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Ann Rheum Dis 63:1419-1426 doi:10.1136/ard.2003.015974
  • Extended report

Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib

  1. H Tannenbaum1,
  2. F Berenbaum2,
  3. J-Y Reginster3,
  4. J Zacher4,
  5. J Robinson5,
  6. G Poor6,
  7. H Bliddal7,
  8. D Uebelhart8,
  9. S Adami9,
  10. F Navarro10,
  11. A Lee11,
  12. A Moore11,
  13. A Gimona11
  1. 1Rheumatic Disease Centre of Montreal, Montreal, Canada
  2. 2Hpital St Antoine, Paris, France
  3. 3CHU de Lige, Lige, Belgium
  4. 4Orthopdische Klinik, HELIOS Klinikum Berlin, Germany
  5. 5Synexus Ltd, Liverpool, UK
  6. 6Orszagos Reumatologiai es Fizioterapias, Budapest, Hungary
  7. 7Frederiksberg Hospital, Frederiksberg, Denmark
  8. 8Universitt Zurich, Zurich, Switzerland
  9. 9Centro di Osteoporosis, Verona, Italy
  10. 10Hospital Universitario Virgen Macarena, Sevilla, Spain
  11. 11Novartis Pharma AG, Basel, Switzerland
  1. Correspondence to:
    Dr H Tannenbaum
    Rheumatic Disease Centre of Montreal, 4060 SteCatherine St West, Suite 740, Montreal, H3Z 2Z3 QC, Canada htannattglobal.net
  • Accepted 21 December 2003
  • Published Online First 27 February 2004

Abstract

Objectives: To compare the efficacy and safety of lumiracoxib with placebo and celecoxib for osteoarthritis OA in a 13 week, multicentre, randomised, double blind study.

Methods: After a 37 day washout period for nonsteroidal antiinflammatory drugs, 1702 patients with knee OA were randomised to lumiracoxib 200 or 400mg once daily od, celecoxib 200mg od, or placebo 2221. A visual analogue scale VAS pain intensity 40mm was required. Primary efficacy variables were OA pain intensity VAS mm in the target knee, patients global assessment of disease activity VAS mm, and WOMAC pain subscale and total scores at 13weeks. OA pain intensity, patients and physicians global assessment of disease activity, and WOMAC total and all subscale scores were analysed by visit as secondary variables.

Results: Lumiracoxib showed significant improvements in all primary and secondary variables compared with placebo. Lumiracoxib 200mg od and celecoxib 200mg od achieved similar improvements in OA pain intensity and functional status. Lumiracoxib 400mg od demonstrated better efficacy for OA pain intensity and patients global assessment of disease activity at weeks 2, 4, and 8 and similar efficacy at week 13 compared with celecoxib 200mg od. The incidence of adverse events AEs, serious AEs, and discontinuations due to AEs was similar in each group.

Conclusion: Lumiracoxib demonstrated significant improvement in OA pain intensity, patients global assessment of disease activity, and the WOMAC pain subscale and total scores compared with placebo. Lumiracoxib was well tolerated in this study, with overall tolerability similar to that of placebo and celecoxib.

Osteoarthritis OA is a highly prevalent, chronic condition associated with a considerable burden for patients due to joint pain, stiffness, and inability to perform normal daily activities. As a result, this condition has a significant negative impact on quality of life.1

Nonsteroidal antiinflammatory drugs NSAIDs are well established as first line treatment for chronic moderatesevere pain in OA, providing effective relief of symptoms in most patients.2–4 Traditional NSAIDs control the pain and inflammation associated with OA by reducing prostaglandin synthesisa direct consequence of inhibitory effects on both isoforms of the cyclooxygenase COX enzymes COX1 and COX2. This nonselective mechanism of action is largely responsible for the development of symptomatic ulcers and potentially serious gastrointestinal GI side effects.5 The incidence of symptomatic ulcers and ulcer complications associated with traditional NSAIDs was reported to be between 2 and 4 a year in 1988,6 and the management of gastropathy associated with traditional NSAID use is estimated to more than double the costs associated with the original treatment.7 The concomitant use of gastroprotective agents with traditional NSAIDs has been reported as one possible approach to managing NSAID related gastropathy.8 The GI side effects are due to reduced synthesis of prostaglandins, which have a cytoprotective role in the GI tract, when COX1 is inhibited by traditional NSAID treatment.9,10

Lumiracoxib is a new COX2 selective inhibitor developed for the treatment of OA, rheumatoid arthritis RA, and acute pain. It has demonstrated selectivity for COX2 in vitro and in vivo11 and in human studies,12 with selectivity maintained at doses up to 1200mg.13 The structure of lumiracoxib distinguishes it from other COX2 selective inhibitors,14 which may explain its preferential distribution into inflamed tissue in animal models an effect not observed with other COX2 selective inhibitors,15,16 and the sustained high concentrations of lumiracoxib seen in synovial fluid compared with plasma in patients with RA.17 Clinical studies show that lumiracoxib is characterised by rapid absorption Tmax 23hours, a short plasma half life 36hours,18 and good oral bioavailability.19 In patients with OA, lumiracoxib demonstrates dose proportional pharmacokinetics.20 Once daily lumiracoxib provides relief from the pain, stiffness, and impaired physical function of OA with efficacy better than placebo and similar to diclofenac.21–23 Furthermore, lumiracoxib is associated with a GI tolerability profile better than ibuprofen and similar to celecoxib in patients with OA or RA.24,25

This study aimed at determining the efficacy of two doses of lumiracoxib 200 and 400mg once daily od in relieving pain and improving functional status in patients with primary knee OA, compared with placebo and celecoxib 200mg od. The safety and tolerability profiles of all treatment groups were also assessed.

PATIENTS AND METHODS

This 13 week international, multicentre, randomised, double blind, double dummy, placebo controlled, active comparator study, was performed in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki and subsequent amendments.

Patients and study design

Men and women aged 18years with a confirmed diagnosis of primary OA of the knee, according to the American College of Rheumatology criteria,26 were recruited after giving written, informed consent. Patients at risk of pregnancy or those who had secondary OA, other connective tissue diseases, or significant medical problems, were excluded.

People meeting the initial inclusion criteria underwent a 37day washout period, during which NSAID treatment was not permitted. At the end of the washout period, patients with pain intensity in the affected knee measuring 40mm on a 100mm visual analogue scale VAS most pain in the past 24hours were deemed eligible for entry into the treatment phase of the study. To best reflect the real life clinical situation, no increaseworsening in OA symptoms flare was required for study entry.

Patients were randomised to 13weeks once daily treatment with lumiracoxib 200mg, lumiracoxib 400mg, celecoxib 200mg, or placebo. Celecoxib was administered at 200mg od according to its label specifications. Blinding was maintained by a double dummy technique. All drugs were taken in the morning at least 1hour before or after a meal, the first dose being taken at the clinic on day 0 baseline. After this, patients returned to the clinic for assessment at weeks 2, 4, 8, and 13.

Patients were permitted to take paracetamol 2gday, supplied by the investigator, as a rescue drug throughout the trial however, they were asked to refrain from using the rescue drug from midnight before each clinic visit. NSAIDs were not permitted during the course of the study, with the exception of low dose aspirin 325mgday for a cardiovascular indication.

Prespecified criteria for discontinuation due to notable changes in laboratory measures were established.

Outcome measures

The following primary efficacy variables were evaluated at the end of the study week 13

  • OA pain intensity VAS mm in the target knee most pain in the previous 24hours

  • Patients global assessment of disease activity VAS mm

  • Patients functional status pain subscale and total score of the Western Ontario and McMaster Universities Osteoarthritis Index WOMAC LK3.1 questionnaire.27

OA pain intensity in the target knee, patients and physicians global assessment of disease activity, and WOMAC total and all three subscale scores pain, difficulty in performing daily activities DPDA, and stiffness were analysed by visit as secondary variables.

Safety was assessed through recording the frequency of adverse events AEs and serious adverse events SAEs at each clinic visit. Physical examinations were performed at baseline and at the study end, vital signs were assessed at each clinic visit, and standard laboratory tests were performed at weeks 2, 4, and 13. Electrocardiogram ECG measurements, analysed centrally, were conducted at screening, week 4, and week 13. A subgroup of patients, whose ECGs after baseline were recorded 14hours after the morning dose of study drug to coincide with the maximum plasma concentration Cmax of lumiracoxib,18 were included into peak time analyses of ECG parameters.

Compliance with study treatment was monitored by pill counting, and rescue drug use was assessed at each study visit.

Statistical analyses

A minimum sample size of 432 patients in each active treatment group and 216 in the placebo group was specified in the study protocolthat is, a total of 1512 patients. Using a two group t test with a 0.025 one tailed significance level, this sample size would have 99 power to reject the null hypothesis of no treatment difference over placebo, assuming a difference of 11mm in favour of lumiracoxib, a withdrawal rate of 15, and a common standard deviation of 25mm. A high power was set to enable tests of noninferiority or superiority of lumiracoxib to celecoxib. To this end, noninferiority margins of 5mm for OA pain and patients global assessment, and of 0.6 points for the pain subscale of the WOMAC questionnaire were predefined.

Patients were randomised in a ratio of 2221 to 13weeks once daily treatment with lumiracoxib 200mg, lumiracoxib 400mg, celecoxib 200mg, or placebo.

Each primary efficacy variable was analysed, using analysis of covariance, with baseline values as the covariate, with treatment group and study centre as the independent variables. Pairwise comparisons between treatments were performed using least square means obtained from the model. Data were analysed by visit at a secondary level using the same model.

All safety and efficacy evaluations were performed using the intention to treat ITT population. The safety and ITT populations were identical and included all patients randomised to treatment who had been exposed to the study drug. Conventional last observation carried forward methodology was used when data were missing.

In addition to the analysis of AE and SAE incidence, the incidence of prespecified AEs was compared in treated and placebo groups using medical terms as coded by a standard medical dictionary.

  • Prespecified GI AEs and ulcers abdominal pain not otherwise specified NOS, abdominal pain lower, abdominal pain upper, abdominal pain aggravated, constipation, constipation aggravated, diarrhoea NOS, diarrhoea aggravated, nausea, nausea aggravated, vomiting NOS, vomiting aggravated, dyspepsia, dyspepsia aggravated, dysphagia, dysphagia aggravated, loose stools, oesophageal ulcer, peptic ulcer, peptic ulcer aggravated, gastric ulcer, duodenal ulcer, duodenal ulcer aggravated, gastroduodenal ulcer, GI ulcer, pyloric ulcer

  • Peripheral oedema AEs oedema peripheral, oedema lower limb, oedema NOS, oedema upper limb

  • Chest pain AEs chest pain not elsewhere classified.

Occurrence of prespecified AEs was summarised and analysed using a logistic regression model, including country and treatment group as variables.

RESULTS

Patient characteristics

The ITT population comprised 1702 patients, randomised to receive lumiracoxib 200mg od n487, lumiracoxib 400mg od n491, celecoxib 200mg od n481 or placebo n243. The study group was predominantly female 68.5 with a mean age of approximately 64 years. There were no significant differences in patient demographics or baseline disease characteristics between the treatment groups table 1.

Table 1

Patient demographics and baseline disease characteristics

A similar number of patients discontinued the study prematurely in each active treatment group fig 1. Most discontinuations resulted from AEs however, the proportion of patients who withdrew for this reason was similar across the four treatment groups. Overall, compliance with the treatment regimens was good, with more than 90 of patients judged to be compliant across the four treatment groups. Proportionately twice as many patients discontinued owing to a lack of efficacy in the placebo group as in the active treatment groups fig 1.

Figure 1

Patient flow diagram. Other includes protocol violation, withdrawal of consent, and condition no longer requiring the study drug.

Efficacy

Primary variables

All active treatments were statistically significantly better than placebo for each of the primary variables at 13weeks.

For OA pain intensity VAS mm in the target knee at week 13, the estimated least square mean differences from placebo in favour of active treatment were 6.33mm p0.001 in the lumiracoxib 200mg od group, 7.94mm p0.001 in the lumiracoxib 400mg od group, and 5.75mm p0.001 in the celecoxib 200mg od group fig 2. The mean change from baseline in OA pain intensity at week 13 was similar for all active treatments 26.0mm for lumiracoxib 200mg od, 27.4mm for lumiracoxib 400mg od, and 25.2mm for celecoxib 200mg od compared with 19.8mm for placebo table 2, and the noninferiority of lumiracoxib 200 and 400mg od to celecoxib 200mg od was demonstrated.

Table 2

Change from baseline in OA pain intensity in the target joint, and patients and physicians global assessments of disease activity at weeks 2 and 13

Figure 2

Osteoarthritis pain intensity VAS mm in the target knee at weeks 2, 4, 8, and 13 with lumiracoxib 200mg and 400mg od, celecoxib 200mg od, and placebo. Values are least square means, except for baseline, which are means. p0.001 all active treatment groups v placebo p0.05 lumiracoxib 400mg od v celecoxib 200mg od p0.05 lumiracoxib 400mg od v lumiracoxib 200mg od.

Significant improvement in patients global assessment of disease activity was seen in all active treatment groups at week 13 compared with placebo all p0.001 v placebo fig 3, table 2. All active treatments were similar and noninferiority of lumiracoxib 200 and 400mg od to celecoxib 200mg od was demonstrated.

Figure 3

Patients global assessment of disease activity VAS mm at weeks 2, 4, 8, and 13 with lumiracoxib 200mg and 400mg od, celecoxib 200mg od, and placebo. Values are least square means, except for baseline, which are means. p0.001 all active treatment groups v placebo p0.05 lumiracoxib 400mg od v celecoxib 200mg od.

The WOMAC pain subscale and total scores at week 13 were significantly better with lumiracoxib and celecoxib than with placebo all p0.01 v placebo for the pain subscale and all p0.001 for the total score. Figure 4 and table 3 show the mean changes from baseline.

Table 3

Change from baseline in WOMAC total and subscale scores at weeks 2 and 13

Figure 4

Mean SEM change from baseline in WOMAC pain subscale A and total B scores at week 13 with lumiracoxib 200mg and 400mg od, celecoxib 200mg od, and placebo. Statistical analyses performed using least square means. p0.01 v placebo p0.001 v placebo.

Secondary variables

Significant improvements were seen in OA pain intensity VAS mm in the target knee from week 2 onwards in all active treatment groups compared with placebo table 2, fig 2. The reduction in pain intensity with lumiracoxib 200mg od was of similar magnitude to that of celecoxib 200mg od at all times. At weeks 2, 4, and 8, lumiracoxib 400mg od provided significantly greater reductions in OA pain intensity in the target knee than celecoxib 200mg od.

The patients global assessment of disease activity VAS mm was significantly improved from week 2 onwards in all active treatment groups compared with placebo table 2, fig 3. In the lumiracoxib 400mg od group, the reduction in the mean score was significantly greater than in the celecoxib 200mg od group at weeks 2, 4, and 8 fig 3. In addition, all active treatment groups were significantly more efficacious than placebo at weeks 2, 4, 8, and 13 according to the physicians global assessment of disease activity table 2.

Significant improvements were seen in WOMAC total and all three subscale scores for all active treatment groups compared with placebo at week 2 all p0.01 v placebo table 3. At week 13, all active treatments were associated with significant improvements according to the DPDA and stiffness subscales all p0.01 v placebo table 3.

The mean number of rescue drug tablets consumed was significantly greater in the placebo group 0.8 tabletsday than in any active treatment group throughout the study 0.5 tabletsday for both lumiracoxib groups and 0.6 tabletsday for celecoxib 200mg od all p0.05 v placebo. Betweentreatment analyses showed that at week 4, the number of rescue drug tablets taken was significantly higher in the celecoxib 200mg od group than in the lumiracoxib 400mg od group no other betweentreatment differences were seen data not shown.

Safety

Lumiracoxib was well tolerated. There were no deaths during the study and the incidence of SAEs was similar in all active treatment groups and the placebo group 2.5 of patients receiving lumiracoxib 200mg od, 2.9 receiving lumiracoxib 400mg od, 2.9 receiving celecoxib 200mg od, and 3.3 receiving placebo table 4. The proportion of patients reporting at least one AE was 57.5 and 58.7 in the lumiracoxib 200mg od and 400mg od groups, respectively, compared with 51.0 for the placebo group and 53.2 for the celecoxib 200mg od group. AEs led to discontinuation from the study in a similar proportion of patients in each treatment group. In all treatment groups the most common AEs leading to discontinuation were those affecting the GI system 18 3.7 patients in the lumiracoxib 200mg od group, 22 4.5 patients in the lumiracoxib 400mg od group, 19 4.0 patients in the celecoxib 200mg od group, and 6 2.5 patients in the placebo group table 4. In a post hoc analysis, no statistically significant differences were detected in discontinuation rates for GI AEs between any active treatments compared with placebo.

Table 4

Summary of adverse events, serious adverse events, and discontinuations due to adverse events

The majority of AEs were mild or moderately severe. The incidence and nature of AEs were similar in both lumiracoxib groups and the celecoxib group overall, nasopharyngitis, headache, and upper abdominal pain, were the most commonly reported AEs in all treatment groups table 5.

Table 5

Incidence of most frequently reported adverse events 3 and prespecified adverse events

Multiple regression analyses of the incidence of prespecified AEs showed no significant differences between lumiracoxib and celecoxib table 5. The proportion of patients reporting prespecified GI events was similar in each active treatment group. The incidence of prespecified peripheral oedema and chest pain was low, and no clinically relevant pattern was seen between treatment groups.

Clinically relevant laboratory abnormalities were uncommon in all treatment groups however, four patients were withdrawn from the study because of abnormal values. As required by study protocol, one patient in the lumiracoxib 400mg od group discontinued because of a raised creatinine level 2 the upper limit of normal. In total, nine patients had increases in liver function parameters alanine aminotransferaseaspartate aminotransferase 3 the upper limit of normal two patients in the lumiracoxib 200mg od group three patients in the lumiracoxib 400mg od group four patients in the celecoxib 200mg od group. Of these nine patients, three were withdrawn from the study one patient in each of the lumiracoxib 200mg od, lumiracoxib 400mg od, and celecoxib 200mg od groups. All cases of raised liver function parameters resolved either while receiving the study drug or after treatment had stopped and none were accompanied by clinical symptoms.

ECG analyses showed that lumiracoxib was not associated with QT interval prolongation or any form of arrhythmia. There was no evidence of drug or dose related changes in ECG recordings or increase in qualitative ECG abnormalities in any treatment group.

DISCUSSION

The results of this large, randomised, double blind, placebo controlled, active comparator study demonstrate the clinical efficacy and tolerability of lumiracoxib, a new COX2 selective inhibitor, at doses of 200 or 400mg od, in patients with OA of the knee. After 13weeks of treatment, patients who had received lumiracoxib 200 and 400mg od had significantly less OA pain intensity in the target knee, and better patients global assessment of disease activity and patients functional status than the placebo group.

Analyses of OA pain intensity in the target knee and patients global assessment of disease activity by clinic visit secondary variables showed that both doses of lumiracoxib provided statistically significant improvements over placebo from the first clinic visit after the start of treatment week 2, an effect sustained throughout the study. The magnitude of improvement was similar for lumiracoxib 200mg od and celecoxib 200mg od at all times. Lumiracoxib 400mg od was significantly more effective than celecoxib 200mg od at weeks 2, 4, and 8, but no significant differences were seen by the study end week 13. For the other secondary efficacy variables, physicians global assessment of disease activity, and WOMAC DPDA and stiffness subscales, both lumiracoxib groups and the celecoxib group were significantly better than placebo throughout the study.

Celecoxib has been shown to provide sustained analgesic effects and improvements in physical function in patients with OA, with efficacy better than placebo and similar to that of the traditional NSAIDs, naproxen and diclofenac.28,29 Celecoxib was therefore chosen as a reference treatment for this study, and was used at the recommended dose for the treatment of OA.30 Thus, it is notable that in this study lumiracoxib 200mg od was found to be similar to celecoxib in all clinical efficacy measures examined.

This study recruited patients without OA flare to replicate the real life clinical situation for patients with OA. In previously reported celecoxib studies in OA, a flare design was used, whereby patients were required to demonstrate a worsening in OA symptoms during an NSAID washout period between screening and baseline.28,31 In both these studies a marked placebo effect was seen in the mean change from baseline in OA pain intensity VAS mm, and celecoxib was associated with mean changes from baseline of up to 30.0mm and differences in comparison with placebo of up to 15.0mm after 2weeks of treatment.28,31 In our study the lack of a requirement for OA flare would be expected to provide an overall less dramatic treatment effect and, consequently, a smaller difference compared with placebo.

In addition, it has recently been suggested that the concept of a minimal clinically perceptible difference is applicable to the WOMAC DPDA subscale, whereby the minimal difference perceived by 75 of patients MDP75 is considered to represent a clinically meaningful difference. In a study sample of 1354 patients with hip and knee OA, the MDP75 for the WOMAC DPDA subscale was found to be 5.2.32 It is notable that in the study reported here, mean changes in WOMAC DPDA subscale scores were 6 for both doses of lumiracoxib at week 2, rising to 9 at week 13.

Celecoxib and rofecoxib are associated with a lower incidence of ulcers and GI events than traditional nonselective NSAIDs.33–35 Although the results of the Celecoxib Outcomes Study CLASS were not positive for celecoxib compared with traditional nonselective NSAIDs for ulcer related complications at 12months,36,37 a recent systematic review of a wide range of celecoxib studies found that it does offer significantly improved GI safety and tolerability including ulcers and serious upper GI events compared with traditional NSAIDs.38 In this study both doses of lumiracoxib and celecoxib were associated with a similar incidence of AEs, including GI disorders, suggesting no dose relationship. In addition, the number of patients who withdrew from the study because of AEs or GIspecific AEs was similar across all active treatment groups. Furthermore, lumiracoxib was not associated with an increase in overall renal AEs or associated symptoms of oedema compared with placebo, and did not result in QT interval prolongation or any form of arrhythmia.

The efficacy and tolerability of lumiracoxib seen in this study confirm findings of earlier studies in patients with OA. In a 4week study of 583 patients with primary OA of the hip and knee, lumiracoxib demonstrated efficacy comparable with the traditional NSAID, diclofenac, for pain relief, improved functional status, and response to treatment.21 In a 13 week study comparing the GI effects of lumiracoxib with ibuprofen and celecoxib in 1042 patients with primary OA of the hip, knee, hand, or spine, lumiracoxib was associated with significantly fewer gastroduodenal ulcers than ibuprofen. In addition, it was notable that lumiracoxib and celecoxib demonstrated a similar GI tolerability profile.24 Lumiracoxib resulted in significantly lower rates of gastroduodenal ulceration than ibuprofen in a separate study of 893 patients with RA the incidence of gastroduodenal ulcers was also similar for lumiracoxib and celecoxib in this study.25 Similarly, in healthy volunteers, lumiracoxib was associated with a reduced incidence of gastroduodenal erosions compared with the traditional NSAID, naproxen.12,39

In summary, our study shows that lumiracoxib at a dose of 200 or 400mg od provides sustained relief from the painful symptoms of OA of the knee and improves functional status with significantly better efficacy than placebo. In addition, lumiracoxib was found to be as effective and well tolerated as the recommended dose of the established COX2 selective inhibitor, celecoxib.

Acknowledgments

We thank JY Robo programmer, A Couturier statistical programmer, and D Jack senior clinical research scientist.

A Lee, A Moore, and A Gimona are employees of Novartis Pharma AG, Basel, Switzerland.

This study was supported by a grant from Novartis Pharma AG, Basel, Switzerland.

INVESTIGATORS
Belgium Dr F Raeman, Merksem Professor JY Reginster, Liege Dr F Van Bruwaene, Roeselare Dr P Van Wanghe, Hasselt Dr L Williame, Antwerp Dr M Wouters, Brussels.

Canada Dr M Bell, Toronto Dr W Bensen, Hamilton Dr J Brown, SteFoy Dr B Haraoui, Montreal Dr S Huang, Vancouver Dr M Luterman, Downsview Dr JP Ouellet, Sherbrooke Dr H Tannenbaum, Montreal Dr E Wasser, Toronto Dr K White, London.

Denmark Dr T Aaboe, Copenhagen Dr J Beier, Odense Dr H Bliddal, Frederiksberg Dr HH Ibfelt, Hilleroed Dr B Lund, Copenhagen Dr O Nedergaard, Hvidovre.

France Dr L Boucher, Murs Erigne Dr S Boutboul, Marseille Dr A Boye, Nantes Dr C Copere, Roanne Dr D Dubourg, Saint Viaud Dr G Etchegaray, Niort Dr P Lafont, Uzes Dr G Mongin, Montpellier Dr S Musso, Eaunes Dr E De Sainte Lorette, Paris Dr R Sarfati, La Seyne Sur Mer.

Germany Dr R Alten, Berlin Professor Dr B Fink, Hamburg Professor J Grifka, Bad Abbach Professor H Grobecker, Regensburg Professor H Haentzschel, Leipzig Professor FW Hagena, Bad Oeynhausen Professor G Hein, Jena Professor HR Henche, Rheinfelden Professor E Hille, Hamburg Dr E Schell, Nuernberg Dr H Schneider, Messkirch Professor J Sieper, Berlin Dr M Talke, Berlin Dr H Thabe, Bad Kreuznach Professor G Weseloh, Erlangen Professor H Wittenberg, Bochum Dr A Wittenborg, Herne Professor Dr J Zacher, Berlin.

Hungary Dr G Genti, Kistarcsa Dr G Poor, Budapest Dr F Szanyo, Gyor Dr L Tamasi, Miskolc.

Italy Professor S Adami, Verona Dr G Bianchi, Arenzano Professor S Bombardieri, Pisa Dr M Broggini, Varese Professor M Carrabba, Milano Dr M Fasani, Roma Professor R Marcolongo, Siena Dr M Muratore, San Cesario di Lecce Dr C Salvarani, Reggio Emilia Professor B Seriolo, Genova.

Spain Dr A Alonso, Bilbao Dr P Benito, Barcelona Dr F Buitrago, Badajoz Dr E Chamizo, Mrida Badajoz Dr E Collantes, Crdoba Dr M Figueroa, San Sebastin Guipzcoa Dr A Garcia, Seville Dr C Gonzez, Madrid Dr F Navarro, Seville Dr J Orte, Madrid Dr V Rodrguez, Santander Dr M Rodrguez, Mlaga Dr JA Roman, Valencia Dr J Sampedro, Toledo Dr J Tornero, Guadalajara.

Switzerland Dr A Aeschlimann, Zurzach Dr G Ambrosini, Bellinzona Dr H Gerber, Zrich Dr P Hasler, Aarau Dr PJ Jenoure, Muttenz Dr N Masina, Lugano Dr M Pellaton, Neuchtel Dr J Sturzenegger, Kreuzlingen Dr R Theiler, Zrich Dr D Uebelhart, Zrich Dr JJ Volken, Sierre.

United Kingdom Dr K Brown, Liverpool Dr D Dev, Manchester Dr G Ding, Didcot Dr J Fraser, Wigan Dr B Grimshaw, Reading Dr C Harding, Cardiff Dr J Robinson, Liverpool Dr M Salman, Birmingham Dr I Smith, Glasgow Dr S Taylor, Chorley.

REFERENCES