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1 TITLE PAGE Title: Safety and efficacy of Arthronat in Indian subjects with painful Osteoarthritis of hips, knees, shoulders, neck or wrists Authors (Qualifications) Dr. Jyoti rao Hegde Dr. Lakshmi Bantwal Shenoy Dr. Girisha R Dr. Raema Nadavati Dr. Prakash N Role in the study CSR author Protocol author Manuscript author Manuscript author Principal Investigator Academic address / Address for correspondence Manipal AcuNova Ltd. Mobius Towers, SJR - I park, EPIP Zone, Whitefield, Bangalore Manipal AcuNova Ltd. Mobius Towers, SJR - I park, EPIP Zone, Whitefield, Bangalore Manipal AcuNova Ltd. Mobius Towers, SJR - I park, EPIP Zone, Whitefield, Bangalore Manipal AcuNova Ltd. Mobius Towers, SJR - I park, EPIP Zone, Whitefield, Bangalore N R N Orthopaedic Clinic, 2422, Kumarakrupa RPC Layout, 1st Main, Vijayanagar, Bangalore Karnataka, India. Grant Support: This clinical study was supported by Rowtasha, Western Australia. Page 1 of 13

2 ABSTRACT Background: Arthronat is a nutritional supplement, derived from Otoliths of salt water fishes. This study was designed to evaluate the potential benefits of Arthronat in subjects with painful Osteoarthritis of hips, knees, shoulders, neck or wrists. Methods: Eighty subjects were randomized in a 1:1 ratio in a double blinded manner to receive either Arthronat or matching placebo. The primary efficacy endpoint was change in the pain scores as evaluated by Visual Analogue Scale (VAS) and improvement in mobility as evaluated by change in the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index Scale) sub-scales of stiffness and physical function at the end of week 1, 2, 3 & 4 as compared to baseline. Results: The mean pain scores as evaluated by VAS at baseline were 68.6 which came down to 65.4 in Arthronat arm and from 70.1 increased to 70.5 in placebo arm at week 1 ( p=0.0013). The mean WOMAC sub-scales of physical function at baseline were 26.8 and 26.7 and at week 1 were 27.0 and 29.0 for Arthronat and placebo group respectively (p=0.0090). The mean WOMAC sub-scales of stiffness at baseline were 3.1 and 3.2 and at week 1 were 3.1 and 3.4 for Arthronat and placebo group respectively (p=0.3154). One (2.5%) subject each in Arthronat and placebo arm reported at least one adverse event which were moderate in nature and possibly related to study medication. Conclusions: Arthronat had a better efficacy profile compared to placebo, for the reduction in pain scores as evaluated by Visual Analogue Scale (VAS) & WOMAC Scale at end of Week 1, 2, 3 & 4 in subjects with painful Osteoarthritis of the hip, knee, shoulders, neck or the wrists and is safe and well tolerated. Key words: Arthronat, Osteoarthritis, Western Ontario and McMaster Universities Osteoarthritis Index Scale, Visual Analogue Scale. Page 2 of 13

3 INTRODUCTION Osteoarthritis (OA) [also known as degenerative arthritis or degenerative joint disease or wear and tear arthritis or old person s arthritis] is a group of diseases and mechanical abnormalities involving the degradation of joints. It is a progressive disease resulting from stresses (normal joint + abnormal stresses or abnormal joint + normal stresses) that may be initiated from abnormality in any of the joint tissues (articular cartilage, subchondral bone, ligaments, menisci, periarticular muscles and peripheral bones and synovium) which results in breakdown of cartilage and bone. Worldwide estimates are that 9.6% of men and 18.0% of women aged over 60 years have symptomatic osteoarthritis 1. India has around 5.3% males and 4.8 % females aged above 65 years and the incidence of OA among this population is as high as 12 % 2. OA can be classified into Primary / Idiopathic (where the underlying cause is not known) and Secondary (where the underlying cause is identifiable). OA commonly affects the hands, wrists, feet, spine, neck and the large weight bearing joints, such as the hips and knees, although in theory, any joint in the body can be affected. Treatment of OA is usually a combination of therapies. The different therapies available are exercise, weight reduction / control, non drug pain therapy (can be achieved by application of heat or cold, massaging, transcutaneous electric nerve stimulation, assistive devices), drugs (NSAIDS, opioids analgesics, corticosteroids, hyaluronic acid - aim mainly at pain relief and reducing the inflammation) and surgery (removal of loose parts of the bone, bone fusion, joint replacement). Alternate treatments also play a very important role in treatment of Osteoarthritis. Extensive research is being performed to improvise the alternate treatments for OA and one of the researched alternate treatments for OA is Arthronat. Arthronat is a nutritional supplement which has shown promising results in the treatment of Osteoarthritis. The active component is derived from Otoliths of salt water fishes. Otolith is a structure found in the saccule and the utricle of the inner ear. It is composed of layers of calcium carbonate (85-90 %) and gelatinous matrix (10-15 %). However Arthronat has been found to reduce the pain and inflammation in the serous membranes of joints and damaged periosteum, relax periarticular ligaments, resolve cartilage calcium build-ups, promote greater bone density, stimulates muscle tissue development and enhances muscle tone. Our primary aim in conducting the study is to observe the potential benefits of the medication in a randomized, placebo controlled, double blinded study design, in accordance with recommended guidance by US FDA. Page 3 of 13

4 MATERIALS AND METHODS This was a Phase II, randomized, double blind, parallel group, placebo controlled study to evaluate the efficacy and safety of Arthronat in Indian subjects with painful Osteoarthritis of hip, knee, shoulders, neck or wrists. Subjects were randomized into two groups in a 1:1 ratio with total of 2 treatment arms in the study. The duration of the study treatment was of 4 weeks which was preceded by a screening period (with one week of single blind placebo run-in phase) not exceeding 14 days. The study population included 80 subjects from a single center, of either sex, aged 18 years providing the written informed consent. Subjects who were previously diagnosed with (at least 3 months prior to screening visit) Osteoarthritis of hip, knees based on ACR (American College of Rheumatology) clinical classification criteria for Osteoarthritis or Osteoarthritis of shoulders, neck and wrists based on clinical and radiographic findings were selected. Subjects who had agreed to discontinue all pain medications (except Paracetamol or Ibuprofen) throughout the study and with screening WOMAC score of between (only for Osteoarthritis of hip and knee) and baseline VAS score of 4 were included in this study. Female subjects of child bearing potential were included if they agreed to use suitable contraception. Pregnant and lactating females were excluded from the study. Subjects with history of disease or trauma or surgery or any planned surgery (diagnostic or therapeutic intervention) involving the index joint or obvious bony deformity or enlargement or any signs of acute inflammation or history of any severe painful condition were excluded from this study. Subjects belonging to Functional class IV as per ACR criteria for functional status and radiographic evidence of grade 4 Osteoarthritis based on the Kellgren and Lawrence radiographic criteria for Osteoarthritis were also excluded. Subjects with the history of previous use of aspirin or corticosteroids or hyaluronic acid or prohibited medication or alcohol intake or drug abuse or history of allergy to fish or fish products were excluded. Subjects with significant medical conditions like chronic liver disease, renal disease, cardiovascular or pulmonary disorder, uncontrolled complicated diabetes mellitus, severe hypertension, HIV positive (by history), Hepatitis B or Hepatitis C positive (by history), neurological and psychiatric condition were excluded from the study. Out of 80 subjects, 40 were assigned treatment A (Arthronat) and remaining 40 subjects were assigned treatment B (placebo). During the active treatment period, the subjects received 3 capsules (500 mg each) twice daily making a total of 3000 mg per day. Capsules were taken before or after the two principal meals of the day, starting from day 0 till the end of 4 weeks and consumed a total of 42 capsules per week (6 capsules per day X 7 days). Safety assessment included AE reporting, physical examination, monitoring of vital signs (heart rate, respiratory rate, blood pressure and temperature) and the laboratory investigations (complete blood count, liver function tests, urea, creatinine and electrolytes and urine routine). The statistical analyses were performed on all patients who received at least one dose of study drug and had relevant efficacy and safety data available. For the primary efficacy endpoints, Page 4 of 13

5 treatment effect was evaluated using an analysis of variance (ANOVA) model with factors for baseline and treatment. Treatment effects were estimated using the least-square means and 95% CIs from the ANOVA model. All other secondary efficacy endpoints were appropriately compared and summarized. RESULTS A single center recruited 80 subjects for this study. All the 80 subjects completed the study. The first subject was enrolled on 14 Jul 2010 and the last subject completed the study on 02 Nov The details of the subject s disposition are depicted in figure 1. All the 80 randomized subjects were included for MITT (modified intention to treat), PP (per protocol) and safety analysis. Table 1 provides the information regarding the baseline characteristics of the subjects. The two treatment groups were comparable with respect to the age, weight, height and BMI measured at baseline. Majority of study population consisted of females and all the subjects were of Indian origin. Figure 1: Patient disposition Page 5 of 13

6 Characteristics Table 1: Summary of patient characteristics at baseline Arthronat Placebo ALL (N=80) Age * (years) (SD) 54.7 (9.13) 51.3 (10.03) 53.0 (9.69) Gender M/F 20/20 13/27 33/47 Weight * (kg) (SD) 67.3 (9.33) 66.2 (11.35) 66.8 (10.34) Height * (cms) (SD) (8.20) (10.12) (9.27) * Mean The VAS (Visual Analogue Scale) was used in the study as measurement instrument. Operationally VAS is usually a horizontal line, 100 mm in length where 0 represents No distress/pain and 100 represents Unbearable distress/pain. The mean pain scores as evaluated by VAS at baseline were 68.0 which came down to 65.4 in Arthronat arm and from 70.1 increased to 70.5 in placebo arm at week 1 which was statistically significant with a p-value of Mean percent change in VAS from baseline is presented in figure 2. Figure 2: Mean percent change in VAS from baseline Formatted: Caption, Left, Adjust space between Latin and Asian text, Adjust space between Asian text and numbers Formatted: Centered WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index Scale) Index scale used in the study is a disease-specific, tri-dimensional self-administered questionnaire, for assessing health status and health outcomes in Osteoarthritis of hip and / or knee. It consists of 3 sub-scales: Pain sub-scale, Physical function sub-scale and Stiffness sub-scale. Only physical function subscale and stiffness subscale were used in this study. The physical function subscale consisted of 17 questions. The scores were measured using the 5 point Likert scale. The highest scores indicated worse physical function. The mean WOMAC sub-scales of physical function at baseline were 26.8 and 26.7 and at week 1 were 27.0 and 29.0 for Arthronat and placebo group respectively with statistically significant p-value of The stiffness subscale consisted of 2 questions. The scores were measured using the 5 point Likert scale. Higher score indicated Page 6 of 13

7 increased stiffness. The mean WOMAC sub-scales of stiffness at baseline were 3.1 and 3.2 and at week 1 were 3.1 and 3.4 for Arthronat and placebo group respectively (p= ). The mean values of VAS and WOMAC scores at the end of week 1, 2, 3 and 4 are summarized in Table 2 to 5 and analysis of VAS pain scores from baseline is given in figure 2 Table 2: Mean values of VAS and WOMAC scores at the end of week 1 compared to the baseline Arthronat Placebo p-value Visits VAS Pain score(s.d) Baseline 68.0 (7.90) 70.1 (8.32) Week (7.99) 70.5 (7.07) Physical Baseline 26.8 (3.88) 26.7 (4.29) function(s.d) Week (3.20) 29.0 (2.79) WOMAC Baseline 3.1 (0.74) 3.2 (0.99) Stiffness(S.D) Week (0.67) 3.4 (0.99) Source Listing: Visual Analogue Scale for Pain, WOMAC Index Questionnaire for Hip and Knee OA Table 3: Mean values of VAS and WOMAC scores at the end of week 2 compared to the baseline VAS Pain score(s.d) Visits Arthronat Placebo Baseline 68.0 (7.90) 70.1 (8.32) Week (9.05) 69.1 (7.80) p-value Physical Baseline 26.8 (3.88) 26.7 (4.29) function(s.d) Week (2.78) 29.0 (2.74) WOMAC Baseline 3.1 (0.74) 3.2 (0.99) Stiffness(S.D) Week (0.70) 3.3 (0.94) Source Listing: Visual Analogue Scale for Pain, WOMAC Index Questionnaire for Hip and Knee OA Page 7 of 13

8 Table 4: Mean values of VAS and WOMAC scores at the end of week 3 compared to the baseline VAS Pain score(s.d) Visits Arthronat Placebo Baseline 68.0 (7.90) 70.1 (8.32) Week (10.00) 68.2 (8.51) p-value Physical Baseline 26.8 (3.88) 26.7 (4.29) function(s.d) Week (3.11) 27.7 (2.89) WOMAC Baseline 3.1 (0.74) 3.2 (0.99) Stiffness(S.D) Week (0.62) 3.3 (1.00) Source Listing: Visual Analogue Scale for Pain, WOMAC Index Questionnaire for Hip and Knee OA Table 5: Mean values of VAS and WOMAC scores at the end of week 4 compared to the baseline VAS Pain score(s.d) Visits Arthronat Placebo Baseline 68.0 (7.90) 70.1 (8.32) Week (11.51) 65.2 (8.21) p-value Physical Baseline 26.8 (3.88) 26.7 (4.29) function(s.d) Week (3.39) 28.2 (2.42) WOMAC Baseline 3.1 (0.74) 3.2 (0.99) Stiffness(S.D) Week (0.69) 3.2 (0.92) Source Listing: Visual Analogue Scale for Pain, WOMAC Index Questionnaire for Hip and Knee OA Page 8 of 13

9 Figure 332: Analysis of absolute change from baseline in VAS pain scores SF 36 questionnaires (Short Form 36 Quality of Life questionnaires) was a self administered questionnaire used in the study that measured the following 8 health concepts: physical functioning, role limitations due to physical problems, social functioning, bodily pain, mental health and role limitations due to emotional problems, vitality and general health perception. Higher scores represented well-being of the subject. The SF-36 scores were similar in both the groups. However the Physical and Mental health scores in the Arthronat group were slightly higher than the placebo group at the end of the study at Week 4. Subject Global Assessment (SGA) of Osteoarthritis is a self administered scale which was completed by the subject during each study visit (Screening, Baseline, Visit 3, Visit 4, Visit 5 and Visit 6). The subject had to assess on a scale of 1 (indicates Very good ) to 5 (indicates Very poor ) as to how severe the OA symptoms were and the severity of limitation of activities due to OA. The mean scores of Subject Global Assessment of Osteoarthritis at the end of the study in the Arthronat arm were 2.98 and in the placebo arm were 3. OMERACT OARSI (Outcome Measures in Rheumatoid Arthritis Clinical Trials Osteoarthritis Research Society International) responder index used in the study is two sets of responder criteria to present the results of changes from baseline in three symptomatic domains (WOMAC Pain subscale, WOMAC Physical function subscale, and Subject's Global Assessment of Osteoarthritis). The number of responders and non-responders during each visit is summarized in the Table 6. At the end of the study, there were 39 (97.5%) responders in Arthronat group as compared to 30 (75.0%) responders in placebo group. Page 9 of 13

10 Table 6: Percentage of responders and non-responders according to OMERACT-OARSI Responder Index at Week 1, 2, 3 and 4 PERCENTAGE OF RESPONDERS AND NON-RESPONDERS Visit Responders/Non-Responders Arthronat Placebo Week 1 Responders Non-Responders Week 2 Responders Non-Responders 0 35 Week 3 Responders Non-Responders Week 4 Responders Non-Responders Source Listing: OMERACT-OARSI Responder Index Prior to the enrolment in the study, most of the subjects were on potent NSAIDs. All the subjects in the study used only the first line of rescue medication i.e. Paracetamol (Tablet Dolo 500mg). Since all the subjects experienced adequate pain relief with the first line rescue medication, none of the subjects required Ibuprofen (second line) as the rescue medication in the study. Total number of tablets of rescue medication (Paracetamol) consumed at each visit was lesser in Arthronat group (273) compared to Placebo (407) and reduced consistently from baseline to Week 4 with a statistically significant p-value of and at week 3 and week 4 respectively. SF-36 scores, SGA scores and details of rescue medication are summarized in Table 7. Formatted: Adjust space between Latin and Asian text, Adjust space between Asian text and numbers Table 7: Mean values of SF-36 score, SGA, Rescue Medication at the end of the study compared to the baseline Visits Arthronat Placebo SF-36 Baseline 46.1 (8.95) 44.9 (8.90) score(s.d) Week (8.74) 43.1 (6.02) SGA(S.D) Baseline 3.03 (0.158) 3.05 (0.221) Week (0.158) 3.00 (0.000) Rescue Baseline 4.5 (1.32) 4.8 (0.64) Medication(S.D) Week (1.11) 4.9 (0.59) Source Listing: SF-36 Quality of Life Questionnaire : Subject Global Assessment for OA. ( 1 indicates very good; 5 indicates very poor) : Rescue Medications Dispensing and Retrieval p-value The adverse events reported were similar in both the arms. Out of 80 subjects, 1 (2.5%) subject each in Arthronat and the placebo arm reported a single adverse event. Both the adverse events were diarrhoea. Adverse event reported was classified as moderate and possibly related to the treatment in both Arthronat and placebo arm. Laboratory investigations showed no clinical significant findings in both the arms throughout the study. Vital signs and physical examination Page 10 of 13

11 were within normal range in both the arms throughout the study. No deaths, SAEs and other significant AEs were reported in this study. Adverse events are summarized in Table 8. Table 8: Summary of Adverse Events Arthronat (N = 40) Placebo (N = 40) At least one AE, n (%) 1 (2.5%) 1 (2.5%) Possible or Probably related to study drug,n(%) 1 (2.5%) 1 (2.5%) Moderate, n (%) 1 (2.5%) 1 (2.5%) Any severe AE, n (%) 0 0 SAE, n (%) 0 0 DISCUSSION Osteoarthritis is one of the major causes of chronic disability in elderly population worldwide. Treatment of OA is usually a combination of therapies which includes exercise, use of assistive devices, non drug therapy, drug therapy and surgery. Extensive research is being performed t o improvise the alternate treatments for OA and Arthronat is one of the researched alternate treatments for OA. It has proved to be very effective in reduction in pain and improvement of joint mobility. This study was conducted primarily to evaluate the efficacy of Arthronat for the reduction in pain and improvement of mobility in subjects with painful Osteoarthritis of the hip, knee, shoulders, neck or the wrists. VAS is considered a very popular tool for pain assessment. Accuracy of VAS has been evaluated by several studies and some studies have compared their results 3, 4. de Boer et al. have shown that VAS is a adequately dependable tool to be used even in acute pain settings, and in clinical trials to assess the global quality of life 5. The mean pain scores as evaluated by VAS at baseline were 68.6 which came down to 65.4 in Arthronat arm and from 70.1 increased to 70.5 in placebo arm at week 1. There was a statistically significant reduction in pain in the subjects receiving Arthronat as compared to placebo at the end of week 1 as evaluated by VAS (p-value = ) which shows that there was improvement in the pain scores in the Arthronat group. WOMAC Index scale is a valid, reliable and responsive measure of outcome, and has been used in diverse clinical and interventional environments. This instrument has been well studied, and many of its psychometric properties are known It is among the most sensitive of all instruments used in the assessment of OA of the knee or hip, and has been widely used in the clinical trials 11, 12. The mean WOMAC sub-scales of physical function at baseline were 26.8 and 26.7 and at week 1 were 27.0 and 29.0 for Arthronat and placebo group respectively which was statistically significant with a p-value of The mean WOMAC sub-scales of stiffness at baseline were 3.1 and 3.2 and at week 1 were 3.1 and 3.4 for Arthronat and placebo group respectively Page 11 of 13

12 (p=0.3154), which infers that Arthronat group had improvement in the WOMAC pain, physical function and stiffness scores from the baseline compared to placebo. There was no significant difference observed in absolute change in SF - 36 score and Subject Global Assessment of Ostearthritis from baseline to the end of the week 1, 2, 3 and 4 between the two treatments. There were 39 (97.5%) responders in Arthronat group as compared to 30 (75.0%) responders in placebo group at the end of study, which infers that response was better in Arthronat when compared to placebo. Total number of tablets of rescue medication (Paracetamol) consumed at each visit was lesser in Arthronat group (273) compared to Placebo (407) and reduced consistently from baseline to Week 4. Arthronat was well tolerated and was comparable with Placebo in safety aspects which were confirmed by the fewer incidences of adverse events and good compliance. One patient (2.5%) in each arm reported adverse event, both adverse events were diarrhoea which was moderate in nature and probably related to study medication. Thus the above results of this study shows that Arthronat had a better efficacy profile compared to placebo, for the reduction in pain as evaluated by VAS and improvement in mobility at the end of week 1, 2, 3 & 4 as evaluated by WOMAC subscales of Stiffness and Physical function in subjects with painful Osteoarthritis of hip, knee, shoulders, neck or the wrists and is safe and well tolerated. REFERENCES 1. Murray CJL, Lopez AD, editors. The global burden of disease. A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to Cambridge (MA): Harvard School of Public Health on behalf of the World Health Organization and The World Bank; Sharma. M. K, Swami H. M, Bhatia. V, Verma. A, Bhatia. S. P. S; An epidemiological study of correlates of osteoarthritis in geriatric population of UT Chandigarh; Indian Journal of Community Medicine; Vol 32; Freeman K, Smyth C, Dallam L, Jackson B. Pain measurement scales: a comparison of the visual analogue and faces rating scales in measuring pressure ulcer pain. J Wound Ostomy Continence Nurs. 2001; 28: Lundeberg T, Lund I, Dahlin L, Borg E, Gustafsson C, Sandin L, et al. Reliability and responsiveness of three different pain assessments. J Rehabil Med. 2001; 33: de Boer AG, van Lanschot JJ, Stalmeier PF, van Sandick JW, Hulscher JB, de Haes JC, et al. Is a single item visual analogue scale as valid, reliable, and responsive as multi item scales in measuring quality of life? Qual Life Res. 2004; 13: Bellamy N, Campbell J, Stevens J, Pilch L, Stewart C, Mahmood Z. Validation study of a computerized version of the Western Ontario and McMaster Universities VA3.0 Osteoarthrtis Index. J Rheumatol 1997;24: Bombardier C, Melfi CA, Paul J, Green R, Hawker G, Wright J et al. Comparison of a generic and a disease specific measure of pain and physical function after knee replacement surgery. Med care 1995;33(4 suppl.):as Page 12 of 13

13 8. Hawker G, Melfi C, Paul J, Green R, Bombardier C. Comparison of a generic (SF-36) and a disease specific (WOMAC) instrument in the measurement of outcomes after knee replacement surgery. J Rheumatol 1995;22: Barr S, Bellamy N, Buchanan WW, Chalmers A, Ford PM, Kean WF et al. A comparative study of signal of signal versus aggregate methods of outcome measurement based on the WOMAC osteoarthritis index. J Rheumatol 1994;21: Bellamy N, Wells G, Campbell J. Relationship between severity and clinical importance of symptoms in osteoarthritis. Clin Rheumatol 1991;10: Bellamy N, Buchanan WW, Chalmers A, Ford PM, Kean WF, Kraag GR et al. A multicenter study of tenoxicam and diclofenac in patients with osteoarthritis of the knee. J Rheumatol 1993; 20: Bellamy N, Kean WF, Buchanan WW, Gerecz-Simon E, Campbell J. Double blind randomized controlled trial of sodium meclofenate (Meclomen) and diclofenac sodium (Voltaren): post validation reapplication of the WOMAC osteoarthritis Index. J Rheumatol 1992; 19: Page 13 of 13