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Effective in the Treatment of Pain Associated with Knee and Hip Osteoarthritis: Results from a Six Center,Open Label German Clinical Study

NEM®Brand Eggshell Membrane

Objective: NEM® brand eggshell membrane is a novel dietary supplement ingredient that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joints. A six-center, open-label clinical study was conducted to evaluate the efficacy and safety of NEM® as a treatment for pain and inflexibility associated with osteoarthritis of the knee and/or hip in a European population. Methods: Forty-four subjects received oral NEM® 500 mg once daily for eight weeks. The primary outcome of the measure was to evaluate the mean effectiveness of NEM® in relieving general pain associated with moderate osteoarthritis of the knee and/or hip at 10,30 and 60 days utilizing a 10-question abbreviated questionnaire based on the WOMAC osteoarthritis questionnaire. Results: Supplementation with NEM® produced a significant treatment response from baseline at 10 days (Q1-6 and Q9) (8.6% to 18.1% improvement) and at 30 and 60 days for all nine pain-related questions evaluated (22.4% to 35.6% improvement) and at 30 and 60 days for stiffness (Q10)(27.4% to 29.3% improvement). In a Patient’s Global Assessment, greater than 59% of patients rated the efficacy of NEM® as good or very good following 60 days of supplementation. Physicians also rated the treatment effective in subjects, with greater than 75% having moderate or significant improvement from baseline after 60 days. There were no serious adverse events reported during the study and the treatment was reported to be well tolerated. Conclusions: Supplementation with NEM® significantly reduced pain, both rapidly (10 days) and continuously (60 days) demonstrating that it is a safe and effective therapeutic option for the treatment of pain associated with osteoarthritis of the knee and/or hip. Results from previous clinical studies on NEM® can likely be extended to the broader European population.

Keywords: Knee, Hip, Osteoarthritis, Eggshell membrane, NEM,
Dietary supplement, Glycosaminoglycans
Estimates of the prevalence of osteoarthritis (OA) in European populations vary widely, however a recent study [1] from a region in Spain places the prevalence of knee OA at 12.2% and that of hip OA at 7.4%. The pain associated with these maladies can be quite debilitating and few treatment options exist outside of easing symptoms. This usually involves the use of analgesics (i.e. acetaminophen, oxycodone,
propoxyphene) or non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. ibuprofen, diclofenac, celecoxib), alone or in combination. Most of these treatments have shown limited effectiveness in randomized
controlled clinical trials (RCTs) [2-5] or are known to have significant and sometimes severe side effects. NEM® brand eggshell membrane has previously demonstrated good efficacy in relieving pain and stiffness
associated with OA of the knee in an RCT [6] and has shown similar efficacy in limited trials for other affected joints [7]. Eggshell membrane is primarily composed of fibrous proteins such as Collagen Type I [8]. However, eggshell membranes have also been shown to contain other bioactive components, namely glycosaminoglycans (i.e. dermatan sulfate, chondroitin sulfate and hyaluronic acid, and keratan sulfate) [9-11]. A number of these
constituents have been shown previously to be beneficial in the treatment of OA [12,13]. Eggshell membrane itself has been shown both in vitro [14] and in vivo [15] to reduce various pro-inflammatory

cytokines, including interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-a), two primary mediators of inflammation. The U.S. company, ESM Technologies, LLC (Carthage, MO USA), has developed methods to efficiently and effectively separate the eggshell membrane from eggshells on a commercial metric-ton scale. The isolated membrane is then partially hydrolyzed using a proprietary process and dry-blended
to produce NEM® brand eggshell membrane. Compositional analysis of NEM® conducted by the manufacturer has identified a high content of protein and moderate quantities of glucosamine (up to 1% by dry
weight), chondroitin sulfate (up to 1%), hyaluronic acid (up to 2%), and collagen (Type I, up to 5%).
The multi-center trial reported herein was designed to evaluate the acceptability of this natural arthritis treatment with European orthopedic surgeons and patients. The success of this trial would also *Corresponding author: Dr. Ulrich Danesch, Weber & Weber GmbH & Co. KG, Biological Medicinal Products, Herrschinger Str. 33, D-82266 Inning/Ammersee, Germany, Tel: +49-081439270; E-mail: Danesch@weber-weber.net Received January 24, 2014; Accepted July 09, 2014; Published July 20, 2014
Citation: Danesch U, Seybold M, Rittinghausen R, Treibel W, Bitterlich N (2014) NEM® Brand Eggshell Membrane Effective in the Treatment of Pain Associated with Knee and Hip Osteoarthritis: Results from a Six

of Pain Associated with Knee and Hip Osteoarthritis: Results from a Six Center, Open Label German Clinical Study. J Arthritis 3: 136.

Citation: Danesch U, Seybold M, Rittinghausen R, Treibel W, Bitterlich N (2014) NEM® Brand Eggshell Membrane Effective in the Treatment

validate the extension of the body of clinical evidence for NEM® from the United States to a European population. Therefore, a 2-month an open-label study was conducted at six different clinical sites throughout
Germany to evaluate the efficacy and tolerability of NEM® for the relief of the pain and discomfort associated with osteoarthritis of the knee and/or hip. Materials and Methods Study design The study was conducted according to a prospective, multi-center, open-label design and was conducted in Germany in accordance with
the International Conference on Harmonization guideline for the principles of Good Clinical Practice (ICH E6) and the Declaration of Helsinki to ensure the protection of human subjects. Patients provided
their written informed consent to participate. Neither the clinical investigators nor the patients were blinded to treatment (open-label design). Treatment consisted once daily orally of Atrosia® (Weber and Weber, GmbH and Co. KG, Germany) providing 500 mg of NEM® in vegetarian capsules that were stored in closed containers at ambient temperature. Clinic visits were scheduled for subjects at study initiation and at 60 days following the onset of treatment. Treatment compliance was checked at clinic visits by patient interview and by counting the number of unused doses of the study medications. Analgesics (i.e. acetaminophen) were allowed for rescue pain relief. However, subjects recorded the time and amount of analgesic taken in patient diaries so
that overall analgesic use could be evaluated as part of the study. Patients All subjects 18 years of age or older who were seeking relief of mild to moderate pain due to osteoarthritis of the knee and/or hip were considered for enrollment in the study. In order to be eligible, subjects must have had moderate persistent pain in the knee and/or hip associated with osteoarthritis and must have had baseline scores within the range of 4-7 on the first three questions dealing with joint pain. Subjects that were currently taking analgesic medications or
NSAIDs every day, currently taking glucosamine, chondroitin sulfate, MSM or collagen was ineligible to participate in the study. Patients were excluded if they were currently receiving remission-inducing drugs such as methotrexate or immunosuppressive medications or had received them within the past 3 months. Other exclusionary criteria were: a known allergy to eggs or egg products, or pregnant or breastfeeding women. Subjects participating in any other research study involving an investigational product (drug, device, or biologic) or a new application of an approved product, within 30 days of screening were also excluded from participating in the trials. Treatment response The primary outcome measure of this study was to evaluate the
mean effectiveness of NEM® in relieving general pain associated with moderate osteoarthritis of the knee and/or hip (Questions 1-9). Additional outcome measures were to evaluate general stiffness
(Question 10) and analgesic use during the study. The primary treatment response endpoints were the 10-, 30-, and 60-day patient assessments utilizing a 10-question ‘Short Form’ questionnaire derived from the Western Ontario and McMasters Universities Osteoarthritis Index questionnaire (WOMAC), which has some precedence [16,17]. Each question included a zero to 10 analog Likert scales, with zero equating to no pain (or no stiffness) and 10 equating to most severe pain (or most severe stiffness). Patients were asked to mark a number corresponding to the perceived pain (or stiffness) from the affected

treatment joint(s). Endpoints were then compared to pretreatment
assessments. At the conclusion of the study, subjects were asked
to provide a Patient’s Global Assessment of treatment efficacy (4
categories-very good/good/moderate/poor) and tolerability (same
4 categories). Clinical investigators were also asked to provide a
Physician’s Global Assessment of treatment efficacy (5 categoriessymptom-free/significant improvement/moderate improvement/
Adverse events
A secondary objective of this study was to evaluate tolerability and
any adverse reactions associated with supplementation with NEM®.
The subject’s self-assessment diaries were reviewed and any discomfort
or other adverse events were recorded and reported in accordance
with applicable ICH Guidelines. Adverse events and serious adverse
events were assessed by the clinical investigator at each study visit and
followed until resolution, as necessary. Serious adverse events were
required to be reported to the clinical monitor immediately.
Statistical analysis
As this was an open-label study, a simple single group sample size
estimate [18] was performed for statistical power determination for a
continuous variable. In previous trials with NEM® [6,7], the standard
deviation for the study subjects for pain (within the inclusion range
of this study) averaged 34.6%. We hoped to be able to detect a 1.5
point difference from baseline within the 10-point Likert scale. Thus
a minimum of 43 subjects would need to be enrolled to have a 95%
likelihood of detecting the expected improvement with a statistical
power of 80%. Comparisons of demographic data from the six clinical
sites were made with a Kruskal-Wallis test for multiple independent
samples at baseline. Statistical significance was accepted at p<0.05.
Post-baseline statistical analyses were done as repeated measures
Analysis of Variance (rm-ANOVA) with a Greenhouse-Geisser
correction. Items found to have statistical significance with rmANOVA were then compared using a Wilcoxon test for dependent
samples. Statistical significance was accepted at p<0.05. Analysis of the
primary outcome measure (the change from baseline in general pain
levels) was conducted in the per protocol population. SPSS Statistics
V19.0 was used for all statistical analyses [19].
Patient recruitment began in March 2012 at six clinical sites in
Germany and the final follow-up was conducted in July 2012. A total
of forty-four subjects between the ages of 32 and 95 were enrolled with
Age, yrs 67.1 ± 14.0 Sex Male (%) 17 (39) Female (%) 27 (61) Height, cm 170.2 ± 9.5
Weight, kg 74.2 ± 13.1 Body-mass Index 25.5 ± 4.1
Affected Joint
Knee (l,r,bilateral) 39 (28,27,16) Hip (l,r,bilateral) 14 (11,10,7)
Ankle (l,r,bilateral) 3 (2,2,1)
*Except where indicated otherwise, values are reported as mean ± standard
deviation (SD) (n=44). BMI was determined as weight in kilograms divided by
height in meters squared.
Table 1: Patient Demographics*