|Year : 2022 | Volume
| Issue : 1 | Page : 44-51
A randomized, open-label, multicentered parallel-group clinical study to evaluate the efficacy and safety of Joint Core™ compared to Jointace DN™ in osteoarthritis patients
Ramesh Kannan1, Sriram Bakthavatchalam2, Sakthibalan Murugesan3, B Aravinda Kumar4, Bijoy Deb5, Chandramohan Marimuthu6, Priya Rajendran7
1 Department of Pharmacology, Government Medical College, Vellore, Tamil Nadu, India
2 Department of Orthopedics, Government Medical College, Vellore, Tamil Nadu, India
3 Department of Pharmacology, Sri Venkateswaraa Medical College Hospital and Research Centre, Puducherry, India
4 Department of Pharmacology, Pondicherry Institute of Medical Sciences, Puducherry, India
5 Medical Advisor, Ki3, Clinical Research Organisation, Chrompet, Chennai, Tamil Nadu, India
6 Managing Director, Microcore Research Lab India Pvt. Ltd., Erode, Tamil Nadu, India
7 Executive Director, Microcore Research Lab India Pvt. Ltd., Erode, Tamil Nadu, India
|Date of Submission||24-Mar-2022|
|Date of Decision||29-Apr-2022|
|Date of Acceptance||29-Apr-2022|
|Date of Web Publication||8-Jul-2022|
Dr. B Aravinda Kumar
Department of Pharmacology, Pondicherry Institute of Medical Sciences, Puducherry - 605 014
Source of Support: None, Conflict of Interest: None
Background: Osteoarthritis (OA) is one of the most common musculoskeletal diseases worldwide, with pain, joint stiffness, fatigue associated with disability, and loss of physical activity. There is a need for an effective and safer alternative medication for the management of OA knee in elderly patients as the current medications possess severe risks to the patient compromising the quality of life.
Methodology: The study design and setting were phase 3, randomized, open-label, multicentered, active-controlled parallel-group interventional trial conducted at secondary care centers in Puducherry. Fifty patients (50) patients with OA knee were enrolled as per study criteria and randomized to receive Joint Core™ and Jointace DN™ for 12 weeks. The outcomes were assessed using various pain scales and subscales, Short-Form Health-12 (SF-12) questionnaire, and inflammatory markers. The data obtained at baseline and weeks 4, 8, and 12 were compared and statistically analyzed.
Results: Joint Core™ showed continuous reduction in the Visual Analog Scale pain scores at 4, 8, and 12 weeks and improvement in Western Ontario and McMaster Universities OA Index subscale and pain global assessment scales and good response rate in the Outcome Measures for Rheumatology Committee and OA Research Society International Standing Committee for Clinical Trials Response Criteria Initiative scores proving it to be efficacious in the treatment of OA knee compared to Jointace DN™. The safety assessed showed that Joint Core™ produces minimal gastrointestinal side effects and does not affect any organs as assessed by the laboratory parameters.
Conclusion: Joint Core™ is effective and safe in the treatment of OA knee when compared to its comparator Jointace DN™. Joint Core™ can be an alternative treatment option in the patients with OA knee who are intolerant to diacerein-based combinations available to treat OA.
Keywords: Anti-inflammatory agents, curcumin, eggshell membrane Boswellia serrata, osteoarthritis knee
|How to cite this article:|
Kannan R, Bakthavatchalam S, Murugesan S, Kumar B A, Deb B, Marimuthu C, Rajendran P. A randomized, open-label, multicentered parallel-group clinical study to evaluate the efficacy and safety of Joint Core™ compared to Jointace DN™ in osteoarthritis patients. J Curr Res Sci Med 2022;8:44-51
|How to cite this URL:|
Kannan R, Bakthavatchalam S, Murugesan S, Kumar B A, Deb B, Marimuthu C, Rajendran P. A randomized, open-label, multicentered parallel-group clinical study to evaluate the efficacy and safety of Joint Core™ compared to Jointace DN™ in osteoarthritis patients. J Curr Res Sci Med [serial online] 2022 [cited 2022 Aug 16];8:44-51. Available from: https://www.jcrsmed.org/text.asp?2022/8/1/44/350135
| Introduction|| |
Osteoarthritis (OA) of the knee is a highly prevalent condition among older adults and it is the fourth leading cause of disability. Functional limitations and restriction of activities gradually reduce the physical, psychological, and social well-being of the elderly population with OA knee leading to poor quality of life. Studies have shown that patients with OA knee experienced worst quality of life, especially for items related to poor general health, pain, and activity limitation. The financial burden on patients, their families, and health-care systems while managing OA knee is very high.
At present, recommendations for the management of OA knee comprise exercise, weight management, and pain medications with the goals to improve physical function and slow the progression of the disease. The first-line pharmacological therapy for OA knee consists of topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs) which only provide symptomatic pain relief and it is associated with serious risk after prolonged use. The elderly population with OA knee on chronic use of NSAIDs are at enhanced risk of gastrointestinal bleeding, hypertension, congestive heart failure, and renal insufficiency. Hence, there is a need for an effective and safer alternative medication for the management of OA knee in elderly patients.
Glucosamine, chondroitin sulfate, methylsulfonylmethane (MSM), and diacerein, available alone or in various combinations, are some of the widely marketed dietary supplements to treat joint pains due to OA. They are considered supplementary to analgesics and NSAIDs. Clinical studies, namely (Glucosamine/Chondroitin Arthritis Intervention) trial and GUIDE trial, have shown promise that these supplements had shown improvement in patients with OA knee.,
Joint Core™ is one such novel product containing Natural Eggshell Membrane (NEM) (Muttai Jow Complex™) 400 mg + Akbacore™ Boswellia serrata (30% Akba) 90 mg + Cumincore™ (curcumin extract 96%) 10 mg. NEM is a naturally rich source of combined proteins, elastin, collagen type 1, glucosamine, chondroitin, dermatan sulfate, and hyaluronic acid. It is a novel dietary supplement that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joint and connective tissues. NEM's high content of bioactive components, as well as properties of moisture retention and biodegradability, suggests that it has potential use for clinical applications. Boswellia serrata extract has gained much attention as a potent anti-inflammatory, anti-arthritic, and analgesic agent. 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) is the most active component of Boswellia extract and has been demonstrated to be a potent inhibitor of 5-lipoxygenase, which is a key enzyme in the biosynthesis of leukotrienes from arachidonic acid in the cellular inflammatory cascade. Curcumin is a spice that comes from the root Curcuma longa with diverse pharmacological and biological properties. The efficacy of curcumin is shown to be similar as ibuprofen for the treatment of OA knee.
Taking into consideration of all the above beneficial effects of individual components of Joint Core™, this study has been planned with the objectives to evaluate the efficacy, safety, and tolerability of Joint Core™ in OA patients.
| Methodology|| |
This trial was designed as a phase 3, randomized, open-label, multicentered, active-controlled parallel-group interventional trial conducted at two secondary care centers in India.
All patients diagnosed to have OA of the knee joint for at least 3 months with no joint deformities and requiring treatment with anti-inflammatory drugs were screened for eligibility after providing written informed consent. Patients meeting the American College of Rheumatology (ACR) criteria for OA knee (confirmed by X-ray), satisfying ACR functional class of III, with Grade 3 or 4 as per Kellgren and Lawrence classification system, and having pain defined by a level of ≥30 mm on a 100-mm in the Visual Analog Scale (VAS) at baseline were included in the study. Patients who have been on stable dose of prescription of paracetamol at least 2000 mg/day, on and off for at least 3 months in the past, were allowed to participate in the study.
The following patients were excluded from the study: those with arthritis of the knee from other causes, having OA pain that requires treatment with potent opioids, systemic corticosteroids, intra-articular injections, duloxetine, or venlafaxine; those with a history of uncontrolled hypertension, diabetes, and moderate-to-severe renal impairment; those who received any other investigational medicine within 7 days before screening which can interfere with study drug activity; those who were suffering from any illness on treatment which can interfere with study drugs; those with history of hypersensitivity to any of the test products and any other condition; and pregnant or lactating women, decided as unfit for study by the clinical investigator. The patients were advised not to change their routine dietary habits and physical activity which can lead to weight gain or loss.
The sample size was calculated based on a previous study's mean difference value between the test group and the placebo group in the improvement of stiffness in OA patients. Assuming a pooled standard deviation (SD) of 25 units, the study would require a minimum sample size of 22 for each group (i.e., a total sample size of 44, assuming equal group sizes), to achieve a power of 80% and a level of significance of 5% (two-sided), for detecting a true difference in means between the test group and the reference group of 21.5 (i.e., 35–56.5) units. Hence, a total sample size of 50 participants were calculated considering the dropouts and randomized into 2 groups with 25 in each group. The test group comprised patients diagnosed with OA knee and was advised to take one tablet of Joint Core thrice daily orally for 12 weeks. The comparator group comprised patients diagnosed with OA knee and was advised to take one tablet of Jointace DN twice daily orally for 12 weeks. Paracetamol and other NSAIDs were used as rescue medications at the discretion of the investigator.
The study drug Joint Core, available as tablet formulation, was sponsored by Microcore Research Laboratories Pvt. Ltd., Erode, Tamil Nadu, India. Active ingredients of one Joint Core tablet contained NEM 96% (Muttai Jow Complex) –400 mg, Akbacore™ Boswellia serrata (30% AKBA) –90 mg, and CUMIN CORE™ curcumin extract 96% –10 mg.
The drug was given orally in a dose of 1 tablet thrice daily after food for 12 weeks.
The comparator or reference drug Jointace DN, available as tablet formulation, was sponsored by Meyer Organics Pvt. Ltd., India. Active ingredients of one Jointace DN tablet contained glucosamine 750 mg + diacerein 50 mg + MSM 250 mg. The drug was given orally in a dose of 1 tablet twice daily after food for 12 weeks.
The study was approved by the Independent Ethics Committees of the study centers, namely PM Ethics Committee and Ki3 Ethics Committee for AYUSH (PM/ECR/JOINTCORE/031/21), and registered prospectively at CTRI [CTRI/2021/08/035335]. Recruitment of participants was done as per the inclusion and exclusion criteria after taking informed written consent from the eligible participants.
Evaluation of the study participants was done at baseline (visit 1) and the end of the study at 12 weeks (visit 2). The initial visit comprised screening for baseline investigations, study recruitment, assessment of baseline outcome parameters, and administration of test/comparator drugs. Demographic data (height, weight, body mass index [BMI], and age), personal history, medical history, vital signs, systemic examination, and clinical laboratory examination (complete hemogram, absolute eosinophil count, biochemistry-blood sugar levels, high-sensitivity-C-reactive protein (hs-CRP), and erythrocyte sedimentation rate [ESR]) were done at screening. Study participants who required additional intervention at any time of the study were withdrawn from the study.
The primary outcome measure was to assess the efficacy of the Joint Core™. The outcome parameters included change from baseline at 12 weeks in Pain visual analog scale (VAS) scale, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale, Patient's Global Assessment of Osteoarthritis scale, response rate measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI), laboratory parameters like Hs-CRP, ESR and fibrinogen and quality of life assessed by Short form health -12 (SF-12) questionnaire. The secondary outcome measures included safety and tolerability parameters by assessment of clinical adverse events and abnormality in clinical and laboratory (hematological and biochemical) parameters.
The data on discrete variables and survey results were represented as n (%) and the data on continuous variables were represented as mean (SD). All the results were evaluated and compared between the test and comparator groups. Pain scale scores between the groups were analyzed using independent t-test. P < 0.05 was considered statistically significant. The data were analyzed using IBM SPSS Statistics for Windows, version 21.0 (IBM Corp., Armonk, N.Y., USA).
| Results|| |
In this study, 50 study participants were enrolled who satisfied the study criteria. The study participants were allotted equally to the test and reference groups as per randomization. There was one patient who was lost to follow-up in the test (Joint Core) group. Hence, 49 subjects' data were only used for data analysis. [Figure 1] the baseline demographic characteristics of the study participants are depicted in [Table 1]. There is no significant difference between the test and reference groups with respect to mean age, BMI, and laboratory parameters. The mean age group of the study participants involved in the study was 55.7 years. Out of the 49 study participants enrolled, 39 (80%) were female and 10 (20%) were male participants. Thus, the baseline demographics were comparable between the two groups.
Both the treatment groups showed a significant reduction in the VAS pain score trend lines on weeks 4, 8, and 12 from their baselines. However, there was no significant difference in reduction in pain intensity between the groups [Figure 2]. With respect to WOMAC pain score and Patient's Global Assessment of improvement of OA, there was a statistically significant improvement at weeks 4, 8, and 12 compared to baseline in both the Joint Core™ and Jointace DN™ groups. However, there is no significant difference between the groups except on week 12 (P < 0.0006) [Figure 3] and [Figure 4]. The OMERACT-OARSI set of response criteria by both the groups showed good response percentage of improvement beginning from week 4 to week 12 [Table 2]. Inflammatory biomarkers such as ESR, hs-CRP, and fibrinogen improved significantly over 12 weeks in both the groups but did not show any significant difference between the test and comparator groups [Table 3].
|Figure 2: Change from baseline to 12 weeks in knee pain intensity measured by Pain VAS. VAS: Visual analog scale|
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|Figure 3: Change from baseline to 12 weeks in the WOMAC pain subscale. WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index|
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|Figure 4: Change From Baseline to 12 Weeks in Patient's Global Assessment of improvement of Osteoarthritis. (0 to 10 point scale: 0 – Less disease activity and 10- more disease activity)|
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|Table 2: Number of participants with a response rate measured by the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative|
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|Table 3: Hematological, inflammatory, and biochemical parameters of study participants at baseline compared to end of study|
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The quality of life assessed by SF-12 questionnaire showed improvement in the mean percentage scores on physical activity status in both groups [Table 4].
|Table: 4: Changes from baseline in quality of life questionnaires (Short-Form Health-12)|
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The adverse effects during the study period comprised mainly gastrointestinal side effects such as nausea, vomiting, diarrhea, and gastritis which were evenly distributed in both the groups [Table 5]. The hematological and biochemical parameters did not show any derangements at the end of the study of period in both the groups [Table 3].
|Table 5: Safety profile of Joint Core™ versus Jointace DN™ in study participants|
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| Discussion|| |
This study demonstrated that Joint Core™ has similar pain-relieving effect on patients with OA knee compared with Jointace DN™. There was a female preponderance of study participants with OA as proposed in previous literatures. Overall, both the treatment groups showed similar continuous reduction in VAS pain scores and improvement in other scales, namely WOMAC, Global Pain Assessment Scale, good response rate in OMERACT-OARSI scale, and improvement in quality of life. The need for rescue medication (paracetamol) was numerically similar in both the groups, and none of the patients required anti-ulcer medications.
The Pain VAS is the most reliable, valid, sensitive to change, and easy to measure severity of pain in OA knee. The effectiveness of specific treatment can be accurately measured as pain relief considering all data points between “no treatment” and “treatment effect.” In this study, Joint Core™ and Jointace DN™ clearly demonstrated the reduction in pain score over the study period denoting pain relief. However, there was no significant difference in pain relief between the two groups (P = 0.05).
The WOMAC scale is a disease-specific instrument that measures the domains of pain, stiffness, and physical function of any joint with a range of 0–10 as the highest level. In our study, the trend for improving in the Joint Core™ group was seen similar to other studies, and the difference between was significant at 12 weeks alone.
The OMERACT-OARSI had developed two sets of responder criteria to represent the results of changes after treatment in three symptomatic domains (pain, function, and patient's global assessment) as a single variable for clinical trials. For each domain, a response was defined by both a relative and an absolute change, with different cutoffs with regard to the drug, the route of administration, and the OA localization. In this study, good response rate was shown by Joint Core™ and Jointace DN™ with respect to improvement in all the domains from the beginning till the end of the study. The 12-item Short-form Health Survey (SF-12) was used to assess the quality of life during the treatment period, which included mental and physical domains ranging from 0 to 100, with higher scores indicating a better quality of life. The study participants of both the groups showed improvement in quality of life along with symptomatic relief.
NEM is reported to comprise combined proteins, elastin, collagen type 1, glucosamine, chondroitin, dermatan sulfate, and hyaluronic acid essential for joint and connective tissue disorders. Boswellia serrata has been reported to reduce pain and considerably improve knee joint functions due to the anti-inflammatory property of its active moiety, namely boswellic acid. The anti-inflammatory effect of curcumin has been reported to be mediated by several mechanisms such as downregulation of cyclooxygenase-2 (COX-2) activity; inhibition of the production of cytokines such as interferons, interleukins (IL), tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase; and suppression of activation of nuclear factor-kappa B. Curcumin has been reported to inhibit COX-2, which results in prostaglandin synthesis and thus anti-inflammatory action. In addition, it is reported to suppress pro-inflammatory cytokines such as TNF, IL-1, IL-8, and nitric oxide synthase. In addition, curcumin is reported to have anti-obesity and antiulcer action, both of which can reduce the symptom of OA knee and prevent gastritis of NSAIDs, respectively. Hence, the combination of all these components in the form of Joint Core™ exhibits clinical efficacy and safety in the treatment of OA knee.
There are some limitations in this study. Both the treatment groups did not show any statistically significant difference between the groups. This could have been overcome by inclusion of a placebo control, which would have provided greater clinical meaning. However, it would have required a significantly larger study population. However, the reference drug Jointace™ is a widely used product indicated in the treatment of OA knee and marketed. Its superiority over placebo has been reliably established and its safety is well documented. The participants and outcome parameters in the present study were also similar to those previously published studies. In addition, a broad spectrum of disease severity was included in both the groups which would have resulted in ambiguous results. Despite these potential pitfalls, the results from these open-label trials suggest that Joint Core™ may be an effective therapeutic option for OA knee patients.
| Conclusion|| |
Joint Core™ is effective and safe in the treatment of OA knee when compared to its comparator Jointace DN™. Joint Core™ can be an alternative treatment option in the patients with OA knee who are intolerant to diacerein-based combinations available to treat OA.
We acknowledge the CRO-Ki3 for supporting us right throughout this study.
Financial support and sponsorship
Conflicts of interest
This study was sponsored by Microcore Research Lab India Pvt. Ltd, Erode, Tamilnadu, India.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]