus, the bi-
ceps femoris, the tibialis anterior, and the medial of the gastrocnemius muscle
Muscles, whose activity is particularly related to the movement and stabilization of the knee-
jointly.
At the beginning of the study the maximum voluntary tension of the ventral and
dorsal muscle groups on the upper and lower limbs. It followed on one
Distance of approx. 20 m a measurement of the resulting muscle action potentials
normal speed above the above mentioned muscles. In order to reduce the
to reduce the normal speed, the cables ran through a
friendly guide rail.
The recorded steps, divided into 100 time units,
software MyoResearch98 represent a representative step sequence
the evaluation included the maximum and mean values of each muscle.
An EMG signal to be evaluated should have a minimum duration of five percent of the Gain-
the amplitude should be at least five percent of the maximum arbitrary
(voluntary contraction = MVC) (94).
2.5.1 EMG measurements
According to the study protocol, an epicutaneous EMG-
Pre-injection monitoring and a 12-week follow-up.
A felt tip pen and two-hole template (distance 2 cm)
for placing the surface electrodes (Medicotest, Denmark, Blue Sensor
Type N-50-K) on the skin. For exact positioning of the electrodes
the widest point of muscle growth, and thus both to improve the
as well as for better reproducibility, the patient clamped the muscle
at. In order to lower the skin resistance and improve the dissipation quality,
before applying the adhesive electrodes the skin with a peeling paste (Orlimed,

Page 15
2: Materials and methods
39
Germany, Nuprep Skin Prepping Gel) and then with 70%
Isopropanol.
The aim was to reduce the skin resistance to below 6 k in order to reduce the voltage
and the surface EMG signal
as few artifacts as possible. Exceeding the resistance 6 k, the
Skin again treated with the above gel or a roughening fiber pencil and a
new electrode is used.
If the resistance was below 6 k, the electrodes were connected to the computer.
In order to influence the gait image as little as possible through the cables, these were combined
with
a mesh hose (Krewifix) and a belt, and during the un-
examination using a guide rail behind the patient. The grounding
followed by an additional electrode equipped with Gel (Aquasonic)
joint.
The measurement data were obtained by an EMG amplifier (Noraxon, USA, MyoSystem
2000) and a computer (processor: Pentium 450 MHz, operating system: Win-
dows 98) is recorded and recorded and then, with the aid of a special soft-
ware (MyoResearch98). The raw data was rectified
and a normalization to a gear cycle (= 100%). Subsequently,
into an Excel table.
At the beginning of the measurement, the examiner checked all channels for potential artifacts.
The patient was used to determine the maximum activity of the tibialis anterior
asked, lying on the examination table, at about 10 plantar flexion
trainees ankle maximum dorsiflexion against the hand of the examiner
to lead. The investigation of the gastrocnemius muscle was also performed in the supine position.
Here-
led to the patient, starting from the neutral zero position, a maximum plantar
flexion against the resistance of the examiner through.
To measure the activity of the quadriceps, the Mm. vasti medial and
lateralis, the semitendinosus and the biceps femoris sat down with the patient
free-hanging legs on the examination table, so that the knee in the source
position was flexed to 90 .

Page 16
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40
The maximum activity of the semitendinosus and the biceps femoris was overall
measured by the patient's knee with maximum force against the manual
bending resistance of the examiner. With an aspect ratio in the knee against manual
Resistance finally the maximum activity of the quadriceps were
and the two Mm. vasti measured.
Following the specific examination of individual muscles there was a Aufzeich-
planning of the complex interplay of all the tested muscles during walking.
To this end, the patient repeatedly durchgequerte the gait laboratory, so that at least 20
Gang cycles were recorded. To assign the EMG activity of individual
Phases of the gait cycle have been with a step-synchronous actuation of two jog
Switch integrates the steps in the recorded EMG and together with the
Software processes.
2.6 implementation of injection therapy
In this double-blind study was either a placebo or a Hyaluronsurepr-
ready injected intra-articularly into the knee joint under sterile conditions. injection
carried out according to the guidelines of the DGOOC for intra-articular punctures and
Injections (41).
2.6.1 Intra-articular hyaluronic acid injections (Durolane)
According to the study protocol the treatment group was one in every patient
Injection with the preparation Durolane (Q-Med AB, Uppsala, Sweden [Distribution by
Smith & Nephew) is performed.
Durolane consists of highly concentrated, non-animal, stabilized hyaluronic acid
with a molecular weight of> 1 million Daltons. Conventional preparations included in the
Rule application doses 15-30 mg (105). contains a pre-filled syringe Durolane
a viscoelastic solution containing 60 mg of non-animal, stabilized hyaluronic acid
(NASHA) and 3 ml of physiological saline solution (pH 7.0), and is in a versie-
apply sterile package delivered. Both the syringe and the solution
sterilized according to the DIN EN 554 and EN 556 with humid heat. This represents a WE
sentlichen view to contributing to safe use. Using a 20 gauge needle
and in strict compliance with sterile conditions and in compliance with general

Page 17
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41
Precautions for performing intra-articular injections was the pre-
ready by an experienced physician over a lateral, patellofemoral access path in
the knee joint gap injected. Thereafter, patients were encouraged by
to im- movement of the knee joint without stress distribution in the joint space
fibers. The doctor performing was neither in the investigation nor the Auswertun-
gen involved to ensure blinding of the investigator safe.
2.6.2 Intra-articular injection of a placebo preparation
According to the study protocol the placebo group was one in every patient
Injection of 3 ml of physiological saline (NaCl 0.9% of B. Braun,
Melsungen) is performed.
Physiological saline solution does not affect inflammatory reactions and
no analgesic effect and is therefore an optimal placebo.
The injection of the placebo was as for the treatment group also with a 20 G
Cannula and in strict compliance with sterile conditions and compliance with the general
my precautions to carry out intra-articular injections. That too
Placebo preparation was by an experienced physician over a lateral, patellofemora-
len access route injected into the knee joint gap. Then the patients were
also stopped, by motion of the knee joint without load distribution
to improve the joint space.
2.7 Statistical analysis of the data
Each study group consisted of 15 participants. In the verum group, four patients and three in the
placebo group terminated the study prematurely. Were aware
small study groups chosen an orientation impression of the
to gain efficacy of non-animal, stabilized hyaluronic acid.
were used in the statistical evaluation for significance of the longitudinal results
various statistical methods are used. The data as Excel spreadsheets
(Microsoft "Excel", Version 2002, Microsoft Corporation, Seattle, USA)
templates were first used to calculate mean values and standard deviations
gen and the formation of frequencies and for graphic display in the pro-

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42
program collection "Statistical Package for the Social Sciences" (SPSS version 11.5,
the company SPSS Inc., Munich, Germany) exported.
Leads to a statistical comparison of mutually exclusive groups of two by,
is generally formulated null hypothesis (H ): There is, with respect to the verified
0

Features no difference between the effects of the compared preparative

te. The alternative hypothesis (H ) is accordingly that at comparable between the two
1

equal groups with respect to the examined characteristics, a significant under-

difference is present. As a probability of error for all statistical evaluations
an of 5 percent (p0.05). If the statistical test reveals an error
greater than 5%, the differences in
and the null hypothesis. If the statistical test yields an error-
probability is less than or equal to 5 percent, the null hypothesis is rejected and
the alternative hypothesis is assumed.
It should be noted that all tests in this study were carried out unilaterally,
ie the differences found to be a better effect of the drug
compared to placebo.
For the individual characteristics, simple test variables such as mean value,
dian, standard deviation and frequency. Subsequently,
Characteristics of both groups by means of comparative procedures. Da die Merkma-
le are not normally distributed in the study population by testing, were non-para-
metric test method of application. In the evaluation of the questionnaires there
seven each paired samples, making this the Friedman test (so-called. non-
parametric analysis of variance) was used. The gait analysis and EMG training
evaluation consisted of two samples (before, after), so that here the Willco-
xon signed rank test for two related variables has been selected.
The application of non-parametric tests has even with small numbers of cases a
good selectivity and a board particularly suited for nominal and ordinal data
net, as these are not normally distributed normally.
The results of this study are listed below.

Page 19
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43
3
Results
The results of this study are presented within each of the scores of the questionnaires and
divided the investigations. If the results are listed according to individual patient
encrypted, each patient is provided with an individual code. All significant
Changes were highlighted. If there is no indication of the significance,
the result was not significant.
3.1 drop-outs
Of the original 30 patients only 23 were both up appointments
perceived, in the evaluation.
Table 3-1: drop-outs
No. Abbr. Preparation
Gender Age Cause

Table 3-1: Study drop-out

No. Abbreviation Preparation Sex Age Cause
1 TK3 Durolane Male 39 Pain, dissatisfaction
2 NA7 Placebo Female 56 Disc prolapse; therefore casual pain
3 HE8 Durolane Female 77 knee-TEP before control examination
4 GA7 Durolane Female 56 Pain, dissatisfaction
5 ND6 placebo male 48 arthroscopy 3 weeks after injection
6 NA5 Durolane Female 59 Pain, dissatisfaction
7 AE6 Placebo Female 49 Pain, dissatisfaction

Of the seven patients who have not completed the study, were among four of the Verumgrup-
pe on. A total of six of the seven patients discontinued the study due to lack of
Efficacy and persistent pain from where two patients already on
Follow-up visit an invasive therapy (arthroscopy, knee replacement) carried
had been leading.
Another patient experienced during the study period herniation
and took pain medication for high doses of NSAIDs, a so
that they had to be excluded from the evaluation. Since these patients
only one record exists, these results are not included in the evaluation.
All other data relate to the remaining 23 participants.

Page 20
3: Results
44
Unwanted side effects attributable to the study treatment
were, did not occur.
3.2 Prospective course of the study population
In hyaluronic acid group ended 11 patients (6 males, 5 females) ER the study
successful. The average age of these patients was 61.3 10.9 years. nine of these
Patients had a Kellgren stage II, two a stage III. Three women and a
Man of the hyaluronic acid group withdrew from the study prematurely. They were throughput
average four years older than the other study participants. Radiological corresponded
two drop-outs a Kellgren stage II and a two stage III.
As regards compliance with the visit dates, the study participants proved
compliant. The follow-up visit was an average of 13.8 2.1 weeks
the studies have begun.
In the placebo group of twelve patients completed (9 men, 3 women) successful study
rich. The average age of these patients was 53.4 years 12.8 years. nine patients had Kellgren stage
II, three and a Kellgren stage III. The
Volunteers (three female, one male), the premature from the placebo group, the study
tig discontinued, two years younger than the rest of the study population on average.
Radiological met two university drop a Kellgren stage II and a
Patient one stage III.
As regards compliance with the visit dates were the study participants in the placebo
group also compliant. The follow-up visit was average
13.3 2.5 weeks after baseline.
3.3 Safety of the investigational
All subjects received an intraarticular injection. One of the study dropouts from the hyaluronic acid
group reported post-interventionem over a new one
occurred Baker's cyst. However, this is more likely within the framework of the basic disease than
caused by the therapy
Page 21
3: Results
45
One patient in the placebo group, which is then not into account in the evaluation
into account was, suffered a herniated disc in the course. This event is aller-
recently also not be seen in causal relationship with the treatment.
Another patient in the placebo group was excluded from the study because he
perform at persistent complaints arthroscopy with cartilage smoothing
left. About side effects of the study medication, the patient did not complain.
Other adverse events (AEs) or serious adverse events (SAEs)
did not occur.
3.4 Results of the questionnaires / scores
3.4.1 Results of the visual analog scale (VAS)
Neither in the verum and the placebo group occurred on the visual analog
Scale to a significant change.

[use data from the tables in the PDF[

3.4.2 Results of the Lequesne scores

The Lequesne score was respectively in the first and the last visit based on patent
tientenangaben determined. A decrease in the value in this point score corresponds egg
ner improve knee function and pain reduction.
In the treatment group, all patients reported a significant improvement in
Scores on average 15.3 percent (p = 0.005). In the placebo group could likewise
if a significant improvement can be achieved by 23.0 percent (p = 0.012).

Page 22
3: Results
46
0.00
2.00
4.00
6.00
8.00
10.00
12,00
14.00
verum
placebo
group
P
unktwe
rt
visit 1
visit 7
Figure 3-2: Number of points during the Lequesne scores
3.4.3 Results of the Knee Society scores
The Knee Society Score was also determined in the first and the last visit.
Looking at the total point value in the Knee Society score occurred in the verum
group to a significant, improvement on average by 12.5 percent
(P = 0.011).
0
20
40
60
80
100
120
140
160
knee score
function Score
total score
P
unktwe
rt
visit 1
visit 7
Figure 3-3: Number of points during the Knee Society score in the verum group
In the placebo group also is reflected in the total score, a significant improve-
provement. This average was 8.2 percent (p = 0.024).

Page 23
3: Results
47
0
20
40
60
80
100
120
140
160
knee score
function Score
total score
P
unktwe
rt
visit 1
visit 7
Figure 3-4: Number of points during the Knee Society score in the placebo group
Looking only at the knee or the functional score, the improvement in both
Study groups was not significant.
3.4.4 Results of the WOMAC score
The WOMAC score was recreational by questionnaire in two weekly intervals
ben. To improve comparability is a subdivision of the total score, as well as in
the three cores listed.
The total score was in the active treatment group no significant change in the plan-
however, cebogruppe a significant improvement of 31.9 percent in the sixth
Visit (p = 0.05).
The assessment of stiffness and function occupied either in the verum still in
Placebo group significant changes.
The pain score, however, showed both the active treatment and the placebo group
significant changes. In the treatment group, the average output was
value was 4.1 2.2. For the second round, the score improved significantly by 29.3
Percent (p = 0.004). After a slight deterioration in four weeks after the
Injection therapy resulted in a significant improvement of the sixth round
19.5 percent compared to baseline (p = 0.026).
Just as in the active treatment group improved in the placebo group of pain
score significantly. The average score was initially at 4.3 1.5 and improved

Page 24
3: Results
48
by 23.3 percent in the fifth visit (p = 0.05) and in the sixth rounds to
34.9 percent (p = 0.034) compared to the baseline.
2.50
3.00
3.50
4.00
4.50
5.00
1
2
3
4
5
6
7
visit
P
u
n
k
tw
e
rt
Pain score Verum
Pain score Placebo
Total score Verum
Total score Placebo
Figure 3-5: Total and pain scores of WOMAC
3.4.5 Results of the SF-36
The SF-36 were significant changes in the treatment group in two dimensions
on. There were in the subgroups "physical role" and "physical
Pain "significant improvements. In the placebo group, there were only in
The "physical pain" a statistically significant improvement.
The dimension "physical role" describes the impairment of daily
union activities and the work of the general health. In the
Verumgruppe this score of the first improved by the last visit
125.0 percent (p = 0.040).
be the extent of the pain with the "physical pain" and
detects the resulting effects on the work. This point value comparable
improved in the treatment group from the first to the fifth round by 30.3 percent (p =
0.040). In the placebo group, a significant improvement of the point value kicked
30.8 percent of the first to the sixth visit (p = 0.036).
No statistically significant changes arise for all other areas.

Page 25
3: Results
49
15
20
25
30
35
40
45
50
55
60
65
1
2
3
4
5
6
7
visit
P
u
n
k
tw
e
rt
physical role Verum
physical role Placebo
physical pain Verum
physical pain placebo
Figure 3-6: Results of the SF-36 (physical role function and pain)
3.5 Results of computerized gait analysis
Basis for, in the gait analysis investigations, determined kinematic
and kinetic data is a double step (= 100% of the gait cycle). this corresponds
speaks to the time interval between two heel performances on the same side
and includes stance and swing phase. were measured both general gait
parameters such as speed, stride length, cadence and stride length, as
Also, the movement amounts of the hip, knee joint and the ankle joint in
three levels. were from these kinematic data, in conjunction with the data of the
Force plates, determines the Extensions, flexion and Abduktionsmomente.
In both study groups were able to to improve the minimum knee joints
lenksflexion by 15.7 percent (p = 0.041) in the placebo group, no significant
Changes in the collected data are determined.
3.6 results of electromyography
In the electromyographic investigation initially carried out to measure the maximum
paint voluntary contraction (MVC) of selected muscles were then
EMG-signals derived during the free walking.

Page 26
3: Results
50
0
20
40
60
80
100
sts
c
tu
s
fe
moris
M. v
a
s
tu
s
med
ia
lis
M. v
a
s
tu
s
late
ra
lis
M. s
e
mini-
th
n
d
in
O
s
u
s
M. b
ic
e
p
s
fe
moris
M. tibia
lis
a
n
th
rior
M. g
a
s
tro
-
c
n
e
m
ius
MV
C
(
V
)
treated Visite1
Treated Visit 7
Untreated Visit 1
Untreated Visit 7
Figure 3-7: Measurement of the maximum activity in the EMG (treated group)
0
20
40
60
80
100
sts
c
tu
s
fe
m
O
ris
M. v
a
s
tu
s
med
ia
lis
M. v
a
s
tu
s
late
ra
lis
M. s
e
mini-
th
n
d
in
O
s
u
s
M. b
ic
e
p
s
fe
m
O
ris
M. tibia
lis
a
n
th
rior
M. g
a
s
tro
-
c
n
e
m
ius
MV
C
(
V
)
treated Visite1
Treated Visit 7
Untreated Visit 1
Untreated Visit 7
Figure 3-8: Measurement of the maximum activity in the EMG (placebo group)
Considering the EMG of both study groups, show up at all measurements
Activity increases arbei- from the proximal to the distal, against gravity
Tenden muscles. The highest reading is the tibialis anterior. It is noticeable that
in the placebo group mostly higher activity in both tests than in
the treatment group were measured. In both study groups, there was for all measurements

Page 27
3: Results
51
gen very high standard deviations by large inter-individual fluctuations
gen are related.
At the vastus lateralis showed in the treatment group on the treated side
significant activity loss by 43 percent (p = 0.01); participated in the vastus medialis
the activity decreased by 28.4 percent (p = 0.033). In the placebo group, the comparison achieved
changes not the level of significance.
A significant decrease in activity in the biceps femoris was only in the placebo group
on the treated side (p = 0.041).
On the remaining muscles were no significant changes in both showed
Groups.
Following the measurement of the maximum activity, the EMG was during the
free walking recorded. Here, about 20 double steps were included in the calculation
the patient-specific EMG pattern. The electromyographic measurements
free transition resulted in the following differences and similarities:
In both groups showed only a few muscles significant Aktivittsnderun-
gen. In the treatment group the% MVC value of the vastus lateralis took on the loading
-treated (p = 0.021) of the tibialis anterior to the untreated side
(P = 0.033) was added. This value is the percentage of the maximum arbitrary
Lich applied force of contraction that is achieved during free walking. fell further
an increase in the average activity in the tibialis anterior of untreated
th page (p = 0.041). In the placebo group, the peak activity at M. took biceps
femoris on the treated side by 16.6 percent (p = 0.033). The% MVC value
of the gastrocnemius muscle on the same side also decreased significantly (p = 0.016).
A lower activity of the quadriceps femoris on the treated side, which
would be characteristic of osteoarthritis, read not be determined in this study. in the
Contrary, in this study were all values for the quadriceps on the
treated side slightly higher than those of the untreated side, but these are lower
differences not significant.
Consistently fell on high peak and average values for the tibialis anterior,
explains the subcutaneous fatty tissue by the only slightly pronounced pretibial

Page 28
3: Results
52
can be. This fact simplifies the derivation of surface electrodes
the decisive role in the tibialis anterior muscle.
0
5
10
15
20
25
30
35
40
45
sts
c
tu
s
fe
moris
M. v
a
s
tu
s
med
ia
lis
M. v
a
s
tu
s
late
ra
lis
M. s
e
mini-
th
n
d
in
O
s
u
s
M. b
ic
e
p
s
fe
moris
M. tibia
lis
a
n
th
rior
M. g
a
s
tro
-
c
n
e
m
ius
center
lwe
rte
(
V
)
treated Visite1
Treated Visit 7
Untreated Visit 1
Untreated Visit 7
Figure 3-9: mean values of the EMG measurements (verum) during free walking
0
5
10
15
20
25
30
35
40
45
M
, re
c
tu
s
fe
m
O
ris
M
,v
a
s
tu
s
m
e
d
ialis
M
,v
a
s
tu
s
late
ra
lis
M
,s
e
m
i-
th
n
d
in O
s
u
s
M
,b
ic
e
p
s
fe
m
O
ris
M
, tibia
lis
a
n
th
rior
M
,G
a
s
tro
-
c
n
e
m
ius
M
itte
lwe
rte
(
V
)
treated Visite1
Treated Visit 7
Untreated Visit 1
Untreated Visit 7
Figure 3-10: mean values of the EMG measurements (placebo) in the free walking

Page 29
3: Results
53
0
20
40
60
80
100
sts
c
tu
s
fe
moris
M. v
a
s
tu
s
med
ia
lis
M. v
a
s
tu
s
late
ra
lis
M. s
e
mini-
th
n
d
in
O
s
u
s
M. b
ic
e
p
s
fe
moris
M. tibia
lis
a
n
th
rior
M. g
a
s
tro
-
c
n
e
m
ius
S
pitz
e
nwe
rte
(
V
)
treated Visite1
Treated Visit 7
Untreated Visit 1
Untreated Visit 7
Figure 3-11: peak values of the EMG measurements (verum) during free walking
0
20
40
60
80
100
sts
c
tu
s
fe
m
O
ris
M. v
a
s
tu
s
med
ia
lis
M. v
a
s
tu
s
late
ra
lis
M. s
e
mini-
th
n
d
in
O
s
u
s
M. b
ic
e
p
s
fe
m
O
ris
M. tibia
lis
a
n
th
rior
M. g
a
s
tro
-
c
n
e
m
ius
S
pitz
e
nwe
rte
(
V
)
treated Visite1
Treated Visit 7
Untreated Visit 1
Untreated Visit 7
Figure 3-12: peak values of the EMG measurements (placebo) during free walking
When considering the output values of individual muscles there remain some
Abnormalities.
The% MVC values of the rectus femoris, vastus medialis, the vastus latera-
lis and the biceps femoris were in the placebo group, both before the study as
also to study termination on both sides considerably lower than the% MVC values of the Verum
group.

Page 30
3: Results
54
Only the% MVC values at semitendinosus were at the same level. The
Values for the tibialis anterior and the gastrocnemius were in the placebo group
over which the treatment group.
0
50
100
150
200
250
300
sts
c
tu
s
fe
moris
M. v
a
s
tu
s
med
ia
lis
M. v
a
s
tu
s
late
ra
lis
M. s
e
mini-
th
n
d
in
O
s
u
s
M. b
ic
e
p
s
fe
moris
M. tibia
lis
a
n
th
rior
M. g
a
s
tro
-
c
n
e
m
ius
%
M
V
C
treated Visite1
Treated Visit 7
Untreated Visit 1
Untreated Visit 7
Figure 3-13:% MVC values of the EMG measurements (treatment group)
0
50
100
150
200
250
300
sts
c
tu
s
fe
m
O
ris
M. v
a
s
tu
s
med
ia
lis
M. v
a
s
tu
s
late
ra
lis
M. s
e
mini-
th
n
d
in
O
s
u
s
M. b
ic
e
p
s
fe
m
O
ris
M. tibia
lis
a
n
th
rior
M. g
a
s
tro
-
c
n
e
m
ius
%
M
V
C
treated Visite1
Treated Visit 7
Untreated Visit 1
Untreated Visit 7
Figure 3-14:% MVC values of the EMG measurements (placebo group)
Because only a few significant changes during the EMG measurement is the
Assessability the investigation clearly limited.

Page 31
4: Discussion
55
4
discussion
4.1 General Discussion
The aim of this study was to further development of established a
th, conservative treatment method of osteoarthritis of the knee to its efficacy,
compared with a placebo preparation to test.
To this end, comparisons were a total of 30 patients with radiologically proved nacelle
arthrosis regarding the effects of intraarticular injected, non-animal,
stabilized hyaluronic acid (Durolane) and those of a placebo preparation (physiolo-
cal saline) to the quality of life that felt pain, the gait
image, the muscle activity in the electromyogram and clinical joint function throughput
guided.
As part of this study showed under therapy with non-animal, stabilized
lized hyaluronic few significant changes both in the questionnaires
gen and scores for quality of life, and in the transition analytical assessment. INS
special on the visual analog scale, as the primary efficacy variable, it came
no significant improvement of symptoms in one of the two study groups. Si
gnifikante improvements in the questionnaires and scores were only in the Lequesne
Score, the WOMAC pain score of and concerning "physical pain" in
find SF-36. However, the results of the verum and the plan- distinction
cebogruppe not significant. includ- in the gait analysis study
Lich electromyography occurred in any study group to a significant improvement
tion of the gait pattern under the therapy.
Ultimately could in this study of patients with osteoarthritis of the knee no superiority
overall intra-articular injection with non-animal, stabilized hyaluronic acid
genber be an injection shown with a placebo. Accordingly
the null hypothesis could not be discarded.
4.2 Methods criticism
4.2.1 choice of sample size
To calculate the number of cases a dropout rate of 20% was assumed. The dropout rate in the
treatment group was 26% and in the placebo group it was 20%

Page 32
4: Discussion
56
pe at 20%. As the number of cases not at 14 but 15 participants per study group
was, gave this to mean a difference of 30 mm between the
Scores on the visual analogue scale, with a significance level of 5%
to recognize and a selectivity of 80%.
Despite the small group sizes, therefore, is a valid statement about the effectiveness
the investigational possible.
4.2.2 choice of patient population
The choice of the patient group was carried out by a rigorous review that the study programs
serving protocol-defined inclusion and exclusion criteria.
As evidence of a deterioration in the quality of life in various study programs
dien required on the visual analog scale output values between 30 and 40 mm,
wherein 40 mm on a visual analogue scale in the overwhelming number of cases
Eingangsvorrausetzung (66, 68, 87, 95). This criterion is also this work
based.
At the beginning there was a two-week wash-out phase in which no non-steroidal
Anti-inflammatory drugs could be taken to ease the pain status unver- possible
falsifies display. Also during the entire course of the study was a dose
not permitted by NSAIDs. was only allows emergency
medication with a maximum of 4 x 500mg paracetamol.
Another inclusion criterion was an age between 35 and 80 years.
This wide range was deliberately chosen to determine the effectiveness of the entire patent
to investigate tientenkollektiv with osteoarthritis of the knee. Younger patients were excluded
closed. With them is often a secondary osteoarthritis shape due to congenital miscarriage
settings or accident before. This may be due to the different genesis
have other curve forms. The upper age limit of 80 years was up
due to the probable multi-morbidity in old age, leading to a comparison
would result in forgery of examination results, set. Through the large Al-
ters differences, however, comes a distortion in the gait analysis investigations
gen and the questionnaires and scores on which the benefit of the wider patient
collective tolerated.

Page 33
4: Discussion
57
4.2.3 Composition of the study population
The composition of both groups are shown in Table 4-1. In brackets are per-
indicated sonen charged of the original participants relating other numbers
to the subjects who completed the study complete.
 Table 4-1: Composition of the study population
patient population Verum (Durolane) Placebo (NaCl)
number of patients 11 (15) 12 (15)
Men 6 (7) 9 (10)
women 5 (8) 3 (5)
Age (years) SD 60.2 11.6 52.3 12.0
Height (cm) SD 171.1 8.7 169.1 6.1
Weight (kg) SD 84.91 12.78 82.29 6.45
BMI (kg / m) 29,00 28.89
Kellgren II 9 (11) 9 (11)
Kellgren III 2 (4) 3 (4)

In terms of body size, body weight, body mass index and the Kell
grenstadium show comparable both groups, wherein it is striking that in both
Groups significantly more patients are assigned to the Kellgrenstadium II.
Regarding the gender distribution shows despite randomization in the placebo
group is a clear predominance of the male participants (p = 0.014). WEI
terhin striking that the patients in the placebo group jn- average of eight years
ger than in the HS group. However, this difference is not significant, so that
the groups can be considered comparable in this respect.
As women indicate on the visual analog scale significantly higher scores than men
(34) would be expected to consistently significantly higher in the treatment group. In the
Visits 1-4 and 7, the value reached was on the visual analogue scale but in the plan-
cebogruppe over the treatment group. In the rounds 5 and 6, he was not only safety-
gnifikant lower than in the Verum group.
In the SF-36 male volunteers reached in almost all dimensions higher scale values
as female subjects of the same age group (28). Further, the point value falls

Page 34
4: Discussion
58
for the dimensions of the physical condition of the lower, the younger the
Subjects (28). Looking at the averages are almost in the placebo group
consistently found higher values than in the active treatment group. This observation
well by the male and younger patients predominance in the
explain placebo group. However, since the composition of the study population
during the study period remained constant, the significance of the results is not
substantially restricted.
Despite the 23 percent comparatively high rate of dropouts was the
required sample size of eleven patients per group for a meaningful assessment
necessary the study (see above) are complied with.
4.3 side effects
Which occurs in about 15 percent of cases granulomatous inflammation is the most common
Side effects after injection with hyaluronic acid Hylan GF 20, a cross-linked,
high molecular weight (6000 - 7000 kDa) hyaluronic acid (30, 42). Under the use of
non-animal, stabilized hyaluronic acid with lower molecular weight
(1000 kDa) has not yet occurred this type of inflammation. Other well-known
Side effects of hyaluronic acid injections are allergic reactions in threaded
reversible 3 weeks ago - voltage of hyaluronic acid based on animal and a within about 1
sible swelling or redness of the joint, possibly connected to a Bewegungsein-
restriction in terms of increased joint stiffness. The latter side effects are
However, often indistinguishable from the symptoms of the underlying disease (4). Rare
If there is septic infections knee (67), said yet a contami-
were due mination of the drug. comes at extra-articular injection
it cause temporary pain subside spontaneously. In the present study
none of these side effects have been observed.
One of the university dropouts reported post-interventionem a newly aufgetrete-
ne Baker's cyst. This is rather in the context of the underlying disease than by the
to evaluate therapy itself.
Other side effects were observed in either group. The
Main cause of dropout provides insufficient relief of symptoms

Page 35
4: Discussion
59
by the medication in both groups. One patient chose to transit
management of a total endoprosthesis before the check-up. Overall, the comparison
presumption of the low rate of side effects by NASHA hyaluronic confirmed WOR
the.
4.4 Special methods criticism
4.4.1 questionnaires and scores to changes in the quality of life
Below are summarized the changes in percent of output
WORTH pain, stiffness and function of the placebo group where the verum
group compared. In each case, the best average of all visits. fat
shown are changes that have reached the level of significance.
Table 4-2: Comparison of percentage improvement with placebo and
Verum injections in the individual scores
parameter
used Score
placebo
verum
VAS
- 54%
- 54%
SF-36 * (Physical pain)
+ 44%
+ 44%
Pain
WOMAC (pain)
- 58%
- 44%
rigidity
WOMAC (stiffness)
- 62%
- 47%
SF-36 * (physical activity)
+ 42%
+ 41%
Lequesne
- 23%
- 15%
Knee score (Function Score) *
+ 5%
+ 2%
function
WOMAC (Function)
- 56%
- 40%
* An increase in the point value in the SF-36 and in the knee score correspond to a complaint
acceptance.
Looking at the table it should be noted that the visual analog scale, the
WOMAC and SF-36 has been collected in seven visits. Whereas in the statistical
calculating the activity tables designate the average values of the individual visits
seeks were, here are the average minimum and maximum values from all visits
averaged. Therefore, the percentage differences in the above graduated Ta appear
belle significantly larger than they are in the statistical analysis in the form of significant
represent edges changes. The Lequesne score and the knee score, however,
were determined only at baseline and after twelve weeks, so that the throughput

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60
-average minimum and average maximum the changes directly
reflect. It can be noted that the percentage improvement in the single-
NEN scores largely corresponds in the verum group the improvement in the placebo group
spoke. In both groups were comparable, significant changes in the SF-36
and in the WOMAC concerning the physical pain and the Lequesne score on.
By Krocker et al. observed superiority of Durolane against a plan-
ceboprparat in "Knee and Osteoarthritis Outcomes Score" (KOOS), in the "European
Quality of life score (EQ-5D) and the visual analogue scale (VAS) was based on the
not be confirmed selected questionnaires (78). This is consistent with the observation
obligations of Altman et al. The study group of Altmann et al. could not
significant improvement in WOMAC score in the group non-animal,
stabilized hyaluronic acid was injected notice (7). The gefunde- in this study
corresponded nen, significant changes with pain and function
Chen approximately to those of the placebo effect. therefore, they are in no way opposed to the
by means of questionnaires for daily activity data collected by Akermark et al. These
Study Group noted an improvement in symptoms after injection of non-animations
Lischer, stabilized hyaluronic acid fixed on the knee joint, without the results of a
Placebo group to face (3).
4.4.2 Computerized Gait Analysis
The gait analysis investigations as reasonable in other hyaluronic acid studies
Wundt were to allow for good sensitivity an objective, prospective documentation
tation of the effects of intra-articular injections of the gait (95.114, 117).
In the evaluation is to be noted that sub-phases in the course of the disease
schiedlicher pain intensity occur. So it may be that patients who exclusively
complain dominated pain, relatively painless, or the time of examination so-
are not symptom-free and, accordingly, the gait is only slightly affected.
This circumstance can comparative statements about ground reaction forces, Gangge-
affect speed, stride length or joint loads.
By the method of gait analysis leads to restrictions on Beurteil-
bility. In the functional area Motion Analysis at the University Hospital Mnster based

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61
the transition analysis system on the recording passive, light-reflective marker,
which must be carefully placed. guarantees only a precise attachment of the markers
advantage good reproducibility of the investigation. However, this is different
dene, external circumstances difficult. This concerns mainly the marker at the iliac ante
rior superior. In obesity, bony structures are significantly worse palpation
bel, making it difficult to pinpoint attachment. In coexistence
pronounced fat aprons can advertising the markers in addition obscured or moved
the. Consequently, the actual joint movements of relative Hautbewegun- be
gen superimposed. Since the additional stress on the joints in obesity egg the emergence
ner primary osteoarthritis of the knee supports, is also this phenomenon in the present study
to be considered (body mass index: verum group: 29,0 kg / m; placebo group
28.9 kg / m). In good agreement of the body mass index between the two
Study populations is given a comparison of both groups.
In the present study did not differ whether the patients once or
bilateral primary gonarthrosis suffered. Basically, the overall more concerned was
steering treated. However, if the disease on both sides and this affects the under-
suchungsergebnisse. So z. As distinct differences between one or both sides
observed affected the duration of the stance and swing phases. With only one-sided
gem infestation is the stance phase of the affected side, the diseased by experiment
relieve joint shortened. With bilateral disease, this difference can
be completely abolished. Since a beidseiti- in the majority of subjects
ge disease was present (7 patients in the treatment group, 9 patients in the placebo group with
bilateral disease vs. 4 patients in the active treatment group and the placebo patients 3
group with unilateral disease), this is a possible explanation for this is that in DIE
ser study the duration of the contact time on the untreated side opposite the behan-
punched side is not increased. However, the double support time, ie the time,
in both feet touch, not extended. This is often the case with beidseiti-
ger disease observed (113).
Other differences when comparing patients with osteoarthritis of the knee to be expected with
healthy volunteers are slowing the transition speed by an ER-
niedrigte stride length and frequency, wider step width and a lower loading

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62
wegungsausma in knee and hip joint (86). Regarding the ground reaction forces
shall in particular from the F1 peak, since the heel counter in a painful overall
directing gap compression leads (113). The On Hip, knee and ankle
measured joint moments are reduced in osteoarthritis patients (5). Indeed
have so far been under conservative treatment measures have little or no Vern-
changes in gait determined in the course (17, 63, 69, 119).
Also in this study, only a few significant arose during the study period
edge changes in gait. One possible explanation is that the Vernde-
Conclusions on gait under conservative treatment measures are so low that they
can not be detected with the computerized gait analysis. Another that
the subjects of this study in the initial examination little Vernderun-
gen in gait exhibited and therefore under therapy a few improvements
gen occurred.
In the comparison of the output values of both groups of reference data, and in particular showed
sondere a significantly decreased transfer speed in both groups (Visit 1:
66,00 m / s in the treatment group or 67,11m / s in the placebo group), also in the
Checkup far below the standard of 80 m / sec was (Visit 7: 67.02 m / s in the
Verum group or 67,92 m / s in the placebo group). The inseam is individually
different and so that a comparison is between 2.5 and 4 foot lengths, with
standard values is only to a limited extent (94). It is in a healthy 60 cm
to 95 cm. In this study, the average stride length was approximately 62 cm
(Both sides in both groups in both Visit 1 and Visit 7) or at the bottom
The normal range. For this parameter under therapy, no significant change is to
been expected. The step width was with 11.82 cm to 12.41 cm still in standard-
is given 13 cm (123) - the 5 range.
In osteoarthritis patients is often the joint motion in the sagittal plane, ie the difference
regions between extension and flexion. Here, too, were the measured values
in both groups is still within the standard deviation. However, it is striking that
overall, the patients in this study to an increased flexion posture in
Knee tended. So in this study was the minimum knee flexion at 5 - 6 ,
while the rate is usually in the negative is (it ie to a Hyperexten-

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63
sion in the joint comes). The theoretically reduced range of motion in the knee joint
steering is off by an increased maximum knee flexion during walking
balanced. Since an increased knee flexion until the flexion contracture in the context
a posture occurs is to see this as an indication of the joint disease.
Because, the only significant change in gait analysis in this study
occurred an improvement of the minimum knee flexion in the placebo group is
to evaluate this outcome very critical.
Other differences in gait compared to the healthy subjects show up in a
increased maximum and a reduced minimum hip flexion on both sides.
Also in the ankle, this can be observed. Both as a compensation of the
to consider increased knee flexion. In normal parameters would occur
to give a functional shortening of the leg. This would make a high to compensate
require energy expenditure.
In summary, it should be noted that the lack of improvement in this study
gait mostly by the few abnormalities in gait to study programs
is used to explain the beginning and this is not necessarily a missing Therapieanspre-
Chen or insufficient recoverability of the gait analysis for the detection of medicinal
neimittelwirkungen is due in the treatment of osteoarthritis of the knee.
4.4.3 Special Methods criticism: electromyography
Also regarding the electromyographic measurement, there are limitations in the
Assessability of results. So complicate both obesity and one with
of osteoarthritis associated muscle atrophy exact placement of the electrodes. The
Use of surface instead of needle electrodes can assessability
also limit the results. On the one hand an inaccurate placement results
Measurement errors, but also interference by neighboring muscles ( "muscle cross
talk ") affect the derived activity pattern. This phenomenon occurs at heaped
the deeper and thus partially superimposed muscles. despite these
Limitations speak several considerations for the use of Oberflchenelek-
trodes. The use is painless, non-invasive and less time-consuming than the
Using needle electrodes and are yet sufficient information on