Clin Rheumatol (2013) 32:15691574
DOI 10.1007/s10067-013-2342-z
REVIEW ARTICLE
Eligibility criteria in knee osteoarthritis clinical trials:
systematic review
Yun Hyung Koog & Hyungsun Wi & Won Young Jung
Received: 24 May 2013 / Accepted: 10 July 2013 / Published online: 23 July 2013
# Clinical Rheumatology 2013
Abstract There is an increasing concern over generalizabil-
ity of trial results. We investigated eligibility criteria of knee
osteoarthritis clinical trials. Eligible trials were randomized,
placebo-controlled trials that were identified by searches
in MEDLINE, SCOPUS, and the Cochrane Central Reg-
ister of Controlled Trials. We then attempted to extract
data on the eligibility criteria by employing predetermined
criteria. From 355 randomized knee osteoarthritis trials,
we reviewed data categorized by non-osteoarthritis-related
and osteoarthritis-related factors. A variety of items were used
in the eligibility criteria. Regarding the non-osteoarthritis-
related factors, ethical considerations, such as inability to give
an informed consent (79.4 %) or medical conditions potential
for risks by test treatments (56.0 %) or by participation in a
trial (57.2 %), were the common reasons for excluding pa-
tients from a trial. Concerning the osteoarthritis-related fac-
tors, most of the trials did not specify age and symptom
severity. When trials specifying these items were investigated,
patients with 40 to 80 years in age and grade 2 in the
KellgrenLawrence scale were mostly included into a trial.
For the pain intensity, patients with 2040 in the 100-mm
visual analog scale and 68 in the WOMAC pain subscale
were commonly enrolled into a trial. These findings warrant
further investigation on the generalizability of trial results.
Y. H. Koog : H. Wi : W. Y. Jung
Honam Research Center, Medifarm Hospital,
Suncheon, South Korea
Y. H. Koog (*)
Department of Oriental Medicine, Medifarm Hospital,
Suncheon, South Korea
e-mail: samlungchim@hanmail.net
W. Y. Jung
Department of Neurology, Medifarm Hospital,
Suncheon, South Korea
Keywords Eligibility criteria . Knee osteoarthritis .
Randomized trial
Introduction
Randomized trials are considered as an important mea-
sure for evaluating efficacy of treatments on knee osteo-
arthritis [1]. The International Multidisciplinary Commit-
tee of experts appointed by the Osteoarthritis Research
Society International recently recommended treatment
guidelines based on scientific evidence from randomized
trials [24]. Although well-conducted randomized trials
are expected to provide unbiased evidence, there are also
concerns over generalizability, that is, whether the results
found from randomized trials are applicable to actual patient
care.
Concerns regarding the generalizability have been de-
scribed in a large number of studies [513]. For example,
when eligibility criteria from the prestigious randomized
trials that were funded by the National Institute for Allergy
and Infectious Diseases were used, 067.6 % of participants
in the largest longitudinal cohort of HIV-positive women
were found to be excluded [13]. Such findings support
caution in generalizing results from randomized trials to
general population with target diseases.
Although broad eligibility criteria are usually recom-
mended to overcome these concerns [14, 15], controversy
exists regarding the use of broad criteria in knee osteoarthri-
tis. Broad eligibility criteria may enlarge the amount of
variation and thus increase sample sizes to detect clinical
change [16]. Despite this controversy, no studies have inves-
tigated eligibility criteria in knee osteoarthritis to date. In this
study, we attempted to examine the eligibility criteria used in
knee osteoarthritis clinical trials.
1570 Clin Rheumatol (2013) 32:15691574

Methods of the method section were focused, other sections were

Search strategy and study selection
The search strategy has been described elsewhere [17, 18].
Briefly, the first search was performed in PubMed,
SCOPUS, and the Cochrane Central Register of Controlled
Trials up to December 2011, by using the knee osteoarthritis-
related terms. The second search was carried out in the
Cochrane Review database to retrieve additional trials. Fi-
nally, the search was expanded to all studies referenced in the
trials. Based on the previous raw set of trials [1719], the
first author selected randomized, placebo-controlled, clinical
trials written in English.
Data extraction and analysis
Because there are no consistent definitions to discriminate
between inclusion and exclusion criteria [20], we preferred
the term of eligibility criteria to the terms of inclusion or
exclusion criteria. Eligibility criteria were considered as
predetermined criteria whereby patients are recruited into trials.
Prior to data extraction, we (YHK and HW) pilot tested items
applied in a previous study [20], using 30 randomly chosen
knee osteoarthritis trials. We modified these items to best cap-
ture the eligibility criteria in knee osteoarthritis trials (Table 1).
Then, the first author extracted data from all trials and the
second author verified the data. Although eligibility criteria
examined in some items. For example, to check the status
of informed consent, the result or acknowledgement sections
were referenced. Several assumptions were also made. First,
mild and moderate osteoarthritis were considered as
grades 2 and 3 in the KellgrenLawrence scale, respectively
[21]. Second, moderate pain was considered as 3040 in a
100-mm visual analog scale (VAS), because it was equally
described as 30, 35, or 40 in nine trials when 14 trials
reporting this relation were examined. Because different
eligibility criteria were sometimes applied to trials in same
study, we present the results in terms of trials.
Results
We identified 36,691 citations (PubMed, 1,646; SCOPUS,
32,246; Cochrane Registered Trials, 2,484; and extra source,
315), out of which 355 studies were identified as potentially
eligible for our analyses (Fig. 1). Of these, seven studies
were excluded because they included other diseases (n=3),
lacked sufficient data (n=2), or reported data combined over
the hip and knee joints (n=2). The total number of studies
analyzed was 348, which reported 355 trials.
Most trials employed non-crossover and non-flare trial
designs (Table 2). Pharmacological treatment modalities
were more commonly investigated than non-pharmacological
modalities. In addition, treatments administered via an oral

Table 1 Reasons for excluding patients from a trial

Non-osteoarthritis-related reasons Description

Inability to give an informed consent
Medical conditions causing risks by
test treatments
Medical conditions difficult to
participate in a trial
Musculoskeletal conditions difficult to
interpret outcomes
Previous experience of test treatment
Recent experience of other potential
treatments
Difficulty in adhering to a trial
Difficulty in completing a trial
Difficulty in communication
Participation in other trials
Patients unwilling to give an informed consent were excluded.
Patients with certain medical conditions may be endangered by a test treatment. For example, patients
receiving medication that can reduce the seizure threshold may be dangerous by the intake of tramadol.
Patients with certain medical conditions may not be encouraged to participate in a trial or adhere to a trial.
For example, patients in a state of malignancy or drug abuse cannot be expected to take part in a trial.
Patients with certain musculoskeletal conditions may be difficult for researchers to interpret outcomes.
For example, patients with hip pain may present confounding results because the results may be
influenced by the pain unrelated to knee.
Patients who previously experienced test treatments may discriminate between true and placebo
treatments. For example, patients having received acupuncture may recognize true or placebo
acupuncture.
Patients who received other potential treatments within a few months may not show a real change in
outcomes. For example, patients receiving a corticosteroid injection within the past 3 months may not
present the real change caused by hyaluronate injections.
Patients who may be expected not to adhere to a trial were excluded.
Patients who may be expected not to complete a trial were excluded.
Patients who used different language were excluded.
Patients who were involved in other trials were excluded.

Osteoarthritis-related reasonsa
Age, gender, treated leg, osteoarthritis
severity, pain status, etc.
a
Osteoarthritis-related reasons were based on previous studies [26, 27]
1570 Clin Rheumatol (2013) 32:15691574

Methods of the method section were focused, other sections were

Search strategy and study selection
The search strategy has been described elsewhere [17, 18].
Briefly, the first search was performed in PubMed,
SCOPUS, and the Cochrane Central Register of Controlled
Trials up to December 2011, by using the knee osteoarthritis-
related terms. The second search was carried out in the
Cochrane Review database to retrieve additional trials. Fi-
nally, the search was expanded to all studies referenced in the
trials. Based on the previous raw set of trials [1719], the
first author selected randomized, placebo-controlled, clinical
trials written in English.
Data extraction and analysis
Because there are no consistent definitions to discriminate
between inclusion and exclusion criteria [20], we preferred
the term of eligibility criteria to the terms of inclusion or
exclusion criteria. Eligibility criteria were considered as
predetermined criteria whereby patients are recruited into trials.
Prior to data extraction, we (YHK and HW) pilot tested items
applied in a previous study [20], using 30 randomly chosen
knee osteoarthritis trials. We modified these items to best cap-
ture the eligibility criteria in knee osteoarthritis trials (Table 1).
Then, the first author extracted data from all trials and the
second author verified the data. Although eligibility criteria
examined in some items. For example, to check the status
of informed consent, the result or acknowledgement sections
were referenced. Several assumptions were also made. First,
mild and moderate osteoarthritis were considered as
grades 2 and 3 in the KellgrenLawrence scale, respectively
[21]. Second, moderate pain was considered as 3040 in a
100-mm visual analog scale (VAS), because it was equally
described as 30, 35, or 40 in nine trials when 14 trials
reporting this relation were examined. Because different
eligibility criteria were sometimes applied to trials in same
study, we present the results in terms of trials.
Results
We identified 36,691 citations (PubMed, 1,646; SCOPUS,
32,246; Cochrane Registered Trials, 2,484; and extra source,
315), out of which 355 studies were identified as potentially
eligible for our analyses (Fig. 1). Of these, seven studies
were excluded because they included other diseases (n=3),
lacked sufficient data (n=2), or reported data combined over
the hip and knee joints (n=2). The total number of studies
analyzed was 348, which reported 355 trials.
Most trials employed non-crossover and non-flare trial
designs (Table 2). Pharmacological treatment modalities
were more commonly investigated than non-pharmacological
modalities. In addition, treatments administered via an oral

Table 1 Reasons for excluding patients from a trial

Non-osteoarthritis-related reasons Description

Inability to give an informed consent
Medical conditions causing risks by
test treatments
Medical conditions difficult to
participate in a trial
Musculoskeletal conditions difficult to
interpret outcomes
Previous experience of test treatment
Recent experience of other potential
treatments
Difficulty in adhering to a trial
Difficulty in completing a trial
Difficulty in communication
Participation in other trials
Patients unwilling to give an informed consent were excluded.
Patients with certain medical conditions may be endangered by a test treatment. For example, patients
receiving medication that can reduce the seizure threshold may be dangerous by the intake of tramadol.
Patients with certain medical conditions may not be encouraged to participate in a trial or adhere to a trial.
For example, patients in a state of malignancy or drug abuse cannot be expected to take part in a trial.
Patients with certain musculoskeletal conditions may be difficult for researchers to interpret outcomes.
For example, patients with hip pain may present confounding results because the results may be
influenced by the pain unrelated to knee.
Patients who previously experienced test treatments may discriminate between true and placebo
treatments. For example, patients having received acupuncture may recognize true or placebo
acupuncture.
Patients who received other potential treatments within a few months may not show a real change in
outcomes. For example, patients receiving a corticosteroid injection within the past 3 months may not
present the real change caused by hyaluronate injections.
Patients who may be expected not to adhere to a trial were excluded.
Patients who may be expected not to complete a trial were excluded.
Patients who used different language were excluded.
Patients who were involved in other trials were excluded.

Osteoarthritis-related reasonsa
Age, gender, treated leg, osteoarthritis
severity, pain status, etc.
a
Osteoarthritis-related reasons were based on previous studies [26, 27]
Clin Rheumatol (2013) 32:15691574
Fig. 1 Study flow diagram
route were examined more than those administered via
invasive routes.
Non-osteoarthritis-related reasons for excluding patients
from a trial are described in Table 3. Inability to give an
informed consent was the most common reason (79.4 %) for
excluding patients from trials, followed by recent experience
of other potential treatments (61.4 %). Medical conditions
that may cause risks by treat treatments or may be difficult to
interpret outcomes were also reported as reasons in more
than 50 % trials.
Categories of osteoarthritis-related reasons for enrolling
patients into a trial are depicted in Table 4. With respect to
age or osteoarthritis severity, exact values were not specified
1571
in a large number of trials. When only trials reporting the
values were considered, most trials enrolled patients between
40 and 80 years in age and focused on patients with grade 2 in
the KellgrenLawrence scale. For the body mass index, most
of 32 trials reporting this index set 40 as maximum criterion.
Categories of pain-related reasons for enrolling patients
into a trial are presented in Table 5. Of 207 trials stating
that painful knee was investigated, VAS was the commonest
pain outcome. For the VAS, patients with more than 20
40 mm were enrolled in 80.3 % of 132 trials. Regarding the
Western Ontario and McMaster Universities Arthritis Index
(WOMAC) pain subscale, patients with more than 68 were
enrolled in 42.1 % of 19 trials.
1572 Clin Rheumatol (2013) 32:15691574

Table 2 Trial characteristics Table 4 Categories of osteoarthritis-related reasons for enrolling pa-
tients into a trial
Trial number (%)
Trial number (%)
Total trial 355
Crossover design Lower boundary of age, years
Non-crossover 332 (93.5) 20 49 (13.8)
Crossover 23 (6.5) 30 17 (4.8)
Flare design 40 103 (29.0)
Flare 32 (9.0) 50 33 (9.3)
Non-flare 323 (91.0) 60 7 (2.0)
Treatment type Unspecified 154 (43.4)
Pharmacological 261 (73.5) Upper boundary of age, years
Non-pharmacological 93 (26.2) 60 2 (0.6)
Mixed 1 (0.3) 70 17 (4.8)
Delivery routea 80 57 (16.1)
Oral 158 (45.4) 90 12 (3.4)
Invasive 100 (28.7) Unspecified 267 (75.2)
Others 90 (25.9) Gender
Female 7 (2.0)
a
Seven trials administering treatments via mixed routes were excluded Mixed 348 (98.0)
Leg treated
Single 6 (1.7)
Classification of gender-specific conditions mentioned in
Bilateral 14 (3.9)
eligibility criteria was also examined. Pregnancy (26.2 %)
Mixed 335 (94.4)
was most commonly indicated as reason for excluding pa-
Osteoarthritis type
tient from a trial, followed by lactation (16.1 %) and no
Primary 79 (22.3)
contraception (14.1 %). Meanwhile, menopause (2.8 %)
Mixed 276 (77.7)
was sometimes pointed out as a reason for enrolling patients
Localization within knee
into a trial.
Medial 24 (6.8)
Lateral 1 (0.3)
Unspecified 330 (93.0)
Discussion
Osteoarthritis severity (KellgrenLawrence scale)
1 1 (0.3)
We reviewed data on eligibility criteria from 355 randomized
12 10 (2.8)
knee osteoarthritis trials and identified several key points.
13 32 (9.0)
First, ethical considerations, such as inability to give an
14 12 (3.4)
informed consent or medical conditions potential for risks
23 62 (17.5)
Table 3 Non-osteoarthritis-related reasons for excluding patients from 24 35 (9.9)
a trial 3 4 (1.1)
34 12 (3.4)
Trial number (%)
Unspecified 187 (52.7)
Inability to give an informed consent 282 (79.4) Pain status
Medical conditions causing risks by test treatments 198 (56.0) Painful 207 (58.3)
Medical conditions difficult to participate in a trial 203 (57.2) Non-painful/unclear 148 (41.7)
Musculoskeletal conditions difficult to interpret 82 (23.1)
outcomes BMI index was excluded because of monotonous information
Previous experience of test treatment 52 (14.7)
Recent experience of other potential treatments 218 (61.4)
Difficulty in adhering to a trial 27 (7.6)
by test treatments or by participation in a trial, were the
Difficulty in completing a trial 9 (2.5)
common non-osteoarthritis-related reasons. Second, al-
Difficulty in communication 26 (7.3)
though a large number of trials did not specify age and
osteoarthritis severity, patients with 40 to 80 years in age
Participation in other trials 25 (7.0)
and grade 2 in the KellgrenLawrence scale were mostly
Clin Rheumatol (2013) 32:15691574 1573

Table 5 Categories of pain-related reasons for enrolling patients into a We also found that some factors such as age, osteoarthritis
trial
severity, and pain intensity were considered as eligibility
Trial number (%) criteria. With respect to several factors, the possibility of
applying trial results to a clinical practice may be conjectured.
Pain confirmation 207a For example, it has been reported that the prevalence of
Visual analog scale 134 (64.7) radiographic and symptomatic osteoarthritis increases sharply
WOMAC pain subscale 19 (9.2) with age [26, 27]. Besides, according to a study comparing the
Failure of previous treatment including analgesics 19 (9.2) prevalence of a Dutch village with those of different popula-
Present use of analgesics 34 (16.4) tions, only 10 % of men and women had evidence of knee
Unspecified 30 (14.5) osteoarthritis by 40 years of age [28]. This fact may justify
Lower boundary of visual analog scaleb (mm) 132 40 years of age considered as a cutoff point in knee osteoar-
020 11 (8.3) thritis trials.
2040 106 (80.3) Regarding other factors, however, it cannot be concluded
4060 14 (10.6) at present whether the generalizability of the trial results is
6080 1 (0.8) possible. This difficulty reflects limitations of our study. In
Upper boundary of visual analog scaleb (mm) 16c this study, eligibility criteria were investigated that were
6080 9 (56.3) considered as a cutoff point in the trials. Because we do not
80100 5 (31.3) know the actual rate of patients with such factors in the trials,
Lower boundary of WOMAC pain subscaleb 19 we cannot determine the possibility of the generalizability.
02 1 (5.3) Likewise, there are few studies showing reference data on
24 3 (15.8) the rate of patients with factors of interest. While there are
46 5 (26.3) numerous studies showing differences between patients with
68 8 (42.1) and without knee osteoarthritis (e.g., prevalence study [26]),
810 2 (10.5) we could not find reports presenting rates of patients with
Upper boundary of WOMAC pain subscaleb 3 specific factors.
1416 2 (66.7) This is a first report that investigated eligibility criteria in
1618 1 (33.3) knee osteoarthritis by using predetermined criteria. This
study revealed that knee osteoarthritis trials employed a
Percentage is category specific variety of items in the eligibility criteria. Whereas numerous
WOMAC Western Ontario and McMaster Universities Arthritis Index trials enrolled patients without specifying factors, other trials
a
Multiple criteria were reported by some trials focused on patients with specific factors. These varied eligi-
b
ab, >a, and b bility criteria may cause severe systematic biases, thus
c
Two trials did not specify criteria impairing the generalizability. As suggested in a previous
study [13], broad or consistent eligibility criteria may be
necessary to reduce such biases. Therefore, future studies
enrolled in other trials. Third, when trials investigating pain- should investigate the impact of such eligibility criteria. We
ful knee were considered, patients with 2040 mm in the believe that these findings will provide useful implications in
VAS and 68 in the WOMAC pain subscale were com- the design and conduct of clinical trials.
monly enrolled.
Previously, a large number of studies investigated the
generalizability of results obtained from clinical trials Disclosures None.
[513]. Although eligibility criteria were found to influence
the characteristics of patients participating in trials [13], few
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