Intra-articular Hyaluronic Acid in Mild to Moderate Knee Osteoarthritis

Overview[ - collapse ][ - ]

Purpose Objective: To assess the impact of intraarticular hyaluronic acid (HA) on clinical outcome and on volumetric and T2 relaxation based changes of articular cartilage in mild to moderate osteoarthritis (OA) of the knee joint. Methods: Patients with moderate OA of the knee [Kellgren-Lawrence II] were recruited for a 6-months prospective, randomized clinical trial evaluating the effect of HA on articular cartilage morphology and composition. Clinical examinations and MRI were performed at baseline, and after 6, 12 and 24 weeks. Cartilage volume, thickness and surface area were determined in cartilage plates and subregions were defined using proprietary software. MRI was performed on a 1.5 Tesla scanner; morphological evaluation was performed using 3D T1-w FLASH Waterexcitation (WE) sequences and T2 maps were calculated from a multiecho, spin-echo sequence.
ConditionOsteoarthritis
InterventionDrug: Hyaluronic Acid
PhasePhase 2
SponsorTechnische Universität München
Responsible PartyTechnische Universität München
ClinicalTrials.gov IdentifierNCT01239810
First ReceivedNovember 9, 2010
Last UpdatedDecember 8, 2010
Last verifiedDecember 2010

Tracking Information[ + expand ][ + ]

First Received DateNovember 9, 2010
Last Updated DateDecember 8, 2010
Start DateJune 2005
Estimated Primary Completion DateDecember 2008
Current Primary Outcome MeasuresWOMAC [Time Frame: 24 weeks] [Designated as safety issue: No]Western Ontario and McMaster University Osteoarthritis Index 24 weeks after drug adminstration
Current Secondary Outcome MeasuresMRI [Time Frame: 24 weeks] [Designated as safety issue: No]quantitative assessment of cartilage morphology using 3D T1-weighted FLASH Waterexcitation (WE) sequence following drug administration

Descriptive Information[ + expand ][ + ]

Brief TitleIntra-articular Hyaluronic Acid in Mild to Moderate Knee Osteoarthritis
Official TitleEffect of Intra-articular Hyaluronic Acid on Articular Cartilage Morphology and Composition in Mild to Moderate Knee Osteoarthritis
Brief Summary
Objective:

To assess the impact of intraarticular hyaluronic acid (HA) on clinical outcome and on
volumetric and T2 relaxation based changes of articular cartilage in mild to moderate
osteoarthritis (OA) of the knee joint.

Methods:

Patients with moderate OA of the knee [Kellgren-Lawrence II] were recruited for a 6-months
prospective, randomized clinical trial evaluating the effect of HA on articular cartilage
morphology and composition. Clinical examinations and MRI were performed at baseline, and
after 6, 12 and 24 weeks. Cartilage volume, thickness and surface area were determined in
cartilage plates and subregions were defined using proprietary software. MRI was performed
on a 1.5 Tesla scanner; morphological evaluation was performed using 3D T1-w FLASH
Waterexcitation (WE) sequences and T2 maps were calculated from a multiecho, spin-echo
sequence.
Detailed Description
Introduction:

The medical management of knee osteoarthritis (OA performing intra-articular treatment with
hyaluronic acid (HA) has recently become more widely accepted. The effectiveness of HA
regarding the improvement of pain and function - also compared to placebo - has been shown
by in vitro and clinical studies. However, most in vivo studies are based on patient well
being, clinical scores and plain radiographs, which have however been shown neither to be an
efficient way of monitoring OA progression nor to analyze the effect of HA on cartilage
changes (1, 2).

Recently MRI has gained increasing importance as imaging modality for assessing cartilage
changes in general but especially regarding degenerative changes in case of OA. Quantitative
MRI (qMRI) studies were used to assess cartilage volume and thickness in patients with OA.
In a longitudinal study Eckstein et al. (3) found an approximated annual loss of cartilage
between 4 to 6%. Moreover, the effect of treatment on morphologic parameters can be
evaluated objectively in-vivo which has been the major limitation of the validation process
of drug therapy in OA so far. However, until now only three studies in the recent literature
have used MRI to evaluate the effect of intraarticular HA on the articular cartilage of the
knee joint. While Ozturk et al. (4) and Cubukçu et al. (5) evaluated the articular cartilage
using a semiquantitative grading only Anandacoomarasamy et al. (6) have utilized validated
techniques to assess cartilage defects and cartilage volume quantitatively for a follow-up
period of six months. The so far published analyses have focused on entire cartilage plates,
although it is likely that certain subregions of these plates are stronger affected by
cartilage loss than others. Wirth et al. (7) demonstrated that cartilage loss can be
measured in subregions (i.e., central, internal, external) of the femoro-tibial cartilage
plates which allows for additional insight into the spatial distribution of tissue loss
throughout the cartilage plates in OA (7, 8). Assuming that cartilage is not homogeneously
lost throughout the plates, this approach may be used to identify subregions with a higher
rate of and sensitivity to change, which may, in turn, permit a reduction of sample size and
follow up periods in clinical studies to be able to demonstrate structure modifying effects
of pharmaceutical compounds on disease progression (7-9).

The T2 relaxation time, another MRI based quantitative parameter, on the other hand is
sensitive to tissue hydration and organizational properties of the collagen fiber matrix. It
is thus considered to reflect compositional and architectural aspects as a surrogate
parameter for cartilage matrix quality in cartilage degeneration (10). In mild OA of the
knee, the mean cartilage T2 values, the standard deviation and the entropy were increased,
indicating that in mild OA the T2 values are not only elevated but also are more
heterogeneous as compared to healthy cartilage (11). It is generally assumed that changes of
cartilage volume and thickness appear later and may also occur at a slower rate than T2
changes of cartilage in OA. Hence, the T2 relaxation properties of cartilage may be useful
as non invasive parameters to analyse the impact of HA, especially with respect to the - in
most cases - relatively short follow up periods available.

Therefore the aim of this study was to assess the impact of intraarticular hyaluronic acid
on clinical outcome and on volumetric (including subregions) and T2 relaxation based changes
of articular cartilage in patients with moderate knee OA.

Material and methods Patients 34 patients with age rang of 40 - 64 years (mean 48 ± 9 yrs)
presenting with a clinical history of mild to moderate OA, unilateral osteoarthritis of the
knee at the time of inclusion were enrolled. All patients were referred from visiting
orthopaedic surgeons and presented with OA grade II of the knee joint radiologically
confirmed according to the Kellgren-Lawrence grading system (12).

Exclusion criteria were as follows: a) intraarticular injections in the affected knee, b)
oral application of glucosamine and chondroitin sulphate during the last 6 months prior to
the beginning of the study, c) clinically significant knee joint effusion or d) if knee
joint infection was known or suspected and/or trauma or other specific conditions such as
neoplasm, diabetes mellitus, osteonecrosis were present, which might potentially interfere
with the completion of the trial. Another exclusion criterion was known rheumatoid arthritis
or any other inflammatory arthritis diagnosed by American College of Rheumatology criteria.

Study design The study was conducted in a prospective, randomized way with a 6-months
follow-up period. The patients were randomly assigned either to the group receiving
treatment with 2ml Na-Hyaluronate (HA; MW 1.2 x 106; Ostenil, TRB Chemedica) or the group
without treatment. The treatment group (n=17) were weekly treated with an intraarticular
injection of HA during the first five weeks on day 0, 7, 14, 21 and 28 (see Table 1). Any
pretreatment with non-steroidal anti inflammatory drugs (NSAID) had to be discontinued 7
days before the study started whereas concomitant physiotherapy was allowed. Patients were
withdrawn from the study if severe reactions to the injections occurred or if there was
evidence of an active infection of the injected joint at any time during the study period.

Clinical Assessments To determine clinical effectiveness of HA therapy, all patients were
clinically evaluated prior to first injection (baseline) and after 6, 12 and 24 weeks (Table
1). Clinical assessment comprised self-reported visual analog pain scale (VAS) and the
Western Ontario and McMaster University Osteoarthritis Index (WOMAC) assessing the three
dimensions of pain, function, and joint stiffness in knee OA. Additionally, the physical
function and the patient as well as the physician global score were measured. Also the body
mass index (BMI) was assessed.

Quantitative MRI: Volumetric Parameters A high resolution 3D T1-weighted FLASH
Waterexcitation (WE) sequence with a thickness of 1.5 mm and an in-plane resolution of 0.31
mm x 0.31 mm was obtained for each patient at baseline and 24 weeks after on a 1.5 Tesla
MR-scanner using a dedicated circularly polarized knee coil (Siemens Medical Solutions,
Erlangen, Germany). This protocol has been validated for quantitative assessment of
cartilage morphology (3, 13-15). Coronal images were acquired for the femoro-tibial
compartiment and transverse images to assess the patellar cartilage.

The MR- data were sent to the image analysis center, quality controlled, and converted to a
proprietary format (Chondrometrics GmbH, Ainring, Germany). Images were read in pairs in a
blinded to acquisition order fashion. The cartilage plates of the patella (P), central
(weight-bearing) medial femur (cMF), central lateral femur (cLF), medial tibia (MT) and the
lateral tibia (LT) were quantified as previously described using a 3D digital
post-processing algorythm using the dedicated Chondrometrics Works software (16). On the
coronal images, cMF and cLF started anteriorly at the first partition with interruption by
the subchondral bone of diverging trochlea into the femoral condyles. Posteriorly, the last
partition showing the circular structure of the posterior femoral condyles (central bone
with surrounding cartilage) was identified. The partition located at 60%(2/3) between the
anterior and posterior landmark was the most posterior one to be included in the cMF and
cLF. Quality control of all segmentations of each dataset was performed by a single person
(FE). Proprietary software was used to determine cartilage volume (VC), total area of the
subchondral bone (tAB) and part of tAB covered with cartilage (cAB), mean cartilage
thickness (ThCcAB), and mean thickness when counting all denuded areas as 0 mm cartilage
thickness (ThCtAB). Changes were computed for the medial and lateral femorotibial
compartments (MFTC/LFTC) by summing up the values of the medial tibia and femur, and the
lateral tibia and femur, respectively, at baseline and follow up (17, 18).

Additionally, five subregions (central, internal, external, anterior, posterior) were
determined based on the subchondral bone area (tAB) in the tibia, with the central subregion
occupying 20% of the total subchondral bone area (7). The central tibial region was defined
by a perpendicular cylinder around the center of gravity of the tibial subchondral bone area
with the diameters being adapted to its individual shape (7). Since the weight-bearing
femoral condyles are limited in anterior-posterior extension (femoral trochlea anteriorly
and posterior femoral condyle posteriorly), they were divided into a central, internal and
external strip-like region of interest, respectively, each occupying 33.3% of the
subchondral bone area (7). Cartilage thickness (ThCtAB) was determined in all subregions.

Quantitative MRI: T2-Mapping For T2 relaxation time calculation a fat-saturated
Multislice-Multiecho Turbo-Spin-Echo-sequence (MSME) (TR 3000ms / TE 13.2ms / 8 echoes, echo
spacing 13.2ms / Bandwidth (BW) 130Hz / interleaved acquisition) and a 3D T1-w fast low
angle shot (FLASH) sequence with selective water excitation (TR 14.2ms / TE 7.2ms / FA 15° /
BW 130Hz) with identical position and spatial resolution were acquired (19) in coronal plane
at baseline, and 6, 12 and 24 weeks after. Both sequences were directed to the center of the
knee joint with a resolution of 0.6² x 3 mm³ (256² matrix interpolated to 512²) and a field
of view of 16 cm. The FLASH sequence is used for cartilage segmentation (19-21) then being
superimposed on the T2 map to calculate the cartilage T2 values. Acquisition time for the
FLASH-sequence was 2 min 55 sec, for the MSME-sequence 12 min 48 sec. Interactive
segmentation and 3D reconstruction (15) of the tibial cartilage plates were performed
consecutively.
Study TypeObservational
Study PhasePhase 2
Study DesignObservational Model: Cohort, Time Perspective: Prospective
ConditionOsteoarthritis
InterventionDrug: Hyaluronic Acid
Intraarticular injection 2ml Na-Hyaluronate (HA; MW 1.2 x 106; Ostenil, TRB Chemedica) weekly for five weeks
Other Names:
Ostenil
Study Arm (s)
  • Control group
    Receiving no treatment
  • hyaluronic acid
    treatment group receiving intraarticular hyaluronic acid

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment34
Estimated Completion DateDecember 2008
Estimated Primary Completion DateNovember 2006
Eligibility Criteria
Inclusion Criteria:

- History of mild to moderate OA

- OA grade II

Exclusion Criteria:

- Intraarticular injections in the affected knee

- Oral application of glucosamine and chondroitin sulphate during the last 6 months
prior to the beginning of the study

- Clinically significant knee joint effusion

- Neoplasm

- Diabetes mellitus

- Osteonecrosis

- Rheumatoid arthritis or any other inflammatory arthritis diagnosed by American
College of Rheumatology criteria.
GenderBoth
Ages18 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesNot Provided

Administrative Information[ + expand ][ + ]

NCT Number NCT01239810
Other Study ID NumbersTBOSTZKM1
Has Data Monitoring CommitteeNo
Information Provided ByTechnische Universität München
Study SponsorTechnische Universität München
CollaboratorsNot Provided
Investigators Principal Investigator: Rüdiger von Eisenhart-Rothe, M.D. Department of Orthopaedics and Traumatology, Technische Universität München
Verification DateDecember 2010