Oxaceprol – a Randomised, Placebo-Controlled Clinical Study in Osteoarthritis with a Non-Conventional Non-Steroidal Anti-Inﬂammatory Drug K

Oxaceprol – a randomised, placebo-controlled clinical study in osteoarthritis with a non-conventional non-steroidal anti-inﬂammatory drug K. Krüger1, M. Klasser2, J. Mössinger3, U. Becker4

1Praxiszentrum St. Bonifazius, Munich, 2Gwd consult, Mühlheim/Main, 3Product Development, Chephasaar GmbH, St. Ingbert, 4Medical Development and Services, MIP International Pharma Research GmbH, St. Ingbert, Germany.

Abstract Objective To evaluate efﬁcacy of therapy with oxaceprol in the treatment of symptomatic osteoarthritis of knee or hip.

Methods A 3-week prospective, multicentric, randomised, double-blind, placebo-controlled study with 167 patients aged between 40 and 75 years with painful and radiologically confirmed knee or hip osteoarthritis. Patients were randomly assigned to receive oxaceprol 1200 mg/day or placebo for 3 weeks. At inclusion, osteoarthritis symptoms were minimum pain following exercise (standardised as pain after climbing 12-15 stairs) of 40 to 90 mm on a 100 mm pain scale and difficulties in climbing stairs. Efficacy criteria were changes in pain shown in a visual analogue scale (VAS), in the Lequesne index, and in assessments of joint limitation, joint complaint and therapeutic success. The primary end point was the pain following exercise. The confirmatory analysis was based on the Full Analysis data set using the t-test for independent samples.

Results Baseline characteristics of both groups were comparable. In the primary endpoint a clinically relevant and statistically signiﬁcant superiority of oxaceprol as compared to placebo could be demonstrated (mean improvement in pain following exercise was 16.6 mm in the oxaceprol and 4.5 mm in the placebo group, p = 0.002). The safety and tolerability was good, showing no statistically signiﬁcant difference between oxaceprol and placebo.

Conclusion A statistically significant and clinically relevant efficacy of oxaceprol was shown. The good safety and tolerability of oxaceprol was confirmed.

Key words Oxaceprol, non-steroidal anti-inﬂammatory agents, placebo, efﬁcacy, osteoarthritis, knee, hip, pain, drug safety.

Clinical and Experimental Rheumatology 2007; 25: 29-34 Oxaceprol-placebo-controlled study / K. Krüger et al.

Dr. Klaus Krüger, Professor; Manfred Introduction patient completed on 16th June 2004. Klasser, PhD; Jürgen Mössinger, PhD; Oxaceprol (INN) is an amino acid de- The study was conducted in accord- Uta Becker, PhD. rivative, which has been used for dec- ance with the German Drug Law, the Chephasaar GmbH is the sponsor of the ades for the symptomatic treatment of Guidelines for Good Clinical Practice study and the manufacturer of the study degenerative and inflammatory joint and with the Declaration of Helsinki. medication. Reimbursement was made disease in Europe (e.g. AHP 200®, Ger- The study concept was approved by according to the time spent on the study many; Jonctum 200 mg gélule, France) all necessary ethics committees before and within the general framework. (1, 2). Oxaceprol has anti-inflamma- starting patient recruitment. Please address correspondence and tory and analgesic efficacy comparable The study design was based on cur- reprint requests to: Dr. Uta Becker, MIP International Pharma Research GmbH, to the conventional non-steroidal anti- rent European recommendations on Mühlstrasse 50, D-66386 St. Ingbert, inflammatory drugs (NSAIDs) but has the conduction of clinical studies in Germany. a different mode of action. Instead of osteoarthritis (7-9). The quality of the E-mail: [email protected] inhibiting the synthesis of prostagland- study conduction was assured by audits Received on February 27, 2006; accepted ins oxaceprol prevents leukocyte infil- of independent experts. in revised form on September 7, 2006. tration into the joints, thus inhibiting an © Copyright CLINICAL AND early step of inflammatory cascade and Patients EXPERIMENTAL RHEUMATOLOGY 2007. presenting a novel class of anti-inflam- Outpatients were included who suffered matory agents ( 3). The limitations of from radiologically confirmed osteoar- NSAIDs in clinical therapy of joint dis- thritis of knee or hip. Further inclusion ease have become obvious during the criteria were age 40-75 years, difficul- last 2 years. Beginning with the COX- ties in climbing stairs, minimum pain selective NSAIDs, also the safety pro- following exercise of 40 to 90 mm on a file of the classical NSAIDs has been 100 mm pain scale. In case of osteoar- reassessed, revealing cardiovascular thritis of more than one joint, the joint risk in addition to the already known with the most severe symptoms was serious risks like gastrointestinal bleed- investigated. Exclusion criteria were ing or renal damage. As a consequence, known secondary osteoarthritis (e.g. the interest in therapeutic alternatives with trauma, dysplasia), rheumatoid has increased. arthritis, neurological disorders of the Oxaceprol could be such an alternative. locomotor system, serious adipositas There are promising results in the pre- or other diseases with influence on os- clinical studies (3, 4). Clinical equiva- teoarthritis symptoms (e.g. gout), ther- lence with diclofenac in recent clinical apies which could interfere with the studies has been shown (5, 6). Due to a study, surgery of the investigated joint potentially strong placebo effect in os- during the last 6 months or planned sur- teoarthritis, current European require- gery within the next 2 years, patients ments additionally ask for placebo with surgery of the lower limbs during control in this indication as a proof of the last year, periarticular or intraar- efficacy (7-9). Therefore, the aim of the ticular injection (especially corticoids) present study was to determine whether or punctation during the last 3 months, oxaceprol would be superior to placebo hypersensitivity to the investigational in the treatment of osteoarthritis. product, pregnancy (screening test before inclusion) or lactation. Before in- Materials and methods clusion all patients gave their written, Study design informed consent. This study was a double-blind, randomised, multicentric clinical trial in Drug administration/treatment 15 orthopaedic or rheumatologic am- Following a wash-out period of at least 5 bulatory centres in Germany compar- times the plasma half life of previously ing parallel groups. Duration of treat- administered analgesic or antiphlogis- ment was 3 weeks with 4 visits: 1st visit tic medication, patients were randomly screening/start of wash-out, 2nd visit assigned to treatment for 3 weeks with start of intake of study medication, 3rd 2 x 200 mg three times daily, i.e. 1200 visit therapy results after 1 week, and mg/day, oxaceprol film-coated tablets 4th visit therapy results after 3 weeks/ or placebo of identical appearance. The end of study. The first patient was en- study medication was made by Chep- rolled on 19th November 2003; the last hasaar GmbH, Germany.

30 Oxaceprol-placebo-controlled study / K. Krüger et al.

During the study analgesic or antiphlo- mm with a common standard devia- different in patients treated with oxace- gistic co-medication was excluded. tion of 20 mm. 128 evaluable patients prol and patients treated with placebo. Rescue medication was acetaminophen would have been required for this ap- The secondary efficacy parameters tablets (0.5 g). Intake was permitted if proach. 140 patients should be recruit- were evaluated according to the same necessary due to pain but not 48 hours ed in order to compensate for drop- principles and the same methods as before visits. It was recorded daily by outs. After inclusion of 40 patients a the primary efficacy variables. Never- the patient in the diary and checked by planned, blinded interim analysis was theless, significant differences of the the physician at each visit (pill count- carried out to check the assumptions of secondary parameters had to be inter- ing of rescue medication and study the sample size calculation. Since the preted descriptively. All data analyses medication). drop-out rate was higher than expected, were carried out using the programme Ongoing physiotherapy was allowed if the sample size was increased to totally SPSS for Windows, version 12.0. there was no change during the study. It 160 patients. An analysis of safety was carried out was documented at each visit. Efficacy variables were evaluated on by comparing the incidences of adverse the basis of a full analysis (FA) accord- events by Fisherʼs exact test. Efficacy variables ing to a modified intent-to-treat prin- The primary end point was pain fol- ciple. For sensitivity reasons an addi- Results lowing exercise after 3 weeks of treat- tional per protocol (PP) analysis was Patient characteristics ment. It was standardised as pain after carried out. The confirmatory analysis Of 167 screened patients, 159 were climbing 12-15 stairs documented by was based on the FA data set using the randomised. One hundred and fifty patient using a 100 mm visual analogue t-test for independent samples. All pa- three received treatment (at least 1 scale (VAS) in the patientʼs diary (0 = tients who received at least one dose tablet of study medication) and were no pain, 100 = maximum pain) at the of study medication entered the safety evaluated for safety analysis (SA data same time of day. The documentation analysis. set). 97 patients could be evaluated for was checked and documented in the Patient allocation was 1:1, with a block efficacy of the primary endpoint after case report form (CRF) by the physi- size of 6 patients, resulting in a list of 3 weeks (FA dataset). Based on blind cian at each visit. numbers 1 – x (computer programme data review 24 patients had to be ex- Secondary endpoints were pain at rest RANCODE, version 3.6, IDV Gauting; cluded from efficacy evaluation due to (VAS, 0 = no pain, 100 = maximum based on random number generator serious protocol violations of inclusion pain), the Lequesne joint function in- of George Massaghia and T. A. Bray, or exclusion criteria (13 VAS < 40 mm dex (0-24 points, 0 = no functional Mathematics Research Laboratory Boe- or > 90 mm at inclusion; 3 without dif- restriction, 24 = highest functional ing Scientific Research Laboratories, ficulties in climbing stairs; 3 intraar- restriction) (10), patientʼs and physi- March 1968). Study centres received ticular medication; 2 joint surgery; 2 cianʼs global assessment of joint dis- study medication with continuing num- > 80 years; 1 BMI > 40); 22 patients ability and joint complaint (VAS, 0 = bers, recruiting the patients ascending, due to serious protocol violations (8 no disability/complaint, 100 = maxi- beginning with lowest number. unauthorised analgesic/antiphlogistic mum disability/complaint), patientʼs Random code was withheld from all medication within 5 plasma half times and physicianʼs global assessment of persons directly involved in the patient before visit; 5 study medication for less efficacy and safety of therapy (VAS, 0 recruitment or involved in statistical than 6 calendar days; 3 acetaminophen = no efficacy/safety, 100 = maximum analysis. The only deblinding which within 6 hours before visit; 2 wash-out efficacy/safety), as well as acetami- was possible during the study, was de- medication during treatment phase; 1 nophen consumption and drop-out due blinding of specified patients in case of lack of compliance in intake of study to lack of efficacy. a severe side reaction, which could not medication; 1 lack of efficacy data; 1 be treated adequately without knowl- attack of gout during the study; 1 start Safety variables edge of the investigational product. of study 20 days before first intake of Adverse events (AEs) were recorded at Therefore, the doctors and the monitors study medication) and 10 lack of VAS each visit. Laboratory variables (hae- received sealed envelopes to enable de- compliance (8 change of VAS > 40 mm matology, clinical chemistry and urine blinding. within 24 hours during the first treat- status) were measured at the beginning The primary study hypotheses for ef- ment week, 1 VAS improvement > 20 and end of the study. ficacy focused on “pain following ex- mm during wash-out time, 1 VAS 1 ercise” and were hierarchically ordered mm at inclusion). Statistical analysis a-priori as follows: 1st null hypothesis: Baseline data of both groups were com- The study was planned as a pivotal The pre-/post-treatment difference (3 parable in the SA data set and in the FA study. Pre-study sample size estimation weeks versus day 0) is not different data set (see Table I). was based on the following assump- in patients treated with oxaceprol and tions: Error levels of alpha = 0.05, and patients treated with placebo. 2nd null Therapeutic efficacy beta = 0.8; clinically relevant differ- hypothesis: The pre-/post-treatment In the primary endpoint, pain following ence in pain measured by VAS = 10 difference (1 week versus day 0) is not exercise, at the end of the study after

31 Oxaceprol-placebo-controlled study / K. Krüger et al.

Table I. Baseline characteristics of the patients. similar result (oxaceprol: -18.6 mm, placebo: -6.4 mm; p = 0.005; 95% con- Variable SA data set FA data set fidence interval for the end-point dif- Oxaceprol Placebo Oxaceprol Placebo ference = -20.4 to -3.9). (n = 77) (n = 76) (n = 56) (n = 41) Mean pain at rest improved by 7.6 mm Male 25 (32.5%) 28 (36.8%) 20 (35.7%) 11 (26.8%) in the oxaceprol group and deteriorated Female 52 (67.5%) 48 (63.2%) 36 (64.3%) 30 (73.2%) by 3.3 mm in the placebo group. The Age (years) 59.9 ± 9.8 60.5 ± 9.4 59.4 ± 9.1 59.9 ± 7.8 difference between the groups was sig- Height (cm) 167.8 ± 9.0 168.1 ± 7.7 169.1 ± 8.7 167.2 ± 6.6 Body weight (kg) 76.8 ± 14.5 78.7 ± 12.9 79.4 ± 13.8 78.7 ± 9.4 nificant (p = 0.016). Significant difference was also seen in the physicianʼs Blood pressure (mmHg) assessment of joint complaint at study Systolic 136 ± 18 139 ± 20 134 ± 15 138 ± 18 end (oxaceprol group: 43.2 mm, pla- Diastolic 84 ± 12 85 ± 11 84 ± 11 84 ± 12 Heart rate (/min) 72 ± 11 73 ± 10 72 ± 12 74 ± 11 cebo group: 53.7 mm; p = 0.020). Statistical trends favouring the oxa- Diagnosis ceprol group were determined for the Gonarthrosis 55 (71.4%) 57 (75.0%) 38 (67.9%) 29 (70.7%) mean patientʼs and physicianʼs assess- Coxarthrosis 22 (28.6%) 19 (25.0%) 18 (32.1%) 12 (29.3%) ment of therapeutic success at study Values are absolute and relative frequencies or means ± standard deviations. end (p = 0.069 and p = 0.095, respectively). Mean Lequesne index and mean joint Table II. Pain following exercise, at start and after 3 weeks measured by 100 mm VAS Data base: Full Analysis data set (FA). limitation clearly improved better in the oxaceprol than in the placebo group Groups Day 0 After 3 weeks Differences Difference 95% confidence (Lequesne index improvement: 2.4 within groups between groups interval points versus 1.5 points; joint limita-

Oxaceprol 61.8 ± 14.9 45.2 ± 22.2 -16.6 ± 19.8 tion improvement: 9.8 mm versus 5.6 n 56 56 mm). Nevertheless – probably due to -12.1 -19.8 to -4.4 relatively low patient number – signifi- Placebo 63.0 ± 13.9 58.5 ± 21.6 - 4.5 ± 17.3 cance was not reached. n 41 41 There was low acetaminophen con- Values are means ± standard deviations, confidence interval and “n”. sumption and few drop-outs due to lack of efficacy, so that differences between the groups were not significant in these parameters. In conclusion, the secondary target parameters confirm the results in favour of oxaceprol. All parameters show clinically relevant improvement under oxaceprol after 3 weeks, even if statistical significance was not met in all parameters.

Safety and tolerability One hundred and seventy-one adverse events were reported in 68 patients. Most of the adverse events were mild (61%). Two patients in the oxaceprol group and 3 patients in the pla- Fig. 1. Mean intensity of the pain following exercise beginning with day 0 for the first week (daily cebo group dropped out due to adverse assessment), after 2 and after 3 weeks. Data base: Full Analysis data set (FA). Means and stand error events. In each administration group of means. there was one serious adverse event. None of them was seen in the context 3 weeks, the improvement on the 100- demonstrated (p = 0.002, 95% confi- with the study medication (placebo: mm-pain-scale was on average 16.6 dence interval for the end-point differ- fracture of hand after falling off a bi- mm in the oxaceprol group and 4.5 mm ence = -19.8 to -4.4). A clear onset of cycle; oxaceprol: acute cervical syn- in the placebo group (Table II). A sta- efficacy is seen beginning from week 2 drome). tistically significant superiority of oxa- (p = 0.021) (Fig. 1). The analysis based The incidence of symptoms observed ceprol as compared to placebo could be on the per protocol sample showed a in at least 3 patients was not relevantly

32 Oxaceprol-placebo-controlled study / K. Krüger et al.

Table III. Adverse events: Symptoms. Data base: Safety Analysis data set (SA). 4.5 mm in the placebo group. Regard-

a b ing the group mean, the net oxaceprol Symptoms (ntotal ≥ 3 patients ) Oxaceprol Placebo effect (minus placebo effect) is an im- Headache 10 (13%) 8 (11%) provement of 12.1 mm. This difference Raise of the C-reactive protein 2 (3%) 8 (11%) is clearly clinically relevant taking into Pruritus 4 (5%) 6 (8%) consideration that already a difference Impaired appetite 4 (5%) 3 (4%) Erythrocyte sedimentation rate raised 1 (1%) 6 (8%) of 10 mm on 100 mm VAS is clini- Dyspepsia 3 (4%) 3 (4%) cally relevant (12). Additionally, the Increased susceptibility to infections 2 (3%) 4 (5%) comparison of the results in this study Raise of uric acid in blood 3 (4%) 3 (4%) with Falgarone et al.ʼs patient-derived Raise of Gamma-GT 1 (1%) 5 (7%) Activated appetite 3 (4%) 3 (4%) parameters Low Disease Activity State Dizziness 4 (5%) 1 (1%) (LDAS) and pain killer intake level Ructus 1 (1%) 4 (5%) (15) shows that in the oxaceprol group Redness 4 (5%) 1 (1%) the VAS pain value at the beginning of Epigastric pain 2 (3%) 3 (4%) Diarrhoea 1 (1%) 3 (4%) the study (61.8 ± 14.9 mm) was a clear th Flatulence 1 (1%) 2 (3%) high disease level (50 percentile of Migraine 2 (3%) 1 (1%) LDAS 36) and there was a need for in- Cold 2 (3%) 1 (1%) take of pain killer (50th percentile of the Sum 50 65 Total number of all treated patients 77 (100%) 76 (100%) pain killer intake level 48). There was a clear improvement at the end (45.2 ± Values are absolute and relative numbers of patients. 22.2 mm). A comparison with NSAID a Preferred Term MedDRA version 7.0. studies confirms this result. After 2 bFurther adverse events. weeks of treatment in patients with knee osteoarthritis, Kivitz reports a net higher in the oxaceprol group than in point for symptom-modifying drugs effect of Valdecoxib 20 mg/day and the placebo group (see Table III). Only for osteoarthritis, functional disability Naproxen 2 x 500 mg/day of 10.88 mm in the parameters “raise of the C-reac- is an important additional primary end- and 9.84 mm respectively (16). Wil- tive protein” and “ESR” (erythrocyte point. VAS or Likert scales are meth- liams reports a net effect of Celecoxib sedimentation rate) almost significant ods recommended to assess pain. Func- 100 mg BID and Celecoxib 200 mg QD differences (more AEs in the placebo tional disability should be assessed by of 10.1 mm and 8.7 mm, respectively group) were observed, which could be the Western Ontario Mac Master Uni- (17). interpreted as an indication of worse versity osteoarthritis index (WOMAC) In previously published studies the inflammatory control under placebo. or the Lequesne index (9). All these equivalence of therapeutic efficacy of In conclusion, the adverse events did indices are validated and give patient oxaceprol and diclofenac was demon- not differ significantly in any aspect, relevant information. In this study the strated. Bauer et al. proved the efficacy neither qualitatively nor quantitatively pain VAS was chosen as the primary of oxaceprol (3 x 200 mg/day orally) in between the treatment groups. The to- endpoint. The Lequesne index, which comparison with the standard therapy tal rate of adverse drug reactions in this had already been established in previ- diclofenac (3 x 25 mg/day orally) in clinical study is low and the rate of side ous studies with oxaceprol, was used as 150 patients with activated painful os- effects in the oxaceprol group is com- secondary endpoint. Although current teoarthritis of hip or knee (5). The bio- parable with the placebo group. publications tend to assess responder metric testing was a confirmatory test of criteria due to their patient-derived equivalence. The main efficacy param- Discussion perspective [e.g. the WOMAC index eter of the study, the Lequesne index The data presented here clearly show contributed to the development of pro- (reflecting pain and function), showed the superiority of oxaceprol as com- posed definitions for responder criteria significant and clinically relevant im- pared to placebo in the treatment of (12, 13)], at the time of the set-up of provement after 20 days of treatment (4 osteoarthritis. Compared to previous the study response criteria required points in the oxaceprol and 3.4 points placebo-controlled studies (11) the additional validation (13) and were in the diclofenac group). Also the sec- present study was planned confirmato- therefore not regarded as sufficient- ondary parameters, e.g. weight-bearing ry in accordance with current Europe- ly validated parameters at that time. pain improved clearly (oxaceprol by 3 an requirements (7-9) and is therefore Therefore, the results were expressed of 10 points, diclofenac by 3.2 points). highly relevant for the proof of efficacy at a group level as mean changes. In conclusion, the study shows that of oxaceprol. The efficacy indices were In the primary endpoint oxaceprol was oxaceprol in the low dosage of 3 x 200 chosen in line with the EMEA recom- significantly (p = 0.002) more effec- mg/day is equivalent to the standard mendations for osteoarthritis clinical tive than placebo after 3 weeks. The therapeutic diclofenac in the low dos- studies: pain attributed to the target pain following exercise improved by age of 3 x 25 mg/day. The study pub- joint is recommended as primary end- 16.6 mm in the oxaceprol group and by lished by Herrmann et al. also showed

33 Oxaceprol-placebo-controlled study / K. Krüger et al. the equivalence of oxaceprol with di- In conclusion, oxaceprol presents a ETARY MEDICINAL PRODUCTS (CPMP): Points to consider on clinical investigation of medici- clofenac in a comparable study design well-established drug for symptomat- nal products used in the treatment of osteoar- but with higher dosage (diclofenac 3 ic treatment of joint disease. Recent thritis. CPMP/EWP/784/97: 1-6. x 50 mg/day orally and oxaceprol 3 x preclinical and clinical publications 10. LEQUESNE MG, MERY C, SAMSON M, GER- 400 mg / day orally) (6). The Lequesne demonstrate that it is a novel class of ARD P: Indexes of severity for osteoarthritis of the hip and knee. Scand J Rheumatology index improved by 2.5 points in the anti-inflammatory agents with better 1987 (Suppl. 65): 85-9. oxaceprol and by 2.8 points in the di- safety profile than classical NSAIDs. 11. FELDMAN S, BERGAL S, NORES JM et al.: clofenac group. The weight-bearing The present study completes the clini- Traitement par la N-acetyl-hydroxyproline pain also improved clearly (oxaceprol cal proof of efficacy showing super- des arthropathies dégénératives. Analyse et synthèse de 7 essais cliniques. Rhumatologie –2.2 of 10 points, diclofenac –2.3 of 10 iority of oxaceprol as compared to 1994; 46: 281-6. points). placebo. 12. BELLAMY N: The WOMAC knee and hip os- As compared to the present study, the teoarthritis indices: development, validation, improvement in these active compara- globalization and influence on the develop- Acknowledgements ment of the AUSCAN hand osteoarthritis in- tor studies seems to be slightly higher We thank all investigators involved in dices. Clin Exp Rheumatol 2005; 23 (Suppl. (in the present study improvement by the study for patient recruitment, medi- 39): 148-53. 16.6 of 100 mm VAS). This might be cal care and data collection and the 13. DOUGADOS M, LECLAIRE P, VAN DER HEIJDE due to higher basic effect of physi- D, BLOCH DA, BELLAMY N, ALTMAN RD: auditor for performance of the on site A report of the Osteoarthritis Research So- otherapy, since the studies of Bauer et audit. We thank all study nurses, study ciety International Standing Committee for al. and Herrmann et al. were performed assistants, monitors and data managers Clinical Trials Response Criteria Initiative. with inpatients receiving physiothera- for their technical contribution. Osteo Arthritis and Cartilage 2000; 8: 395- py. The present study was performed 403. 14. KELLY AM: The minimum clinically signifi- with outpatients; only 28.6% of the References cant difference in visual analogue scale pain patients in the oxaceprol group and 1. Fachinformationsverzeichnis Deutschland score does not differ with severity of pain. 31.7% of the patients in the placebo AHP 200®, BPI Service GmbH CD-version, Emerg Med J 2001; 18: 205-7. issue 2005/4. 15. 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