CS b-Bioactive® Scientific Evidence and Clinical Data
CS b-Bioactive®, Bioiberica’s Chondroitin Sulfate, based on several randomized controlled clinical trials, has shown to be effective compared to placebo or anti-inflammatory drugs for pain relief and improvement of functional disability in patients with osteoarthritis. Moreover, it has also demonstrated to slow-down the progression of the disease.
Several data demonstrate that CS b-Bioactive® is absorbed after oral administration and promotes the modification of the clinical picture of osteoarthritis acting as a SYSADOA (symptomatic slow acting drugs for osteoarthritis).
A randomized, multicenter, double blind, double dummy study was designed to assess the clinical efficacy of CS b-Bioactive® in comparison with the non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium (DS). 146 patients with knee osteoarthritis were randomized to be treated with DS during one month, or with CS b-Bioactive® during three months. Both groups received placebo during a follow-up period of 6 months. Clinical efficacy was evaluated by assessing the Lequesne Index, spontaneous pain, pain load, and paracetamol consumption. CS b-Bioactive® was associated with relatively slow variation in the symptoms, later presenting a global efficacy comparable to that of diclofenac with a longer duration of the therapeutic effects. [Morreale P, et al. J Rheumatol 1996;23:1385-91]
Leeb et al. examined the clinical efficacy of CS b-Bioactive® in a meta-analysis of double blind, randomized controlled clinical trials. Seven trials of 372 patients were enrolled into the analysis. CS b-Bioactive® was shown to be significantly superior to placebo with respect to the Lequesne index and pain visual analog scale (VAS). Pooled data showed at least 50% improvement in the study variables in the CS group compared to placebo. The frequencies of side effects were consistently higher in the placebo groups compared to the CS treated patients. [Leeb BF, et al. J Rheumatol 2000;27:205-211]
Recently, a randomized controlled trial including 162 symptomatic patients with radiographic evidence of hand osteoarthritis has demonstrated that CS b-Bioactive® improves hand pain and function significantly more than placebo, showing a good safety profile. [Gabay G, et al. Arthritis Rheum 2011;63(11):3383-3391]
A new randomized, double-blind clinical trial has shown that CS b-Bioactive® treatment attenuates brain response to painful stimulus on the knee in patients with osteoarthritis. 64 patients were treated with CS b-Bioactive® for 4 months, and assessed at baseline and post-treatment by applying painful pressure on the patella surface and on the knee medial interline, during the acquisition of two fMRI sequences of the brain. fMRI has proven its ability to comprehensively map brain activity associated with pain experience. fMRI of patella pain, showed a larger activation reduction in the CS b-Bioactive® group than in placebo in key regions of pain-processing network. These results confirmed the analgesic effect of CS on knee pain, assessed by an objective imaging technique as fMRI. [Monfort J, et al. Ann Rheum Dis 2014;73(Suppl2)]
- ANTI-INFLAMMATORY EFFECT - SYNOVITIS
CS b-Bioactive® has shown to be effective reducing synovitis in patients with knee osteoarthritis. This is important, since synovitis is correlated with the structural damage during disease progression, and its prevalence is about 50% of the population that suffers osteoarthritis. In the NIH-funded GAIT study, treatment with CS b-Bioactive® was associated with a significant decrease in the incidence of joint swelling, effusion or both. [Clegg DO, et al. N Engl J Med 2006,23;354(8):795-808].
These results were confirmed in a pilot study comparing the effect of CS b-Bioactive® on synovitis of osteoarthritic patients vs. acetaminophen. Compared to baseline, CS b-Bioactive® treated patients presented a 25.45% reduction of synovitis (p<0.05) and, specifically, a 61.93% reduction of synovial hypertrophy (p<0.05). No effect was observed in the acetaminophen group over time. Therefore, according to these findings, CS seems to be a more effective therapeutic tool than analgesics for patients with osteoarthritis and synovial inflammation [Monfort J, et al. Osteoarthr Cartil 2012;20:S283-S284].
In addition, CS b-Bioactive® has shown to be effective slowing down the progression of osteoarthritis, i.e. it has demonstrated that has a disease modifying effect.
In the international double-blind STOPP study, 622 patients were randomly assigned to treatment with 800 mg of CS b-Bioactive® (n = 309) or placebo (n = 313) over two years. The osteoarthritic knee joint was examined by x-ray at inclusion visit and after 12, 18 and 24 months, and the minimum joint space in the medial part of the tibio-femoral joint was measured by image digitalization. The primary endpoint of the study was joint space narrowing within two years. In the Intention-to-treat analysis joint space narrowing under treatment with CS b-Bioactive® (0.07 ± 0.03 mm) was significantly lower than in the placebo group (0.31 ± 0.04 mm; p<0.0001). X-ray progression defined as change by ? 0.25 mm was observed in 28% of the patients of the CS b-Bioactive® group and 41% of the patients of the placebo group (p < 0.0005), which corresponds to a relative risk-reduction of 33% (95% confidence interval 16–46%). According to these results, CS b-Bioactive® at long-term therapy may act as a disease-modifying agent in patients with knee osteoarthritis [Kahan A, et al. Arthritis Rheum. 2009;58:524-533].
In a recent study, Wildi et al. have shown the efficacy of CS b-Bioactive® with the aid of magnetic resonance imaging (MRI). In their multi-center, randomized, double-blind, controlled pilot study, 69 patients with knee osteoarthritis were administered 800 mg of CS b-Bioactive®/day or placebo for 6 months, followed by a 6 months open-label phase with CS b-Bioactive® for both groups. Cartilage volume loss and subchondral bone marrow lesions (BML) were assessed at baseline as well as after 6 and 12 months by MRI. The results showed significantly less cartilage volume loss in the CS b-Bioactive® group than in the placebo group at 6 and 12 months, and significantly lower BML scores for CS b-Bioactive® group at 12 months. [Wildi LM, et al. Ann Rheum Dis 2011;70:982-989]. A subgroup of 51 patients participating in this trial was selected to evaluate retrospectively the incidence of total knee replacement (TKR) of the study knee. A total of 13.7% TKRs were performed upon this sub-population in the time frame of 4 years after patient enrolment. More TKRs were performed within the placebo (71%) than the CS b-Bioactive® group (29%), suggesting that CS may delay the progression of the disease and the need of knee replacement [Raynauld JP, et al. Ann Rheum Dis 2012;71(Suppl3):420].
A meta-analysis performed by Hochberg et al. demonstrated that CS b-Bioactive® reduces joint space narrowing in patients with knee osteoarthritis. Evaluation of three studies of two years duration showed that patients randomized to receive orally administered CS b-Bioactive® had a significant reduction in the rate of decline in joint space width of 0.13 mm (0.06–0.19) compared to those randomized to placebo (p = 0.0002) [Hochberg MC, et al. Osteoarthr Cartil 2010;(Suppl 1):S28-31]. Similar results were obtained in a meta-analysis of four studies conducted by Lee et al. [Lee YH, et al. Rheumatol Int. 2010;30:357–363]. These meta-analysis conclude that CS b-Bioactive® has a significant effect of slowing the rate of joint space narrowing in patients with symptomatic radiographic knee osteoarthritis, indicating that the substance may retard degenerative processes affecting knee joint cartilage.
The disease modifying effect has also been studied in finger joints. In two randomized double-blind, placebo-controlled trials, hand osteoarthritis was less progressive in CS b-Bioactive®-treated patients, with fewer patients of the treatment group developing erosive osteoarthritis compared to placebo group [Vergruggen G, et al. Osteoarthr Cartil 1998;6(SupplA):37-38], [Verbruggen G, et al. Clin Rheumatol 2002;21:231–243].
In order to determine the association between the use of CS b-Bioactive® and the need for total knee replacement, an analysis was carried out on data sourced from SIDIAP. This is a public database that includes registers of more than 3400 general doctors, pharmacy invoice data and hospital admissions from Catalonia (North-East Spain), being representative of an 80% of the total population (>5 million of patients). The use of 800 mg/day of CS b-Bioactive® during 6 and 12 months was analyzed to study its association with the need for knee prosthesis. Propensity scores matching were used to minimize the bias due to confounding factors. This method has been shown to replicate randomized controlled trial results using electronic medical records data. Preliminary results show a significant reduction of the risk of knee replacement in patients treated with CS b-Bioactive®, namely 13% after 6 months of treatment and 23% after 12 months of treatment. These results provide new evidence about the structure-modifying effect of the molecule. [Prieto-Alhambra D, et al. Basic Clin Pharmacol Toxicol 2013;113(Suppl.2)CP51:34]
- THE COMBINATION OF CS B-BIOACTIVE® AND GLUCOSAMINE
The combination is based on the combination of two active ingredients: CS b-Bioactive®, a polysaccharide group of glycosaminoglycans, and glucosamine (as glucosamine hydrochloride), a natural aminomonosaccharide.
It has been proved that the combination promotes formation of new cartilage in vitro by stimulating the synthesis of collagen and proteoglycans; is synergistic effect when both are used in combination. [Calamia V, et al. Arthritis Research & Therapy 2010, 12:R138]
The combination is indicated for the treatment of osteoarthritis of the knee in patients with moderate to severe pain.
Several clinical trials have also demonstrated the effectiveness of this combination in the treatment of osteoarthritis of the knee.
The most important are the GAIT study (Glucosamine / Chondroitin Arthritis Intervention Trial) conducted by the National Institute of Health (NIH) in the US published in the New England Journal of Medicine, and more recently the MOVES study (Multicentre Osteoarthritis InterVEntion trial with Sysadoa) that has been published in the The journal Annals of the Rheumatic Diseases (the highest impact journal in rheumatology worldwide with an impact factor of 9.270) showing that the combination of these two drugs reduces pain, functional disability, joint stiffness, swelling and effusion in knee osteoarthritis.
The GAIT study (Glucosamine and Chondroitin Arthritis Intervention Trial) was designed to evaluate the efficacy and safety of glucosamine and CS b-Bioactive® administered in combination and separately compared to placebo and an active comparator in 1583 patients with KOA, randomized to 1 of 5 treatment groups during 24 weeks.
The primary outcome assessment was the 20% reduction in the score of the WOMAC pain from baseline to week 24. In analyzing the results of all randomized patients in the study with respect to the primary efficacy endpoint it was noted that the response rate to the combination treatment of glucosamine plus CS b-Bioactive® tended to be higher than in the placebo group (p = 0.09).
In analyzing the results for the main parameter depending on the severity of disease at baseline, it was observed in those patients with more severe pain according to the WOMAC scale (moderate to severe), the percentage of positive response to treatment. It was 54.3% in the placebo group, 61.4% for CS b-Bioactive®, 65.7% in the glucosamine hydrochloride, 69.4% for celecoxib, and 79.2% in the group receiving glucosamine hydrochloride and CS b-Bioactive® together (p = 0.002).
In analyzing the response OMERACT-OARSI a statistically significant difference between the results of celecoxib group (p = 0.007) and treated with glucosamine plus chondroitin (p = 0.02) compared with the results of the placebo group was observed.
In patients who at baseline had a degree of moderate to severe pain (n = 354, 22% of all patients), a statistically significant difference between the group treated with glucosamine plus chondroitin group versus placebo group was observed for main parameter of efficacy evaluation as well as for most secondary parameters.
Moreover, no differences were observed regarding the safety of treatments. Adverse reactions were mild and evenly distributed among the groups.
[Clegg DO. et al. New England Journal of Medicine 2006;354 (8):795-808.]
MOVES is a multicenter, randomized, parallel-group, double-blind, controlled clinical trial, sponsored by Bioibérica, in which 606 patients with primary knee osteoarthritis and moderate to severe pain were recruited from 42 centers in Spain, Germany, France and Poland. A multidisciplinary team of investigators including rheumatologists, orthopaedists and primary care physicians participated in the study.
Designed according to good clinical practice guidelines, current legislation and regulations for drug research in osteoarthritis, the study also included a Scientific Committee formed by internationally renowned specialists for its supervision.
The primary objective was to show that the combination of CS b-Bioactive® plus glucosamine is comparable in efficacy to celecoxib in the treatment of moderate to severe pain in patients with knee osteoarthritis. Patients were given pharmaceutical grade CS b-Bioactive® (1200 mg/day) and glucosamine hydrochloride (1500 mg/ day) or 200 mg of celecoxib (anti-inflammatory drug) daily for six months.
The main conclusion of the study is that the combination of chondroitin sulfate plus glucosamine has comparable efficacy to the anti-inflammatory drug celecoxib after six months of treatment in severe osteoarthritis. Specifically, it was seen that the combination of these two drugs caused a clinically relevant reduction in pain, functional disability, stiffness, swelling and joint effusion, improving all the parameters studied:
- Reduction in pain: 50.1%.
- Reduction in functional disability: 45.5%.
- Reduction in stiffness: 46.9%.
- Reduction in swelling: 53%.
- Reduction in joint effusion: 56%.
This study confirms the efficacy of the combination of pharmaceutical grade-chondroitin sulfate and glucosamine in the long term and suggests that, considering its excellent safety profile, it may be a good alternative for patients with cardiovascular or gastrointestinal problems, for whom chronic treatment with NSAIDs cannot be recommended
[Hochberg MC, et al. Ann Rheum Dis. 2015 Jan 14. pii: annrheumdis-2014-206792. [Epub ahead of print]
The results confirmed those obtained in the GAIT study by Clegg's group in 2006 and published in the New England Journal of Medicine, where the combination was superior to placebo in patients with moderate to severe pain.
These results provide final confirmation of the efficacy and safety of the combination of CS b-Bioactive® plus glucosamine for the treatment of knee osteoarthritis in patients with moderate to severe pain.
Besides clinical results, CS b-Bioactive® effects have been investigated in many in vitro and in vivo studies. In their review, J. Monfort et al. summarized several mechanisms of action, such as reducing pro-inflammatory factors, modifying the cellular death process and improving the anabolism/catabolism balance of cartilage matrix. CS b-Bioactive® has also proven to have positive effect on some of the pathological processes involving the synovial tissue and subchondral bone. [Monfort J, et al. Ann Rheum Dis 2008;67:735-740]