Current Medical Research & Opinion Vol. 30, No.

2, 2014, 279–286

0300-7995 Article RT-0338.R1/855631

doi:10.1185/03007995.2013.855631 All rights reserved: reproduction in whole or part not permitted

Original article
A randomized saline-controlled trial of NASHA
hyaluronic acid for knee osteoarthritis

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Curr Med Res Opin Downloaded from informahealthcare.com by Queen's University on 01/01/15

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Nigel K. Arden Abstract

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NIHR Musculoskeletal Biomedical Research Unit,

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University of Oxford, UK Objective:

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NASHA hyaluronic acid is administered as a single intra-articular injection to treat the symptoms of

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Christian Åkermark

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osteoarthritis (OA). In a previous trial, post-hoc analysis indicated that NASHA provides significantly

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fo ers tr
Sport Med, Stockholm, Sweden

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greater pain relief than saline in patients with OA confined to the study knee. We aimed to evaluate the

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Mats Andersson safety and efficacy of NASHA in patients with unilateral knee OA.

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Q-Med AB, Uppsala, Sweden

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Research design and methods:
Martin G. Todman le is al
rin ted m fo

Smith & Nephew UK Ltd, Research Centre, York

This was a randomized, double-blind, saline-controlled trial. All patients had knee OA confirmed by
ng or i
For personal use only.

American College of Rheumatology criteria and a WOMAC pain score of 7–17 in the study knee, but no
si th rc

Science Park, York, UK

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co ed
pain in the previous 3 months in the non-study knee. Treatment comprised a single intra-articular injection
Roy D. Altman
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of NASHA or saline control. The follow-up period was 6 weeks.

14

UCLA David Geffen School of Medicine, LA, USA

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Clinical trial registration:

Address for correspondence: ClinicalTrials.gov NCT01806207.
la d le ©

Prof. Nigel Arden, NIHR Musculoskeletal Biomedical

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Research Unit, Nuffield Orthopaedic Centre, University

Main outcome measures:
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of Oxford, Windmill Road, OX3 7LD, UK.

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nigel.arden@ndorms.ox.ac.uk
The primary efficacy endpoint was the responder rate, defined as the percentage of patients with 40%
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improvement from baseline in WOMAC pain score and an absolute improvement of 5 points.
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Keywords:
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Results:
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Knee – NASHA hyaluronic acid gel – Osteoarthritis –

A total of 218 patients received study treatment (NASHA: 108, saline: 110). In the main intention-to-treat
Co

Saline control
(ITT) analysis, no statistically significant difference in responder rate was found between the two groups at
au fo

Accepted: 10 October 2013; published online: 4 November 2013 6 weeks (NASHA: 30.6%; saline: 26.4%). A post-hoc subgroup analysis of patients without clinical effusion
Citation: Curr Med Res Opin 2014; 30:279–86
in the study knee at baseline showed a significantly higher 6 week responder rate with NASHA than with
Un t
No

saline: 40.6% versus 19.7% (p ¼ 0.0084). A total of 68 adverse events were reported among 44 patients in
t

the NASHA group, compared with 69 adverse events among 44 patients in the saline group. The main
weakness of the study was the short, 6 week follow-up duration. In addition, image guidance was not used
to ensure injection as intended into the intra-articular space.

Conclusions:
Single-injection NASHA was well tolerated and, although there was no significant benefit versus saline
control in the primary analysis, post-hoc analysis showed a statistically significant improvement in pain relief
at 6 weeks among patients without clinical effusion at baseline.

Introduction
Intra-articular (IA) injection of hyaluronic acid (HA) is a well established
means of treating pain in patients with osteoarthritis (OA) of the knee.
According to the American College of Rheumatology guidelines, such treat-
ment is indicated for patients who have not responded to a program of non-

! 2014 Informa UK Ltd www.cmrojournal.com NASHA hyaluronic acid for knee osteoarthritis Arden et al. 279
 Current Medical Research & Opinion Volume 30, Number 2
pharmacologic therapy and simple analgesics1, while the
2008 and 2010 OARSI guidelines conclude that injections
of IA hyaluronate may be useful in patients with knee
or hip OA2,3.
The risks associated with the most commonly used
medications for OA pain management – hepatic toxicity
with acetaminophen4, gastrointestinal safety concerns
with non-steroidal anti-inflammatory drugs (NSAIDs)5,6
and cardiovascular safety concerns with cyclooxygenase-2
(COX-2) inhibitors7 – have received increasing attention
in recent years3. This has prompted renewed interest in
alternative treatment options, including viscosupplemen-
tation with IA HA. A number of HA products are avail-
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able for the treatment of knee OA pain, with dosing
regimens ranging from one to five weekly injections.
NASHA hyaluronic acid has a unique cross-linked
molecular structure8 that provides a prolonged IA resi-
dence time (half-life of 4 weeks)8–10. This allows adminis-
tration of NASHA as a single injection, providing benefits
such as improved patient convenience and potential cost
reductions through fewer clinic visits. The cross-linking
(stabilization) process used to produce NASHA introduces
only minimal molecular changes, thereby preserving the
inherent biocompatibility of HA. This, together with the
For personal use only.
sourcing of HA from bacterial fermentation as opposed to
animal tissue, may reduce the risk of allergic reactions
and other adverse events. Clinical studies of NASHA
administered as a single injection have demonstrated
that it provides significant improvement in the symptoms
of OA compared to baseline, both in the knee11–14 and
the hip15,16.
A previous 6 month, randomized, saline-controlled
study of NASHA for the treatment of knee OA pain13
included patients with late-stage OA (Kellgren–
Lawrence grade IV), OA or clinically significant pain
from joints other than the knee (poly-articular pain),
and clinical effusion at baseline. Improved efficacy was
observed in patients with OA confined to the study
knee. Other studies have also shown that pain from
joints other than the one being treated can mask the treat-
ment effect of IA HA injection13,17. We designed a 6
week, saline-controlled study to investigate the safety
and efficacy of NASHA in patients with mild–moderate
structural OA confined to the study knee.
Patients and methods
Study design and participants
This was a saline-controlled, double-blind, multicentre
study of NASHA, with a 6 week follow-up period.
Patients were enrolled at 13 sites in Sweden, Germany
and the UK. The study was conducted in accordance
with the Declaration of Helsinki 1975, as revised in
280 NASHA hyaluronic acid for knee osteoarthritis Arden et al.
February 2014
2000, and the International Conference on
Harmonization Guidelines for Good Clinical Practice.
All patients provided signed, informed consent upon
enrolment for the study. The results are presented in line
with Consolidated Standards of Reporting Trials
(CONSORT) guidelines18. Independent Ethics
Committee (IEC)/Institutional Review Board (IRB)
approval was obtained at each participating site in the
UK and Germany. In Sweden, the Independent Ethics
Committee at Lunds University served as co-ordinating
IEC for all sites. In Germany, the protocol was approved
by ‘Bundesamt für Strahlenschutz’ prior to commencement
of the study. The study is registered at ClinicalTrials.gov
(NCT01806207).
Normally active men and women aged 450 years with
the ability to walk 50 metres unaided and with knee pain
meeting the American College of Rheumatology criteria
for the diagnosis of OA1 were eligible for inclusion,
provided that OA was confirmed in the study knee radio-
graphically (Kellgren–Lawrence grades II or III) and by a
Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC) pain score of 7–17 at
the baseline visit. Key exclusion criteria were: pain
during the previous 3 months in the non-study knee, radio-
graphically verified OA of the non-study knee (Kellgren–
Lawrence grade4I), OA or clinically significant pain from
any part of the musculoskeletal system other than the study
knee, previous IA steroid injection into the study knee
within the last 3 months, previous IA HA injection into
the study knee within the last 9 months, use of systemic
steroids (excluding inhaled steroids) within the last
3 months, and arthroscopy or other surgical procedures
in the study knee within the last 12 months. The first
patient was enrolled on August 15, 2003 and the last
patient completed the 6 week visit on April 22, 2004.
Study participants were randomized 1:1 to receive a
single IA injection in the study knee of either NASHA
(Durolane* 60 mg in 3 ml) or saline (3 ml phosphate-
buffered saline, pH 7). Investigators with experience of
administering intra-articular treatment administered
NASHA or saline into the synovial space; lateral mid-
patellar, lateral upper-patellar or medial injection tech-
nique was advised. Image guidance was not used. Rescue
medication with acetaminophen up to 4 g per day was
allowed throughout the study except during the 48 hour
period preceding each study visit, and all such medication
was recorded. NSAIDs, including topical agents for the
knee, were not permitted during the study period or
during the week before administration of study treatment.
Follow-up visits were scheduled at 2, 4 and 6 weeks
post-treatment. Randomization codes were computer gen-
erated by the contract research organization running the
study, with stratification by site. Patients’ initials were
*
Durolane is a registered trade name of Q-Med AB, Uppsala, Sweden.
www.cmrojournal.com ! 2014 Informa UK Ltd
 Current Medical Research & Opinion Volume 30, Number 2 February 2014

written on the outside of treatment code envelopes after Statistical methods

randomization and, to determine which product to admin-
ister (NASHA or saline), the treating investigator opened
each patient’s envelope before treatment. Patients were
enrolled by the evaluating investigator, and the treating
investigator administered the study treatment (any joint
effusion was removed prior to NASHA or saline injec-
tion). Patients were not informed which treatment they
received and they were blinded to the injection with the
use of surgical drapes. The evaluating investigator, who
was blinded to the treatment given (no access to the treat-
ment code envelopes and no involvement in the treatment
procedure), conducted the post-treatment assessments.
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The intention-to-treat (ITT) and safety populations con-
sisted of all patients who were randomized and treated. The
primary population for all efficacy analyses was ITT, with
supportive analyses performed on the per-protocol (PP)
population (patients in the ITT population who com-
pleted all scheduled efficacy evaluations without major
protocol violations).
Improvements from baseline in WOMAC pain score,
WOMAC stiffness score and WOMAC physical function
score and total number of rescue medication tablets were
compared between treatments using a two-sample t-test.
WOMAC pain responder rates were compared between

The study was terminated when the sample size (see

Statistical methods below) was fulfilled and the last patient
enrolled had completed the 6 week follow-up visit.
Adverse events were reported at all study visits and
classified according to World Health Organization
(WHO) preferred terms and body systems. All adverse
events occurring on or after the day of injection were con-
sidered as treatment emergent.
For personal use only.
treatments using chi-squared tests. Treatment-group dif-
ferences in the percentage of patients reporting adverse
events were assessed with Fisher’s exact test. Within-
patient analysis of WOMAC pain responder rate over
time was performed using McNemar’s test.
As a post-hoc analysis, treatment-group differences in
WOMAC pain responder rates were assessed within
patient subgroups defined by the variables shown in
Table 1. The continuous variables were dichotomized as
follows: age (below/at least 60), body mass index (BMI)

Outcomes
The primary endpoint was the WOMAC pain responder
rate, defined as the percentage of patients achieving
at least 40% reduction from baseline in WOMAC
pain score, together with an absolute improvement of
at least 5 points19. A Likert version of the WOMAC
pain score was used (range 0–20). Secondary outcome
measures included Likert versions of the WOMAC
stiffness score (range 0–8), WOMAC physical function
score (range 0–68) and patient assessment of global
status (range 1–5).
(below/at least 27), duration of diagnosed knee OA
(below/at least 2 years) and WOMAC pain score at base-
line (below/at least 10 units).
Sample size calculation was based on the assumption
that the proportion of patients responding to treatment
would be 45% with NASHA and 25% with saline. Using
a two-sided 5% significance level and a power of 80%, a
sample size of 172 patients (86 per group) was calculated.
To compensate for patients lost to follow-up, the total
sample size was increased to 218. All statistical analyses
were performed using SAS software.

Table 1. Baseline characteristics of the study population.

Variable NASHA (n ¼ 108) Saline (n ¼ 110) p-Value

Age in years, median (range) 64.5 (29–84) 60.9 (30–86) 0.0403

Female:male, n (%) 59:49 (55:45) 51:59 (46:54) 0.2223
BMI female, median (range) 26.4 (20.4–39.7) 26.9 (20.1–41.0) 0.7198
BMI male, median (range) 28.2 (20.3–37.8) 28.1 (22.2–39.5) 0.7984
Duration of OA in years, median (range) 2.2 (0–21.2) 3.1 (0–44.1) 0.0794
Kellgren–Lawrence score*
II, n (%) 33 (30.6) 40 (36.4) 0.3636
III, n (%) 75 (69.4) 70 (63.6)
WOMAC pain score, median (range)* 10.0 (7–17) 9.5 (7–15) 0.6284
Clinical effusion present, * n (%) 39 (36.1) 44 (40.0) 0.5544
NSAIDs or analgesics for OA in the last 3 months, n (%) 45 (41.7) 45 (40.9) 0.9096
Previous treatment with IA steroids in the study knee, n (%) 21 (19.4) 32 (29.1) 0.0969
Previous treatment with IA HA in the study knee, n (%) 8 (7.4) 16 (14.5) 0.0923
Previous knee surgery in the study knee, n (%) 46 (42.6) 45 (40.9) 0.8010

p-values: chi-squared test (categorical variables) and Wilcoxon rank-sum test (other variables).
*Relating to the study (signal) knee.
BMI, body mass index; HA, hyaluronic acid; IA, intra-articular; NSAID, non-steroidal anti-inflammatory drug; OA, osteoarthritis;
WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

! 2014 Informa UK Ltd www.cmrojournal.com NASHA hyaluronic acid for knee osteoarthritis Arden et al. 281
 Current Medical Research & Opinion Volume 30, Number 2 February 2014
All efficacy analyses were based on a last observation
carried forward (LOCF) approach. The p-values obtained
for secondary and post-hoc analyses were not adjusted
for multiple testing. A result was considered statistically
significant when the statistical test yielded a two-tailed
p-value of 0.05 or less.
Results
A total of 218 patients were randomized to receive study
treatment (NASHA: 108, saline: 110). There were five
discontinuations during the 6 week study period, all from
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the NASHA group (Figure 1). Demographic and other
baseline characteristics of the patients are presented in
Table 1. A statistically significant difference in age was
seen between groups but, within the context of OA as a
chronic condition, this was not considered to be clinically
significant. The volume of effusion removed immediately
before administration of NASHA or saline was higher in
the saline group (median 12.5 ml [range 1–50 ml], versus
5.0 ml [1–20 ml] in the NASHA group), but the percent-
age of patients with effusion was similar in the two groups.
For personal use only.
There was no statistically significant difference between
the two study groups in the primary outcome measure at
any time point (both ITT and PP analyses; Table 2).
Randomized (n=218)
Allocated to NASHA (n=108)
Allocation Received allocated intervention (n=108)
Premature discontinuation (n=5*)
Consent withdrawn (n=2)
Unrelated serious adverse event (n=1)
Lost to follow-up (lost interest) (n=1)
Lack of effect (n=1)
Follow-up Major protocol deviation (n=25 in 22 subjects)
Assessment of masking by treating investigator (n=10)
Randomization envelope signed by both investigators (n=1)
Treatment with the other study product (n=1)
Prohibited medication (NSAID/analgesic/anticoagulant) (n=3)
Rescue medication within 48 hours prior to visit 7 (n=8)
WOMAC pain score missing on at least one visit (n=2)
ITT population (n=108)
Analysis PP population (n=83)
Without clinical effusion ITT population (n=69)
*Two patients who discontinued prematurely also had major protocol deviations. ITT, intention to treat; NSAID, non-steroidal
anti-inflammatory drug; PP, per protocol.
Figure 1. Study population.
282 NASHA hyaluronic acid for knee osteoarthritis Arden et al.
A significant improvement in responder rate was observed
in the NASHA group between 2 and 6 weeks (30.6% vs
19.4%, p ¼ 0.0143). There was no significant improve-
ment in the saline group over this period (26.4% vs
25.5%, p ¼ 0.8273).
For all secondary efficacy endpoints (WOMAC pain
score, WOMAC stiffness score, WOMAC physical func-
tion score and patient assessment of global status),
improvements from baseline were numerically larger in
the NASHA group compared with saline, but the differ-
ences did not reach statistical significance. Data for the
three WOMAC subscales are shown in Table 3. In the PP
population, a statistically significantly higher percentage
of patients receiving NASHA showed improvement in
global status of at least one point versus baseline at 4
weeks (NASHA: 44.6% [37/83]; saline: 26.4% [24/91];
p ¼ 0.0119) and 6 weeks (NASHA: 37.3% [31/83];
saline: 20.9% [19/91]; p ¼ 0.0165). No other statistically
significant between-group differences were observed in
secondary outcomes. Mean consumption of rescue medi-
cation during the follow-up phase was 34.2 tablets in the
NASHA group and 26.1 tablets in the saline group
(p ¼ 0.3057).
The post-hoc subgroup analysis showed statistically
significantly higher WOMAC pain responder rates at
4 weeks (p ¼ 0.0292) and 6 weeks (p ¼ 0.0084) with
Allocated to saline (n=110)
Received allocated intervention (n=110)
Premature discontinuation (n=0)
Major protocol deviation (n=19 in 19 subjects)
Assessment of masking by treating investigator (n=10)
Treatment with the other study product (n=1)
Prohibited medication (NSAID/analgesic/anticoagulant) (n=3)
Rescue medication within 48 hours prior to visit 7 (n=5)
ITT population (n=110)
PP population (n=91)
Without clinical effusion ITT population (n=66)
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 Current Medical Research & Opinion Volume 30, Number 2 February 2014

Table 2. WOMAC pain responder rates in study populations.

Time post-treatment Analysis NASHA responder Saline responder p-Value

population rate, % (n/N) rate, % (n/N)

2 weeks ITT 19.4 (21/108) 25.5 (28/110) 0.29

PP 19.3 (16/83) 19.8 (18/91) 0.93
4 weeks ITT 26.9 (29/108) 26.4 (29/110) 0.94
PP 28.9 (24/83) 24.2 (22/91) 0.48
6 weeks ITT 30.6 (33/108) 26.4 (29/110) 0.49
PP 34.9 (29/83) 27.5 (25/91) 0.29

ITT, intention to treat; PP, per protocol.

Table 3. Analysis of WOMAC subscale scores at baseline and 6 weeks (ITT population). Data shown are
mean  standard deviation.
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NASHA Saline p-Value

WOMAC pain score

Baseline 9.98  2.09 9.83  2.03 –
6 weeks 7.42  3.80 7.37  3.43 –
Change from baseline at 6 weeks 2.56  3.46 2.45  3.06 0.86
WOMAC stiffness score
Baseline 4.03  1.39 3.90  1.34 –
6 weeks 3.09  1.71 3.08  1.67 –
Change from baseline at 6 weeks 0.94  1.62 0.82  1.58 0.71
WOMAC physical function score
Baseline 30.42  10.65 30.19  10.24 –
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6 weeks 24.16  13.62 24.60  12.66 –

Change from baseline at 6 weeks 6.26  10.81 5.59  10.58 0.77

ITT, intention to treat; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

NASHA than with saline among patients without clinical 45

WOMAC pain responder rate (%)

NASHA Saline
effusion in the study knee at baseline (Figure 2). Only 40
minor differences between the study groups were evident 35
in the other subgroups. 30
A total of 68 adverse events were reported among 25
44 patients in the NASHA group, compared with 20
69 adverse events among 44 patients in the saline group. 15
There were no treatment-related serious adverse events. 10
The percentage of patients reporting treatment-related
5
adverse events was higher in the NASHA group than
0
in the saline group: 15.7% (17 patients, 18 adverse Week 2 Week 4 Week 6
events) versus 5.5% (6 patients, 6 adverse events) NASHA 23.2 34.8 40.6
(p ¼ 0.0154). The nature of treatment-related adverse Saline 22.7 18.2 19.7
p-value 0.9492 0.0292 0.0084
events was as anticipated in both groups – primarily
knee pain or knee swelling. Specific treatment-related
Figure 2. WOMAC pain responder rates among patients without clinical
adverse events (defined by preferred terms) occurred effusion in the study knee (intention to treat population).
with similar frequency in the two groups, except for
‘injection site pain’ which was reported in seven patients
in the NASHA group and none in the saline group
(p ¼ 0.0066). subgroup analysis suggested that NASHA was superior in
patients without clinical knee effusion at baseline.
Overall, NASHA injections were well tolerated with no
reported treatment-related serious adverse events. There
Discussion was a higher rate of treatment-related adverse events in the
Although the current 6-week study of patients with knee NASHA group, although these were generally categorized
OA failed to demonstrate that NASHA provides a statis- as mild to moderate in severity, transient and resolved
tically significant benefit over saline injection, post-hoc without issue.

! 2014 Informa UK Ltd www.cmrojournal.com NASHA hyaluronic acid for knee osteoarthritis Arden et al. 283
 Current Medical Research & Opinion Volume 30, Number 2
Development of therapies often involves a process of
clinical investigation to identify patients with the most
favourable risk–benefit profile. A previous, randomized
double-blinded saline-controlled clinical study identified
poly-articular pain as a confounding factor in the inter-
pretability of HA clinical data, hence the exclusion
of patients with poly-articular pain from this study13.
Other clinical factors that may predict effectiveness of
HA injections are of great interest, and the current study
suggests that clinical effusion fits this category. Previous
studies have shown that viscosupplementation is likely to
have reduced effectiveness in the presence of effusion20,21.
Consequently, clinical studies investigating HA therapies
in knee OA typically exclude patients with clinical effu-
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sions22–24. While care must be taken when conducting and
interpreting post-hoc subgroup analysis, interpretation is
aided when the number of sub-populations analyzed is low
and based on sound clinical observations.
To investigate further the effects of excluding patients
with poly-articular pain and clinical effusion, we per-
formed a pooled analysis of patients from this study and
the previously published randomized controlled trial of
NASHA13. A total of 284 patients meeting these criteria
were treated, 151 with NASHA and 133 with saline. The
For personal use only.
WOMAC pain responder rate at 6 weeks was statistically
significantly higher with NASHA than with saline (43.0%
vs 24.8%, p ¼ 0.0013). These data suggest that future stu-
dies of NASHA among patients without clinical effusion
could provide improved insight into treatment efficacy.
The majority of knee OA patients exhibit some form of
effusion. In one magnetic resonance imaging (MRI) study
of 111 OA patients, 73% exhibited effusion on contrast
enhanced images; this figure dropped to 38% for moderate
to severe effusions and only 7% for the most severe grading
of effusion. Synovitis was found to occur in 96% of knees
with effusion and 70% of knees without effusion25. In this
respect it is notable that synovitis has been linked to pain
in OA26–29 and is often present in the absence of effusion.
A smaller study reported a higher rate of MRI-detected
effusion, 93–96% in 30 OA patients. Successful synovial
joint volume measurement by arthrocentesis was achieved
in 60% of patients and was moderately correlated with
MRI detection of effusion30. These studies indicate that
joint effusion is a common finding in OA patients, that
some patients with an effusion detectable on MRI do not
have successful arthrocentesis, and that more severe
effusion detected by MRI correlates with higher joint
volume measurements (by arthrocentesis). It is not clear
what relationship clinical evidence of effusion has to MRI
findings or what relationship joint effusion has to pain
beyond the most serious cases of joint distension. The pres-
ence of clinical effusion may signify a more pronounced
inflammatory process with the potential for increased
degradation of HA and loss of responsiveness to such ther-
apy31. As IA HA therapy has been proposed to exhibit
284 NASHA hyaluronic acid for knee osteoarthritis Arden et al.
February 2014
anti-inflammatory effects32, it would be of interest to
explore further this possible mechanism of action of HA
in the reduction of OA pain (possibly relating to
synovitis).
The main weakness in the reported study was the short,
6 week follow-up duration. Significant improvement in
the NASHA responder rate was observed between 2 and
6 weeks. This is in line with a previous study of NASHA
for knee OA, where maximum response was seen at
6 weeks13. However, assessments in that study were rela-
tively infrequent (2, 6, 13 and 26 weeks) meaning that the
treatment effect could potentially have peaked later than
6 weeks. The maximal effect of HA has been reported to
occur at around 8 weeks33, and it is possible that maximal
response is delayed in a patient population that included
clinical effusion at baseline. Thus, a study with longer
follow-up than 6 weeks would be valuable to provide
insight into the duration of effect of NASHA in patients
with OA confined to the study knee. In addition, the
absence of image guidance in this study introduces the
possibility that not all of the fluid was injected precisely
as intended into the intra-articular space. The potential
for variations in injection technique, increased by the mul-
ticentre design of the study, may have hampered detection
of statistically significant between-group differences.
However, block randomization ensured that both treat-
ment groups were affected equally and the inclusion of
multiple centres increased the generalizability of the
results. Key strengths of this study are the randomized con-
trolled design, and the provision of insight into the OA
patient population likely to respond to NASHA (i.e.
patients with clinically active inflammation in the
knee as evidenced by overt clinical effusion are not good
candidates for HA therapy).
Conclusion
We found NASHA to be clinically effective and well tol-
erated in an appropriately selected patient population.
Post-hoc subgroup analysis in patients without clinical
effusions at baseline demonstrated that NASHA was stat-
istically and clinically significantly superior to saline at
6 weeks post-treatment. Further randomized controlled
trials are required to confirm this finding and to improve
our understanding of the effects of clinical and sub-clinical
effusion on IA therapies.
Transparency
Declaration of funding
This clinical trial was supported by Q-Med AB, Uppsala, Sweden
(study design, data collection, data analysis). Early versions of the
manuscript were supported by Q-Med AB and Smith & Nephew
www.cmrojournal.com ! 2014 Informa UK Ltd

UK Ltd through a Medical Writer (Ken Sutor whilst at
Fishawack Communications, 100–102 King Street, Knutsford,
UK, WA16 6HQ).
Declaration of financial/other relationships
N.K.A. is a paid consultant for Q-Med AB and Smith & Nephew
Inc.; C.Å. has disclosed that he has no significant relationships
with or financial interests in any commercial companies related
to this study or article; R.D.A. is a Ferring consultant, speaker,
Abbott consultant, Novartis consultant, Astra Zeneca speaker,
Rotta consultant, Johnson & Johnson consultant, Novozyme
consultant, Covidien consultant and Lilly consultant; at the
time of the study M.A. was a full time employee of Q-Med AB
and M.G.T. was a full-time employee of Smith & Nephew
UK Ltd.
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CMRO peer reviewers may have received honoraria for
their review work. The peer reviewers on this manuscript have
disclosed that they have no relevant financial relationships.
Acknowledgements
The Durolane Study 2 group recruited patients in Sweden: Jan
Ericsäter, Malmö; Torsten Adalberth, Malmö; Johan Isacson,
Stockholm; Christian Åkermark, Stockholm; Anders
Björkman, Uppsala; Per-Erik Melberg, Göteborg; UK: Nigel
Arden, Southampton; John Dickson, Middlesbrough; Terry
For personal use only.
Daymond, Sunderland; James Richardson, Oswestry; David
Scott, London; and Germany: Jürgen Krämer, Bochum; Tobias
Schlegel, Mülheim/Ruhr (Nigel Arden was the coordinating
investigator). Thanks to Ulf Olsson (Q-Med, AB) who provided
critical insight during the writing of this manuscript.
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