Treating Osteoarthritis of the Knee with a Homeopathic Preparation

Results of a Randomized, Controlled, Clinical Trial

in Comparison to Hyaluronic Acid

ABSTRACT

This multicentric, randomized, singleblind, controlled study compared the efficacy and tolerance of Zeel® compositum and Hyalart brand of hyaluronic acid in the treatment of patients wich osteoarthritis of the knee. Over the five week course of the study, each patient received either 10 injections of Zeel compositum (two 2 ml intra-articular injections per week) or 5 injections of Hyalartt (one 2 ml intrarticular injection per week). Key parameters were the intensity of pain in the arthritic joint during active movement, and the glnbal assessment nf tolerance, both as reported by the patient. Out of a total of 121 patients, the data on 114 (2 treatment groups of 57 patients each) were suitable for stacistical analysis. Zeel® compositum and Hyalarr® proved to be equally efficacious in treating patients wich either milder or more severe pain. Undesirable incidents occurred in 6 patients receiving Zeel® compositum and in 13 of those receiving Hyalart®.In both treatment groups, the most fre- quencly reported side effects were signs of local inflammation or irritation after the intra-articular injections.

INTRODUCTION

Osreoarthritis of the knee is a painful, degenerative joint disease that occurs in approximately 10% of all individuals over the age of 65 and in approximately 2% of the total adult population. At present there is no effective means of treating the cause. Depending on the stage of the illness, however, good therapeutic results can be achieved with non-steroidal anti-inflammatories, corticosteroids, hyaluronic acid, homeopathic remedies, and organ lysates. Age-related cartilage degeneration is a crucial Factor in the development of arthritis, since all bradytrophic tissues due in large part ro the fact that they are poorly supplied with blood vessels are subject to regressive aging processes with increasing loss of elasticity. Because of the chronic and generally progressive nature of the disease,the best possible ratio of therapeutic efficacy to risk of undesirable side effects is a prime consideration in the selection of pharmaceutical cherapy.

The goal of this multicenter, randomized, controlled, singleblind, clinical equivalence study was to prove the therapeutic efficacy of Zeel® compositum in treating knee arthritis. According to the symptom pictures of its individual ingre- dients (Rhus toxicodendron, Arnica montana, Solanum dulcamara, Sanguinaria canadensis, and Sulphur), Zeel® compositum, a combinacion homeopathic preparation, is appropriate for effectively alleviating arthricic symptonms with little risk. Hyalart® brand of hyaluronic acid (a polysaccharide and a natural component of synovial fluid) was selected as the comparative drug. Controlled studies have demonstrated the therapeutic efficacy of Hyalart in treating arthritis. Because Hyalart®is visibly more viscous than Zeel compositum and because the manufacturer recommends less frequent applications than are recommended for Zeel® compositum, it was not possible to conduct this trial on a strict double-blind basis, so it was conducted as a single-blind study. Additional injections of a placebo to equalize application frequencies berween the two drugs were rejected as unethical.

Editor’s note: The formula of the complex bomeopathic preparation featured in this study, Zeel® compositum, is not avail- able in the U.S. In the U.S. Zeel is distributed ointment, tablets, and oral vials, all of which contain the same ingredients of Zeel® compositum,plus others.

METHODOLOGY

Between July 1994 and February 1995,12 orthopedic physicians in active practice in Germany and Austria accepted a total of 121 patients of boch sexes with primary osteoarthritis of the knee into this clinical trial.

Criteria for inclusion were:

presence of primary (idiopathic) arthritis, verified by:

a typical X-ray (medial narrowing of the joint cavity, peripheral osteo- phyte development, compact ossifi- cation of subchondral bone)

chronic pain in one or both knee joints for at least three months, with no sign of acure inflammation

Written statement of patient consent. Criteria for exclusion were:

• age <35 or>85 years
• arthritis resulting from prior deforma- tions, injuries, or metabolic causes (secondary arthritis)
• other ailments with symptoms similar to arthricis of the knece, such as archri- tis of the hip, varicosis, bone and muscle disorders, rheumatoid archritis
• signs of acute inflammation (acure active arthritis)
• non-ambulatory or bedridden patients ·patients who stated their intention to change their level of physical activity during the study
• probable surgical treatment of the arthritic joint in the near furure
• intra-articular corticosteroid treatment of the arthricic joint within the past 2 months
• low-grade pain (<75 mm on the 100 mm visual analog scale)
• a history of allergic reactions to Zeel® compositum or Hyalart®
• serious liver or kidlney disease
• long-term treatment wih immuno- suppressives during the last month
• ongoing concomitant therapy with analgesics/anti-inflammatories

Random assignment to one of the two

treatment groups was accomplished with the help of a special EDP program (Rancode,IDV), which also sorted the patients into subgroups on the basis of pain intensity during active movement of the arthritic joint. Less severe pain was defined as 25-60 mm on the VAS-SB, severe pain as 61-100 mm. Treatment proceeded according to the manufactur- ers’ recommendations. Over the five- week course f the study, each patient received eicher 10 injections of Zeele compositum (two 2 ml intra-articular injections per week) or 5 injections of Hyalart® (one 2 ml intra-articular injection per week). To ensure that the parients did not know which medication they were receiving,the physicians were requested to prepare and administer the injections in such a way that the patients could not see the packaging and to make sure that participants in the study were not in the same room at the same time.

Primary parameters were:

• subjective experience of pain in the arthritic knee joint during active movement, measured on a standard- ized visual analog scale(VAS) 100 mm in length (0 mm =pain-free,100 mm =worst pain to date)
• the patients’ final assessment of toler- ance ar the end of five weeks of treat- ment,measured on the 100 mm VAS (0 =extremely poorly tolerated, 100=extremely well tolerated)

Secondary parameters were:

• pain in the arthritic knee joint during the night,measured on the 100 mm VAS (0 mm = pain-free,100 mm= worst pain to dare)
• duration of moming stiffness (in minutes)
• maximum distancc the patient was capable of wallcing (as a functional criterion for assessing the severity of the arthritis)
• time required (in seconds) to walk up and down a standard series (one flight) of stairs (relative change)
• final assessment of efficacy by physician and patienc ac the end of five weeks of rreatment,measured on the 100 mm VAS (0 mm = no improvement,100 mm =extreme improvement)
• final assessment of tolerance by physician and patient ar the end of five weeks of treatment,measured on che 100 mm VAS (0 mm = cxtremely poorly tolerated,100=extremely well tolerated)
• drop-out rate in both groups resulting from inadequate product efficacy
• reporting of undesired side effects dur- ing treatment(recorded weekly)

All of the compiled data were recorded on standardized questionnaires. The study was conducted in accordance witl the European Union’s Good Clinical Practice guidelines and German and Austrian national laws.

Data Preparation and Statistical Analysis

A two-tailed Wilcoxon’s rank-sum test (=0.05 and =0.20) was used to analyze the differences between the treatment groups with regard to efficacy and tolerance. In calculating required sample size, the efficacy or tolerance of the two forms of treatment was assumed to be therapeutically equivalent if the absolute dif- ference in therapeutic efficacy (defined as reduction in pain during active move- ment after five weeks of treatment, as measured on the VAS) or tolerance (defined as final assessment after five weeks of treatment, as measured on the VAS) between Zeel® compositum and Hyalart® was no greater than 33%. Minimum group size was calculated ar nl=n2=51, without including dropouts amounting to approximarely 10%. Comparabilicy of treatment groups with regard to baseline characteristics was cested by means of either the Wilcoxon test (pain during active movement or during the night when the study began) or the chi-square test.(number of affected knee joints); the difference in frequency of side effects was tesred by means of the chi-square tesr. Taking into account the patierics’ subjective experierce of pain intensity during active movcinent when the study began (as per VAS-SB), therapeutic efficacy and tolerance in each trearment group were compared by means of either covariance analysis or the Wilcoxon test (patiencs with more or less severe pain were assigned to subgroups). A descriptive statistical analysis of baseline characteristics and all secondary parameters was performed wich a chosen level of significance of =0.05.

Results

In accordance wich the intent-to-treat principle, all available analyzable dara on 114 parients, including dropouts and protocol violators, were used in analyzing efficacy and tolerance. Of a total of 121 randomly selected patients, three did not meer the minimum pain requirement (at least 25 mm on the VAS-SB). Four patients who had been mistakenly treated with both products (in different knees)were studied only with respect to undesired incidents and excluded from the analysis of efficacy, resulting in 114 assessable patients (Table 1). The two treacment groups (n=57) were comparable both with regard to all baseline characteristics (age, gender, height and weight, concomitant illnesses and medications) and with regard to anamnestic data on the artchricis (duration of illness, intensity of pain,and morning stiffness ar the inception of the study, Table 2). In accordance with the exclusion criteria, concomitant use of analgesics and antinflammatories was prohibited. Protocol violations on this count occurred in one patient receiving Zeel® compositum and in three receiving Hyalart®. Other protocol violations were premature termina- tion of therapy for non-medical reasons (one patient), failure to adhere to trear- ment schedule (one parient),and prema- ture termination of therapy because of inadequate improvement (two patients receiving Zeel® compositum and one receiving Hyalart®).

a) Therapeutic Efficacy

The patients’ arthritic symptoms clearly decreased both under treatment with Zeel® compositum and under treatment with Hyalart.® In boch treatment groups there was a roughly linear decrease in pain due to active movement of the arthricic joint.This decrease aver- aged 36 mm for Zeel® compositum (from 67 mm to 31 mm) and 37 mm for Hyalart®(from 63 mm to 26 mm).The reduction in nocturnal joint pain fol- lowed a similar pattern, with a linear decrease during treatment (from 33 mm ro 9 mra for Zeel® compositum and from 35″mm to 7 mm for Hyalart). Duration of morning stiffness in the arthricic joint was reduced from 5 min- utes to 2 minutes for Zeel® compositum and to 1 minute for Hyalare®(Table 3). According to analysis of the difference in therapeutic efficacy berween Zeel® compositum and Hyalart® by means of a two-tailed Wilcoxon’s rank-sum test, these two forms of treatment can be seen as therapeutically equivalent (pain during movement: p = 0.4298; pain during the night:p=0.3077;duration of morning stiffness:p=0.9211).An increase in functional ability was associated with pain reduction during treatment.After five weeks of treatment, the percentage of patients who were able to walk more than 1 km increased from 55% to 67% for Zeel® compositum and from 68% to 79% for Hyalart®. In 3 out of 5 pacients in the Zeel® compositum group and 1 out of 3 patients in the Hyalart® group, symptoms improved so much that they were able to do without the cane they had needed when treatment began.The time needed to climb one flight of stairs also decreased by an average of 18% for patients treated with Zeel compositum and by an average of 9% for those treated with Hyalart®.

The results of the final assessment confirmed the comparable therapeutic efficacy of the two products (Table 4). Noticeable improvement in symptoms was reported for 87.3% of the patients treated with Zeel® compositum and 93.0% of those treared wich Hyalart®.In boch treatment groups, The patients’ subjective assessment was slighdy more favorable than that of the physicians who treated them. VAS values assigned by patients were 2 mm greater for Zeel® compositum and 4 mm greater for Hyalart® than the values assigned by the physicians.In both treatment groups, co-variance analysis reveals that the suc- cess of treatment depends significanly on pain intensity at the inception of the study (p =0.0060).When initial pain was considered as a co-variable, no significant difference between Zeel® compositum and Hyalart which regard to therapeutic success could be derermined (p =0.7555). This means that the effica- cy of Zeel® compositum must be seen as equivalent to that of Hyalart® boch in patients witch less severe pain (25 to 60 mm as per VAS) and in cases of more severe pain (61 to 100 mm as per VAS). The fundamental character of the results is not changed if, instead of conducting che assessment according to the intent- to-treat principle, the analysis comprises only the data on the 103 patients who completed the study according to plan.

b) Tolerance

In terms of tolerance, the trend favored Zeel® compositum.A total of 6 patients(11%)treated wich Zeel° compositum and 13 patients (23%) treated with Hyalart® developed undesirable side effects (chi-square test: p=0.079). While receiving twice-weekly injections of Zeel® compositum 3 patients developed low-grade joint effusions that had tapped. Renewed applications of Zeel® compositum induced new effu- sions in 2 of these 3 patients, and as a result treatment was prematurely termi- nated(after 9 injections) in one case. The two other patients completed the study according to plan in spite of intermittent joint effusions. One patient reported a temporary sensation of heaviness in the leg after the first injection of Zeel® composicum Another Zeel® compositum patient terminated treatment prematurely after two weeks because of headaches and insomnia. Two patients from the Zeel® compositum group and 9 from the Hyalart group complained of increased pain in the knee joint after the intra-articular injections; the pain lasted from 3 to 7 days. One patient from the Hyalart® group had to terminate therapy after the first injection because of an allergic reaction (pain, swelling and redness from the knee to the mid thigh). In contrast to Zeel® compositum, no joint effusions were observed in the Hyalart group, but one patient complained of a hot burning sensation in the knee joint that appeared 24 hours after cach of the first two Hyalart®injections and Iasted approximately 24 hours. Another Hyalart® patient reported a mild sensation of pressure and fullness in the joint for about 15 minutes after the third injection. In one patient, nausea and repeated vertigo were experienced after intra-articular applications of Hyalart®. The physicians of two additional patients from the Hyalart® group reported that side effects had appeared but they failed to specify further. In all of these cases, the side effects subsided without medication during the course of the study.

The final assessment of tolerance (as per VAS) upon conclusion of treatment indicated very good tolerance of both ested products wichout significant differences berween the two treatment groups. According to the Wilcoxon tesc: patients’ assessment of tolerance p=0.1213; physicians’ assessment p=0.7287; in the great majority of cases, the physicians’ assessments coincided with those of their patients. (The difference between physician and pacient assessments was 2mm for both treatment groups; Table 4).

Discussion

Many studies restrict themselves to statistically substantiating improvement over the course of therapy in comparison to the starting point (pre-post comparison). However, since symptom patterns do not remain constant over the course of an illness, patients generally tend to see a physician only when the pain has already increased. As a result, there is a high degree of probability that the pain will revert spontaneously to its previous level. This is also known as ‘regression to the mean.” Thus analyses based on pre-post comparisons are not always reliable because, taken by themselves, they cannot separate spontaneous improvement from stricly therapeutic effects. A different route was chosen in the context of this present study, namely comparison of improvement in the two treatment groups at the end of a predefined course of therapy (post-post comparison). The definition of therapeutic equivalence that was used here was not purely statistical but primarily clinical, namely a certain range within which the improvement in one group would be considered equivalent to that in the other. In this study, equivalence was assumed if the maximum difference in decrease in pain between the two groups was no more than 33% (pain at inception of study= 100%). In fact, this investigation showed the difference to be only five percentage points (59% for Hyalart vs. 54% for Zeel® compositum),meaning thac wich regard to therapeutic efficacy, Zeel”compositum and Hyalart” are equivalent. There is a linear correlation between improvemenc in pain and duration of treatment. The criterion ‘pain during movement’ yields a coefficient of r=- 0.80 while the criterion ‘pain during the night’ yields a coefficient of=-0.69. A similarly linear relationship was also found in a recently compleced prospective study in which 446 patients wich knee arthritis were treated with Zeel® compositum.

In addition, it is especially interesting to note that the therapeutic efficacy of Zeel® compositum was found to be equivalent to that of Hyalart® not only in the subgroup wich less severe pain but also in the group which more severe pain. Analysis of the assessments of functional capacity(climbing stairs, distance patients were able to walk) that also contributed to improving the patients’ quality of life.

In this trial, a trend in Favor of Zeel® compositum was noted with regard to tolerance. Although Zeel® compositum was injected twice as often as Hyalart and the probabilicy of complications was therefore greater, Zeel® compositum had only half as many undesired incidents. While one patient terminated treatment prematurely because of a suspected allergic reaction after being injected with Hyalart®, no allergic reactions of any kind appeared in the Zeele composirum group.

The results of this clinical study and of the prospective study of Zeel® compositum confirm the favorable empirical reports of this homeopachic preparation that have accumulated over the years. A 1992 prospective study of Zeel® P (which has 10 more ingredients than Zeel® compositum) involved 1845 patients with osteoarthritis of the knee. That study also documented a significant linear decrease in pain symptoms. Like Zeelr compositum, Zeel® P was also found to be therapeutically effective for mild, moderate, and severe symptoms, wich 93.1% of the patients rating the therapeutic success as positive, i.e. satisfactory to very good.