EXHIBIT E 

Case: 1:11-cv-07972 Document #: 30-5 Filed: 07/20/12 Page 1 of 9 PageID #:184
Randomized, Double-Blind, Placebo-Controlled

Glucosamine Discontinuation Trial in Knee

Osteoarthritis

JOLANDA CIBERE,1 JACEK A. KOPEC,1 ANONA THORNE,2 JOEL SINGER,3 JANICE CANVIN,4

DAVID B. ROBINSON,5 JANET POPE,6 PAUL HONG,7 ERIC GRANT,8 AND JOHN M. ESDAILE1

Objective. To assess the efficacy of glucosamine sulfate in knee osteoarthritis (OA).

Methods. A 4-center, 6-month, randomized, double-blind, placebo-controlled glucosamine discontinuation trial was

conducted in 137 current users of glucosamine with knee OA who had experienced at least moderate improvement in

knee pain after starting glucosamine. Study medication dosage was equivalent to the dosage of glucosamine taken prior

to the study (maximum 1,500 mg/day). Followup continued for 6 months or until disease flare, whichever occurred first.

The primary outcome was the proportion of disease flares in the glucosamine and placebo groups using an intent-to-treat

analysis. Secondary outcomes included time to disease flare; analgesic medication use; severity of disease flare; and

change in pain, stiffness, function and quality of life in the glucosamine and placebo groups.

Results. Disease flare was seen in 28 (42%) of 66 placebo patients and 32 (45%) of 71 glucosamine patients (difference

–3%; 95% confidence interval [95% CI] –19, 14; P 0.76). In the Cox regression analysis, after adjustment for sex, study

site, and OA radiographic severity, time to disease flare was not significantly different in the glucosamine compared with

placebo group (hazard ratio of flare 0.8; 95% CI 0.5, 1.4; P 0.45). At final study visit, acetaminophen was used in 27%

and 21% of placebo and glucosamine patients, respectively (P 0.40), nonsteroidal antiinflammatory drugs were used in

29% and 30% (P 0.92), and both were used in 20% and 21% (P 0.84). No differences were found in severity of disease

flare or other secondary outcomes between placebo and glucosamine patients.

Conclusion. In patients with knee OA with at least moderate subjective improvement with prior glucosamine use, this

study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate.

KEY WORDS. Glucosamine; Knee osteoarthritis; Randomized discontinuation trial.

INTRODUCTION

Osteoarthritis (OA) is the most common joint disease

worldwide. Symptomatic knee OA occurs in 6% of the

population older than 30 years (1) and increases in prevalence with age. Knee OA causes significant disability,

including work disability (2–5), and is associated with

substantial economic costs (6,7). With the aging of the

population, the economic burden of OA is projected to

increase considerably by the year 2020 (8). Current treatments are limited to nonpharmacologic interventions,

such as weight reduction and exercise, pharmacologic

Supported by grants from the Mary Pack Research Fund,

Vancouver, British Columbia, Canada and by the Doris

Alma Mary Anderson Fund for Geriatric Research, London,

ON, Canada. Dr. Cibere’s work supported by a Canadian

Institutes of Health Research Clinician Scientist Award and

a Michael Smith Foundation for Health Research Postdoctoral Fellowship Award. 1

Jolanda Cibere, MD, Jacek A. Kopec, MD, PhD, John M.

Esdaile, MD, MPH: Arthritis Research Centre of Canada and

University of British Columbia, Vancouver, British Columbia, Canada; 2

Anona Thorne, MSc: University of British

Columbia, Vancouver, British Columbia, Canada; 3

Joel

Singer, PhD: University of British Columbia and Centre for

Health Evaluation and Outcome Sciences, Vancouver, British Columbia, Canada; 4

Janice Canvin, MD: University of

Manitoba, Winnipeg, Manitoba, Canada, and GlaxoSmithKline, Stevenage, United Kingdom; 5

David B. Robinson, MD,

MSc: University of Manitoba, Winnipeg, Manitoba, Canada;

6

Janet Pope, MD, MPH: University of Western Ontario, St.

Joseph’s Health Care London, London, Ontario, Canada;

7

Paul Hong, BSc (Hons): University of Ottawa, Ottawa, Ontario, Canada; 8

Eric Grant, MD: Dalhousie University, Saint

John, New Brunswick, Canada.

Address correspondence to Jolanda Cibere, MD, Arthritis

Research Centre of Canada, 895 West 10th Avenue, Vancouver, BC, Canada, V5Z 1L7. E-mail: jcibere@arthritisresearch.ca.

Submitted for publication October 22, 2003; accepted in

revised form February 9, 2004.

Arthritis & Rheumatism (Arthritis Care & Research)

Vol. 51, No. 5, October 15, 2004, pp 738 –745

DOI 10.1002/art.20697

© 2004, American College of Rheumatology

ORIGINAL ARTICLE

738

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management of pain, and surgical treatment for severe OA.

Therefore, the search for and evaluation of new treatments

for OA is an important step toward better management of

this disease. Glucosamine has been widely publicized in

North America and is currently one of the top-selling

nutritional supplements. However, the evidence for efficacy of glucosamine is controversial.

Glucosamine has been evaluated for the symptomatic

treatment of knee OA in a number of studies (9 –20), most

of which have reported benefit (9 –17). However, systematic reviews of these studies have commented on methodologic issues relating to study design, publication bias, and

the tendency for pharmaceutical sponsorship to be associated with positive study findings (21,22). Two trials have

reported the benefit of glucosamine on the radiographic

progression of OA as well as symptomatic improvement

over 3 years (23,24). In contrast, 3 recent studies have

reported no efficacy of glucosamine in the treatment of

symptomatic knee OA (18 –20). The differences in these

studies has been highlighted in a recent review of the

glucosamine literature by McAlindon in an attempt to

provide insight into why clinical trials of glucosamine are

no longer uniformly positive (25). However, the conclusion from this review was that more research was needed.

As a result, despite numerous studies, the evidence for the

efficacy of glucosamine in knee OA is inconclusive.

This study was initiated to assess the efficacy of glucosamine. Because glucosamine is freely available as an

over-the-counter nutritional supplement, its use has become widespread in the community. As a result, this study

was designed as a randomized discontinuation trial (RDT)

(26) to evaluate the effect of continuing or withdrawing

glucosamine in patients with knee OA.

PATIENTS AND METHODS

Patients. Participants were recruited through newspaper advertising and local posters. Subjects were included

if they met the following eligibility criteria: 1) OA of the

knee(s) according to the American College of Rheumatology diagnostic criteria (27), 2) Kellgren-Lawrence grade 2

on anteroposterior radiograph of the knee (28), 3) current

daily use of glucosamine for at least 1 month, 4) at least

moderate improvement in knee pain since starting on glucosamine, measured on a 6-point scale of knee pain

(worse, unchanged, mildly improved, moderately improved, markedly improved, completely subsided). Subjects were excluded if they met any of the following criteria: 1) chondroitin sulfate use within the previous 2

months, 2) knee injection with hyaluronate in the previous

6 months or with corticosteroids in the previous 3 months,

3) surgical procedure on either knee in the previous 3

months, 4) narcotic analgesic use, 5) uncontrolled medical

condition or planned surgery that could interfere with

followup, 6) baseline potassium 5.3 mEq/liter or baseline

creatinine 120 mmol/liter.

Study design. The study was a 6-month, randomized,

double-blind, placebo-controlled parallel-group glucosamine discontinuation trial performed at 4 centers in

Canada. The study was conducted in accordance with the

Declaration of Helsinki (1975) and was approved by the

Institutional Review Board at each study site. All patients

provided written informed consent.

Randomization. A central computer-generated randomization code was produced by a researcher not affiliated

with the study. Block randomization with a randomly

variable block size of 2– 6 was used. The randomization

code was forwarded to the manufacturer of the study medication and was used to label the study medication bottles

consecutively from 1 to 160. The randomization codes

remained sealed until after the blinded analysis had been

carried out. Thus, allocation concealment was maintained

and study investigators and patients were blinded

throughout the study. Eligible subjects were assigned the

next consecutive study number.

Intervention. Glucosamine and placebo tablets were

supplied by VitaHealth (Winnipeg, Manitoba, Canada).

The active drug consisted of glucosamine sulfate formulated as a potassium salt preparation (500-mg tablets). The

placebo tablets were indistinguishable from the glucosamine tablets and contained excipients only. Patients

were randomized to receive either glucosamine sulfate or

placebo. The study medication dosage was equivalent to

the dosage of glucosamine taken prior to the study with a

maximum of 1,500 mg per day. Patients who used a dosage

1,500 mg per day prior to the study were treated with

1,500 mg per day during the study. Compliance with study

treatment was evaluated by pill count at each visit, except

at week 2. Rescue analgesic medications including acetaminophen and nonsteroidal antiinflammatory drugs

(NSAIDs) were allowed and recorded by the patient in a

daily diary. Other concomitant treatments, including

chondroitin sulfate and intraarticular injections with corticosteroids or hyaluronic acid, were not allowed during

the study. Followup continued for 6 months or until disease flare, whichever occurred first.

Outcome assessments. Following the screening visit

and determination of eligibility, patients were assessed at

weeks 0 (baseline), 2, 4, 8, 12, and 24 or at any time if a

flare occurred. Each study visit included an evaluation of

knee symptoms, review of medications and adverse

events, an assessment of acetaminophen and NSAID use

over the preceding study interval, and a knee examination

including warmth, joint effusion, crepitus, joint line tenderness, end-of-range stress pain, and range of motion

measured by goniometer. At each visit, patients completed

the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, version VA3.0), which is a validated disease-specific questionnaire frequently used in

OA trials assessing pain, stiffness, and function (29); patients also completed the European Quality of Life questionnaire (EQ-5D), a validated generic health assessment

tool that includes a utility score and a 0 –100 visual analog

scale (VAS) (30). Following all assessments, a physician

global assessment was recorded, rating patient status on a

scale from 1 to 5 as very poor, poor, fair, good, or excellent

(31). A determination of whether disease flare had occurred was made at each visit. If a disease flare was

present, the patient was withdrawn from the study. At the

final study visit, patient blinding was assessed by asking

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the patient’s opinion whether glucosamine or placebo was

received in the study. When all patients had completed the

study, a random selection of 11% of glucosamine study

drugs (n  8) and a random selection of 2 placebo study

drugs were analyzed for glucosamine sulfate content. The

glucosamine sulfate content analysis was performed by JR

Laboratories Inc. (Vancouver, British Columbia, Canada)

using an internally validated Hamilton high performance

liquid chromatography system.

Study outcomes. The primary endpoint was the proportion of patients with disease flare in the glucosamine and

placebo groups. Disease flare was defined a priori as either

the patient’s perception of worsening of symptoms with a

concomitant increase by at least 20 mm in WOMAC pain

on walking, or a significant worsening in the physician

global assessment by at least 1 grade (1–5 scale). This

definition of disease flare was determined by study rheumatologists to be a clinically important change in

WOMAC. Secondary outcomes included the time to disease flare; change from baseline to flare visit in WOMAC

pain, stiffness, function, and total scores; change from

baseline to flare in EQ-5D utility and VAS; and the proportion of patients using acetaminophen, NSAIDs, or both

in the 2 treatment groups at final study visit. In addition,

severity of disease flare was assessed in the placebo and

glucosamine groups by comparing mean change scores in

WOMAC pain, stiffness, function, total WOMAC, and

EQ-5D utility and VAS scores in patients who experienced

a flare.

Statistical analysis. Baseline characteristics were compared between the placebo and glucosamine treatment

groups. The proportion of patients with disease flare was

assessed using the chi-square test. Time to disease flare

was evaluated by survival analysis. Kaplan-Meier curves

were generated for the placebo and glucosamine treatment

groups and the log-rank test was used to test for a statistical difference between the curves. Because of baseline

imbalances between treatment groups, a Cox regression

analysis was performed with adjustment for imbalanced

covariates. The effect of treatment group on the hazard of

developing a disease flare was evaluated in an initial univariate model. Sex, study site, and OA radiographic severity were then added to the model to evaluate the effect of

treatment on the hazard of developing a disease flare after

adjustment for these covariates. In addition, other clinically important covariates were assessed in the Cox regression analysis including age, duration of glucosamine use,

glucosamine dosage, duration of OA, and analgesic medication use. The assumptions underlying the proportional

hazards model were assessed using residual plots and

log-log plots. There was no evidence of violation of any

model assumptions.

An intent-to-treat approach was used. It was decided a

priori that patients who were lost to followup would be

considered to have flared for the purpose of the primary

analysis. For the survival analysis, patients lost to followup were right censored, and hence they were followed

only to their last visit.

The sample size calculation was based on assumptions

of a 10% flare rate in the glucosamine group and a 30%

flare rate in the placebo group. With a power of 80% and

an alpha error of 5%, a sample size of 62 patients per group

was calculated. Under the assumption of a 10% dropout

rate, the target for recruitment was 138 patients.

RESULTS

A total of 209 patients were screened for the study (Figure

1). Of these, 137 met the inclusion and exclusion criteria

and were randomized to receive glucosamine (n  71) or

placebo (n  66). In total, 134 patients completed the

study to the predefined outcome of disease flare or 6

months of completed followup. Of the remaining 3 patients, 1 was lost to followup after week 4, 1 withdrew

from the study at week 2 due to a cerebrovascular accident,

and 1 withdrew at week 4 due to a diagnosis of metastatic

adenocarcinoma of unknown origin. These 3 patients had

been assigned to the glucosamine treatment group and

were considered to have flared for the primary analysis.

The baseline characteristics of placebo and glucosamine

patients were comparable except for sex and OA radiographic severity (Table 1). Women made up 70% of patients in the placebo group, compared with 44% in the

glucosamine group. Mild radiographic knee OA (KellgrenLawrence grade 2) was present in 64% of the placebo

group and 46% of the glucosamine group. In contrast,

moderate OA (grade 3) was present in 33% and 44%,

respectively, and severe OA (grade 4) was seen in 3% and

10%, respectively. As a result, patients in the glucosamine

group had more severe knee OA based on radiography.

However, severity based on WOMAC pain (possible score

of 0 –500) and function (possible score of 0 –1,700) was

comparable in the 2 groups with median (range) WOMAC

pain scores of 86 (2–279) and 86 (4 –301), and median

(range) WOMAC function scores of 268 (0 –1,376) and 294

(2–1,240) in the placebo and glucosamine groups, respectively (Table 1). Because no analgesic washout was used in

this discontinuation trial, these scores, although lower

than those reported in standard trials, are consistent with

a moderately severely affected patient population, as indicated by the range of scores. The majority of patients in

both groups used a glucosamine dosage of 1,500 mg per

Figure 1. Flow diagram of study enrollment and conduct.

740 Cibere et al

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day prior to the study, with only 3 (5%) placebo and 5

(7%) glucosamine patients using a larger dosage. The maximum prestudy dosage was 2,000 mg per day. Similarly,

the majority of patients had used glucosamine sulfate prior

to the study with only 4 (6%) placebo and 3 (4%) glucosamine patients having used prestudy glucosamine hydrochloride.

The primary endpoint of a disease flare in the intent-totreat analysis was seen in 28 (42%) of 66 patients in the

placebo group and 32 (45%) of 71 patients in the glucosamine group (Figure 2). The between-group difference

of –3% was not statistically significant (95% confidence

interval [95% CI] –19, 14; P  0.76).

No differences were seen for acetaminophen and NSAID

use between the placebo and glucosamine groups (Figure

3). At final study visit, acetaminophen was used by 27%

and 21% of placebo and glucosamine patients, respectively (difference 6%; 95% CI – 8, 20; P  0.40), NSAIDs

were used by 29% and 30%, respectively (difference –1%;

95% CI –16, 14; P  0.92), and both acetaminophen and

NSAIDs were used by 20% and 21%, respectively (difference –1; 95% CI –15, 12; P  0.84). Dosages of acetaminophen and NSAIDs were also not different between the 2

treatment groups at final study visit (data not shown).

Other secondary outcomes of WOMAC pain on walking,

pain score, stiffness score, function score, total WOMAC,

and quality of life (EQ-5D utility and VAS) were not significantly different in the placebo and glucosamine groups

(Table 2).

Time to disease flare, assessed by survival analysis, was

also similar in the placebo and glucosamine groups. There

were no statistically significant differences in KaplanMeier survival curves for patients who continued on glucosamine compared with those who were withdrawn from

glucosamine (log-rank test, P  0.96; Figure 4). A univariate Cox regression analysis with treatment group as the

explanatory variable revealed a hazard of disease flare of

0.98 (95% CI 0.6, 1.6; P  0.93) in the glucosamine group

compared with placebo (Table 3). After adjustment for sex,

study site, and OA radiographic severity, there was no

difference in the risk of disease flare between the placebo

and glucosamine patients (hazard ratio 0.8; 95% CI 0.5,

1.4; P  0.45; Table 3). Age, duration of glucosamine use,

Table 1. Baseline characteristics of placebo and glucosamine groups*

Placebo

n 66

Glucosamine

n 71

Age, mean (range) years 65 (43–88) 64 (40–83)

Female, % 70 44

Body mass index, mean (range) kg/m2 27 (21–45) 28 (19–49)

Duration of glucosamine use, median (range) years 1.5 (0.1–6.8) 1.7 (0.1–5.4)

Prestudy type of glucosamine, %

Glucosamine sulfate 94 96

Glucosamine hydrochloride 6 4

Prestudy glucosamine dosage, %

1,500 mg per day 5 7

1,500 mg per day 53 61

1,000 mg per day 33 26

500 mg per day 9 6

Duration of physician-diagnosed OA, median (range) years 3 (0–29) 3 (0–29)

Radiographic OA severity, %

K-L grade 2 64 46

K-L grade 3 33 44

K-L grade 4 3 10

WOMAC pain on walking, median (range) 0–100 mm 12 (0–78) 13 (0–63)

WOMAC pain, median (range) 0–500 mm 86 (2–279) 86 (4–301)

WOMAC function, median (range) 0–1,700 mm 268 (0–1,376) 294 (2–1,240)

WOMAC total, median (range) 0–2,400 mm 414 (26–1,796) 444 (10–1,671)

Analgesic medication use, %

Acetaminophen only 24 17

NSAIDs only 35 35

Both acetaminophen and NSAIDs 14 16

* OA  osteoarthritis; K-L  Kellgren-Lawrence; WOMAC  Western Ontario and McMaster Universities

Osteoarthritis Index; NSAIDs  nonsteroidal antiinflammatory drugs.

Figure 2. Proportion of disease flare in the placebo and glucosamine treatment groups in the intent-to-treat population.

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glucosamine dosage, duration of OA, and analgesic medication use were not significant in the Cox regression analysis (data not shown) and hence were not included in the

final model.

Severity of disease flare was similar in the placebo- and

glucosamine-treated patients who flared (Table 4). There

were no statistically significant differences in mean

change in WOMAC pain on walking, pain, stiffness, or

function scales; total WOMAC score; or quality of life

between flare patients in the placebo and glucosamine

groups. However, mean change scores of flare patients

were substantially different from those of nonflare patients. Worsening of WOMAC and EQ-5D scores was seen

in patients who had a flare, as indicated by negative

change scores, whereas improvement of these outcomes

occurred in patients who did not have a flare, as indicated

by positive change scores (Table 4).

Compliance with study drug was excellent. Greater than

80% compliance was seen in 97% of patients receiving

placebo and 97% of patients receiving glucosamine. There

was no evidence of unblinding at the end of the study. No

serious adverse events were reported during the study and

Figure 3. Proportion of analgesic drug use at final study visit in the intent-to-treat population. NSAID  nonsteroidal antiinflammatory

drug; 95% CI  95% confidence interval.

Table 2. Mean change in WOMAC and EQ-5D at final visit compared with baseline and between-group differences in the

intent-to-treat population*

Mean (SD) Change from baseline*

mean  SD

Between-group

difference (95% CI) P

Placebo

(n 66)

Glucosamine

(n 71)

WOMAC

Pain on walking, 0–100 mm 8  25 5  21 3 (11, 4) 0.40

Pain scale, 0–500 mm 28  104 25  98 3 (37, 32) 0.88

Stiffness scale, 0–200 mm 6  48 2  42 4 (11, 20) 0.57

Function scale, 0–1,700 mm 63  318 58  270 5 (105, 94) 0.92

Total scale, 0–2,400 mm 85  453 81  388 4 (145, 139) 0.96

EQ-5D

Utility score, 0–1 0.04  0.20 0.03  0.16 0.01 (0.07, 0.05) 0.68

Visual analog scale, 0–100 2  12 0.1  16 2 (7, 3) 0.42

* Positive mean change indicates improvement, negative mean change indicates worsening. WOMAC  Western Ontario and McMaster Universities

Osteoarthritis Index; EQ-5D  European Quality of Life questionnaire; 95% CI  95% confidence interval.

742 Cibere et al

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there were no differences in adverse events between the

glucosamine and placebo groups. Because of the discontinuation design of this study, minimal adverse effects

were expected, since all subjects had previously tolerated

glucosamine. Mean glucosamine sulfate content was

found to be 618 mg per tablet in the glucosamine samples

and 0 mg per tablet in the placebo samples.

DISCUSSION

Efficacy of glucosamine in knee OA has been reported

predominantly in trials with pharmaceutical sponsorship

(21). With recent publications of glucosamine studies reporting no therapeutic value (18 –20), the issue of whether

glucosamine is efficacious has become more controversial.

In this study, we found that knee OA disease flare occurred

as frequently, as quickly, and as severely in patients who

were randomized to continue receiving glucosamine compared with those who received placebo. As a result, the

efficacy of glucosamine as a symptom-modifying drug in

knee OA is not supported by our study.

The randomized discontinuation trial approach has

been used infrequently to demonstrate efficacy. A key

underlying assumption for the RDT study design is that

the disease process will worsen or flare when the drug is

discontinued. This presumes that the disease under study

has not been cured by the drug treatment prior to the trial.

Although glucosamine is frequently promoted as a disease-modifying drug, there is no evidence that it is curative, and hence an RDT study design is appropriate. A

6-month study design was felt to be sufficient to allow for

disease flares to occur. Because pain relief occurs within

2–3 months of treatment with glucosamine, it seems reasonable to expect development of a flare within a similar

timeframe after discontinuation of glucosamine, assuming

no curative effect. Because patients in this study were

enrolled only if they had subjective improvement while

taking glucosamine, the question of whether glucosamine

has an initial beneficial effect cannot be answered. Any

initial perceived benefit may have been due to a placebo

response or natural fluctuation in symptoms over time and

hence a null finding would be expected in a discontinuation trial. Alternatively, a temporary initial benefit could

be due to glucosamine itself or another component of the

nutritional supplement, such as sulfate. However, even if

an initial benefit had been derived from glucosamine or

sulfate, our findings suggest that there is no evidence of

benefit with continued use of glucosamine sulfate for the

symptomatic treatment of knee OA.

Our negative study findings need to be interpreted in the

context of the observed confidence interval, which indicates with 95% confidence that a true difference in proportion of flares is no greater than 14% in favor of glucosamine. Because this study was designed to detect a

clinically important difference of 20%, these findings are

consistent with our a priori null hypothesis.

Furthermore, our negative study findings cannot be explained by a lack of compliance, in view of the fact that

97% of study participants had excellent compliance. Contamination with nonstudy glucosamine is also an unlikely

explanation, because the study procedures were clearly

understood by participants, the use of all medications was

ascertained at each study visit, and participants understood the importance of rigorously evaluating the efficacy

of glucosamine. Similarly, cointerventions were not allowed in the study and no protocol violations occurred.

Hence, this is an unlikely explanation for our negative

findings.

A potential bias toward nonefficacy occurred because

patients lost to followup were considered to have flared

according to our a priori decision. Because all 3 patients

lost to followup were in the glucosamine group, this resulted in more flares in the glucosamine group and hence

introduced a bias toward nonefficacy of glucosamine.

However, even with the exclusion of these 3 patients, there

was no difference in the proportion of flares in the glucosamine and placebo groups.

In addition, if glucosamine hydrochloride has no or

minimal efficacy compared with glucosamine sulfate, the

use of glucosamine hydrochloride prior to the study may

result in a study finding of no difference. Only 4 placebo

and 3 glucosamine patients had used the hydrochloride

formulation of glucosamine prior to the study and similar

proportions experienced a flare (2 patients in each group).

Exclusion of these 7 patients did not change the results.

Table 3. Multivariate hazard ratio of disease flare in the

Cox regression analysis*

Variables Hazard ratio (95% CI) P

Univariate analysis

Placebo 1.0

Glucosamine 0.98 (0.6, 1.6) 0.93

Multivariate analysis

Placebo 1.0

Glucosamine 0.8 (0.5, 1.4) 0.45

* The multivariate analysis was adjusted for sex, study site, and

radiographic severity of osteoarthritis. 95% CI  95% confidence

interval.

Figure 4. Kaplan-Meier survival curves for time to disease flare in

the placebo (dashed line) and glucosamine (solid line) groups.

Log-rank test, P  0.96.

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Finally, because OA disease activity can fluctuate naturally, a difference between treatment groups may not be

appreciable based solely on the primary outcome of disease flare. For this purpose, we evaluated as secondary

outcomes the severity of change in WOMAC pain, stiffness, and function scores, as well as the time to disease

flare in the placebo and glucosamine groups. However, no

differences were found in the severity of disease flare or

time to disease flare, lending further support to our conclusion of no symptomatic benefit from continued glucosamine use in knee OA.

Our findings are in keeping with other recent studies

with negative results (18 –20). Houpt et al (18) evaluated a

population of knee OA patients with predominantly early

radiographic changes in which 74% of patients had Kellgren-Lawrence grade 1 or 2 changes (28). They reported no

significant difference in WOMAC pain, stiffness, or function scores after 2 months of treatment with glucosamine

compared with placebo. In the study by Rindone et al (19),

in which approximately half of the patients had early knee

OA (Kellgren-Lawrence grade 1 or 2), they found no differences in pain at rest and pain on walking after 2 months

of treatment with glucosamine or placebo. The most recent

study by Hughes and Carr (20) evaluated patients with

more advanced knee OA— 60% of the study population

had moderate to severe knee OA (Kellgren-Lawrence grade

3 or 4). In that study, no differences were seen between

glucosamine and placebo groups in pain, use of analgesic

medications, or the proportion of responders to treatment

over a 6-month study period. These findings suggest that

the radiographic stage of OA is likely not a factor in nonresponse to glucosamine treatment. This is further supported by the results of our Cox regression analysis, in

which adjustment for radiographic OA severity did not

have a significant effect on the result of treatment as a

predictor of disease flare and hence glucosamine was

found to be nonefficacious regardless of radiographic OA

severity. Similarly, glucosamine dosage, duration of glucosamine use, and analgesic medication use were not significant in the Cox regression analysis and hence did not

have an effect on the risk of disease flare in our study.

There are a number of strengths and limitations of this

study. As discussed previously, a disadvantage of the RDT

study design is that any initial benefit of glucosamine

cannot be evaluated. A further limitation is that the RDT

study design has never been used in OA. As a result, no

validated definition of disease flare exists. Our definition

of disease flare was adopted a priori and was thought to be

of clinical importance. Moreover, since the initiation of

our study, additional publications have lent support to our

choice of flare criteria (31,32). The minimal clinically perceptible difference (MCPD) in WOMAC pain on walking

was reported by Ehrich et al (31) to be 11 mm on a 100-mm

VAS. Similarly, the MCPD for physician global assessment

was reported to be 0.43 on a 0 – 4 Likert scale (31). As a

result, the definition for disease flare used in this study

was adequate to detect a difference in patient status. Furthermore, in the recent Osteoarthritis Research Society

International (OARSI) guidelines on response criteria, the

committee recommended that treatment response in an

NSAID trial be defined as an absolute decrease in VAS

pain by 20 mm in association with a relative decrease of

pain by 45% (32). An absolute difference of 20 mm should

therefore be applicable as a flare criterion and hence the

OARSI guidelines lend further support to the validity of

our choice of flare criteria.

The need for rescue medication in a discontinuation

trial may be seen as a further limitation due to the potential confounding effect. However, analgesic medication

use was included in the secondary analysis of the data and

was similar in the placebo and glucosamine groups. In

addition, the inclusion of acetaminophen and NSAID use

in the Cox regression analysis showed that there was no

confounding effect. Furthermore, the use of acetaminophen and NSAIDs may be viewed as a strength of this

study, because their use reflects common practice in OA. If

a benefit of glucosamine cannot be detected under real

world circumstances, then the applicability of glucosamine is limited, even if it is found to be efficacious.

There are several advantages to using an RDT study

design, including the ability to test the efficacy of a drug

that is widely used and minimization of exposure to plaTable 4. Mean change scores in patients who did not experience a flare and those who did in the intent-to-treat population

and comparison of severity of change in placebo and glucosamine patients who experienced a flare*

Change from baseline mean  SD Between group

difference (95% CI)

for placebo and

glucosamine

flarers P

No flare Flare

Placebo

(n 38)

Glucosamine

(n 39)

Placebo

(n 28)

Glucosamine

(n 32)

WOMAC

Pain on walking, 0–100 5  15 5  12 25  26 17  23 8 (21, 4) 0.20

Pain subscale, 0–500 24  75 30  47 97  98 92  103 5 (58, 47) 0.83

Stiffness subscale, 0–200 20  42 25  34 13  50 26  34 13 (9, 36) 0.24

Function subscale, 0–1,700 69  264 96  178 243  300 246  243 3 (138, 143) 0.97

Total scale, 0–2,400 114  368 151  237 354  422 364  347 10 (188, 209) 0.92

EQ-5D

Utility score, 0–1 0.02  0.18 0.02  0.14 0.13  0.2 0.10  0.16 0.03 (0.13, 0.06) 0.46

Visual analog scale, 0–100 2  9 6  14 6.6  15 6.9  16 0.3 (8, 8) 0.95

* Positive mean change indicates improvement, negative mean change indicates worsening. 95% CI  95% confidence interval; WOMAC  Western

Ontario and McMaster Universities Osteoarthritis Index; EQ-5D  European Quality of Life questionnaire.

744 Cibere et al

Case: 1:11-cv-07972 Document #: 30-5 Filed: 07/20/12 Page 8 of 9 PageID #:191
cebo (26). Furthermore, a particular strength of this study

is the selection of patients with at least moderate perceived response to prior glucosamine treatment. The use of

such a selective population allows for a more efficient

trial, since patients who have previously responded to

treatment with glucosamine are more likely to flare on

discontinuation of glucosamine than nonresponders.

Therefore, a treatment difference between glucosamine

and placebo, if one exists, can be shown more easily in

such a preselected population (26). Despite this greater

ability to show efficacy, our study results were negative

and hence this serves to strengthen our conclusions.

In summary, for patients with knee OA with at least

moderate subjective improvement with prior glucosamine

use, this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate over and

above that found with placebo.

ACKNOWLEDGMENTS

We would like to thank all the study participants for their

interest and participation and we would like to acknowledge the late Leonard Marks for his assistance in obtaining

the medication. We thank Allen Lehman for providing the

randomization codes and JR Laboratories Inc. for performing the glucosamine sulfate content analysis.

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