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 mini- mum 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 follow- ing 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 be- fore inclusion) or lactation. Before in- Materials and methods clusion all patients gave their written, Study design informed consent. This study was a double-blind, ran- domised, 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).