Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator

Vol. 56, No. 2, February 2007, pp 555-567 2007, American College of Rheumatology A Randomized, Double-Blind, Placebo-Controlled Study Using Acetaminophen as 'n Ivorra,2 Mari'a del Carmen Trabado,3 Francisco Javier Blanco,4 Pere Benito,5 Emilio Marti'n-Mola,6 Javier Paulino,7 ' Luis Marenco,8 Armando Porto,9 Armando Laffon,10 Domingos Arau Objective. To assess the effects of the prescription
108), or placebo (n ؍ 104). The primary efficacy out-
formulation of glucosamine sulfate (1,500 mg adminis-
come measure was the change in the Lequesne index
tered once daily) on the symptoms of knee osteoarthritis
after 6 months. Secondary parameters included the
(OA) during a 6-month treatment course.
Western Ontario and McMaster Universities Osteoar-
Methods. Three hundred eighteen patients were
thritis Index (WOMAC) and response according to the
enrolled in this randomized, placebo-controlled, double-
Osteoarthritis Research Society International criteria.
blind trial in which acetaminophen, the currently pre-
These outcome measures were assessed using an intent-
ferred medication for symptomatic treatment of OA,
to-treat analysis.
was used as a side comparator. Patients were randomly
Results. At baseline, the study patients had mod-
assigned to receive oral glucosamine sulfate 1,500 mg
erately severe OA symptoms (mean Lequesne index ϳ11
once daily (n ؍ 106), acetaminophen 3 gm/day ( n ؍
points). Glucosamine sulfate was more effective than
placebo in improving the Lequesne score, with a final
ClinicalTrials.gov identifier: NCT00110474.
decrease of 3.1 points, versus 1.9 with placebo (differ-
ence between glucosamine sulfate and placebo
[95% confidence interval ؊2.3, ؊0.8]) (P ؍ 0.032). The
Peset, Valencia, Spain; 3Mari'a del Carmen Trabado, MD: Hospital 2.7-point decrease with acetaminophen was not signifi-
Clinic, Barcelona, Spain; 4Francisco Javier Blanco, MD: HospitalUniversitario Juan Canalejo, A Corun cantly different from that with placebo (difference ؊0.8
Hospital del Mar, Barcelona, Spain; 6Emilio Marti'n-Mola, MD: [95% confidence interval ؊1.9, 0.3]) (P ؍ 0.18). Similar
Hospital Universitario La Paz, Madrid, Spain; 7Javier Paulino, MD: results were observed for the WOMAC. There were more
Completo Hospitalario De Ciudad Real, Ciudad Real, Spain; 8Jose responders to glucosamine sulfate (39.6%) and acet-
Spain; 9Armando Porto, MD: Hospital Universitario Coimbra, Portu- aminophen (33.3%) than to placebo (21.2%) (P ؍ 0.004
gal; 10Armando Laffon, MD: Hospital De La Princesa, Madrid, Spain;11Domingos Arau'jo, MD: Hospital Conde de Bertiandos, Ponte de and P ؍ 0.047, respectively, versus placebo). Safety was
Lima, Portugal; 12Manuel Figueroa, MD: Hospital Donostia, San good, and was comparable among groups.
Sebastian, Spain; 13Jaime Branco, MD: Centro Hospitalar de Lisboa Conclusion. The findings of this study indicate
Occidental, EPE/Hospital Egas Moniz, Lisbon, Portugal.
Dr. Herrero-Beaumont has received speaking fees (less than that glucosamine sulfate at the oral once-daily dosage
of 1,500 mg is more effective than placebo in treating
Address correspondence and reprint requests to Gabriel knee OA symptoms. Although acetaminophen also had
Herrero-Beaumont, MD, Rheumatology Department, Fundacio 'nez Di'az-Capio, Autonomous University of Madrid, Avenida a higher responder rate compared with placebo, it
Reyes Catolicos 2, 28040 Madrid, Spain. E-mail: gherrero@fjd.es.
failed to show significant effects on the algofunctional
Submitted for publication May 16, 2006; accepted in revised indexes.
Current treatment options for osteoarthritis PATIENTS AND METHODS
(OA) include both nonpharmacologic and pharmaco- Study design. The GUIDE trial was conducted accord-
logic interventions (1,2). Published evidence-based rec- ing to a prospective, randomized, placebo- and reference- ommendations for the treatment of knee OA (3) have controlled, double-blind, double-dummy, parallel-group de- attributed to oral glucosamine sulfate the highest level of sign, in 13 rheumatology referral centers in Spain and Portugal.
evidence and strength of recommendation as a pharma- The study protocol was approved by the institutional reviewboard of each participating center, and patients provided their cologic intervention, acknowledging the high quality of written informed consent to participate. During the baseline the trials performed; only 6 of 34 therapeutic interven- period after screening, the results of routine laboratory tests tions considered were ascribed the same degree of were collected, radiographic assessments were conducted (if evidence and recommendation as glucosamine sulfate not performed during the previous 3 months), and symptom-atic medications currently being taken were discontinued.
(3). Two 3-year clinical trials have independently pro- Patients were then randomly assigned to 1 of the 3 treatment vided evidence of efficacy in the long-term management arms, i.e., glucosamine sulfate, acetaminophen, or placebo.
of knee OA symptoms, and their results suggested that Clinic visits were carried out after 15 days of treatment and glucosamine sulfate may potentially delay joint structure then at monthly intervals from the time of randomization until the end of the 6-month treatment course.
Patient selection. Male and female outpatients who
While the glucosamine sulfate substance and were seen in rheumatology clinics at the participating centers formulation used in those studies is a prescription drug were selected if they had been diagnosed as having primary in continental Europe and elsewhere, many glucosamine symptomatic knee OA (in 1 or both knees) according to the salts (e.g., glucosamine hydrochloride), formulations, clinical and radiographic criteria of the American College ofRheumatology (14), and did not meet standard criteria for and dosages are available as dietary supplements in the exclusion (15). Enrollment of patients who were obese (body US, due to different regulations (6). In some studies mass index [BMI] Ͼ30 kg/m2) was discouraged by the study using different glucosamine preparations (7,8), the fa- protocol, to avoid any bias introduced by this factor. Disease vorable results in terms of symptom modification ob- stage was determined based on the Kellgren/Lawrence radio-graphic system (16) (either grade II or grade III as a condition tained in former trials, in which the prescription formu- of enrollment), and symptom severity was quantified with the lation was used, were not replicated. This drew attention algofunctional indexes selected as outcome measures (see to the pharmaceutical and pharmacologic differences, as noted in a recent Cochrane review (9), and to the limita- Treatment, blinding, and randomization. Crystalline
glucosamine sulfate is a chemically well-characterized pure tions in study design (10) as possible explanations for the substance in which glucosamine, sulfate, chloride, and sodium ions are present in stoichiometric ratios of 2:1:2:2, and it is Two recent randomized, controlled, double-blind approved as a prescription drug in Ͼ45 countries (Dona, trials have assessed the efficacy of different glucosamine Viartril-S, Xicil, and other trade names of the RottapharmGroup, Monza, Italy); it is also available as a branded dietary preparations, compared with placebo, in the manage- supplement in the US (Dona). The product was used in its ment of knee OA symptoms over a medium-term treat- once-daily formulation (sachets of powder for oral solution, ment course. Both studies used an active medication as containing 1,500 mg of glucosamine sulfate). Acetaminophen a side comparator. In the Glucosamine/Chondroitin was administered in 1-gm tablets 3 times per day, for a totaldaily dosage of 3 gm (the recommended daily dosage in Arthritis Intervention Trial (GAIT study) celecoxib was used as the side comparator, while in the Glucosamine Patients receiving either of the 2 active treatments also Unum In Die (once-a-day) Efficacy (GUIDE) trial received placebo for the other medication, while controls acetaminophen was used, the latter being the currently received double placebo consisting of once-daily sachets and3-times-a-day tablets. The double-dummy placebo formula- preferred symptomatic medication in OA (2,3). The tions were identical in appearance to the active medications, GAIT study was sponsored by the National Institutes of but contained only inactive excipients. Treatment compliance Health (NIH) and conducted in the US with glu- was checked at clinic visits by patient interview and by counting cosamine hydrochloride at a dosage of 500 mg 3 times the number of unused doses of the study medications.
A block randomization list was generated by computer daily, whereas the GUIDE trial is an industry-sponsored and was maintained by individuals who had no contact with study conducted in Europe with the glucosamine sulfate investigators who assigned patients to their randomized treat- prescription formulation of 1,500 mg once daily. Prelim- ments, performed any patient assessment, or conducted the inary results of both studies were presented in 2005 statistical analysis. The block size was also kept secret tomaintain blinding; each block consisted of only 3 patients, to (11,12), and the GAIT study report was recently pub- avoid imbalances in treatment allocation at each clinical site.
lished as a full article(13). We report herein the final Patients were sequentially assigned their randomization num- ber at each site, and the individual code was kept in single- sealed, opaque envelopes to be opened only in case of a physical function subscale), and patient global assessment medical emergency. Double-blinding conditions were success- (35%, 15%, and 15% relative changes, with 10, 20, and 15 standardized units of absolute change, respectively).
The pure analgesic acetaminophen was the side com- Additional efficacy outcomes included the OARSI-B parator treatment in the GUIDE study, and therefore it could responder criteria (high degree of improvement in pain or not be used as a rescue medication as is the common proce- function, or moderate improvement in 2 of the 3 domains dure in OA clinical trials (15). Thus, the rescue medication listed above) (19) and the proportion of patients reporting at consisted of the conventional nonsteroidal antiinflammatory least minimal clinically important improvement (MCII) or drug (NSAID) ibuprofen, in 400-mg tablets. To avoid con- reaching the patient acceptable symptom state (PASS) in pain founding in the efficacy assessments, the use of the rescue and function based on the WOMAC subscales, as recently medication in case of persistent pain was carefully standard- ized according to the following sequential instructions: 1) leave Assessment of safety. Reporting of adverse events was
the painful joint at rest for at least 1 hour; 2) take 1 ibuprofen elicited with a nonleading question during clinic visits. All tablet every 8 hours; 3) limit intake to a maximum of 3 days; 4) events were coded according to the Medical Dictionary for if needed, resume the rescue medication intake after a washout Regulatory Activities, as currently required by all regulatory period of at least 7 days; and 5) in all cases, suspend any use of authorities including the US Food and Drug Administration the rescue medication at least 7 days before a clinic visit. The and the European Agency for the Evaluation of Medicinal use of rescue ibuprofen was recorded in a patient daily diary.
Products. Routine laboratory tests, including measurement of Prior analgesic (narcotic and non-narcotic) or antiin- serum glucose levels for estimating effects on glucose ho- flammatory symptomatic medications, including topical meostasis and administration of liver function tests, were agents, were discontinued for the duration of at least 5 performed at enrollment and after 3 months and 6 months of half-lives or 72 hours, whichever was longer, before random- ization and were prohibited during the study. The recom- Statistical analysis. The primary comparison in this
mended duration of washout prior to randomization was at study was between glucosamine sulfate and placebo. The least 3 months for corticosteroids and 6 months for glu- sample size was calculated on the basis of the difference cosamine or other drugs considered specific for OA. These and between glucosamine sulfate and placebo in the change in the any other agents for the treatment of this condition were Lequesne index from baseline to end of treatment, which was prohibited throughout the study. Physical and/or occupational at least 1 point in previous trials (9,22). With such a simulated therapy were allowed if the regimen had been stable for at least difference, a standard deviation of the mean response of 2.25, a Type I error of 5%, and a Type II error of 20%, a sample size Assessment of efficacy. The Lequesne algofunctional
of 80 patients per group was calculated (23), and this was index of severity for OA of the knee (17) was used for sample increased to at least 100 patients per group to take into size calculation and was designated as the primary efficacy account an expected dropout rate of ϳ30%. The size of the outcome in the GUIDE trial. It is a disease-specific, aggre- group receiving acetaminophen was also set at 100 patients.
gated multidimensional index consisting of 5 questions ad- The GUIDE is a regulatory trial agreed upon by the dressing knee pain, 4 questions on knee function in activities of sponsor (Rottapharm) and the relevant health authorities.
daily living, and a scale of maximum distance walked. The Following protocol approval and implementation, the statisti- worst possible total index score is 24, but disease is considered cal analysis protocol was planned by the sponsor in June 2001.
extremely severe if the score is Ͼ13 (17). At randomization, It was amended in December 2004, prior to database lock, only after washout of previous symptomatic medications, patients to add the MCII and PASS assessments that had become had to have a Lequesne score that was at least as high as the available in the summer of the same year (20,21).
score at the screening visit. For continuation in the study The primary efficacy analysis performed was assess- protocol, this score had to be Ն4, corresponding to at least ment of the difference between groups in the change from mild-to-moderate disease severity (17).
baseline in the Lequesne index after 6 months, in the intent- The secondary efficacy end points were the Western to-treat (ITT) population (i.e., including all randomized pa- Ontario and McMaster Universities Osteoarthritis Index tients with at least 1 efficacy assessment after randomization).
(WOMAC) (18) and the Osteoarthritis Research Society The last observation carried forward (LOCF) approach was International (OARSI) responder criteria (19). The 0-4-point used for patients who did not complete the study according to Likert scale (LK 3.0) WOMAC version was used, addressing the protocol. A per-protocol completer analysis was also severity of knee pain (5 questions), limitation of physical performed. To assess the differences between each of the function (17 questions), and stiffness (2 questions) in the 48 active groups (glucosamine sulfate or acetaminophen) and hours before assessment. The worst possible scores on the placebo, a general linear model approach was applied in WOMAC subscales are therefore 20, 68, and 8 in the 3 one-way analysis of variance, with treatments as fixed effect domains, respectively, and can be used to normalize the Likert and application of Dunnett's 2-tailed test to adjust for multiple scores to a 0-100 scale, i.e., similar to a 100-mm visual analog pairwise comparisons. Results were expressed as the difference scale (VAS) (18). The OARSI-A responder criteria for oral between final group means and 95% confidence intervals OA-specific drugs consist of a dichotomous outcome measure (adjusted for multiple comparisons). In addition, the magni- that defines as responders those patients with either a high tude of each treatment effect was described as effect size, i.e., degree of improvement in pain (at least 55% relative change the difference between the mean change from baseline with on the WOMAC pain subscale, with an absolute change of at the active drug and with placebo, divided by the pooled least 30 on a 0-100 standardized scale) or moderate improve- standard deviation (24).The same analysis was performed on ment in 2 of the 3 domains of pain, function (on the WOMAC the secondary efficacy outcome represented by the WOMAC, Figure 1. Study profile. ء ϭ patients who agreed to baseline evaluation but did not qualify for randomization. Pl ϭ
placebo; Ac ϭ acetaminophen; GS ϭ glucosamine sulfate; ITT ϭ intent-to-treat.
while the difference between each active group and placebo in patients considered for the study could be randomized.
the proportion of OARSI-A responders in the ITT population Seven patients did not provide any efficacy data after was analyzed by 2-tailed chi-square test. The chi-square testwas also used to compare each active group with placebo for randomization and were not included in the analysis, the proportion of ITT patients satisfying the additional efficacy leaving a total of 318 patients in the ITT population parameters, in the following order: OARSI-B responders, pain (Figure 1). Twenty-six percent of the patients receiving MCII, function MCII, pain PASS, and function PASS. To glucosamine sulfate or acetaminophen did not complete adjust for the multiplicity represented by the 2 active groupcomparisons with placebo for the dichotomous secondary the 6-month treatment period according to the study outcome (OARSI-A) and additional efficacy parameters, the protocol, compared with 33% of the patients in the sequentially rejective Bonferroni method was applied, setting ␣ at 0.05 divided by the number (n) of comparisons (0.05/2 ϭ There were no significant differences in the rea- 0.025) for the lowest P value obtained in the 2 comparisons, sons for dropout (Figure 1). The acetaminophen group and ␣ ϭ 0.05/(n Ϫ 1) (0.05/1 ϭ 0.05) for the second compar-ison if the first yielded a significant result (25,26).
tended to have a higher number of dropouts due to To achieve meaningful comparisons across groups over adverse events, but there was a trend in this group a standardized period, the use of the rescue medication was toward fewer withdrawals due to other reasons; these assessed in per-protocol completers over the 6-month treat- observations are probably of minor clinical significance ment course. The mean number of days of use was tabulatedfor descriptive purposes, with calculation of the daily average given the low number of events. Protocol deviations ibuprofen tablet consumption, while the proportion of patients consisted mainly of patients not meeting some of the with any use of the rescue medication was compared between inclusion/exclusion criteria (mostly presence of concom- each active treatment group and the placebo group, by chi- itant diseases, insufficient symptom severity, or violation of required demographic characteristics); these patientswere therefore withdrawn early from the protocol and were then assigned a negative efficacy outcome, often Recruiting started in May 2000, and the last corresponding to no change from baseline. Other rea- followup was performed in December 2002. Most of the sons for withdrawal were evenly distributed throughout Number of patients withdrawn from the protocol after each the study. The number of patients, by treatment group, Figure 2. Mean and SEM changes in the Lequesne index after 1, 3,
who were withdrawn from the protocol at each study and 6 months of treatment, in the intent-to-treat population (n ϭ 104 in the placebo group, 108 in the acetaminophen group, and 106 in the The demographic and clinical characteristics of glucosamine sulfate group). ء ϭ P ϭ 0.032 versus placebo.
the randomized patients were comparable at baseline(Table 2). As expected, the majority of patients were ϳ11, indicating disease with moderate symptom sever- female. The mean age was between 60 and 65 years. On ity. This was confirmed by the baseline WOMAC pain average, patients were overweight, and 5% of them were and function subscale scores, which averaged ϳ40 when obese (BMI Ͼ30 kg/m2). The mean duration of knee OA normalized to a 0-100 scale (i.e., similar to 40 mm on a was ϳ7 years, and slightly more than half of the patients had a Kellgren/Lawrence radiographic grade of 2, al- Compliance with the study medication regimen though grading of 2 or 3 was not firmly assigned to was good in all treatment groups. In trial completers, the ϳ10% of the patients. Inflammatory joint disease was an exclusion criterion, but signs of modest inflammation, The changes in the Lequesne index after 1, 3, and i.e., mild joint effusion, were present in 12-15% of the 6 months of treatment in the ITT population are re- patients. The mean Lequesne index score at baseline was ported in Figure 2. The primary outcome measure was Demographic and baseline clinical characteristics of patients in the intent-to-treat * Except where indicated otherwise, values are the mean Ϯ SD. WOMAC ϭ Western Ontario andMcMaster Universities Osteoarthritis Index.
the 6-month change in the index. There was a change ofalmost Ϫ2 with placebo treatment, but the change was Ϫ3.1 with glucosamine sulfate (P ϭ 0.032 versus pla-cebo) (Table 3). The 2.7-point decrease in the acetamin-ophen group was not significantly different from thedecrease observed with placebo (P ϭ 0.18). For all 3treatments, the degree of improvement in per-protocolcompleters was higher than that in the ITT population;compared with placebo, the difference in the degree ofimprovement was significant in the glucosamine sulfategroup (P ϭ 0.01), but not in the acetaminophen group(P ϭ 0.26).
Similar results were observed for the secondary outcome measure represented by change in theWOMAC total index (Table 3), for which the differencebetween the glucosamine sulfate group and the placebogroup was statistically significant in both the ITT andper-protocol analyses (P ϭ 0.039 and P ϭ 0.018, respec-tively). Conversely, the improvement observed with acet-aminophen just failed to reach statistical significancewhen compared with placebo (P ϭ 0.08 in both the ITTand per-protocol populations), although it was onlymarginally lower than that achieved with glucosaminesulfate. Both glucosamine sulfate and acetaminophenwere significantly more effective than placebo in termsof improvement in the WOMAC function subscales, but Figure 3. Effect size of glucosamine sulfate and acetaminophen in the
for the WOMAC pain subscale, the difference from intent-to-treat and per-protocol completer populations. Diamonds placebo, for both glucosamine sulfate and acetamino- show the effect size point estimate; bars show the 95% confidence phen, failed to reach statistical significance in the ITT interval. WOMAC ϭ Western Ontario and McMaster Universities analysis. However, the better trend shown with glu- cosamine sulfate (P ϭ 0.12 versus placebo in the ITTanalysis) was statistically significant in per-protocol com-pleters (P ϭ 0.014). The small improvements in the low knee pain as the first threshold to qualify as a responder, scores on the WOMAC stiffness subscale (Ͻ3 points on the proportion of responders in the glucosamine sulfate average at baseline) did not differ significantly among group was almost 40%, i.e., 18.4% more than with placebo (P ϭ 0.004) (Table 4). The response rate was As shown in Figure 3, the effect size of glu- also higher with acetaminophen than with placebo, with cosamine sulfate relative to placebo was 0.32, based on a difference of 12.1% (P ϭ 0.047). When the OARSI-B the ITT analysis of the Lequesne index results. This responder criteria were considered, i.e., when the first effect size was similar to that for the WOMAC total threshold for response was a high degree of improve- index (0.31), and only slightly lower than that for the ment in either knee pain or function, similar results were WOMAC function subscale (0.34). The effect sizes of obtained for this additional efficacy outcome (Table 4).
glucosamine sulfate according to the per-protocol ana- Almost 50% of the patients in the glucosamine lysis were larger and exceeded 0.40 in all analyses. This sulfate group reported a decrease in pain above the included the WOMAC pain subscale, for which the ITT threshold for MCII, compared with slightly more than analysis yielded a small effect size of 0.25 with 95% 30% of the patients treated with placebo (P ϭ 0.023).
confidence limits that crossed the zero line. Effect sizes More than 40% of the patients in the acetaminophen in the acetaminophen group were smaller and, in most group achieved the MCII for pain, but the difference from placebo was not significant (P ϭ 0.11). Conversely, As assessed using the OARSI-A responder crite- the difference between acetaminophen and placebo was ria, which are characterized by high improvement in significant for the proportion of patients achieving the Proportion of patients meeting the dichotomous secondary efficacy outcome measure (responders according to the OARSI-A criteria), or the additional efficacyoutcome measures (OARSI-B responders, achievement of MCII in pain and function, orachievement of PASS in pain and function) at the end of treatment, in the intent-to-treatpopulation* * P values are versus placebo; all P values less than 0.05 are significant after correction formultiple comparisons according to the sequential Bonferroni method (see Patients andMethods). OARSI ϭ Osteoarthritis Research Society International; MCII ϭ minimalclinically important improvement; PASS ϭ patient acceptable symptom state. See Patientsand Methods for explanation of OARSI-A and OARSI-B responder criteria.
MCII on the WOMAC function scale (P ϭ 0.025), was a trend toward a lower number of days of use in the although the proportion of patients in the glucosamine glucosamine sulfate and acetaminophen groups (both 28 sulfate group who reached this end point was even days, versus 35 days with placebo). Only 9% of the higher (P ϭ 0.008 versus placebo). Indeed, PASS was completers in the placebo group did not use rescue achieved in well over 60% of the patients receiving medication at all, compared with 21% in the acetamin- glucosamine sulfate, with highly significant differences ophen and 22% in the glucosamine sulfate group (P ϭ from the placebo group for pain (difference of 21.7% 0.045 and P ϭ 0.027, respectively, versus placebo).
compared with placebo; P ϭ 0.001) and function (dif- The number of adverse events reported during ference of 19.0% compared with placebo; P ϭ 0.006).
treatment was similar in all 3 groups: 89 with placebo, 96 The differences between the acetaminophen and pla- with acetaminophen, and 95 with glucosamine sulfate.
cebo groups in these PASS outcomes did not reach The most frequent adverse events were of minor clinical statistical significance (P ϭ 0.22 and P ϭ 0.10, respec- significance and did not differ in frequency between groups. Table 5 summarizes the adverse events reported When a sensitivity analysis was performed on the by at least 3 patients in any group. There were 5 serious primary and the 2 principal secondary outcome mea- adverse events in the placebo group (precordial chest sures, in which the 7 patients for whom there were no pain, apnea, pneumonia, elective surgery, and lumbar efficacy data after randomization were included (assign- pain), 5 in the acetaminophen group (atrial flutter, ing to them no changes on all outcomes, according to the carpal tunnel syndrome, vertebral fracture, meniscus LOCF approach), the results were virtually identical and rupture, and crush injury), and 2 in the glucosamine the differences between glucosamine sulfate and pla- sulfate group (meniscus rupture and elective surgery).
cebo were significant for all parameters (Lequesne index Routine laboratory examinations indicated that P ϭ 0.034, WOMAC total index P ϭ 0.041, and more patients in the acetaminophen group developed OARSI-A responder criteria P ϭ 0.004). A significant abnormalities in liver function (as reflected by levels of difference between the acetaminophen group and the transaminases and gamma glutamyl transferase [GGT]); placebo group was again found only for the OARSI-A abnormalities were detected in 21 patients in the acet- aminophen group versus 2 and 6 in the glucosamine During the 6-month treatment period, the need sulfate and placebo groups, respectively. These abnor- for recourse to the rescue medication was low, occurring malities were the cause of study withdrawal after the an average of 1 in every 5-6 days, with a mean consump- 3-month assessment in only 2 patients, whose baseline tion of 0.20-0.26 tablets of 400 mg ibuprofen per day values were found to be increased almost 2-fold above across groups. Compared with the placebo group, there the normal range (alanine aminotransferase in 1 patient Summary of adverse events occurring in at least 3 patients any individual patient, either among those who com- pleted the protocol or among those in whom treatment was withdrawn. One patient taking placebo had anabnormal serum glucose level (132 mg/dl) at the time of screening and was withdrawn after 3 months because the level was still 139 mg/dl. There were no significantchanges in other routine laboratory parameters.
DISCUSSION
The results of the GUIDE trial show that crys- talline glucosamine sulfate, administered once daily at a dose equivalent to 1,500 mg glucosamine sulfate, is more effective than placebo in relieving knee OA symptoms.
These data confirm the results obtained in previous long-term (3-year) clinical studies (4,5) and the general clinical trial experience with this particular glucosamine formulation (9). However, compared with these previous trials, the GUIDE is the first trial with this glucosamine preparation to be conducted over a 6-month treatment period, which is currently regarded to be the minimumtrial duration for study of a symptomatic medication in * Adverse events are grouped by system organ class and reported asMedical Dictionary for Regulatory Activities (MedDRA) lower-level OA (27). In addition, the study explored a complete term except for respiratory tract infections and respiratory disorders, panel of symptom outcomes and included an active for which similar events were grouped under MedDRA high-level medication, acetaminophen, as a side comparator.
According to current OA practice guidelines (2,3), acetaminophen is the oral analgesic that should be receiving placebo) and almost 3-fold above the normal tried first and, if successful, the preferred long-term range (GGT in 1 patient receiving acetaminophen), symptomatic medication, due to its safety profile and respectively. Clinically significant abnormalities in GGT, common use. For this reason, and not for its efficacy, i.e., levels 2-3 times above the upper reference limit, acetaminophen was chosen as a side comparator in the were found in an additional 2 patients receiving acet- present study. In fact, acetaminophen failed to show a aminophen and 1 patient in the glucosamine sulfate statistically significant difference from placebo in the group, but did not necessitate treatment withdrawal. The primary efficacy outcome (Lequesne algofunctional in- remaining abnormalities were mostly transient and mild dex of severity) and in some of the secondary end points, (i.e., from slightly above the normal range to less than including pain outcomes. A marginally significant differ- twice the maximum normal values) and were recorded as ence between acetaminophen and placebo was seen in adverse events in only 2 patients taking acetaminophen.
function outcomes, and the response rate was higher in In no cases were these alterations judged to necessitate the acetaminophen group than in the placebo group.
any particular followup that might have interfered with Conversely, glucosamine sulfate was significantly more effective than placebo in the primary and virtually all Serum glucose levels were virtually unaltered in secondary efficacy outcomes, with a trend toward supe- acetaminophen- and glucosamine sulfate-treated pa- riority compared with acetaminophen, although directly tients who completed the protocol and had both baseline comparing these 2 active treatments was not an aim of and 6-month assessments (mean Ϯ SD 99 Ϯ 14 mg/dl at baseline and 99 Ϯ 13 mg/dl at 6 months in the acetamin- In most but not all previous trials, acetaminophen ophen group, and 98 Ϯ 15 mg/dl at both time points in was globally more effective than placebo but less effec- the glucosamine sulfate group). A minimal increase was tive than NSAIDs in the treatment of OA pain, espe- seen in patients receiving placebo (99 Ϯ 15 at baseline cially in patients whose pain was moderate to severe; and 102 Ϯ 16 mg/dl at 6 months). Similarly, there was no acetaminophen and NSAIDs showed similar efficacy in clinically significant change in the serum glucose level in patients with mild OA pain (28). In contrast, acetamin- ophen exerted no significant effects on the Lequesne or reach statistical significance in comparison with placebo WOMAC score (28), consistent with the present find- in the ITT population, the change was significant in ings in the GUIDE study. It should be noted that the per-protocol completers. Furthermore, the threshold for dosage of acetaminophen used in this study was 3 minimally clinically important improvement in pain (20) gm/day as is most commonly used in Europe, whereas up was reached by significantly more ITT patients in the to 4 gm/day is usually advised in the US (15). The 4 gm glucosamine sulfate group, and almost 70% of them daily dosage was used in the majority of previous clinical reported an acceptable pain state (21) at the end of the trials, and there are insufficient data to determine trial, with a significant difference from placebo (Ͼ20%).
whether daily dosages of 3 gm and 4 gm have compara- A nearly 20% difference from placebo was also found ble effects; use of this lower dosage might have further for the proportion of patients who were classified as compromised the efficacy of acetaminophen in the treatment responders based on the OARSI composite present study. On the other hand, safety considerations with regard to acetaminophen dosage selection also had The results of GUIDE study are at variance with to be taken into account, since there were no previous those of the recently reported GAIT study (13), in which OA clinical trials in which acetaminophen at 4 gm/day glucosamine failed to show a significant difference in had been administered for periods longer than 12 weeks efficacy compared with placebo over a similar 6-month (28) at the time the present trial was designed and treatment period. However, the editorial accompanying conducted; in addition, the gastrointestinal safety of the report of the GAIT study (32) states that this finding acetaminophen at Ͼ2 gm/day has been questioned (29).
was not surprising given the nonconventional glu- The efficacy results observed with glucosamine cosamine preparation used in the NIH-sponsored study, sulfate in the present study were clinically relevant. The which differed from the glucosamine sulfate formulation effect size on the primary outcome measure, repre- used in previous successful trials of glucosamine treat- sented by the Lequesne index, was 0.32 compared with ment and in the present study. Indeed, the regimen of placebo, while the minimal difference that is considered glucosamine hydrochloride at a dosage of 500 mg 3 times clinically relevant is achieved with an effect size of 0.20 per day used in the GAIT study (13) is not approved as (30). Effect sizes between 0.20 and 0.50 are considered a prescription formulation and was previously used in "small" (30), but this is a common finding for interven- only 1 randomized controlled trial, which yielded mostly tions in OA. An effect size of 0.32 or lower was even described for NSAIDs for their principal use in knee The glucosamine sulfate prescription formulation OA, i.e., short-term pain relief, while the effect size was used in the GUIDE trial and in most previous glu- 0.29 for the reduction in functional disability (31).
cosamine trials, i.e., once-daily administration of 1,500 Unlike NSAIDs, glucosamine sulfate is not a drug for mg (4,5), yielded steady-state plasma and synovial fluid short-term analgesia, but is intended for medium- to glucosamine concentrations in the 10 ␮M range (34,35).
long-term management of the disease. In this respect, While these levels may be insufficient to directly stimu- the small but clinically relevant effect size on symptoms late the synthesis of cartilage glycosaminoglycans (36), found in the GUIDE study, being of the magnitude they have been found to be effective in inhibiting observed with purely symptomatic medications adminis- interleukin-1-induced gene expression (37), which has tered on a short-term basis, further supports the long- been proposed as the most probable, although hypothet- ical, mechanism of action of glucosamine sulfate in OA The Lequesne index is a combined measure of (38). Conversely, the glucosamine hydrochloride prepa- pain and functional disability, in which pain parameters ration used in the GAIT study resulted in plasma account for one-third of the total score and functional glucosamine levels that were at least 3-fold lower (39) parameters for the rest (17). Glucosamine sulfate exhib- and therefore might have fewer pharmacologic effects.
ited efficacy in all physical function outcome measures in In addition, while no relationship was found the GUIDE study, with an effect size of 0.34 on the between OA development and fasting serum sulfate relevant WOMAC subscale. Therefore, functional im- levels (40), sulfates have been suggested to be an provement might be the main determinant of glu- important component of glucosamine's mechanism of cosamine sulfate's effectiveness in knee OA. However, action (41,42). Interestingly, the most significant results efficacy of glucosamine sulfate was also demonstrated in the GAIT study were achieved in a subgroup analysis for several of the pain outcomes. In fact, although the of patients with more severe symptoms when glu- improvement on the WOMAC pain subscale failed to cosamine hydrochloride was combined with chondroitin sulfate (13), presumably increasing sulfate plasma levels backgrounds, reflecting differences between the Euro- (42), and possibly even levels of glucosamine metabo- pean and North American continents. Finally, the level lites, to concentrations closer to those achieved with the of pain at the time of enrollment was apparently lower in prescription glucosamine sulfate formulation used in the the GUIDE trial than in the GAIT study (ϳ40 versus ϳ47, on a 0-100 normalized scale). However, the base- The response to placebo in the GUIDE study line Lequesne index scores indicated at least moderate ranged from 20-25% (for the primary end point and the symptomatic disease severity in the GUIDE study (17), responder rate) to 40-45% (for the additional efficacy and the present results are therefore applicable to this outcomes). This placebo response rate was therefore in subset of patients with knee OA. Conversely, previous the expected range for OA trials and much lower than long-term trials have focused on the effects of glu- the rate of Ͼ60% observed in the GAIT trial (13). Such cosamine sulfate in patients with milder disease (4,5,44).
a high rate of response to placebo is difficult to interpret Early withdrawal from the study occurred in and might have partly clouded the results concerning 26-33% of patients. Protocol violations were among the efficacy of the experimental treatments in the GAIT most frequent reasons for this, and they were mainly study. OA trials are often add-on studies of test treat- represented by patients not meeting the inclusion/ ments with a rescue analgesic medication, whose indis- exclusion criteria suggested by current guidelines criminate use might increase the placebo response. The (14,15), who were thus misrandomized. The proportion use of the rescue medication was strictly regulated in the of such patients was comparable in all 3 treatment present study, and this might account for its low con- groups, and they were conservatively and appropriately sumption and the observed low rate of response to accounted for in the statistical analysis. Their early withdrawal immediately after randomization necessi- A possible limitation of the present study may be tated assigning them a negative efficacy outcome for all the requirement of a 6-month washout from prior glu- assessments, according to the LOCF approach.
cosamine sulfate use, since patients who had potentially Adverse events were the other main reason for had a poor response to previous glucosamine treatment dropout, although treatment safety was good throughout would not be as willing to participate as those who had the study. Glucosamine sulfate was well tolerated, and not previously been treated with this agent. However, did not differ from placebo in terms of frequency of appropriate washout from previous treatment is manda- adverse events or abnormal findings of laboratory eval- tory in clinical trials of compounds such as glucosamine uations, including glucose serum levels. These observa- sulfate, which are thought to have a persistent effect tions confirm the good safety profile of this agent, as observed in all previous meta-analyses (3,9,45,46) and Among other possible limitations of the present study, it should be noted that although Ͼ90% of the To our knowledge, the GUIDE is the first OA patients were overweight (BMI 25-30 kg/m2), only 5% trial to assess the safety of acetaminophen in compari- were actually obese (BMI Ͼ30 kg/m2), due to the son with placebo over a treatment period of 6 months.
protocol restrictions, and the average BMI was slightly Previous trials using naproxen as a comparator docu- lower than 28 kg/m2. In most knee OA trials the average mented the good safety profile of acetaminophen at BMI is higher than this, and it was even Ͼ30 kg/m2 in doses of 2,600 mg/day for 2 years (47) and 4 gm/day for some North American trials, including, e.g., the GAIT 6-12 months (48); acetaminophen was also well toler- study (13). This is due to the high prevalence of obesity ated in the present study, with no findings that would among patients with symptomatic knee OA in the US.
cause concern with regard to gastrointestinal safety (29).
The results of the GUIDE trial therefore might not be However, abnormalities in liver function were found in generalizable to obese patients, and the effectiveness of ϳ20% of the acetaminophen-treated patients, even glucosamine sulfate in such patients would require fur- though the drug was used at a relatively low dosage of 3 ther assessment. We also enrolled a slightly higher gm/day, further supporting this dosage selection. The proportion of female patients, i.e., almost 90% com- alterations in liver function were mostly mild and tran- pared with almost 80% in previous glucosamine sulfate sient, and in only 5 patients were they either deemed trials (4,5), but the results seem to have been in the same clinically significant, reported as adverse events, or the reason for treatment withdrawal (compared with 1 each Additional differences in the study populations of in the placebo and glucosamine sulfate groups).
the GUIDE and GAIT trials include genetic and ethnic In conclusion, the results of the GUIDE trial demonstrate that glucosamine sulfate at the once-daily 2. American College of Rheumatology Subcommittee on Osteoar- dosage of 1,500 mg is an effective medication for knee thritis Guidelines. Recommendations for the medical managementof osteoarthritis of the hip and knee: 2000 update. Arthritis OA symptoms, compared with placebo. These data were obtained during a 6-month period, which is the currently 3. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, recommended minimum treatment duration for the Dieppe P, et al. EULAR recommendations 2003: an evidencebased approach to the management of knee osteoarthritis: report management of OA, and they complement those ob- of a task force of the Standing Committee for International tained over long-term treatment periods of 3 years (4,5).
Clinical Studies Including Therapeutic Trials (ESCISIT). Ann To date, no studies have demonstrated any other phar- 4. Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere macologic treatment to have the same efficacy as glu- O, et al. Long-term effects of glucosamine sulfate on osteoarthritis cosamine sulfate for the long-term treatment of OA progression: a randomised, placebo-controlled clinical trial. Lan- symptoms (49). The efficacy results obtained with glu- 5. Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, cosamine sulfate were significant and clinically relevant Rovati LC. Glucosamine sulfate use and delay of progression of in the present study in which acetaminophen, the cur- knee osteoarthritis: a 3-year, randomized, placebo-controlled, rently recommended preferred medication (2,3), was double-blind study. Arch Intern Med 2002;162:2113-23.
6. Russell AS, Aghazadeh-Habashi A, Jamali F. Active ingredient used as a side comparator. A trial specifically designed consistency of commercially available glucosamine sulfate prod- to directly compare it with acetaminophen and possibly an NSAID would be needed in order to assess whether 7. McAlindon T, Formica M, LaValley M, Lehmer M, Kabbara K.
Effectiveness of glucosamine for symptoms of knee osteoarthritis: glucosamine sulfate could be regarded as the preferred results from an internet-based randomized double-blind con- trolled trial. Am J Med 2004;117:643-9.
8. Cibere J, Kopec JA, Thorne A, Singer J, Canvin J, Robinson DB, et al. Randomized, double-blind, placebo-controlled glucosamine AUTHOR CONTRIBUTIONS
discontinuation trial in knee osteoarthritis. Arthritis Care Res2004;51:738-45.
Dr. Herrero-Beaumont had full access to all of the data in the 9. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, study and takes responsibility for the integrity of the data and the Robinson V, et al. Glucosamine therapy for treating osteoarthritis.
Cochrane Database Syst Rev [serial online]. 2005;(2):CD002946.
Study design. Dr. Herrero-Beaumont.
URL: http://www.thecochranelibrary.com.
Acquisition of data. Drs. Herrero-Beaumont, Ivorra, Trabado, Blanco,
10. McAlindon T. Why are clinical trials of glucosamine no longer Benito, Marti'n-Mola, Paulino, Marenco, Porto, Laffon, Arau uniformly positive? Rheum Dis Clin N Am 2003;29:789-801.
11. Clegg DO, Reda DJ, Harris CL, Klein MA, for the GAIT Analysis and interpretation of data. Drs. Herrero-Beaumont, Ivorra,
Investigators. The efficacy of glucosamine and chondroitin sulfate Trabado, Blanco, Benito, Marti'n-Mola, Paulino, Marenco, Porto, in patients with painful knee osteoarthritis (OA): the Glu- cosamine/chondroitin Arthritis Intervention Trial [abstract]. Ar- Manuscript preparation. Drs. Herrero-Beaumont, Ivorra, Trabado,
Blanco, Benito, Marti'n-Mola, Paulino, Marenco, Porto, Laffon, 12. Herrero-Beaumont G, Roman JA, Trabado MC, Blanco FJ, Benito P, Martin-Mola E, et al. Effects of glucosamine sulfate on Statistical analysis. Dr. Giampaolo Giacovelli (nonauthor; Rotta-
6-month control of knee osteoarthritis symptoms versus placebo and acetaminophen: results from the Glucosamine Unum In DieEfficacy (GUIDE) trial [abstract]. Arthritis Rheum 2005;52 Suppl9:S460.
ROLE OF THE STUDY SPONSOR
13. Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper GUIDE is a regulatory trial agreed upon by the sponsor MM, et al. Glucosamine, chondroitin sulfate and the two in (Rottapharm) and the relevant health authorities and designed with combination for painful knee osteoarthritis. N Engl J Med 2006; the principal investigator (Dr. Herrero-Beaumont). Following proto- col approval and implementation, the statistical analysis plan was 14. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et prepared and executed by the sponsor. The statistical analysis was al. Development of criteria for the classification and reporting of supervised by the principal investigator, and each author had the osteoarthritis: classification of osteoarthritis of the knee. Arthritis opportunity to review the data and the analysis. The sponsor provided the study medication and funding for the trial. In addition, it moni- 15. Altman R, Brandt K, Hochberg M, Moskowitz R. Design and tored the study according to Good Clinical Practice standards and conduct of clinical trials of patients with osteoarthritis: recommen- according to all applicable laws and guidelines, to preserve the dations from a task force of the Osteoarthritis Research Society.
integrity of the data and their collection. However, Rottapharm as a Osteoarthritis Cartilage 1996;4:217-43.
corporate entity had no control over the writing, contents, or decision 16. Kellgren JH, Lawrence JS. Radiological assessment of osteoar- to submit the present manuscript for publication.
throsis. Ann Rheum Dis 1957;16:494-501.
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