Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis

Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis

Z. Jajic, M. Malaise, K. Nekam, É. Koó, K. Dankó, M. Kovacs, C. Scarpignato1

Department for Rheumatology, Physical Medicine and Rehabilitation, Medical Faculty University of Zagreb, Referral Centre for Inflammatory Rheumatic Disease, Zagreb, Croatia;

1Laboratory of Clinical Pharmacology, School of Medicine and Dentistry, University of Parma, Parma, Italy.

Multicentre Study from the Department of Rheumatology, Physical Medicine and Rehabilitation, Medical FacultyUniversity, Zagreb (Croatia); Department of Rheumatology, University of Liege, Liege (Belgium); Department ofClinical Medicine III, Carl Gustav University, Dresden (Germany); Department of Rheumatology, Clinical Medi-

cine IV, Carl-Thiem Clinic, Cotbus (Germany); Department of Rheumatology, Hospital of Horovice, Horovice(Czech Republic); Department of Rheumatology, University Hospital, Klimentskà Polyclinic, Prague (Czech

Republic); Department of Allergology and Immunology and Department of Rheumatology II, Polyclinic of theHospitaller Brothers of St. John of God in Budapest, Budapest (Hungary); Department of Internal Medicine 1,County Hospital of Zala, Zalaegerszeg (Hungary); Department of Rehabilitation, “Markusovsky” Hospital andoutpatient Clinic of Vas County, Szombathely (Hungary); University of Debrecen, Medical and Health Science

Centre, Institute for Internal Medicine, III Department, Division of Immunology, Debrecen (Hungary)

Abstract Objective

Selective inhibitors of cyclo-oxygenase-2 (COX-2) appear to be safer than conventional NSAIDs on the gastrointestinal (GI)tract. Amtolmetin guacyl (AMG), a NSAID that inhibits both COX-1 and COX-2, has an anti-inflammatory effect compara-

ble to that of traditional NSAIDs, with a better GI safety profile. The primary end-point of this study was to evaluate the gas-trointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients affected with rheumatoid arthritis. The

assessment of efficacy was the secondary end-point.

MethodsThis study was a 24-week, randomized, parallel group, double-blind, double dummy, multicentre trial; 235 patients were

enrolled and 180 patients (85 in the AMG group and 95 in the celecoxib group) completed the study. Each patient receivedtwice daily amtolmetin guacyl 600 mg or celecoxib 200 mg. Assessment of safety was performed by upper GI endoscopy,gastrointestinal symptoms evaluation, electrocardiography, blood and urine laboratory tests, adverse events recording.

Assessment of efficacy was performed by using the American College of Rheumatology (ACR-20) responder index.

ResultsNeither amtolmetin guacyl nor celecoxib determined a worsening of baseline gastro-duodenal endoscopy findings. The per-centage of patients with normal findings did not significantly change after treatment with both drugs, being virtually identi-

cal with AMG (i.e. 75.29%) and increasing from 75.79% to 77.66% with celecoxib. Moreover an evaluation of the othersafety parameters did not reveal any difference between the two treatment groups. Therapeutic efficacy was equivalent in

both groups, with no statistical difference between the two drugs at all time intervals.

ConclusionsIn patients affected with rheumatoid arthritis, AMG and celecoxib proved to be equivalent, showing comparable

gastrointestinal safety and therapeutic efficacy of treatment.

Key wordsAmtolmetin guacyl (AMG), celecoxib, NSAIDs, gastrointestinal safety, rheumatoid arthritis.

Clinical and Experimental Rheumatology 2005; 23: 809-818.

Zrinka Jajic, MD, PhD; Michel Malaise,MD, PhD; Kristof Nekam, MD, PhD; Éva Koó, MD, PhD; Katalin Dankó, MD,PhD, Monika Kovacs, MD; CarmeloScarpignato, MD, DSc, PharmD.

Please address correspondence and re-print requests to: Prof. Zrinka Jajic, MD,Department for Rheumatology, PhysicalMedicine and Rehabilitation, Medical Faculty University of Zagreb, ReferralCentre for Inflammatory Rheumatic Disease, Vinogradska c. 29, 10000 Zagreb, Croatia. E-mail: [email protected]

Received in February 11, 2005; acceptedin revised form on July 14, 2005.

© Copyright CLINICAL AND EXPERIMEN-TAL RHEUMATOLOGY 2005.

IntroductionRheumatoid arthritis is an autoimmunedisease characterized by chronic jointinflammation with a fluctuating coursethat can lead to progressive and des-tructive arthropathy, followed by defor-mities and disability (1, 2). Its manage-ment involves the use of new and tradi-tional disease-modifying anti-rheumat-ic drugs (DMARDs) (3), which canaffect the course of the disease, andnon-steroidal anti-inflammatory drugs(NSAIDs), which provide symptomaticrelief by controlling pain and inflamma-tion. Although these latter compoundsrepresent a very effective class of drugs,their use is associated with a broadspectrum of untoward reactions in theliver, kidney, skin and gut (4, 5); gas-trointestinal (GI) side effects are, how-ever, the most common adverse eventencountered with this class of drugs (6-10). GI problems encompass a widerange of different clinical pictures,spanning from mild symptoms such asdyspepsia, heartburn and abdominaldiscomfort to more serious events, likepeptic ulcer and its life-threateningcomplications, bleeding and perfora-tion. Indeed, gastroduodenal mucosapossesses an array of defensive mecha-nisms and NSAIDs have a deleteriouseffect on most of them (11). These drugs appear to cause gastroduo-denal damage by two main mecha-nisms: a physiochemical disruption ofthe gastric mucosal barrier and a sys-temic inhibition of gastric mucosal pro-tection, through inhibition of cyclo-oxygenase (prostaglandin endoperoxideG/H synthase, COX) activity of the GImucosa. A reduced synthesis of mucusand bicarbonate, an impairment of mu-cosal blood flow and an increase in acidsecretion represent the main conse-quences of NSAID-induced prosta-glandin (PG) deficiency (12). Addition-al mechanisms which may add to thedamage have been demonstrated. Theseinclude the uncoupling of oxidativephosphorylation, reduced mucosal cellproliferation and DNA synthesis as wellas neutrophil activation (12). The out-standing candidate mechanism for initi-ating NSAID damage is their action toinhibit cyclo-oxygenase-1 (COX-1) asall conventional NSAIDs have this ac-tion (and not other agents) and all are

essentially associated with similar dam-age. The strength of this idea is that it issimple; there are reasonable associa-tions between NSAID-induced reduc-tions in mucosal prostaglandin levelsand the damage ,and one report (13)suggests that antibodies directed againstCOX cause in rabbits damage to thegastrointestinal tract that is identical tothat induced by NSAIDs. After the discovery of the two COX iso-forms (that is COX-1 and COX-2) com-pounds specifically designed to inhibitCOX-2, sparing COX-1 at therapeuticdoses, have been developed. Althoughincreasing evidence indicates that alsoCOX-2 is normally expressed in themucosa of the digestive tract where itplays a physiological role, assisting thehousekeeping action of COX-1 in gas-troprotection (14, 15), the so-called“selective COX-2 inhibitors” display asignificantly improved risk-benefit ratiocompared with non-selective NSAIDs.Indeed, COX-1 expression representsthe dominant isoform in healthy mucosa(14) and PGs generated by COX-2 be-come important only during ulcer heal-ing (14, 15) and in the presence of Heli-cobacter pylori infection (14,16). In ad-dition, it is worth mentioning that selec-tive COX-2 inhibitors, like celecoxiband rofecoxib, besides sparing PG syn-thesis in the GI mucosa, do not displayany topical irritancy as they are non-acidic, nor do they increase gastric orintestinal permeability or cause mucosalinflammation (17). Their failure to sig-nificantly affect the two basic biochem-ical mechanisms of NSAID-induceddamage may account for their remark-able GI tolerability. Large clinical trialshave indeed demonstrated that they areas therapeutically effective as conven-tional NSAIDs (18,19), while being saf-er at gastroduodenal level (20,21). Notonly have endoscopic studies shown asignificant reduction in the incidence ofgastric and duodenal ulcers (22, 23), butclinical trials have pointed out a signifi-cant reduction in peptic ulcer complica-tions .Amtolmetin guacyl (2-methoxyphenyl-1-methyl-5-p-methylbenzoyl-pyrrole-2-acetamido acetate, AMG) is anNSAID (24) recently introduced intothe Italian market and approved for thetreatment of rheumatoid arthritis, os-

Safety and efficacy of amtolmetin guacyl and celecoxib / Z. Jajic et al.

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teoarthritis, extra-articular rheumatismand post-surgical pain. It affects bothCOX-1 and COX-2, the COX-2/COX-1 selectivity ratio, evaluated in studiesusing bovine aortic endothelial cellsand LPS-stimulated macrophages, be-ing 4.4 (Vane et al., unpublished re-sults). Like COX-2 selective com-pounds, the drug displays an effectiveanti-inflammatory action with improv-ed GI tolerability, but, conversely fromthem, maintains an antiplatelet activity(25, 26).Clinical trials have shown that its anti-inflammatory, analgesic and antipyreticeffects are comparable to those of ref-erence NSAIDs (27-29). Two meta-analyses (30, 31) provided evidencethat AMG displays a substantially low-er incidence (7.2% and 28.3% respec-tively) of gastric adverse events incomparison with traditional NSAIDs.The frequency and severity of gastricmucosal lesions at endoscopic evalua-tion was lower for AMG in comparisonwith other NSAIDs, the odds ratiobeing 0.3 (95% CI 0.1 to 0.7) for severelesions and 0.1 (95% CI 0.1 to 0.4) formild and severe lesions, respectively(30). Pharmacological studies performed invarious animal models have shown thatAMG is not only devoid of any damag-ing effect on gastric mucosa, but actu-ally displays a gastroprotective effect(26), which extends down to the bowel(32). This peculiar pharmacologicalactivity has been confirmed in humanswhere AMG protects the gastric mu-cosa from ethanol damage with an effi-cacy comparable to that of misoprostol(33). Gastric mucosal protection is like-ly to be due to the presence of a vanillicmoiety in the molecule of AMG which,through stimulation of capsaicin recep-tors, causes Calcitonin Gene RelatedPeptide (CGRP) release and a conse-quent increase in nitric oxide (NO) pro-duction, which both counterbalance thedeleterious effects of prostaglandindepletion due to COX inhibition (34).Activation of capsaicin receptors takesplace through direct contact of the drugwith the gastric mucosa and therefore itis maximal when the product is givenon an empty stomach. This suggestedthe fasting administration of AMG inclinical practice to better exploit its

gastroprotective activity.Taking all the above considerations in-to account, this study was designed tocompare the GI safety and the clinicalefficacy of AMG and celecoxib, awidely used and GI safe COX-2 selec-tive inhibitor, in patients affected byrheumatoid arthritis.

Patients and methodsPatientsOut-patients of either sex aged over 18years who fulfilled the American Col-lege of Rheumatology (ACR) criteriafor clinical diagnosis of rheumatoidarthritis in acute phase with FunctionalCapacity Classification of I-III, requir-ing continuous, prolonged NSAIDtherapy were eligible for the study.Patients were excluded from the trial ifthey had other rheumatic diseases, pso-riasis, uncontrolled diabetes, untreatedhyperthyroidism, significant renal im-pairment (serum creatinine > 1.5 mg/dl), significant hepatic impairment(AST or ALT values over twice theupper limit of the normal range), neu-rological, haematological or autoim-mune (other than rheumatoid arthritis)diseases, cancer or any chronic disease.Patients were also excluded if they hada history of ulcer or gastric bleeding orany clinically significant upper gastro-intestinal mucosal damage (i.e. > 10erosions in the stomach and/or duode-num; oesophageal, gastric or duodenalulcers). Other exclusion criteria were:treatment with steroids at doses greaterthan the equivalent of 7.5 mg of pred-nisone per day; treatment initiation ordosage alteration of any DMARD and/or Disease–Controlling Anti-Rheumat-ic Drug (DCARD) during the 90 dayspreceding the study and throughout thestudy; intake of anti-ulcer drugs; aller-gy, sensitivity or intolerance to studydrugs and/or study drugs formulationingredients; use of antineoplastics (oth-er than methotrexate as antiarthritictherapy) during the 30 days precedingthe study; history of alcohol or drugabuse; pregnancy or lactation.

Number of subjectsA total of 304 patients (152 per eachtreatment group) had to be randomizedin the study in order to reach the 90%power of the test on the basis of the

percentage of gastrointestinal eventsinduced by both treatments and fore-seen dropouts. Since the number of pa-tients lost during the study was lessthan that expected, the sample size wasrecalculated and the trial was stoppedafter the randomization of 235 patients(118 to the AMG group and 117 to thecelecoxib group).

Study designThis was a multicentre, double-blind,double dummy, active controlled, ran-domized, parallel group trial. It consist-ed of 2 phases: a single-blind placeborun-in period (one week) and a double-blind active treatment period (24weeks). Using a computer-generated1:1 randomization list by the coordinat-ing centre, the patients were assignedto receive one of the following treat-ments: AMG 600 mg tablets or cele-coxib 200 mg capsules, both giventwice a day. AMG tablets (kindly pro-vided by Medosan Ricerca, Rome, It-aly) were administered 2-3 hours frommeals, while celecoxib capsules wereadministered regardless of meal con-sumption (Fig. 1).Prior to enrolment, the patients receiv-ed a full explanation of the nature andpurpose of the study, provided writteninformed consent and underwent aphysical examination and laboratorytesting. Follow-up clinic visits tookplace at weeks 4, 12 and 24 after thestart of both treatments.This study, conducted in accordancewith the current ICH-GCP Guidelinesand the Declaration of Helsinki asamended, was approved by the Nation-al Authorities of each Country involvedand the Local Ethical and Drug Com-mittees of each participating Centre.

Concomitant treatments Concomitant medications (except forthe drugs reported in the exclusion cri-teria), considered necessary for patienthealth and wellbeing, were allowed atthe discretion of the Investigator.

Assessment of safetyPrimary safety criteria were: gastricand/or duodenal damage (erosions, ul-cers or both), assessed by an upper gas-trointestinal endoscopy performed atthe beginning and at the end of the


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study; the assessment included the ex-amination of the oesophagus, stomach,pyloric channel and duodenum. Theendoscopic findings were scored from0 to 7 as follows: 0 = normal mucosa;1 = 1 – 10 petechiae; 2 = > 10 petechi-ae; 3 = 1 – 3 erosions; 4 = 4 – 10 ero-sions; 5 = > 10 erosions; 6 = oozing orintraluminal blood; 7 = ulcer or visiblevessels. A break in the mucosa withouta fibrous base was considered as anerosion whereas, when a fibrous basewas present, the mucosal lesion wasdefined as an ulcer. Score 0-2 was con-sidered normal findings, while score 3-7 was considered abnormal. Each patient was given a gastric score(based on gastric mucosal findings)and a duodenal score (based on the py-loric channel and duodenal mucosalfindings). Moreover, each patient wasgiven a “maximal” gastro-duodenalscore defined as the higher of the gas-tric or duodenal ones.Secondary safety criteria were: gas-trointestinal symptoms, ECG abnor-malities, blood and urine laboratorytests and adverse events. Gastrointesti-nal symptoms (including heartburn,epigastric and/or abdominal pain, nau-sea, vomiting, dyspepsia, flatulence,diarrhoea) were evaluated by using aspecific questionnaire at the beginningand after 4, 12 and 24 weeks of treat-ment.A 12-lead ECG and laboratory tests,including haematological and bio-chemical analysis, performed on bloodand urine samples collected under fast-ing conditions, were assessed at studyentry and at study end or withdrawal.All adverse events observed by the in-vestigator or reported by the patientswere recorded during the entire studyperiod.

Assessment of efficacyThe assessment of efficacy was per-formed at the beginning of the study

and after 4, 12 and 24 weeks of treat-ment. The primary outcome measurewas ACR-20 Responder Index (35, 36),representing the number of patientsachieving 20% improvement in tenderand swollen joint counts and 20%improvement in 3 of the 5 followingcore set measures: Patient’s global as-sessment, Physician’s global assess-ment, pain, functional disability, acutephase reactants.The Physician’s global assessment andthe Patient’s global assessment werescored from 1 (very good) to 5 (verypoor) with higher scores indicatinggreater disease activity. Pain wasscored on a 4-point scale (mild, moder-ate, severe, incapacitating). FunctionalCapacity was evaluated in accordancewith the ACR classification (36).

Statistical analysisStatistical analysis was performed onthe Per Protocol (PP) cohort, defined asall treated patients that had completedthe study. When the GI safety data wereconsidered, also the Intent-to-Treat(ITT) analysis was done, i.e. all ran-domized patients who received at leastone dose of study medication weretaken into account. Indeed, both GIsymptoms and mucosal lesions canoccur even after one single administra-tion of an NSAID (8, 10). For this kindof analysis, the LOCF (Last Observa-tion Carried Forward) method was ap-plied in the presence of missing or notavailable observations.Descriptive analysis was performed forall demographic variables. Analysis toassess the normal distribution was per-formed by Fisher’s exact test or, whereappropriate, by Wilcoxon two-sampletest, applied in order to verify thehomogeneity of means at baseline. Theanalysis of safety parameters wasbased on the comparison of the propor-tions of patients with or without gas-trointestinal diseases. The hypothesis

of frequencies equivalence was testedby means of Fisher’s exact test for con-tingency tables; comparisons of safetyparameters within and between groupswas tested by Fisher’s exact test and,where appropriate, by McNemar’s testand t-test for paired samples. Efficacyparameters were evaluated by Fisher’sexact test.The statistical tests were two-sided atthe 5% level of significance. Statisticalanalysis was performed by using SAS8.2 statistical modules running underWindows OS.

ResultsPatientsData analysis was performed on the180 patients that completed the study(85 in the amtolmetin guacyl group and95 in the celecoxib group). Patients notincluded in the analysis were consid-ered withdrawals. Demographic andclinical characteristics of the two groupsof patients (Table I) show that theywere quite homogeneous.

SafetyEndoscopy. Gastric and duodenal scoresare considered separately and arereported in Tables IIa and IIb, while inTable III the number of patients withnormal or abnormal gastroduodenalfindings is reported. No differences be-tween the two treatments were observ-ed: in fact both groups, homogeneousat baseline, remained comparable at theend of treatment; both AMG and cele-coxib failed to worsen gastro-duodenalendoscopic findings. In actual fact,with both drugs, the number of patientswith normal gastric score increased,albeit not significantly. At baseline, allpatients with abnormal scores present-ed only gastric erosions (i.e. score 3 or4); at the end of treatment, 1 patient inthe group treated with AMG and 4patients treated with celecoxib had ascore 7, corresponding to the presenceof ulcers or visible vessels.As far as the duodenal score is con-cerned, the number of subjects withnormal score increased after treatmentwith AMG, while it decreased aftertreatment with celecoxib. At the end oftreatment, the patients with abnormalscores were 3 and 6 in the AMG groupand celecoxib group, respectively.

Fig. 1.

Week -1 0 4 12 24Visit 1 2 3 4 5


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When maximal gastroduodenal scoresare considered, among 64 patients ofthe AMG group with normal endo-scopy at baseline, 54 remained normal

also at the final visit and out of 21 whohad abnormal endoscopy at baseline,10 improved at the final examination,showing normal findings. In the cele-

coxib group, among 71 patients withnormal endoscopy at baseline, 61 re-mained normal also at the final visit (1patient was excluded due to lack offinal endoscopy) and out of 23 who hadabnormal endoscopy at baseline, 12improved at the final visit, showingnormal findings. Between groups, thecomparison did not highlight statisti-cally significant differences in gastro-duodenal endoscopy findings at base-line, nor at the final examination, aswell as the within-groups comparison(McNemar’s test, p = 0.6698 for cele-coxib and p = 1.0000 for AMG). Whenthe number of patients with normal andabnormal gastro-duodenal findings areconsidered (Table III), both PP and ITTanalyses did not reveal any significantchange from baseline values after treat-ment with either AMG or celecoxib.Gastrointestinal symptoms. Table IVlists gastrointestinal symptoms report-ed by patients at the beginning and atthe end of the study. Statistical analysisshowed no significant difference in anyof them between the two treatments.However, the symptom evaluation per-formed after 4 weeks of therapy reveal-ed for AMG a significant lower inci-

Table I. Baseline characteristics of the patients included in the trial.

Characteristic AMG Celecoxib(n = 85) (n = 95)

Age (yrs) 57.2 ± 11.4 55.3 ± 11.9Males/females (n) 18 / 67 21 / 74Weight (Kg) 73.3 ± 16.0 71.9 ± 13.6 Height (cm) 164.1 ± 8.7 164.6 ± 7.5

Concomitant treatment for rheumatoid arthritis (n)Glucocorticoids 39 (44.7%) 48 (50.5%)Metotrexate 42 (49.4%) 44 (46.3%)Other disease-modifying drugs 34 (40.0%) 42 (44.2%)

Prior use of NSAIDs (n) 42 (49.4%) 48 (50.5%)User of low-dose aspirin (n) 4 (4.7%) 4 (4.2%)

Clinical evaluation of RA:Tender joints (n) 21.9 ± 15.7 22.2 ± 15.9Swollen joints (n) 11.0 ± 7.4 11.8 ± 7.4Physician’s global assessment (score) 3.3 ± 0.8 3.0 ± 0.8Patient’s global assessment (score) 3.3 ± 0.7 3.2 ± 0.9Pain (score) 2.5 ± 0.6 2.4 ± 0.7CRP (µg/ml) 16.5 ± 17.8 16.8 ± 23.0

American College of Rheumatology functional class (n) I 6 (7.1%) 12 (12.6%)II 43 (50.6%) 53 (55.8%)III 36 (42.3%) 30 (31.6%)

Values are expresses as means ± SD.Baseline characteristics did not differ significantly between groups.

Table II. Gastric and duodenal scores at baseline and 24 weeks after drug treatment in patients given AMG or celecoxib.a

Treatment Visit Gastric score

Normal Abnormal

0 1 2 3 4 5 6 7

AMG (n = 85) Baseline 48 (56.47%) 16 (18.82%) 0 (0%) 13 (15.29%) 8 (9.41%)

Celecoxib (n = 95) Baseline 56 (59.95%) 16 (16.84%) 1 (1.05%) 12 (12.63%) 10 (10.53%) p = 0.9597

AMG (n = 85) 24 weeks 50 (58.82%) 12 (14.12%) 3 (3.53%) 11 (12.94%) 5 (5.88%) 3 (3.53%) 0 (0%) 1 (1.18%)Celecoxib (n = 94) 24 weeks 62 (65.96%) 8 (8.51%) 5 (5.32%) 8 (8.51%) 5 (5.32%) 1 (1.06%) 1 (1.06%) 4 (4.26%)

p = 0.5532

b

Treatment Visit Duodenal score

Normal Abnormal

0 1 2 3 4 5 6 7

AMG (n = 85) Baseline 77 (90.59%) 4 (4.71%) 0 (0%) 2 (2.35%) 2 (2.35%)Celecoxib (n = 95) Baseline 86 (90.53%) 6 (6.32%) 0 (0%) 2 (2.11%) 1 (1.05%)

p = 0.8950AMG (n = 85) 24 weeks 78 (91.76%) 4 (4.71%) 0 (0%) 0 (0.%) 0 (0%) 0 (0%) 0 (0%) 3 (3.53%)Celecoxib (n = 95) 24 weeks 81 (85.26%) 6 (6.32%) 2 (2.11%) 2 (2.11%) 3 (3.16%) 0 (0%) 0 (0%) 1 (1.05%)

p = 0.1818

Statistical analysis: Fisher’s exact test.


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dence of dyspepsia (Fisher’s exact test,p = 0.0301). Electrocardiographic evaluation. Atscreening, in the AMG group 92.9% ofpatients had normal tracings, while inthe celecoxib group 90.5% of patientshad normal tracings; at the final visitthe normal tracings for AMG and cele-coxib groups were 94.1% and 93.6%,respectively. No statistically significantdifferences in ECG findings were ob-served, neither in the between-groupscomparison (at baseline Fisher’s exacttest, p = 0.6004 and at final examina-tion Fisher’s exact test, p = 1.0000) norin the within-groups comparison (Mc-Nemar’s test: p=0.5637 for the AMGgroup and p = 0.1797 for the celecoxibgroup). Laboratory tests. Laboratory tests onblood and urine did not evidence anystatistically significant alteration in theexamined parameters except for uricacid, in the AMG group, which slightly

increased, without exceeding in anycase the upper reference value and pro-bably being of no clinical relevance.Blood haemoglobin values before andafter treatment were not significantlydifferent in patients of both groups,suggesting the absence of any gastroin-testinal bleeding during the study peri-od. The mean values of systolic anddiastolic blood pressure, as well asheart rate, did not change during thetreatment with both drugs.

EfficacyClinical improvement, assessed byACR-20 responder index, (Table V) didnot show any differences between thetwo groups at the different time intervalsduring treatment. In particular, bothdrugs showed a similar efficacy at 4, 12and 24 weeks. The observed responserates were comparable with those re-ported in literature for conventionalNSAIDs in rheumatoid arthritis (37) .

Adverse events (AEs)The incidence of adverse events (AEs),calculated on all randomized patients,during the study period was similar forboth drugs (Table VI). The percentageof patients with treatment-related gas-trointestinal AEs (reported in TableVII) was 21.2% for the AMG groupand 26.5% for the celecoxib group.Figure 2 shows the cumulative inci-dence of gastrointestinal events duringthe study.Non-gastrointestinal adverse eventswere 12 and 11 for AMG and celecoxib,respectively; the AMG-treated patientscomplained of headache (n = 3), aller-gic skin reactions (n = 3), worsening ofpathology (n = 3), hypotension (n = 1)and abnormal laboratory parameters (n= 2); the celecoxib treated patientsexperienced tinnitus (n = 1), ECGraphicabonormalities (n = 1), allergic skin re-actions (n=3), abnormal laboratory par-ameters (n = 4), hypertension (n = 1),haemorrhage (n = 1).Serious adverse events. During the stu-dy, 11 serious adverse events were re-ported in 7 patients (4 in the AMGgroup and 3 in the celecoxib group);none of these events was considereddrug-related for AMG and only 1 (an-gioedema) was connected to celecoxibadministration.Withdrawal. 54 patients over a total of235 prematurely interrupted the study;the most frequent reason for drop outwas the lack of cooperation or consentwithdrawal from patients (Table VIII).Only 11 withdrawals were due to treat-ment-related adverse events: 7 forAMG and 4 for celecoxib. These ad-verse events were gastrointestinal com-plaints (n = 4), allergic reaction (n = 1),hypotension (n = 1) and headache (n =

Table III. Number of patients given AMG or celecoxib with normal and abnormal findings at endoscopy at baseline and 24 weeks afterdrug treatment.

PP analysis ITT analysis

Treatment Patients Time Patients with Patients with p Treatment Patients Time Patients with Patients with pnormal abnormal normal abnormalfindings findings findings findings

(score 0-2) (score 3-7) (score 0-2) (score 3-7)

AMG 85 Baseline 64 (75.3%) 21 (24.7%) n.s. AMG 118 Baseline 94 (79.7%) 24 (20.3%) n.s.

Celecoxib 95 Baseline 72 (75.8%) 23 (24.2%) Celecoxib 116 Baseline 90 (77.6%) 26 (22.4%)

AMG 85 24 weeks 64 (75.3%) 21 (24.7%) n.s. AMG 118 24 weeks 92 (78.0%) 26 (22.0%) n.s.

Celecoxib 94 24 weeks 73 (77.7%) 21 (22.3%) Celecoxib 116 24 weeks 91 (78.4%) 25 (21.6%)

Table IV. Gastrointestinal symptoms in patients given AMG or celecoxib at baseline and24 weeks after drug treatment.

Symptom AMG Celecoxib p AMG Celecoxib pT = 0 T = 0 24 weeks 24 weeks

Heartburn 3 (3.5%) 3 (3.2%) n.s. 5 (5.9%) 8 (8.4%) n.s.

Epigastric pain 0 1 (1.0%) n.s. 4 (4.7%) 5 (5.3%) n.s.

Abdominal pain 0 0 n.s. 1 (1.2%) 4 (4.2%) n.s.

Nausea 1 (1.2%) 0 n.s. 2 (2.3%) 2 (2.1%) n.s.

Vomiting 0 1 (1.0%) n.s. 0 1 (1.0%) n.s.

Dyspepsia 0 2 (2.1%) n.s. 5 (5.9%) 4 (4.2%) n.s.

Flatulence 0 1 (1.0%) n.s. 7 (8.2%) 6 (6.3%) n.s.

Diarrhoea 2 (2.3%) 0 n.s. 1 (1.2%) 2 (2.1%) n.s.

Other 0 0 n.s. 1 (1.2%) 0 n.s.

Total 6 8 n.s. 26 32 n.s.

Statistical analysis : Fisher’s exact test.


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1) for AMG; those reported for cele-coxib were gastrointestinal complaints(n = 2) and allergic reactions (n = 2).

DiscussionGastrointestinal toxicity induced byNSAIDs represent one of the mostcommon serious adverse drug events inthe industrialized world, with a signifi-cant impact both on public health andcosts related to the management of sideeffects. Different strategies have beenadopted in order to reduce the NSAID-associated gastro-duodenal damage:

the addition of a gastroprotective agent,such as proton pump inhibitor or miso-prostol, a synthetic PGE1 derivative, orthe use of cyclooxygenase-2 selectiveinhibitors which, while maintaining thesame activity of traditional NSAIDs inreducing arthritis pain and inflamma-tion, markedly improves the disease-related quality of life (38,39) as a resultof their better gastrointestinal tolerabil-ity. A prospective study (40) that com-pared conventional NSAIDs alone withNSAIDs plus misoprostol reported that0.95% of patients with rheumatoid

arthritis who were taking a NSAIDalone had upper gastrointestinal com-plications over a period of 6 months;the combined treatment determined a40% reduction in the risk. Along the same lines, studies carriedout with selective COX-2 inhibitors,like celecoxib (22) and rofecoxib (23),showed on average a 50% reduction inthe incidence of clinically significantupper gastrointestinal events and ulcercomplications, in comparison withnon-selective NSAIDs. Amongst thedifferent COX-2 inhibitors so far dev-eloped and available on the market, theselectivity ratio towards the two isoen-zymes varies greatly depending on themethodology employed (in vivo, ex-vivo or in vitro assays, intact cells orpurified enzyme as drug target, varia-tions in substrate concentration andincubation time) (41, 42). As a conse-quence, classification of these agentsclinically is difficult because there areinsufficient data to predict the correla-tions between biochemical and phar-macological properties and the clinicaleffect of a given agent. In any case,from a clinical standpoint selectivity,COX-2 selectivity should translate ineffective anti-inflammatory and anal-gesic activities while sparing COX-1

Table V. Evaluation of ACR-20 responders amongst patients with rheumatoid arthritisgiven AMG or celecoxib for 24 weeks.

Treatment Week ACR ACR presponders (%) non responders (%)

AMG 0 1.2 98.8Celecoxib 0 2.1 97.9 1.0000

AMG 4 24.7 75.3Celecoxib 4 26.3 73.7 0.8649

AMG 12 34.1 65.9Celecoxib 12 37.9 62.1 0.6428

AMG 24 43.5 56.5Celecoxib 24 51.6 47.4 0.2950

Fisher’s exact test.

Table VI. Drug-related adverse events in patients with rheumatoid arthritis given AMG orcelecoxib for 24 weeks.

Parameter AMG Celecoxib

N° of patients with adverse events 32 34

N° of patients with gastrointestinal adverse events 25 31

N° of total adverse events 57 68

N° of gastrointestinal adverse events 45 57

Table VII. Number of gastrointestinaladverse events in patients with rheumatoidarthritis given AMG or celecoxib for 24weeks.

Adverse event AMG Celecoxibn n

Heartburn 7 13

Epigastric pain 7 7

Abdominal pain 4 5

Nausea 6 3

Vomiting 0 2

Dyspepsia 3 6

Flatulence 7 6

Diarrhoea 1 3

Lost of appetite 1 1

Esophagitis 0 1

Esophageal ulcer 1 2

Gastric petechiae 3 1

Gatric erosions 1 1

Gastric ulcer 1 1

Duodenal petechiae 0 2

Duodenal erosions 0 1

Duodenal ulcer 2 1

Other 1 1

Total 45 57

Fig. 2. Cumulative inci-dence of GI adverseevents in patients withrheumatoid arthritis givenAMG or celecoxib for 24weeks.


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associated physiological functions like,for instance, mucosal PG synthesis andplatelet aggregation (42, 43). Althoughin some assays, celecoxib displayed alow selectivity ratio (44, 45), it fulfillsthe “clinical definition” of selectiveCOX-2 inhibitor and large clinical tri-als (19, 20) and meta-analyses (22)have provided strong evidence for itsgastrosparing activity.The present study shows that bothAMG and celecoxib are similarly ef-fective in controlling the symptoms ofrheumatoid arthritis. Like the therapeu-tic efficacy, the GI safety and tolerabil-ity of both drugs are also similar, con-firming the results of previous endo-scopic studies where AMG was com-pared to traditional NSAIDs (27, 28,46).The lack of correlation between symp-toms and mucosal damage afterNSAID administration has been repeat-edly shown in clinical trials and thelack of symptoms cannot therefore beconsidered a mirror of the lack of mu-cosal damage; in fact, a large propor-tion of serious NSAID induced gas-trointestinal complications can beasymptomatic (47, 48). In this study,both symptoms and mucosal damagehave been investigated by specificquestionnaires and GI endoscopy, re-spectively; the subjective and objectiveevaluations highlight the remarkablegastroduodenal tolerability of AMGand celecoxib, with a similar incidenceof adverse events possibly or probablyrelated to treatment; in particular, gas-trointestinal events resulted for bothdrugs comparable in frequency, intensi-ty and type. Despite COX inhibition and prostanoiddepletion, AMG does not damage the

gastroduodenal mucosa but rather pro-tects it from noxious stimuli. Mucosalprotection is achieved via the inhibitionof acid secretion, increase of bicarbon-ate production and stimulation of mu-cosal blood flow, mechanisms all dri-ven by the increase of CGRP and NOproduction (26,49-51). It is now clearly established that mi-crovascular damage represents the ear-liest event following NSAID adminis-tration (52), preceding and contributingto the development of epithelial le-sions. In a recent experimental study(53), electron microscopic examinationof gastric mucosa did show that eventhe selective COX-2 inhibitor celecox-ib induced, like conventional NSAIDs,marked endothelial damage. However,under the same experimental condi-tions, both acute and chronic AMG ad-ministration produced very limited da-mage, most likely thanks to the releaseof the vasodilator and endothelial pro-tective NO.Both COX isoforms (COX-1 andCOX-2) are constitutively expressed inthe adult mammalian kidney and con-tribute to the biosynthesis of prosta-noids. Inhibition of COX activity in thekidney by NSAIDs has relatively mildconsequences in healthy individuals,but can lead to serious adverse eventsin patients whose renal function is PGdependent. Most studies have reportedtransient decreases in sodium excretionupon initiation of therapy with eithertraditional NSAIDs or coxibs that, inpatients whose renal function is depen-dent on prostanoids, can affect theglomerular filtration rate (GFR).Changes in renal function may result inhypertension and edema; as a conse-quence, patients who are at risk for

adverse renal events (e.g. patients withcongestive heart failure, renal or hepaticdisease, as well as those of advancedage receiving therapy with diuretics orangiotensin-converting enzyme (ACE)inhibitors) should be monitored with thesame caution when receiving selectiveCOX-2 inhibitors as when receivingtreatment with conventional NSAIDs. Itis therefore evident that COX-2 selec-tive NSAIDs do not offer any advantageover non-selective drugs in terms ofrenal safety (54). On the contrary, AMGdoes not impair renal function, evaluat-ed with clinical and biochemical para-meters after repeated administration(55). Here again, maintenance of renalblood flow by the released NO is likelyto be the underlying mechanism ofAMG renal safety.Although the use of selective COX-2inhibitors in place of conventionalNSAIDs for the treatment of arthritisappears to reduce the risk of seriousgastrointestinal toxicity, the role playedby these inhibitors in the generation orexacerbation of ischaemic cardiovascu-lar disease is less clear. Clinical studiesdemonstrate that hypertension can beinduced or aggravated by COX-2 inhi-bitors to a degree similar or higher thanthat which occurs with non-selectivedrugs (56). Endothelial dysfunction, anindicator of cardiac ischaemia, may al-so be exacerbated by COX-2 inhibition(57) and there is much debate as towhether these changes lead to an abso-lute increase in ischaemic cardiac ev-ents (58). These effects on cardiovascu-lar risk factors appear all more impor-tant in patients with rheumatoid arthri-tis where there is an increase in the in-cidence of ischaemic heart disease(59).Soon after the introduction of celecox-ib and rofecoxib into the market, it wasreported that both drugs suppressed theformation of prostacyclin I2 (PGI2) inhealthy volunteers (60). PGI2 had pre-viously been shown to be the predomi-nant COX product in endothelium,inhibiting platelet aggregation, causingvasodilatation and preventing the pro-liferation of vascular smooth musclecells in vitro (61). However, it was as-sumed that PGI2 was derived mainlyfrom COX-1, the only isoform ex-pressed constitutively in endothelial

Table VIII. Reasons for withdrawal among patients with rheumatoid arthritis given AMGor celecoxib.

Reason AMG Celecoxib (n = 33) (n = 21)

Did not cooperate/withdrew consent 39.4% 52.4%Adverse events 21.2% 19.0%Intercurrent illness 15.2% 4.8%Loss of follow-up 9.1% 9.5%Lack of compliance/poor compliance 3.0% 0Lack of safety 3.0% 0Other protocol violations 3.0% 0Other reasons 6.1% 14.3%


817

cells. This assumption later proved tobe incorrect, since studies in mice andhumans showed that COX-2 was thedominant source (62, 63). The individ-ual cardiovascular effects of PGI2 invitro contrast with those of thrombox-ane A2 (TXA2), the major COX-1 prod-uct of platelets, which causes plateletaggregation, vasoconstriction and vas-cular proliferation (64). Whereas tradi-tional NSAIDs inhibit both TXA2 andPGI2, the coxibs leave TXA2 genera-tion unaffected, reflecting the absenceof COX-2 in platelets, and thus in-crease thrombotic risk, predisposingpatients to heart attack and stroke (64).As a matter of fact, a series of epidemi-ologic analyses (65, 66) have also rais-ed questions about the cardiovascularsafety of the coxibs and both the USFDA and EMEA(67, 68), followed bythe Italian Drug Agency [AIFA (69)],have issued warnings about the cardio-vascular risk of COX-2 selective inhi-bitors as well as non-selective NSAIDsand given guidance on their use in pa-tients with cardiovascular risk factors.Conversely from COX-2 selectiveNSAIDs which do not affect plateletaggregation (70-72), AMG displaysboth in vitro and ex vivo an antiplateletactivity comparable to that of aspirin(25). This pharmacological actionshould render the drug more suitablethan selective COX-2 inhibitors forpatients with one or more CV risk fac-tors.Taken together, all these data allow theconclusion that AMG is an effectiveanti-inflammatory drug, with a safetyprofile encompassing the GI tract, thekidney and the CV system. Due tothese properties and its peculiar mecha-nism of action, this compound seems tobe particularly suitable for long-termuse, especially in older subjects andpatients with renal or CV disease.

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Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis