CLINICAL EFFICACY OF GLUCOSAMINE PLUS DIACEREIN VERSUS MONO-THERAPY OF GLUCOSAMINE: A RANDOMIZED CONTROLLED TRIAL
JATUPON KONGTHARVONSKUL
A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (CLINICAL EPIDEMIOLOGY) FACULTY OF GRADUATE STUDIES MAHIDOL UNIVERSITY 2015
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Thesis entitled CLINICAL EFFICACY OF GLUCOSAMINE PLUS DIACEREIN VERSUS MONO-THERAPY OF GLUCOSAMINE: A RANDOMIZED CONTROLLED TRIAL
...... m.*...... % ~.7.'k&u2?4~:&.~~. Mr. Jatupon Kongthavonskul Candidate
...... fi ... ..)...hc+. .: ...... Assoc. Prof. Patarawan Woratanarat, M.D.,Ph.D.(Clinical Epidemiology) Major advisor
Ph.D.(Clinical Epidemiology & Community Medicine) Co-advisor
...... Assist. Prof. Sasivimol Rattanasiri, Ph.D.(Statistics) Co-advisor
...... A- W&h rnJ 1u4 Asst. Prof. Auemphorn Mutchimwong, Prof. Ammarin Thakkinstian Ph.D. (Air Quality Assessment) Ph.D.(Clinical Epidemiology & Acting Dean Community Medicine) 17aculty of Graduate Studies Program Director Mahidol University Doctor of Philosophy Program in Clinical Epidemiology Faculty of Medicine, Ramathibodi Hospital Mahidol University Thesis entitled CLINICAL EFFICACY OF GLUCOSAMINE PLUS DIACEREIN VERSUS MONO-THERAPY OF' GLUCOSAMINE: A RANDOMIZED CONTROLLED TRIAL
was submitted to the Faculty of Graduate Studies, Mahidol University for the degree of Doctor of Philosophy (Clinical Epidemiology) on August 14,20 1 5'
...... fiwt2 N ....~w~P&!L?!% Utc.~. Mr. Jatupon Kongthavonskul Candidate
Assoc. Prof. Atiporn Ingsathit, M.D.,Ph.D.( Clinical Epidemiology) Chair
Prof. Kit ti Jirarattanaphochai, Assoc. Prof. Patarawan Woratanarat, M.D.,Ph.D.( Clinical Science) M.D.,Ph.D.(Clinical Epidemiology) Member Member
Assist. Prof. Sasivimol Rattanasiri, AS.&. Prof. Ammarin Thakkinstian, Ph.D.(Statistics) Ph.D.(Clinical Epidemiology & Member Community Medicine) Member
~ .-- ...... Asst. Prof. Auemphorn ~Gchimwon~, Prof. Winit Phuapradit, Ph.D. (Air Quality Assessment) M.D., M.P.H.(Matemal and Child Health) Acting Dean Faculty of Graduate Studies Dean Mahidol University Faculty of Medicine, Ramathibodi Hospital Mahidol University iii
ACKNOWLEDGEMENTS
I would like to express the deepest appreciation to my co- advisor Assoc. Prof. Dr. Ammarin Thakkinstian, who has the attitude and the substance of a genius: she continually and convincingly conveyed a spirit of adventure in regard to research and scholarship, and an excitement in regard to teaching. Without her guidance and persistent help this dissertation would not have been possible. I am infinitely grateful to Assoc. Prof. Patarawan Woratanarat, my major advisor, for providing me not only the great recommendations and suggestions, but also giving me continuous emotional support and encouragement. Thanks for their patience and thoughtful insight. This enterprise would not have been realized without their nurturing. I would like to thank my other co-advisors, Dr. Siwadol Wongsak and Assoc. Prof. Viroj Kawinwonggowit for their valuable suggestions and recommendations. I would like to show my gratitude to Assist. Prof. Dr. Sasivimol Rattanasiri and all personnel of the Section of Clinical Epidemiology and Biostatistics, Ramathibodi Hospital, Mahidol University for their grateful help and support especially about data management and administrative management of my project. I am also thankful to Assoc. Prof. Viroj Kawinwonggowit and Dr. Siwadol Wongsak (Department of Orthopedics, Ramathibodi Hospital, Mahidol University) for their permission and support in collecting the patients, data collection, and radiographic data. Without their support, I could not have successfully conducted this randomized controlled trial. I am also thankful to Alisara Arirachakaran (Orthopedics Department, Police General Hospital) for her support and English language corrections. I am also thankful to Prof. Dr. Kitti Jiraratanapochai who has the attitude and the substance of a genius: he continually and convincingly conveyed a spirit of adventure in regard to research and scholarship. Without his guidance and persistent help this dissertation would not have been possible. Lastly, I would like to express my deepest gratitude to God, my mother and my father. Their endless love and support are the wind beneath my wings. Special thanks to my beloved significant other (Alisara Arirachakaran) for making me smile at times that I felt so sad. You are the answer for the meaning of life and love of mine. My dissertation was supported by the Ramathibodi hospital and Mahidol University”
Jatupon Kongthavonskul
Fac. of Grad. Studies, Mahidol Univ. Thesis / iv
CLINICAL EFFICACY OF GLUCOSAMINE PLUS DIACEREIN VERSUS MONO-THERAPY OF GLUCOSAMINE: A RANDOMIZED CONTROLLED TRIAL
JATUPON KONGTHAVONSKUL 5238119 RACE/D
Ph.D. (CLINICAL EPIDEMIOLOGY)
THESIS ADVISORY COMMITTEE: PATARAWAN WORATANARAT, M.D., Ph.D., AMMARIN THAKKINSTIAN, Ph.D., SASIVIMOL RATANASIRI, Ph.D.
ABSTRACT Background: glucosamine or diacerein monotherapy has been recommended for symptomatic treatment of mild to moderate osteoarthritis (OA), but evidence of efficacy for combined treatment is lacking. Objective: 1) To conduct a systematic review and network meta-analysis of randomized controlled trials (RCTs) with the aims of comparing relevant clinical outcomes (that is, visual analog scores (VAS), total and sub-Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) scores, Lequesne algofunctional index, joint space width change, and adverse events) between diacerein, glucosamine, and placebo. 2) To determine clinical outcomes and safety during 6 months after receiving diacerein plus glucosamine versus glucosamine alone. Methods: For the first objective, a systematic review and network meta-analysis of randomized controlled trials were performed to evaluate the clinical outcomes between diacerein, glucosamine, and placebo. Medline and Scopus databases were searched from inception to 29 August 2014, using PubMed and Scopus search engines and included RCTs or quasi- experimental designs comparing clinical outcomes between treatments. Data were extracted from original studies. A network meta-analysis was performed by applying weight regression for continuous outcomes and a mixed-effect Poisson regression for dichotomous outcomes. For the second objective, a randomized, double blind, controlled trial was conducted between August 2013 and August 2014 at the Orthopedics outpatient clinic, Ramathibodi Hospital, Bangkok, Thailand. A total of 147 patients were randomly allocated to receive Glucosamine (1500 mg) plus diacerein (50 mg) daily or Glucosamine (1500 mg) plus placebo daily. Adult patients were eligible if they had knee OA with a Kellgren and Lawrence grade of 2 or 3. The primary outcome was pain measured by VAS at 4, 8, 12, 16, 20 and 24 weeks after receiving treatment. Results: For the efficacy between diacerein, glucosamine, and placebo. Compared to placebo, glucosamine showed a significant improvement with unstandardized mean differences (UMD) in total WOMAC, pain WOMAC, function WOMAC, and Lequesne score of −2.49 (95% confidence interval (CI) −4.14, −0.83), −0.75 (95% CI: −1.18, −0.32), −4.78 (95% CI: −5.96, −3.59), and −1.03 (95% CI: −1.34, −0.72), respectively. Diacerein clinically improved visual analog scores, function WOMAC, and stiffness WOMAC with UMD values of −2.23 (95% CI: −2.82, −1.64), −6.64 (95% CI: −10.50, −2.78), and −0.68 (95% CI: −1.20, −0.16) when compared to placebo. For the combine glucosamine and diacerein group compared to glucosamine alone, the mean VAS measured at 1, 2, 3, 4, 5, and 6 months were 4.07, 3.58, 3.61, 3.35, 3.32, and 3.16 respectively in the glucosamine plus diacerin group; and 4.72, 4.19, 3.74, 3.48, 3.29, and 2.77 respectively in the glucosamine plus placebo group. These were not statistically significant difference (P>0.05 for all). Conclusions: From the network meta-analysis suggested that diacerein and glucosamine were equally efficacious for symptom relief in knee OA, but that the former had more side effects. Whereas, co-administration of diacerein with glucosamine sulfate did not improved pain and WOMAC score when compared with glucosamine sulfate monotherapy in mild to moderate osteoarthritis of the knee.
KEY WORDS: GLUCOSAMINE/ DIACEREIN/ COMBINE THERAPY/ MONO-THERAPY/ OSTEOARTHRITIS KNEE
157 pages Fac. of Grad. Studies, Mahidol Univ. Thesis / v
การศึกษาประสิทธิผลทางคลินิกของการรักษาดวยยากล้ ูโคซามีนคูก่ บยาไดอะซั ีรีนเปรียบเทียบกบการรั ักษาดวยยากล้ โคซามู ีนตวเดั ียว CLINICAL EFFICACY OF GLUCOSAMINE PLUS DIACEREIN VERSUS MONO-THERAPY OF GLUCOSAMINE
จตุพล คงถาวรสกุล 5238119 RACE/D
ปร.ด. (วิทยาการระบาดคลินิก)
คณะกรรมการที่ปรึกษาวิทยานิพนธ์: ภัทรวณยั ์วรธนารัตน,์ M.D., Ph.D.,อัมรินทร์ ทักขิญเสถียร, Ph.D., ศศิวิมล รัตนสิริ, Ph.D.
บทคดยั อ่ ความเป็นมาและความสาคํ ญของปั ัญหา: แนวทางการรักษาโรคขอเข้ าเส่ ื่อมระดบเรั ่ิมตนถ้ ึงระดบกลางดั ้วยการใช้ยาเสริม นํ้าขอเข้ ากล่ ูโคซามีน และยาไดอะซีรีนมีการใช้กนอยั างกว่ ้างขวาง แตยั่ งไม่มีการศึกษาการใชยาท้ ้งสองชนั ิดพร้อมกนั ดุษฏีนิพนธ์นี้ประกอบไปดวย้ 2 การศึกษา วัตถุประสงค:์ 1) เพื่อศึกษาประสิทธิภาพ ผลขางเค้ ียง และ ภาพเอกซเรยเปร์ ียบเทียบระหวาง่ ยากลุมกล่ โคซามู ีน ไดอะซีรีน ยาแก้ อักเสบ ยาหลอกในการลดอาการปวดและลดดชนั ีชี้วัดขอเข้ าเส่ ื่อมในผู้ป่วยขอเข้ าเส่ ื่อมระดบเรั ่ิมตนถ้ ึงระดบกลางั 2) เพื่อศึกษาประสิทธิภาพ ผลขางเค้ ียง และ ภาพเอกซเรย ์ ยากลุมกล่ ูโคซามีนและไดอะซีรีน เปรียบเทียบกบยากลูั โคซา มีนกบยาหลอกั ในการรักษาผู้ป่วยขอเข้ าเส่ ื่อมระดบเรั ่ิมตนถ้ ึงระดับกลาง วิธีดําเนินการวิจัย: สําหรับวตถั ุประสงค์ข้อ 1 ทําการศึกษาแบบ การทบทวนวรรณกรรมอยางเป่ ็นระบบและวิเคราะห์อภิ มานแบบเครือขาย่ เพื่อ ประเมินผลการรักษาขอเข้ าเส่ ื่อมของยากลุมกล่ ูโคซามีน ไดอะซีรีน ยาแกอั้ กเสบ ยาหลอกโดยสืบคนข้ อม้ ูลจาก ฐานขอม้ ูล Medline และ Scopus จนถึง พ.ศ. 2557 ผู้วิจัย 2 คน คัดเลือกและสกดขั อม้ ูลอยางอ่ ิสระตอก่ นั ใช ้ random effect model ในการ รวมเปรียบเทียบผลของ ยากลุมกล่ ูโคซามีน ไดอะซีรีน ยาแกอั้ กเสบ ยาหลอกสาหรํ ับวตถั ุประสงค์ข้อ 2 การศึกษาแบบแบบสุ่มและมีกลุม่ ควบคุมในผู้ป่วยโรคขอเข้ าเส่ ื่อมที่ตึกผู้ป่วยนอกรพ.รามาธิบดีตั้งแต ่ ส.ค. 2556 ถึง ส.ค. 2558 จํานวนผู้ป่วยท้งหมดั 147 ราย เขาร้ ับการสุ่ม เลือกการรักษาดวยยากล้ ูโคซามีนคูก่ บไดอะซั ีรีน หรือ กลโคซามู ีนคูก่ บยาหลอกั โดยผู้ป่วยทีเหมาะสมในการเขาร้ ับการสุ่มตองม้ ีอาการเขา่ เสื่อมในระดบเรั ่ิมตนถ้ ึงระดบกลางั อาการปวดที่ได้จากการประเมินในสปดาหั ์ที่ 4 8 12 16 20 และ 24 เป็นผลการศึกษาหลัก ผลการวิจัย: สําหรับการประเมินผลของ ยากลุมกล่ ูโคซามีน ไดอะซีรีน ยาแกอั้ กเสบ ยาหลอก โดยการการวิเคราะห์อภิ มานแบบเครือขายในผ่ ู้ป่วยขอเข้ าเส่ ื่อม พบวา่ กลโคซามู ีน ลดดชนั ีข้อเขาเส่ ื่อม โวแมค(WOMAC total, pain, function) และ เลเควน (lequesne) ไดอย้ างม่ ีนัยสาคํ ญทางสถั ิติ pool UMD -2.49 (95% CI: -4.14, -0.83), -0.75 (95% CI: -1.18, -0.32), -4.78 (95% CI: -5.96, - 3.59), and -1.03 (95% CI: -1.34, -0.72) ตามลาดํ บเมั ื่อเปรียบเทียบกบยาหลอกั , ขณะที่ ไดอะซีรีนไดผลด้ ีในการรักษาขอเข้ าเส่ ื่อมในการลด อาการปวด VAS และดชนั ีชี้วัดขอเข้ าเส่ ื่อมโวแมค (WOMAC function, stiffness)ไดอย้ างม่ ีนัยสาคํ ญทางสถั ิติ pool UMD -2.23 (95% CI: - 2.82, -1.64), -6.64 (95%CI: -10.50, -2.78) และ -0.68 (95% CI: -1.20, -0.16) ตามลาดํ บเมั ื่อเปรียบเทียบกบยาหลอกั สําหรับการเปรียบเทียบ ผลการรักษาดวยยากล้ ูโคซามีนคูก่ บไดอะซั ีรีน และ กลโคซามู ีนคูก่ บยาหลอกั คากลางของอาการปวดเข่ าขณะท่ ี่ยังไม่ได้รับยาคือ 5.1 ใน กลุมกล่ โคซามู ีนคูก่ บไดอะซั ีรีนอาการปวดในเดือนที่ หนึ่งถึงเดือนที่หกเป็น 4.07, 3.58, 3.61, 3.35, 3.32 และ 3.16 ตามลาดํ ับ ขณะที่อาการ ปวดในกลุมกล่ ูโคซามีนคูก่ บยาหลอกเปั ็น 4.72, 4.19, 3.74, 3.48, 3.29 และ 2.77 ตามลาดํ ับ อาการปวดของท้งสองกลั ุมไม่ มี่ ความแตกตาง่ อยางม่ ีนัยสาคํ ญทางสถั ิติ สรุปผลการวิจัย: การทบทวนวรรณกรรมอยางเป่ ็นระบบและวิเคราะห์อภิมานแบบเครือขายแสดงให่ เห้ ็นผลการ รักษาดวยยากล้ โคซามู ีนและไดอะซีรีน ลดอาการปวดไดไม้ แตกต่ างก่ นั ขณะที่ไดอะซีรีนมีผลขางเค้ ียงมากกวาอย่ างช่ ดเจนั การรักษาขอเข้ า่ เสื่อมระดบเรั ่ิมตนถ้ ึงระดบกลางโดยการใชั ยากล้ โคซามู ีนคกู่ บไดอะซั ีรีน ไมมี่ ความแตกตางในแง่ ลดอาการปวดและ่ ลดดชนั ีชี้วัดขอเข้ า่ เสื่อมเมื่อเปรียบเทียบกบการใชั ยากล้ โคซามู ีนอยางเด่ ียว
157 หน้า vi
CONTENTS
Page ACKNOWLEDGEMENTS………………………………………………………iii ABSTRACT (ENGLISH)...... iv ABSTRACT (THAI)...... v LIST OF TABLES...... viii LIST OF FIGURES...... x LIST OF ABBREVIATIONS………………………….………..…..………...... xii CHAPTER I INTRODUCTION...... 1 1.1 Background and rationale…...…………………………..……...….1 1.2 Research questions...... 19 1.3 Research objectives……...…………………………………....….19 1.4 Conceptual framework………………………………………...... 19 CHAPTER II LITERATURE REVIEW...... 21 2.1 Glucosamine in OA knee...... 21 2.2 Diacerein in OA knee ………………………………………...... 26 2.3 Systematic review and network meta-analysis of efficacy and safety of glucosamine, diacerein, and NSAIDs in osteoarthritis knee……………………...... …………….....……....29 2.4 Definition……………….……………….………………….….....66 2.5 Drug mechanism…………..…………………………….…….….67 CHAPTER III METHODOLOGY…………………………...... 69 3.1 Study design…....…………...... …….…………….……...…...….69 3.2 Inclusion criteria……………………..……….…….………….…69 3.3 Exclusion criteria……………………..…....………….………….69 3.4 Treatment regimen and blinding………..…..……..…….…...... 70 3.5 Randomization……………………..…….……….……...... 71 3.6 Outcome measures………………...... ………….…………...... 71
vii
CONTENTS(cont.)
Page 3.7 Co-intervention……………….....………………...…………….72 3.8 Protocol violation………………………..….….…………...... 73 3.9 Data collection……………...….……….……….…...... ………..76 3.10 Sample size estimation………………………….…………...... 78 3.11 Statistical analysis…………………….………….……...……....79 3.12 Ethical considerations…..………....……………….………..…..80 3.13 Budget…………………………..………….…….………..…….81 3.14 Time frame……………………..……………….……...... 81 3.15 Trial organization………….……....……………….……………84 CHAPTER IV RESULTS……………………………………...... 85 4.1 Patient characteristics………………………..……...……..…….85 4.2 Pain VAS score……………………………….…….…………...89 4.3 WOMAC score…………………………………………..……...90 4.4 Minimal Joint Space Width (JSW)…………………...…..……..94 4.5 Adverse events…….…………….…………………………...... 99 CHAPTER V DISCUSSION ………………………...... 102 5.1 Our findings...... 102 5.2 Measures taken for protocol violation ……….…………..……103 5.3 Strengths and limitations...... 104 5.4 What we have learned from this study ……………...……..…..105 5.5 Suggestion for further studies...... 106 5.6 Conclusions……………………………………………...……..107 REFERENCES...... 108 APPENDICES…………………………………………..…………...…………...126 BIOGRAPHY…...……………………………………..…………………………157
viii
LIST OF TABLES
Table Page 2.1 Previous systematic reviews or meta-analyses of glucosamine with all included outcomes and their conclusions reported by each study...... 23 2.2 Previous systematic reviews or meta-analyses of diacerein with all included outcomes and their conclusions reported by each study……………28 2.3 Characteristics of included studies...... 35 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score according to treatment...... 39 2.5 Summarize results of direct comparisons according to type of interventions………………………………………………………………...... 47 2.6 Sample Size, Mean, and SD between treatment groups for studies included in a Network Meta-analysis...... 49 2.7 Comparisons of treatment effects: a network meta-analysis...... 52 2.8 Frequency of overall adverse events between Treatment groups...... 59 2.9 Summarization all Treatment Effects for Osteoarthritis patients...... 65 3.1 Minimal clinical significance (MCS) and SD of VAS scores, WOMAC total and sub scores of Glucosamine and diacerein from systematic review……...... …..….79 3.2 Budget……………...……………………………………………………..…..82 3.3 Time frame…………………….…………..……………………………….....83 4.1 Baseline characteristics of patients between treatment groups...... 87 4.2 Mean of VAS, WOMAC total, WOMAC sub-score and Joint space width compared between two groups at 1 month to 6 months follow up….....95 4.3 Mean of VAS, WOMAC total, WOMAC sub-score and adverse event (diarrhea and dyspepsia) compared between two groups with or without co-variable (age and BMI) adjusted………………………………………….97
ix
LIST OF TABLES(cont.)
Table Page
4.4 Mean of VAS, WOMAC total, WOMAC sub-score and Joint space width within group at difference time compared to 1 month follow up…...... 99 4.5 Incidence and risk ratio of adverse events between treatment group….....…100 4.6 Proportion of patients in each group reporting adverse events and co-intervention…………….…………………….…………………….…….101
x
LIST OF FIGURES
Figure Page 1.1 Radiographic progressions and changed of knee osteoarthritis…………..…...3 1.2 Kellgren and Lawrence (KL) radiographic criteria for assessment of OA knee...... 4 1.3 X-ray demonstrating primary osteoarthritis knees……………………….....…6 1.4 X-ray demonstrating post-traumatic osteoarthritis knee…………………....…6 1.5 Etiology and pathophysiology of osteoarthritis…………….……………...….8 1.6 Quadriceps strengthening exercise for OA knee……………………….….…10 1.7 Knee brace with the OdrA system (PROTEOR, France)………….………....10 1.8 Arthroscopic findings in lateral joint space. Lateral menisci were damaged and torn. Articular surfaces show eburnation…………..…....…….14 1.9 Macroscopic appearance of representative condyles immediately following the autologous chondrocyte transplantation procedure…..…..…...15 1.10 A series of intraoperative fluoroscopy images depicting the medial opening wedge HTO technique. (A) An osteotomy guide pin is drilled through the medial tibia………………….……………………….…..16 1.11 Unicondylar knee arthroplasty………………………………………….…....17 1.12 Total knee arthroplasty……………………………………………….………17 1.13 Conceptual framework...... 20 2.1 Flow of study selection………………………………………..……...... 34 2.2 Network meta-analysis of treatment effect on VAS...... 54 2.3 Network meta-analysis of treatment effect on total WOMAC score...... 55 2.4 Network meta-analysis of treatment effect on pain WOMAC score...... 56 2.5 Network meta-analysis of treatment effect on function WOMAC score...... 57 2.6 Network meta-analysis of treatment effect on stiffness WOMAC score...... 58 2.7 Network meta-analysis of treatment effects on drug adverse effect…...….…63
xi
LIST OF FIGURES (cont.)
Figure Page 2.8 Drug mechanism of action of Diacerein………..……...……..……...... 67 2.9 Drug mechanism of action of Glucosamine sulfate. ……………...... 68 3.1 Placebo capsules and diacerein were prepared identically to diacerein by appearance, smell, and taste by TRB Chemedica…………...…70 3.2 Weight-bearing metatarsophalangeal radiography……………..……...….....73 3.3 Flow of the patients along with the responsible personnel…………..…...….77 3.4 Trial organization……………………………...... ………………….…...…..84 4.1 Flow diagram……………………………………………...……...…...... 86 4.2 Mean VAS by treatment groups and time………...……………………...... 90 4.3 Mean total and sub-WOMAC scores by treatment groups and time...…...... 93 4.4 Mean difference of JSW between glucosamine plus diacerein group and glucosamine and placebo group at 3 and 6 months follow-up.……...... 94
xii
LIST OF ABBREVIATIONS
AAOS American Academy of Orthopaedic Surgeons ACI autologous chondrocyte implantation ACR American College of Rheumatology AMIC autologous matrix induced chondrogenesis ASU avocado soybean unsaponifiables BMI body mass index CI Confidence intervals CVS Cardiovascular system COX Cyclooxygenases DALYs disabilities adjusted life years EC Ethical committee EULAR European League Against Rheumatism GI Gastro-intestinal HA hyaluronic acid IL-1 Interleukin 1 IFG-I Insulin-like growth factors ITT intention-to-treat analysis JSW joint space width KL Kellgren-Lawrence NSAIDs Non-steroidal anti-inflammatory drugs KAM Knee adduction moment MRI Magnetic resonance image OA Osteoarthritis OARSI Osteoarthritis Research Society International RRP Platelet rich plasma RCT randomized control trial
xiii
LIST OF ABBREVIATIONS(cont.)
ROME Range of motion exercise RR risk ratio SD standard deviation SYSADOA symptomatic slow acting drugs for OA TENS Transcutaneous electrical nerve stimulation TKA Total knee arthroplasty UKA Unicompartmental knee arthroplasty UMD unstandardized mean difference VAS visual analog scores WOMAC Western Ontario and McMaster osteoarthritis index
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 1
CHAPTER I INTRODUCTION
1.1 Background and rationale Knee osteoarthritis (OA) is the most common type of OA. More than 10 million Americans have knee OA. It is also the most common cause of disability in the United States, United Kingdom and Asia. Early diagnosis and treatment help manage knee OA symptoms. An overview of knee OA will help you understand symptoms, diagnosis, and treatment options 1.
1.1.1 Definition OA is also known as degenerative joint disease, osteoarthrosis, and wear- and-tear arthritis. It can affect the body in many areas including the joints of the fingers, hips, knees, feet and spine. It is the result of both biological and mechanical events that results in the destabilization of the normal process of degradation and synthesis of articular cartilage chondrocytes, extracellular matrix, and subchondral bone. This then leads to loss of cartilage, sclerosis and eburnation of the subchondral bone, development of osteophytes and subchondral cysts. It involves the entire joint, including the subchondral bone, articular cartilage, pericapsular muscles, capsule, and the synovium. OA is clinically characterized by joint pain, stiffness, and functional limitation 2, 3.
1.1.2 Prevalence of osteoarthritis OA is the most prevalent type of arthritis, being just one of more than 100 types of arthritis and related diseases. It occurs most commonly among adults over 65 years of age but people of any age may develop OA 4. Prevalence will raise significantly after the age of 50 years in men and after age 40 in women. According to the ACR, 70% of people over the age of 70 have radiographic evidence of OA. OA of the knee is one of the most common health problems in the United States 5. The elderly population collectively shows a trend toward increased longevity and obesity, resulting in the Jatupon Kongtharvonskul Introduction/ 2
likelihood of the incidence of OA knee increasing dramatically within the next decade 5, 6. Increases in life expectancy and ageing populations are expected to make OA the fourth leading cause of disability by the year 2020 7 In the United States, the prevalence was approximately 15% 8, whereas the recorded prevalence of patients in other countries was 5.5% 4. Many countries in Asia have a large ageing population. It has been estimated that the prevalence of OA knee in the elderly population > 65 years of age in Asia will more than double within the next two decades. The most recently estimated prevalence in elderly Thai patients was approximately 34.5-45.6 percent 9.
1.1.3 Etiology There is no distinct single cause for OA, and the exact etiology for OA is still unknown. There are several mechanical and biological factors that result in the development of OA. Risk factors that increase risk of OA including as follows: - Age, the risk of OA increased with age of more than 50 years in men and 40 years in women2. - Sex, females are more likely to develop OA10. - Obesity, being overweight or obese contributes to OA in several ways. Stress is added to weight-bearing joints11, 12. - Repetitive use of joints and occupation, this includes tasks that place repetitive stress on a particular joint, such as participation in a certain sport. That particular joint may eventually develop OA11. - Previous trauma or injuries, injuries from sport or accident related may increase the risk of OA11, 12. - Family history, a family history of OA of the knee may indicate a greater risk of increased multiple knee structural abnormalities in the medial tibiofemoral compartment11-13. - Congenital or developmental deformities, congenitally malformed joints or defective cartilage can increase the risk of OA11. - Genetic factors, A tendency to develop OA can be genetically inherited11, 14. The above factors may lead to a joint environment that is susceptible to trauma and to external mechanical stressors that are exacerbated by certain physical Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 3
activities. Local mechanical factors (e.g.,periarticular muscle weakness, misalignment, and structural joint abnormality (e.g., meniscal tear)) further enable the progression of the disease. The combination of internal and external factors eventually lead to a failed joint3, 15 .
1.1.4 Diagnostic criteria The American College of Rheumatology (ACR) classification criteria for OA of the knee is one of most widely used tools for clinical diagnosis of OA16 . It includes the criteria as follows: Knee pain with osteophytes, with at least 3 out of 6 other criteria: aged 50 years or older, bony tenderness, stiffness lasting less than 30 minutes, bony enlargement, crepitus, or warmth to touch.
1.1.5 Radiographic classification of OA knee The hallmarks of knee OA are the same for most other joints (see Figure 1.1): - Joint space narrowing: usually asymmetric, typically of the medial tibiofemoral compartment and/or patellofemoral compartment17 - Subchondral sclerosis - Osteophyte formation: patellofemoral osteophytes are more associated with pain17
Figure 1.1 Radiographic progressions and changed of OA knee Jatupon Kongtharvonskul Introduction/ 4
Plain radiographs are the workhorse of imaging including follow-up, although there is poor correlation between radiographic findings and clinical symptoms 18, 19 Most physicians routinely use radiographic classification systems to grade the extent of joint space narrowing in patients considered for treatment. Common clinical approaches to radiographic assessment provide a semi-quantitative judgment of the extent of osteoarthritis, the most common being the Kellgren-Lawrence (KL) 20 or the Osteoarthritis Research Society International (OARSI) classification systems.21, 22 23 or Ahlbäck classification system . 1.1.5.1 The Kellgren and Lawrence system20 is a method of classifying the severity of knee OA using five grades as follows (see Figure 1.2): Grade 0: No feature of OA Grade 1: Doubtful narrowing of joint space and possible osteophytic lipping Grade 2: Definite osteophytes and possible narrowing of joint space Grade 3: Moderate multiple osteophytes, definite narrowing of joint space, and some sclerosis and possible deformity of bone ends Grade 4: Large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity of bone ends
Figure 1.2 KL radiographic criteria for assessment of OA knee 20 Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 5
1.1.5.2 OARSI grading system for medial and lateral tibiofemoral joint space narrowing (% narrowed) Grade 0: normal Grade 1: mild (1-33) Grade 2: moderate (34-66) Grade 3: severe (67-100) 1.1.5.3 Ahlbäck classification system estimates the severity of 23 OA of knee joint, in patients with chronic knee pain . According to Ahlbäck system knee joint OA is classified as: Grade 1: joint space narrowing (less than 3 mm) Grade 2: joint space obliteration Grade 3: minor bone attrition (0-5 mm) Grade 4: moderate bone attrition (5-10 mm) Grade 5: severe bone attrition (more than 10 mm) The main problem with the Ahlbäck classification were that the same observer classified the radiographs twice according to Ahlbäck, the repeatability was fair in both medial OA (kappa values = 0.15–0.65) and lateral OA (0.59–0.76), and between different observers it was poor (kappa: 0.1) and joint space could often be seen radiographically despite the presence of bone attrition on the preparations 24.
1.1.6 Types of Osteoarthritis OA can be classified as primary or secondary according to the following: Primary (idiopathic) OA that there have no preceding joint injury and its can be categorized into localized OA, which mostly affects the hands, knee (Figure 1.3), hip, or foot (especially the first metatarsophalangeal), or generalized OA, usually affecting the hands and another joint. Secondary OA is a previous trauma or other insult to the joint, such as a congenital abnormality (e.g., congenital hip dysplasia), previous trauma, inflammatory arthropathies (e.g., rheumatoid, other forms of arthritis, trauma, metabolic causes, endocrine factors and congenital factors), and ongoing strenuous occupations or physical activity that could lead to joint damage over time 14, 25 (Figure 1.4).
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Figure 1.3 X-ray demonstrating primary OA knees
Figure 1.4 X-ray demonstrating post-traumatic OA knee
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1.1.7 Pathophysiology In the affected joint, there is a failure in maintaining the homeostatic balance of the cartilage matrix synthesis and degradation, resulting from reduced formation or increased catabolism 26. The matrix metalloproteinases (e.g., collagenase) are enzymes that catalyze both collagen and proteoglycan degradation, and these are found in increased concentrations in OA cartilage. These enzymes are produced by chondrocytes. Synthesis of these enzymes can also be stimulated by interleukin 1 (IL-1). IL-1, which is an example of a catabolic cytokine that has been found high levels in the serum of patients with knee OA. On the other hand, levels of anabolic cytokines such as insulin- like growth factors (IGF), are decreased in OA. Another factor is nitric oxide, which is thought to activate the metalloproteinases and has a role in cartilage degradation. Mechanical loading can also contribute in the harming of the chondrocytes and cartilage. The process of OA involves not only the cartilage but also other structures in the joint (Figure 1.5), resulting in bone remodeling and bone marrow lesions of the subchondral bone, capsular stretching and periarticular muscle weakness, synovial inflammation and ligament laxity 27.
The pathophysiology of knee pain starts in the cartilage matrix that is made up of glycosaminoglycans, proteoglycans, chrondrocytes and collagen (see Figure 1.5). All of these usually work synergistically for smooth, pain free movement of the joint. This is why the supplements of glucosamine or chondroitin sulfates are a popular choice of treatment for OA. Any change in the structure of proteoglycans causes inflammation of the synovium lining which then instigates production of intracellular inflammatory mediators, which directly damage the cartilage. The brain and feedback mechanism increases blood flow, causing increased pain and swelling of the joint. Disease progression results in repeated inflammation and repetition of the cycle 28-31.
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Figure 1.5 Etiology and pathophysiology of OA
1.1.8 Treatment There is currently no proven treatment that reverses joint damage from OA. The goal of treatment is to reduce pain and improve function of the affected joints and to slow the progression of disease. This is attained with a combination of physical measures and drug therapy and ultimately surgically. There are many guidelines for the treatment of OA knee such as the European League Against Rheumatism (EULAR) recommendations for the non-pharmacological core management of hip and knee OA, OARSI recommendations for the management of hip and knee OA and the Treatment of OA of the knee of American Academy of Orthopaedic Surgeons (AAOS)
The treatment of OA of the knee is divided into non-operative and operative treatment. Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 9
1.1.8.1 Non-operative treatment is divided into non- pharmacologic treatment and pharmacologic treatment. For non-operative treatment in clinical practice, the combination of pharmacologic and non-pharmacologic therapy is frequently used and is universally recommended in clinical practice guidelines for OA knee 32, 33. Non-pharmacologic treatment Patient education and lifestyle modification Education of patients, social support, and counselling are often helpful. Self-help groups are often organized by charitable organizations. Formal interventions include self-management programs, (e.g., the arthritis self-help course and cognitive behavioral approaches) which are designed to teach patients ways of coping 1, 26, 34-36 with their pain . Physical therapy Physical therapy can help in reduction of pain, swelling, and stiffness of knee OA, and can also improve knee joint function. It can make it easier for the patients to walk, bend, kneel, squat, and sit 37-39. Physical therapy can be divided to passive and active treatment as follow: Passive treatment - Cold therapy: can decrease swelling by reducing circulation. - Heat therapy (e.g. hot pack or ultrasound): Increases blood flow to decrease stiffness in the knee joints and muscles around the knee. - Hydrotherapy: Sometimes referred to as aquatic therapy, this method uses water to decrease knee OA symptoms. - Transcutaneous electrical nerve stimulation (TENS): Using electric currents to stimulate the nerves for therapeutic purposes. Active Treatments - Strengthening exercises: Certain exercises that can be done at home to strengthen the muscles. Exercising muscles in the leg can help make the knee joints stronger. Strengthening these muscles alone can help decrease the pain of knee OA.
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Figure 1.6 Quadriceps strengthening exercise for OA knee40
- Flexibility exercises: Performing these regularly can help increase range of motion, make the knees more flexible, and restore normal knee joint function. Bracing and orthosis: Braces or orthotic devices (see Figure 1.7) appear to have good effect on knee OA in improving pain and function, with an acceptable safety profile and good patient compliance 41.
Figure 1.7 Knee brace with the OdrA system (PROTEOR, France) 41 Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 11
Mechanical intervention Knee adduction moment (KAM), usually used to estimate intra- articular overload, has been strongly related to OA severity and its progression 42, 43. Braces for alignment of the knee and foot splinting are commonly used and frequently recommended as interventions for the management of knee OA 44. Acupuncture has been studied in clinical trials for pain in a number of conditions including OA. Massage therapy has also been studied for pain; however, there are very few studies that look at massage therapy and OA specifically.
Pharmacologic treatment Symptomatic slow acting drugs for OA (SYSADOA) include glucosamine sulfate, chondroitin sulfate and diacerein have symptomatic effects and 45 may modify structure within the joint . Glucosamine and Chondroitin Sulfate (complementary medicine or Dietary Supplements) are a commonly used as complementary and alternative medicine product in the North America. Typically derived from the ground shells of shellfish or from processed grains, it has components that are claimed to restore glycosaminoglycans in arthritic joints and reduce pain and inflammation 46. The OARSI guidelines state that “treatment with glucosamine and/or chondroitin sulfate may provide symptomatic benefit in patients with knee OA,” but “if no response is apparent within 6 months treatment should be discontinued 47. Other guidelines, such as those for the AAOS, make a recommendation that physicians do not prescribe glucosamine. Both sets of guidelines are based on level I evidence 47, 48. Evidence regarding chondroitin sulfate is similarly inconsistent 47. Diacerein is a drug that is recommended in EULAR guidelines as a second line drug in treatment of OA. 45 Analgesic or pain relievers: Acetaminophen is a common first-line analgesic for treatment of knee osteoarthritis. Both the OARSI and EULAR recommend the use of acetaminophen to be a first-line recommendation
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NSAIDs are among the most commonly used analgesics worldwide and often are used as first-line medications 45, 47 for joint pain. However, these are associated with more adverse effects (GI discomfort, renal toxicity and cardiovascular risk) when compared to acetaminophen. GI discomfort occurs more frequently and serious complications such as peptic ulcers, perforations, and bleeds are more likely to occur47, 48. COX-2 inhibitors or gastric protection is recommended in the guidelines where NSAIDs are considered for the management of knee OA45, 47. CVS risk is another concern as COX-2 inhibitors increase risk of thrombotic events. Opioids Weak opioids have increasingly been used recently for the treatment of refractory pain in patients with OA of the hip or knee. Benefits associated with the use of opioids are limited by common side effects such as nausea (30%), constipation (23%), dizziness (20%), somnolence (18%), and vomiting (13%) 47. Topical treatments Topical NSAIDs or capsaicin can be effective adjunctive treatments or alternatives to oral analgesics in knee OA. Side effects are limited to local reactions such as burning, itching, and rashes 47. Intra-articular injections Viscosupplementation Hyaluronic acid (HA) or hyaluronan is a glycosaminoglycan constituent of synovial fluid. Injection of HA preparations into the knee is commonly used to treat pain on weight bearing in OA patients. Corticosteroid therapy Despite the indistinct role of inflammation in the pathogenesis and progression of osteoarthritis, treatment guidelines recommend injection of corticosteroids for OA before considering surgical management. OARSI guidelines state that intra-articular injections with corticosteroid can provide short-term symptomatic relief of knee OA, and should be considered in cases of moderate to severe pain unresponsive to other analgesics and non-pharmacologic modalities 47.
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Potential side effects may include post-injection flares of pain, crystal synovitis, hemarthrosis, joint sepsis, articular cartilage atrophy, and steroid- induced arthropathy. Side effects such as bruising and lipodystrophy may also occur but can be minimized with careful techniques. 1.1.7.2 Operative treatment Choice of surgical treatment is based on symptoms (e.g., pain and knee function), OA stage, and patient-related factors such as age, level of physical activity, and patient’s comorbidities. Radiological evidence of OA alone (joint space narrowing, osteophytes, etc.) does not justify surgical intervention, which is indicated only in combination with relevant symptoms. Ultimately, it is the patient’s degree of suffering in correlation to radiological evidence of OA that determines the point in which surgery is considered. It is important to understand that for OA, surgery is always relatively indicated 49. Operative treatment includes arthroscopic debridement and lavage, cartilage repair techniques, osteotomy 50 and arthroplasty (e.g., Unicompartmental knee arthroplasty (UKA) 51-55, (TKA) 56-59. Arthroscopic Lavage and Debridement Arthroscopic techniques include lavage and debridement of the knee i.e., shaving of rough cartilage or smoothening of the degenerated meniscus (see Figure 1.8). Theoretically, arthroscopy for OA should relieve symptoms by removing debris and the inflammatory cytokines that cause the synovitis 60, 61. Debridement can also remove torn meniscal fragments and loose cartilage flaps. However, the role of arthroscopy in treating knee OA is controversial 47, 62, 63, as arthroscopic debridement may provide only temporary relief of symptoms 64. Patients with less extensive arthritis as seen by radiography, less severe involvement of articular cartilage, and are younger age at the time of surgery have a higher probability of improvement with arthroscopic 65 management . A short duration of pain and mechanical symptoms and mild-to- 66 moderate radiographic stages of arthritis correlate with better results .
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Figure 1.8 Arthroscopic findings in lateral joint space. Lateral menisci were damaged and torn. Articular surfaces show eburnation 67
Cartilage Repair Techniques Damaged articular cartilage has only limited to virtually no healing capacity [21]. Therefore, repair of the cartilage surface has been proposed. Cartilage repair is only indicated for focal cartilage defects, which can been seen as a precursor of OA. If the defect is to extended cartilage, repair is no longer indicated. The different techniques can be divided in bone marrow stimulating techniques (abrasion, drilling, or microfracture), replacement techniques (mosaicplasty or osteochondral allograft transplantation and in grafting) and combined techniques (periost flap transplantation, and autologous chondrocyte implantation (ACI) (see Figure 1.9), autologous matrix induced chondrogenesis (AMIC)) 49
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Figure 1.9 Macroscopic appearance of representative condyles immediately following the autologous chondrocyte transplantation procedure 68
Osteotomy Osteotomy is a standard treatment option for unicompartmental OA of the knee. The classic osteotomy of Coventry was a closed-wedge valgization including a fibula osteotomy and was carried out proximal to the tibial tuberosity 69. This was the most widely used technique for several years. In the 1980s and 1990s, osteotomy around the knee lost its importance due to the success of knee arthroplasty. Compared to arthroplasty, osteotomy was considered a demanding procedure with an unpredictable outcome and was associated with significant complications. During the last decade, after the development of new plates (particularly plates with angular stability) and increasingly used open-wedge osteotomy without bone graft interposition with decreasing risk of damage to the peroneal nerve, so the return of osteotomy for younger 70-72 patients around the knee much more popular (see Figure 1.10) .
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Figure 1.10 a series of intraoperative fluoroscopy images depicting the medial opening wedge HTO technique. (A) An osteotomy guide pin is drilled through the medial tibia73
Arthroplasty In advanced knee OA with multiple compartment involvement and failure of conservative treatments, UKA (Figure 1.11) and TKA (Figure 1.12) have been shown to be highly effective treatments that result in substantial improvement in patient function and health-related quality of life 74. Until now, it is the first-line procedure for end-stage knee OA. The long-term results of TKA have been well documented with survival rates of up to 98% at 15 years 75. Results in younger patients are mostly reported 49, 76 to be inferior with 76% survival rates at 10 years .
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Figure 1.11 Unicompartmental knee arthroplasty 77
Figure 1.12 Total knee arthroplasty 78 Jatupon Kongtharvonskul Introduction/ 18
1.1.8 Knowledge gaps For the pharmacologic therapy, the first-line drug therapy in OA is purely symptomatic with analgesic agents and NSAIDs including COX-2 inhibitors, which are being the most widely prescribed drugs. However, the well-known side effect profiles of currently used treatments, which include an increased risk of cardiovascular events such as heart attacks and stroke 79, indicate that they should be used with caution and avoided in OA patients who have cardiovascular disease 80. There is therefore a need for a therapeutic agent in OA that has symptom-modifying effects, an improved safety profile, and positive (or at least no negative) effects on cartilage structure, medications 81 that are called symptomatic slow acting drugs for OA (glucosamine sulfate, chondroitin sulfate and diacerein) Glucosamine can be naturally found in the human body and is utilized as one of the major building blocks of cartilage and as a precursor for glycosaminoglycan, which a major component is of joint cartilage. It can be taken in pill form as a dietary supplement, or administered by direct injection. It also comes in combination with other supplements (such as chondroitin), or on its own in the form of glucosamine hydrochloride or sulfate. The usual dose recommended on packages is 1500 mg per day or 500 mg three times daily 82. Diacerein (Artrodar) is a drug used in the treatment of OA and works by inhibiting interleukin-1, which is one of the initial cytokines that induce fever, control lymphocytes, increase the number of bone marrow cells and cause degeneration of the bone joint 83. The efficacy of NSAIDs, glucosamine and diacerein compared to placebo are been shown in randomized controlled trials (RCTs) 84, 85 and systematic reviews 86, 87,but none study compares efficacy among them. We have therefore performed a systematic review and network meta-analysis. Our review suggests that glucosamine and diacerein are able to reduce pain but diacerein is more effective. Both glucosamine and diacerein are able to improve function But not for joint space. Diacerein also has more gastrointestinal adverse effects than glucosamine. Although the systematic review and network meta-analysis showed positive effects of diacerein, glucosamine and NSAIDs, it is still unable to compare the outcomes of mono-therapy and combination therapy. This thesis was therefore conducted a randomized controlled trial study with the aims of determining pain and osteoarthritis index at 6 months of mild degree OA Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 19
patients treated with diacerein combined with glucosamine, as compared to treatment with glucosamine alone.
1.2 Research Questions Do combined treatments of diacerein and glucosamine have better efficacy in reducing pain and improving physical function than glucosamine alone in OA patients?
1.3 Research Objectives 1.3.1 To compare pain scores at 4, 8, 12, 20 and 24 weeks between dual- therapy of diacerein and glucosamine versus mono-therapy of glucosamine in OA patients. 1.3.2 To compare total WOMAC scores at weeks 0, 4, 8, 12, 20 and 24 between dual-therapy of diacerein and glucosamine versus mono-therapy of glucosamine in OA patients. 1.3.3 To compare WOMAC sub-scores at weeks 0, 4, 8, 12, 20 and 24 between dual-therapy of diacerein and glucosamine versus mono-therapy of glucosamine in OA patients. 1.3.4 To compare the actual change of joint space width at weeks 0, 4, 8, 12, 20 and 24 between dual-therapy of diacerein and glucosamine and mono-therapy of glucosamine in OA patients. 1.3.5 To compare the rate of and side effects (gastric pain and diarrhea) between dual-therapy of diacerein and glucosamine versus mono-therapy of glucosamine in OA patients.
1.4 Conceptual framework The conceptual framework has been shown in Figure 1.13 Jatupon Kongtharvonskul Introduction/ 20
As the figure describe below, there are many treatments that are associated with OA. These treatments include regular education, exercise, appliances, weight reduction, pain medication (first-line or second-line drugs), intra-articular injection and all the treatments are modifiable and increase/decrease clinical symptoms of OA knee (e.g., pain, function, disability and radiographic change) and delayed time to surgery (joint replacement). The conceptual framework of all possible non-operative treatments that can be improve OA knee symptoms has been drawn and described in Figure 1.13
Figure 1.13 Conceptual frameworks Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 21
CHAPTER II LITERATURE REVIEW
2.1 Glucosamine in OA knee Glucosamine is an amino sugar that is a building block for the glycosaminoglycans that are part of the structure of articular cartilage and proteoglycans82. Once ingested, glucosamine is partially absorbed in the intestine, and it has been suggested that the ingested amount that manages to reach the joints is a natural substance. The rationale for the use of glucosamine in OA is based largely on in-vitro and animal models of osteoarthritis. Glucosamine has been shown to demonstrate mild anti-inflammatory properties, normalize cartilage metabolism, and rebuild experimentally damaged cartilage. Recently, an additional option for pharmacological therapy of OA has included biological compounds 88. Although it has not been yet proved, these compounds are potentially being chondroprotective, in that they may favorably modify the natural progression and course of OA. Glucosamine compounds, in particular, have attracted a great deal of attention. There appears to be controversy as to the relative efficacy of glucosamine, and as to whether glucosamine can indeed modify the progression of OA 89. Both glucosamine sulfate and glucosamine hydrochloride are referred to glucosamine 90-98. Results from randomized trials about the efficacy of glucosamine are inconsistent 85, 99-120. Trials that had reported large effects on joint pain were often 80, 121, 122 debatable due to poor study quality and small sample sizes ,, whereas large methodologically sound trials often found only small or no effects121, 122. To attempt to resolve this conflict, numerous authors have performed systematic reviews on the existing RCTs with or without meta-analysis, see Table 2.1. The first systematic review and meta-analysis 123 of RCTs to evaluate benefits of glucosamine for OA knee or hip was published in the year 2000. The results of glucosamine for treatment of OA symptoms from the pooling of 4 studies demonstrated moderate to large effects, but quality issues and potential publication bias suggest that Jatupon Kongtharvonskul Literature Review / 22 these effects are exaggerated. Nevertheless, some degree of efficacy appears probable for some of glucosamine preparations. The second study (N = 7 studies)89 ,published in year 2003, showed highly significant efficacy of glucosamine on outcomes including joint space narrowing and WOMAC scores. Safety was excellent for this compound. The third review was published in the Cochrane Library 2005 85, included 25 studies with primary outcomes of pain VAS, WOMAC total, pain, function, stiffness, Lequesne index and adverse events. Pooled results using a non-Rotta glucosamine preparation with adequate allocation concealment failed to show benefit in pain and WOMAC function, whereas Rotta glucosamine preparation showed superior effects in the treatment of pain and functional impairment resulting from symptomatic OA. The fourth study assessed the clinical effectiveness and cost-effectiveness of glucosamine sulfate or hydrochloride and chondroitin sulfate in modifying the progression of OA of the knee124. There was evidence that glucosamine sulfate shows some clinical effectiveness but cost-effectiveness was not conclusively demonstrated. The fifth study included 10 studies which evaluated pain and joint space width change98. This study was concluded that when compared with placebo, glucosamine does not reduce joint pain or have an impact on narrowing of joint space. The last two studies125, 126 reported results regarding brand and preparation, and concluded that glucosamine sulfate from Rottapharm/Madaus had a superior outcome to other brands in improving joint function in OA knee patients for more than 6 months, but not for joint pain. In this study, glucosamine hydrochloride was ineffective for relieving pain in OA patients. Summary of results of these reviews are displayed in Teble 2.1. According to previous systematic reviews comparing glucosamine sulfate (Rottapharm and non-Rottapharm), glucosamine hydrochloride and placebo, the current highest level of evidence suggests that glucosamine sulfate (Rottapharm) is superior for relieving pain and improving function when compared to other options. In term of structural change Joint space width narrowing (JSN) and cost-effectiveness, results were still inconclusive. No studies comparing glucosamine with diacerein or a combination of the two have been published.
Table 2.1 Previous systematic reviews or meta-analyses of glucosamine with all included outcomes and their conclusions reported by each Fac. of Grad. Studies, Mahidol Univ. study Author Year N Methodological Subject Sex KL Mean Outcome Full title (studies) quality (patients) (%) grading age McAlindon 2000 4 11 non-RCTs 1710 NM I-IV NM Pain VAS and LI Glucosamine and chondroitin TE (JAMA) 4 studies: RCTs for treatment of osteoarthritis: 124 1 study: Allocation a systematic quality concealment assessment and meta-analysis 2 studies: ITT Richy F 2003 8 8 studies: RCTs 1203 NM I-III NM Pain VAS, Structural and symptomatic (Archives of 5 studies: ITT WOMAC, LI, JSN efficacy of glucosamine and internal and adverse event chondroitin in knee Ph.D.(Clinical Epidemiology) /23 medicine)128 osteoarthritis: a comprehensive meta-analysis Towheed TE 2005 25 25 studies: RCTs 4960 69 I-III 60.7 Pain VAS, Glucosamine therapy for (The 12 studies: method of WOMAC, LI, JSN treating osteoarthritis Cochrane randomization and adverse event database)80 13 studies: Allocation concealment VAS = (visual analog score), LI = Lequesne index, WOMAC = Western Ontario and McMaster index, JSN = Joint space narrowing
Table 2.1 Previous systematic reviews or meta-analyses of glucosamine with all included outcomes and their conclusions reported by Jatupon Kongtharvonskul Literature Review/ / each study (Cont.) Author Year N Methodological Subject Sex KL Mean Outcome Full title quality (patients) (%) grading age (studies)
Black C 2009 8 8 RCTs NM NM I-III NM Cost-effectiveness The clinical effectiveness of (Health Not mention about glucosamine and chondroitin Technol method of supplements in slowing or Assess)125 randomization and arresting progression of Allocation osteoarthritis of the knee concealment Wandel S 2010 10 10 RCTs 3803 62 I-III 68 Pain and joint space Effects of glucosamine, BMJ 99 8: method of width change chondroitin, or placebo in randomization patients with osteoarthritis of 6 studies: Allocation hip or knee: network meta- concealment analysis. 7 studies: ITT 9 studies: blinding Wu D (Int J 2013 17 17 RCTs 3159 NM I-III NM Pain (VAS and Efficacies of different Clin Pract) 126 12 studies: Allocation WOMAC) and LI preparations of glucosamine concealment for the treatment of 12 studies: ITT osteoarthritis: a meta-analysis of randomized controlled trials
VAS = (visual analog score), LI = Lequesne index, WOMAC = Western Ontario and McMaster index, JSN = Joint space narrowing 24
Table 2.1 Previous systematic reviews or meta-analyses of glucosamine with all included outcomes and their conclusions reported by Fac. of Grad. Studies, Mahidol Univ. each study (Cont.)
Author Year N Methodological Subject Sex KL Mean Outcome Full title quality (patients) (%) grading age (studies)
Eriksen P 2014 25 125 RCTs 3458 61 I-III 65.9 Pain (VAS and Risk of bias and brand explain (Arthritis 25 RCTs WOMAC) the observed inconsistency in Care Res) 127 17 studies: method of trials on glucosamine for randomization symptomatic relief of 11 studies: Allocation osteoarthritis: a meta-analysis concealment of placebo-controlled trials 16 studies: ITT Ph.D.(Clinical Epidemiology) /25 16 studies: blinding
VAS = (visual analog score), LI = Lequesne index, WOMAC = Western Ontario and McMaster index, JSN = Joint space narrowing
Jatupon Kongtharvonskul Literature Review / 26
2.2 Diacerein in OA knee Diacerein, an anthraquinone derivate, has been shown in vitro and in vivo to inhibit the production and activity of the cytokine IL-1B 128. This then prevents the IL-1B effect of reducing production of cartilage-specific macromolecules. Diacerein will equally diminish the IL-1B stimulated secretion of metalloproteinases and 129 aggrecanases, thereby preventing breakdown of cartilage by these enzymes . There is strong evidence of a contribution of additional pro-inflammatory cytokines to cartilage degradation in OA 130-133. One of these is IL-1 which stimulates the degradation process and suppresses cartilage-matrix synthesis, with the overall result of a severe degradation of cartilage and following appearance of conditions known to be characteristic of OA 134. A further finding, which may increase the deleterious effect of IL-1, is that human OA cartilage may be more responsive to IL-1 than other healthy cartilage 135, 136. A further potential advantage of using diacerein in OA treatment is that diacerein does not 137 affect the synthesis of prostaglandins and does thereby not have a deleterious effect on the upper gastro-intestinal mucosa 138. This is an important advantage when compared to NSAID treatment. There is some evidence that diacerein has both a symptomatic and a structural effect on cartilage, and clinical trials 139-145 suggest that diacerein therapy significantly decreases OA symptoms when compared to placebo 142. Three systematic review and meta-analysis were published recently 87, 120, 146 (Table 2.2). Firstly, Fidelix et al 87 published a study in Cochrane review year 2006 which suggested from the pooling of 7 studies that diacerein therapy slightly improves of pain. Secondly, Rintelen et al 120 published a study in the Archives of Internal Medicine in the year 2006, in which pooling of 19 studies showed that diacerein was significantly superior to placebo during the active treatment phase. Both diacerein and NSAIDs were similarly efficacious during the treatment period; however, diacerein showed a sustained persisting effect up to 3 months after treatment, with a significant analgesic- sparing effect during the follow-up period, whereas NSAIDs did not. Tolerability assessment revealed no differences between diacerein and NSAIDs, although the latter showed more severe events. Lastly, Bartels et al 146 performed a meta-analysis of 6 randomized controlled trials (RCTs) and conclude that diacerein may be an alternative therapy for OA for patients who cannot take paracetamol or NSAIDs because of adverse effects or lack of benefit. However, it is associated with increased risk of diarrhea, and
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 27 the symptomatic benefit after 6 months remains unknown. The results of these systematic reviews suggests that diacerein decreases pain with a persistent effect after treatment for 3 months when compared to NSAIDs and placebo.
Table 2.2 Previous systematic reviews or meta-analyses of diacerein with all included outcomes and their conclusions reported by each Jatupon Kongtharvonskul Literature Review/ / study
Author Year N Methodological Subject Sex (%) KL Mean Outcome Full title (studies) quality (patients) grading age Fidelix TS 2006 10 10 RCTs 2069 NM I-III 59.69 Pain VAS, LI and Diacerein for (Cochrane 6 studies: method of adverse event osteoarthritis review randomization (diarrhea) database) 82 1 studies: Allocation concealment 6 studies: blinding 2 studies: free of Incomplete outcome report Rintelen B 2006 19 19 RCTs 1328 NM I-IV 60.5 Pain VAS, WOMAC A meta-analysis of (Arch Intern 11 studies: ITT (total, pain, function controlled clinical Med)121 and stiffness), LI, GS studies with diacerein and adverse event in the treatment of osteoarthritis Bartel EM 2010 6 6 studies: RCTs 1533 61 I-IV 63 Pain (VAS and Symptomatic efficacy (Osteoarthritis 6 studies: method of WOMAC) and adverse and safety of diacerein and cartilage) randomization event in the treatment of 3 studies: Allocation osteoarthritis concealment
28
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 29
2.3 Systematic review and network meta-analysis of efficacy and safety of glucosamine, diacerein, and NSAIDs in osteoarthritis knee Diacerein and glucosamine have the greatest amount of RCTs studies and meta-analysis when compared to all other SYSADOA. The results of all the studies show that diacerein and glucosamine improve symptoms and decrease structural progression in OA of the knee when compared to NSAIDs and placebo. Previous systematic reviews 85, 87, 89, 98, 120, 123-126, 146 showed that diacerein had higher efficacy in reducing pain and Lequesne algofunctional index, but increased risk of diarrhea when compared to placebo 120, 146. Similar effects were observed in systematic reviews of the efficacy of glucosamine, which showed a significant reduction in pain when compared to placebo but no effect on minimal joint space narrowing or adverse events85, 98. However, RCT directly compared the clinical efficacy and safety of diacerein with glucosamine. We therefore conducted a systematic review with a network meta-analysis of RCTs with the aim of comparing relevant clinical outcomes (i.e. visual analog score, WOMAC score, Lequesne algofunctional index, joint space width and adverse events) between diacerein, glucosamine, NSAIDs and placebo. The main outcomes that were focused on in this study included pain, functional assessment, joint space width change, and safety issues of the medications.
2.3.1 Methods 2.3.1.1 Search Strategy The Medline and Scopus databases were used to identify relevant studies published in English from the date of inception to August 29th, 2014. The PubMed and Scopus search engines were used to locate studies using the following search terms: (osteoarthritis, degenerative arthritis, adult, elderly), (Symptomatic Slow Acting Drug for Osteoarthritis; SYSADOA, diacerein, glucosamine), (pain, function, score, grade, WOMAC, Knee society score (KSS), motion, radiographic grading, x-ray, MRI, KellgrenLawrance), (clinical trial, RCT, randomized controlled trial). Search strategies for Medline and Scopus are described in the appendix. Relevant studies from the reference lists of identified studies and previous systematic reviews were also explored.
Jatupon Kongtharvonskul Literature Review / 30
2.3.1.2 Selection of studies Identified studies were selected by one author (J.K) and randomly checked by A.T. Titles and abstracts were initially screened; full papers were then retrieved if a decision could not be made from the abstracts. The reasons for ineligibility or exclusion of studies were recorded and described. 2.3.1.3 Inclusion criteria Randomized controlled trials or quasi-experimental designs comparing clinical outcomes between treatments in primary OA patients knee were eligible if they met the following criteria: - Compared clinical outcomes between glucosamine (either glucosamine sulfate or glucosamine hydrochloride) and diacerein, or each of these treatments with other comparators (e.g. placebo, non-steroidal anti-inflammatory drugs) - Compared at least one of following outcomes: pain score, function, patient/physician global assessments, range of motion, joint space width difference and adverse events. - Had sufficient data to extract and pool: reported mean, standard deviation (SD), numbers of subjects according to treatments for continuous outcomes, number of patients according to treatment for dichotomous outcomes. 2.3.1.4 Data extraction Two reviewers (J.K. and T.A.) independently performed data extraction using standardized data extraction forms. General characteristics of the study (mean age, gender, body mass index, duration of OA, pain score and functional scores at baseline) were extracted. The number of subjects, mean, and SD of continuous outcomes (pain by visual analog score (VAS), WOMAC total and sub-scores, and Lequesnen Algofunctional index) between groups were extracted. Cross-tabulated frequencies between treatments and adverse events were also extracted. Any disagreements were resolved by discussion and consensus with a third party (A.T.). 2.3.1.5 Risk of bias assessment Two authors (J.K. and T.A) independently assessed risk of bias for each study. Six study quality domains were considered, including sequence generation, allocation concealment, blinding (participant, personnel, and outcome
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 31 assessors), incomplete outcome data, selective outcome reporting, and other sources of bias147. Disagreements between two authors were resolved by consensus and discussion with a third party (A.T). 2.3.1.6 Outcomes measures The outcome of interests were pain VAS, total and sub- WOMAC scores (pain, stiffness, and function), Lequesne Algo-functional index, joint space width (minimum) and adverse events. Methods of measure for these outcomes were used according to the original studies. Briefly, this includes the VAS pain scale from 0-10; the WOMAC score that consists of pain (0-20), stiffness (0-8), and function (0- 68) with total scores of 0 to 96148. The Lequesne Algo-functional index measured pain (0-10), maximum distance walked (0-6) and activities of daily living (0-8) with total scores of 0 to 24148, 149. For joint space width change, lower values of these scores refer to better outcomes. Adverse events were considered as composite and separate outcomes of the following: a musculoskeletal disorder, respiratory disorder, genitourinary tract disorder, or central nervous system disorder, and GI adverse effects. 2.3.1.7 Statistical analysis Direct comparisons of continuous outcomes were measured at the end of each study between glucosamine versus placebo, and diacerein versus placebo, and were then pooled using an unstandardized mean difference (UMD). Heterogeneity of the mean difference across studies was checked using the Q statistic and the degree was quantified using the I2 statistic. If heterogeneity was present (p-value < 0.10 or the I2 > 25%), the UMD was estimated using a random effects model; otherwise a fixed effects model was applied as in the following equations: Fixed effect model (Inverse-variance method)
∑ ∑
95% Confidence interval (CI) = 1.96
Jatupon Kongtharvonskul Literature Review / 32
Random effect model
∗ ∑ = ∗ ∑
∗ = = ∑ ∑ ∑
=
Q test and I2 statistic were used to assess the presence and degree of heterogeneity as equations below: Q = ∑
= ln e.g., ln , ln , ln
= ln = Q ~Chi-square with k-1 degree of freedom
For dichotomous outcomes, a relative risk (RR) of adverse reactions of treatment comparisons at the end of each study was estimated and pooled. Heterogeneity was assessed using the same method as mentioned previously. If heterogeneity was present, the Dersimonian and Laird method150 was applied for pooling; otherwise, the fixed effects model by inverse variance method was applied. Meta-regression was applied to explore the source of heterogeneity (e.g., mean age, percentage of females, Bone Mass Index (BMI), Kellgran-Lawrance grading, duration of OA) if data was available. Publication bias was assessed using contour-enhanced funnel plots127, 151 and Egger tests152. For indirect comparisons, network meta-analyses were applied to assess all possible effects of treatment measured at different times if summary data were available for pooling153-155. A linear regression model weighted by inverse variance was applied to assess the treatment effects with adjustment for study effects and time for continuous outcomes. For adverse events, a mixed-effect Poisson regression was
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 33 applied to assess treatment effects154. Summary data was expanded to individual patient data using the “expand” command in STATA. Treatment was considered as a fixed- effect whereas the study variable was considered as a random-effect in a mixed-effect model as in the following equation:
yij 0 jTreatmentj j ij,
where y binary distribution, which linked with independent variables using a family of log-link function i is random effect with normal distribution as
ζ i ~ N (0, ψ ) . The error term is normal distribution with mean 0 and variance of θ,
~ 0, . The pooled RR and its 95% confidence intervals (CIs) were estimated by exponential coefficients of treatments. All analyses were performed using STATA version 12.0 156. A p-value < 0.05 was considered statistically significant, except for the test of heterogeneity where p-value < 0.10 was used.
2.3.2 Results Among 505 identified studies and 2 referred studies, 31 studies 99-117, 139- 145, 157-161 were eligible for data extraction. Reasons for ineligibility are described in Figure 2.1. Characteristics of the 31 studies 99-117, 139-145, 157-161 are described in Table 2.3. Among 23 glucosamine studies85, 104-125, the comparators included placebo, NSAIDs, and both placebo and NSAIDS in 17 studies104, 105, 107-111, 113, 115-117, 119-121, 123-125, 4 studies106, 112, 114, 118, 166, and 2 studies106, 122 respectively. All studies used glucosamine sulfate, except for one study 109 which used glucosamine hydrochloride. Among 8 diacerein studies, 5 studies144-148, 2 studies149, 150 and 1 study144 had comparators as placebo, NSAIDs, and both NSAIDs and placebo respectively. Most studies (24/27) included OA of the knee and the rest were OA of the hip. Mean age, body mass index (BMI), and duration of OA varied from 42 to 69 years, 24.0 to 32.6 kg/m2 and 1.6 to 13 years respectively. Percentage of females in each study ranged from 5.1% to 88%. Duration of treatment ranged from 4 weeks to 3 years. Various outcomes were compared between treatment groups (see Figure 2.1).
Jatupon Kongtharvonskul Literature Review / 34
Figure 2.1 Flow of study selection
Table 2.3 Characteristics of included studies Fac. of Grad. Studies, Mahidol Univ.
Author Years Follow up Intervention Comparator Age Female BMI Duration Outcome (mg) (%)
Pujalte JM 1980 8 weeks GS(1500) Placebo 61.7 85 - - VAS, AR Lopes VA 1982 8 weeks GS (1500) NSAIDSs 56.4 74 - 3.2 VAS, AR Muller FH 1994 4 weeks GS(1500) NSAIDSs 54 42.3 - 4.8 Lequesne, AR Noack W 1994 4 weeks GS (1500) Placebo 55 60.3 - Lequesne, AR - Nguyen M 1994 8 weeks D (50) NSAIDs, 62 62.7 5.25 placebo - VAS, Lequesne, AR Qiu GX 1998 4 weeks GS(1500) NSAIDs 56.4 79 - - VAS, AR Houpt JB 1999 8 weeks GH (1500) Placebo 64.5 64.4 8.3 - WOMAC, AR Rindone JP 2000 4, 8 week GS(1500) Placebo 63.5 5.1 13 Ph.D.(Clinical Epidemiology) /35 - VAS, AR Pelletier JP 2000 24 weeks D (50,100,150) Placebo 62.8 76 31.28 7.9 VAS Reginster JY 2001 3 year GS (1500) Placebo 65.8 79.4 7.8 WOMAC, JSW, AR 27.35 Dougados M 2001 3 years D (100) Placebo 62.6 84 - - Lequesne, JSW Hughes R 2002 6 months GS(1500) Placebo 62.3 68 7.63 - AR Pavelka K 2002 1,2,3 years GS (1500) Placebo 62.4 78.5 10.55 25.7 Lequense, JSW, AR Braham R 2003 3 months GS(2000) Placebo 42.2 28.3 12.97 - AR Cibere J 2004 24 weeks GS (1500) Placebo 64.5 57.7 1.6 AR 25.26 GS = glucosamine sulfate, GH = glucosamine hydrochloride, D = diacerein, VAS = visual analog score, JSW = joint space width, AR = adverse event
Jatupon Kongtharvonskul Literature Review/ / Table 2.3 Characteristics of included studies (Cont.) Author Years Follow up Intervention Comparator Age Female BMI Duration Outcome (mg) (%) McAlindon T 2004 12 weeks GS(1500) Placebo - 64 32.57 - WOMAC, AR Pham T 2004 1 year D (100) Placebo 64.7 65.3 29.6 - Lequesne 2006 24 weeks GS (1500) Placebo, 10 Clegg DO NSAIDs 58.7 42.2 31.73 WOMAC, AR Zheng WJ 2006 12,16 weeks D (100) NSAIDs 56.2 66.2 26.13 7.23 VAS, WOMAC, AR Herrero- 2007 24 weeks GS(1500) Placebo 7.31 Beaumont G 63.9 88 27.65 Lequesne, AR Louthrenoo W 2007 12,24 weeks D (50) NSAIDs 54 73 26.85 3.58 WOMAC
Pavelka K 2007 12,24 week D (50) Placebo 63.7 65.5 28.9 6.497 WOMAC, AR Frestedt JL 2008 12 weeks GS(1500) Placebo 59.1 60 32.24 - WOMAC, AR 2008 18 weeks GS (1500) Placebo - JSW Kawasaki T 68.9 - 23.95 2008 3,12,24 month GS(1500) Placebo - Rozendaal RM 63.4 69.4 27.95 JSW, AR 2008 2 months GS (1500) placebo, 8.52 Sawitzke AD NSAIDs 50.6 55.7 - JSW Brahmachari B 2009 12 weeks D (50) Placebo 49.1 83.6 24.66 2.76 VAS, WOMAC, AR Madhu K 2013 6 weeks GS (1500) Placebo 56.8 70 27.9 - VAS, AR Chopra A 2013 24 weeks GS (1500) NSAIDs 55.5 - 27.7 - WOMAC, AR
Durmus D 2013 12 weeks GS (1500) Placebo 55.8 - 27.7 - WOMAC Kwoh CK 2014 24 weeks GS (1500) Placebo 52.24 48.9 28.9 - WOMAC, AR
GS = glucosamine sulfate, GH = glucosamine hydrochloride, D = diacerein, VAS = visual analog score, JSW = joint space width, AR = adverse event 36
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 37
2.3.2.1 Direct comparisons Data used for direct comparisons for all treatments and outcomes were measured at the end of each study, as described in Table 2.3. Pooling according to outcomes was performed if there were at least two studies for each comparison, as clearly described below. Visual analog score Among 8 studies107, 112, 113, 115, 139, 140, 144, 160, 5 studies compared glucosamine pain VAS with comparators of placebo112, 115, 119 and NSAIDs107, 113 respectively. Three studies compared diacerein with placebo139, 140 and NSAIDs144. Most studies assessed pain using the VAS at 4 weeks to 3 years. Data for the mean and SD of VAS scores are described in Table 2.4. The mean VAS was -0.90 (95% CI: -1.67, -0.14) units significantly lower in glucosamine than NSAIDs (see Table 2.4). The mean VAS score was about -1.44 (95% CI: -3.01, 0.12) units lower in glucosamine than placebo, but this was not significant. The pooled effects of diacerein versus placebo from three studies (n =103 vs 98) displayed no heterogeneity (I2 =0%) with an UMD of -2.23 (95% CI: -2.82, -1.64). The effect of diacerein versus NSAIDs was not statistically different with an UMD of 0.149 (95% CI: -0.29, 0.59). There was no evidence of publication bias for both pooled effect estimates. WOMAC score As described in Table 2.4 and summarized in Table 2.5, the total WOMAC scores were compared as change from baseline and the actual scores measured at the end of each study. Among 6 studies 100, 102, 103, 106, 108, 111 with total WOMAC score changes, the effects displayed no heterogeneity (I2 =0%) with an UMD of -2.49 (95% CI: -4.14, -0.83). The actual total WOMAC scores from 2 studies 102, 104 were not statistically significant with an UMD of 5.67 (95% CI: -11.26, 22.61). The actual total WOMAC scores and change in WOMAC sub-scores (pain, stiffness, and function) were also compared (Table 2.4). Compared with placebo, glucosamine resulted in a significantly greater change in WOMAC pain scores with an UMD of - 0.75 (95% CI: -1.18, -0.32). In addition, mean functional and stiffness WOMAC scores were significantly lower in the diacerein groups when compared to NSAIDs and placebo groups (6.64 (95% CI: -10.50, -2.78) and -0.68 (95% CI: -1.20, -0.16)).
Jatupon Kongtharvonskul Literature Review/ 38
Lequesne score and joint space width Only glucosamine resulted in a significantly greater change of Lequesne score when compared to placebo (UMD =-1.030 (95% CI: -1.34, -0.72)) (see Table 2.5). However, glucosamine did not result in a significant change in joint space when compared to placebo with an UMD of 0.008 (95% CI: -0.232, 0.248). Adverse events Compared with a placebo control, composite adverse events were 1.12 (95% CI: 1.02, 1.23) and 5.58 (95% CI: 2.14, 14.59) times significantly higher in glucosamine and diacerein than in placebo (see Table 2.5). When considering only GI adverse events, the pooled RR of glucosamine was 0.99 (95% CI: 0.82, 1.19) when compared with placebo, and 0.393 (95% CI: 0.157, 0.588) when compared with NSAIDs. Conversely, diacerein respectively had 2.00 (95% CI: 0.69, 5.74) and 1.37 (95% CI: 0.89, 2.10) times more GI effects than placebo and NSAIDs, but this data was not statistically significant.
Table 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score according Fac. of Grad. Studies, Mahidol Univ. to treatment
Author Outcome a Active treatment Comparator Treatment NSAIDs Placebo No. of Score, mean(SD) No. of Score, mean(SD) No. of Score, mean(SD) participant participant participant Pain score Glucosamine Pujalte JM, (1980) VAS 10 3.13 (0.63) 10 5.9 (1.98) Rindone JP, (2000) VAS 49 4.9 (2.8) 49 4.9 (2.2) Mudhu K, (2013) VAS 30 2.93 (2.06) 30 4.60 (2.08) UMD (95%CI) -1.44 (-3.01, 0.12) Lopes VA, (1982) VAS 18 2.7 (1.6) 20 4 (2) Ph.D.(Clinical Epidemiology) /39 Qiu GX(1998 VAS 88 3.6(4.07) 90 4.18(2.81) UMD (95%CI) -0.90 (-1.67, -0.14 )* Diacerein Brahmachari B VAS 28 3.39 (1.193) 27 6.03(1.3) (2009) Nguyen M, (1994) VAS 75 4.0 (2.6) 75 3.8 (2.7) 71 4.8 (2.4) UMD (95%CI) -2.23 (-2.82, -1.64)* Zheng WJ, (2006) VAS 106 2.86 (1.97) 107 2.73 (1.83) UMD (95%CI) VAS 0.15 (-0.29, 0.59)
Table 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score Jatupon Kongtharvonskul Literature Review /
according to treatment (Cont.) Author Outcome a Active treatment Comparator Treatment NSAIDs Placebo No. of Score, mean(SD) No. of Score, mean(SD) No. of Score, mean(SD) participant participant participant Glucosamine Houpt JB, (1999) Total WOMAC 58 36.57 (19.50) 60 38.57 (19.30) Score Frestedt JL, (2008) Total WOMAC score 15 70.2 (17.6) 16 54.8 (22.7) UMD (95%CI) 5.67 (-11.26, 22.61) Diacerein Louthrenoo W, Total WOMAC score 82 16.67 (17.76) 79 35.86 (27.69) (2007) Pavelka K, (2007) 82 30.36 (20.45) 83 39.4 (21.87) Glucosamine Score change Pavelka K, (2002 Total WOMAC change 101 -8 (8.72) 101 -4.9 (8.72) Cibere J, (2004) 71 -3.24 (15.52) 66 -3.4 (18.12) McAlindon T, (2004) 101 7.8 (13.1) 104 7.8 (13.5) Herrero-Beaumont G, 106 -12.9 (14.71) 104 -8.2 (16.13) (2007) Frestedt J, (2008) 15 -10.9 (15.6) 16 -6.1 (17.6) Kawasaki T, (2008) 39 -14.9 (15.9) 32 -11.5 (13.2) UMD (95%CI) -2.49 (-4.14, -0.83)*
40
Table 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score Fac. of Grad. Studies, Mahidol Univ.
according to treatment (Cont.) Author Outcome a Active treatment Comparator Treatment NSAIDs Placebo No. of Score, mean(SD) No. of Score, mean(SD) No. of Score, mean(SD) participant participant participant Glucosamine Houpt JB, (1999) Pain WOMAC score 58 7.14 (4.01) 60 7.65 (4.13) Clegg DO, (2006) 317 5.97 (4.64) 318 5.43 (4.33) 313 6.04 (4.52) Frestedt JL, (2008) 15 14.58 (3.52) 16 10.58 (4.28) Durmus D (2013) 18 0.55 (0.7) 19 1.94 (1.99) UMD (95%CI) 0.06 (-1.33, 1.45) Diacerein Ph.D.(Clinical Epidemiology) /41 Louthrenoo W,(2007) Pain WOMAC score 82 3.32 (3.53) 79 8.05 (3.53) Pavelka K, (2007) 82 4.36 (1.49) 83 4.2 (1.6)
Glucosamine Score change Pavelka K, (2002) Pain WOMAC score 101 -2.0 (2.56) 101 -1.3 (11.18) Ringister JY, (2001) 106 -1.35 (3.78) 106 -0.33 (4.46) Cibere J, (2004) 71 -1 (3.92) 66 -1.12 (4.16) McAlindon T, (2004) 101 2 (3.4) 104 2.5 (3.8) Clegg D, (2006) 317 -3.36 (4.62) 318 -4 (4.12) 313 -3.44 (4.57) Herrero-Beaumont G, 106 -2.7 (3.15) 104 -1.8 (3.64) (2007)
Table 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score Jatupon Kongtharvonskul Literature Review /
according to treatment (Cont.) Author Outcome a Active treatment Comparator Treatment NSAIDs Placebo No. of Score, mean(SD) No. of Score, mean(SD) No. of Score, mean(SD) participant participant participant Frestedt J, (2008) 15 -12.6 (16.3) 16 -2.9 (19.9) Kawasaki T, (2008) 39 -3.6 (4.4) 32 -2. (2.7) Rozendaal R, (2008) 111 -1. 9(1.6) 111 -0.3 (1.6) Chopra A (2013) 108 -2.72(3.29) 105 -1.9(3.03) Kwoh CK (2014) 98 -3.48(4.2) 103 -4.18(10.67) UMD (95%CI) -0.75(-1.18, -0.32)* -0.07 (-1.5, 1.36) Glucosamine Score change Houpt JB, (1999) Stiffness WOMAC score 58 3.39 (1.81) 60 3.73 (1.76) Clegg DO, (2006) 317 2.82 (2.09) 318 2.67 (2.06) 313 2.82 (1.95) Frestedt JL, (2008) 15 2.49 (0.79) 16 1.85 (1.01) UMD (95%CI) 0.091 (-0.381, 0.564) Diacerein Louthrenoo W,(2007) 86 1.44(1.49) 79 2.28 (2.25) Pavelka K, (2007) 82 2.68 (1.87) 83 3.52 (2.06) Brahmachari B(2009) 28 1.82 (1.35) 27 2.06 (2.31)) UMD (95%CI) -0.681 (-1.200, -0.162)*
42
Table 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score Fac. of Grad. Studies, Mahidol Univ.
according to treatment (Cont.) Author Outcome a Active treatment Comparator Treatment NSAIDs Placebo No. of Score, mean(SD) No. of Score, mean(SD) No. of Score, mean(SD) participant participant participant Glucosamine Score change Pavelka K, (2002) Stiffness WOMAC score 101 -0.31 (1.95) 101 0.11 (1.18) Cibere J, (2004) 71 0.08 (1.68) 66 0.24 (1.92) McAlindon T, (2004) 101 0.7 (1.6) 104 0.8 (1.5) Clegg D, (2006) 317 -1.39 (2.1) 318 -1.66 (2.41) 313 -1.46 (2.09) Frestedt J, (2008) 15 -0.42 (0.96) 16 -0.24 (0.73) Kawasaki T, (2008) 39 -1.5 (1.7) 32 -0.7 (1.3) Ph.D.(Clinical Epidemiology) /43 Rozendaal R, (2008) 111 -0.14(1.05) 111 -0.09 (0.96) UMD (95%CI) -0.019 (-0.063, 0.026) Glucosamine Houpt JB, (1999) Function WOMAC score 58 25.98 (14.7) 60 27.17 (14.1) Clegg DO, (2006) 317 21.27 (15.54) 318 20 (15.31) 313 21.61 (14.96) Frestedt JL, (2008) 15 48.08 (12.51) 15 38.35 (16.32) Durmus (2013) 18 2.94(2.91) 19 9.89 (1.13) UMD (95%CI) -4.78(-5.96, -3.59)* Diacerein Zheng WJ, (2006) Function WOMAC score 107 12.31 (9) 106 14.60 (9.84) Louthrenoo W,(2007) 82 11.91 (12.92) 79 25.56 (20.66) UMD (95%CI) -7.721 (-18.833, 3.391)
Table 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score Jatupon Kongtharvonskul Literature Review /
according to treatment (Cont.) Author Outcome a Active treatment Comparator Treatment NSAIDs Placebo No. of Score, mean(SD) No. of Score, mean(SD) No. of Score, mean(SD) participant participant participant Pavelka K, (2007) 82 21.76 (14.64) 83 28.2 (15.68) Brahmachari B 28 24.51 (13.47) 27 31.6 (13.06) (2009) UMD (95%CI) -6.637 (-10.500, -2.775)* Glucosamine Score change Pavelka K, (2002) Function WOMAC score 101 -5.8 (7.18) 101 -3.7 (6.15) Ringister JY, (2001) 106 6.53 (9.61) 106 2.67 (13.73) Cibere J, (2004) 71 -2.32 (10.8) 66 -2.52 (12.72) McAlindon T, (2004) 101 5.2 (9.5) 104 4.6 (9.6) Clegg D, (2006) 317 -8.89 (15.53) 318 -289.3 (340.7) 313 -9.09 (14.51) Herrero-Beaumont G, 106 -9.2 (10.51) 104 -5.5 (11.47) (2007) Frestedt J, (2008) 15 -10.6 (15.4) 16 -7 (18.4) Kawasaki T, (2008) 39 -9.8 (11) 32 -7.5 (9.8) Rozendaal R, (2008) 111 -1.69 (1.3) 111 0.38 (1.3) Chopra (2013) 105 -8.12(11.02) 108 -6.93(10.04) 98 103 UMD (95%CI) -0.58 (-1.98, 0.81) -0.84 (-2.95, 4.63) 44
Table 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score Fac. of Grad. Studies, Mahidol Univ.
according to treatment (Cont.) Author Outcome a Active treatment Comparator Treatment NSAIDs Placebo No. of Score, mean(SD) No. of Score, mean(SD) No. of Score, mean(SD) participant participant participant Glucosamine Muller FH, (1994) actual Lequesne score 94 9.6 (5.82) 95 9.6 (5.85) Noack W, (1994) actual Lequesne score 120 7.4 (5.48) 121 8.4 (4.4) Diacerein Nguyen M, (1994) actual Lequesne score 75 7.7 (4.6) 75 6.9 (4.6) 71 8.4 (4.1) Glucosamine Pavelka K, (2002) Lequesne score change 101 -1.7 (2.56) 101 -0.82 (1.59) Ph.D.(Clinical Epidemiology) /45 Herrero-Beaumont G Lequesne score change ) 106 -3.1 (4.2) 104 -1.9 (3.64) UMD (95%CI) -1.03 (-1.34, -0.72)* Diacerein Dougados M, (2001) Lequesne score change 255 -0.5 (4) 252 -0.5 (4.2) Pham T, (2004) Lequesne score change 85 -18.8 (14.7) 85 -18.9 (16.9) UMD (95%CI) 0.002 (-0.704, 0.708) Glucosamine Ringister JY, (2001) Joint space width 106 -0.06(0.79) 106 0.31 (0.95) Pavelka K, (2002) Joint space width 101 0.04 (0.51) 101 -0.19 (0.51) Kawasaki T, (2008) Joint space width 39 0.0 (1.0) 32 -0.3 (1.0) Rozendaal R, (2008) Joint space width 111 -0.094 (0.32) 111 -0.057 (0.32) UMD (95%CI) 0.008 (-0.232, 0.248)
Table 2.4 Direct comparison of means VAS, WOMAC (total, pain, stiffness and function), Lequesne actual and difference score Jatupon Kongtharvonskul Literature Review /
according to treatment (Cont.) Author Outcome a Active treatment Comparator Treatment NSAIDs Placebo No. of Score, mean(SD) No. of Score, mean(SD) No. of Score, mean(SD) participant participant participant Diacerein Dougados M, (2001) Joint space width 246 0.18 (0.25) 247 0.23 (0.23) aoutcome score: VAS, total WOMAC, pain WOMAC, stiffness WOMAC, function WOMAC, actual Lequesne, Lequesne score change, joint space width *statistically significant difference (P < 0.05)
46
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Table 2.5 Summarize results of direct comparisons according to type of interventions
Clinical outcomes No. studies I2 No. subjects UMD (95% CI) VAS Glu vs. Pla 3 83.4 89 vs. 89 -1.44 (-3.01, 0.12) Glu vs. NSAIDs 2 0 106 vs. 110 -0.90 (-1.67, -0.14)* Dia vs. Pla 2 0 103 vs. 98 -2.23 (-2.82, -1.64)* Dia vs. NSAIDs 2 0 181 vs. 182 0.15 (-0.29, 0.59) Total WOMAC score change Glu vs. Pla 6 0 437 vs. 423 -2.49 (-4.14, -0.83)* Actual score Glu vs. Pla 2 79.8 73 vs. 76 5.67 (-11.26, 22.61) Pain Womac score change Glu vs. Pla 10 66.3 1069 vs. 1056 -0.75(-1.18, -0.32)* Glu vs. NSAIDs 2 85.5 425 vs. 423 -0.07 (-1.5, 1.36) Actual score Glu vs. Pla 4 81 408 vs. 418 0.06 (-1.33, 1.45) Functional WOMAC score change Glu vs Pla 10 67.6 1069 vs. 1056 -0.58 (-1.98, 0.81) Glu vs. NSAIDs 2 77.1 425 vs. 423 -0.84 (-2.95, 4.63) Actual score Glu vs. Pla 4 90.5 408 vs. 418 -4.78(-5.96, -3.59)* Dia vs. Pla 2 0 110 vs. 110 -7.72 (-18.83, 3.39) Dia vs. NSAIDs 2 92.9 189 vs. 185 -6.64 (-10.50, -2.78)* Stiffness WOMAC Score change Glu vs. Pla 7 68.1 759 vs. 743 -0.02 (-0.06, 0.03) Actual score Glu vs. Pla 3 31.5 390 vs. 389 0.09 (-0.38, 0.56) Dia vs. Pla 2 1 110 vs. 110 -0.68 ( -1.20, -0.16)* Lequesne score Scores change Glu vs. Pla 2 87.7 207 vs. 205 -1.03 (-1.34, -0.72) * Dia vs. Pla 2 0 340 vs. 337 0.002 (-0.704, 0.708) Joint space width Gu vs Pla 4 86.4 357 vs. 350 0.008 (-0.232, 0.248)
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Table 2.5 Summarize results of direct comparisons according to type of interventions (Cont.)
Clinical outcomes No. studies I2 No. subjects UMD (95% CI) All adverse events RR (95% CI) Glu vs. Pla 16 7.3 1366 vs. 1365 1.12 (1.02, 1.23)* Glu vs. NSAIDs 5 81.9 631 vs. 632 0.53 (0.24, 1.20) Dia vs. Pla 4 76.6 275 vs. 278 5.58 ( 2.14, 14.59)* Dia vs. NSAIDs 2 97.6 181 vs. 182 1.59 ( 0.47, 5.44) GI Adverse event Glu vs. Pla 14 0 1217 vs. 1211 0.99 ( 0.82, 1.19) Glu vs. NSAIDs 5 74.3 631 vs. 632 0.51 ( 0.22, 1.20) Dia vs. Pla 6 94.9 937 vs. 701 2.00 ( 0.69, 5.74) Dia vs. NSAIDs 3 86.6 373 vs. 267 1.37 ( 0.89, 2.10) *statistically significant difference (P < 0.05)
2.3.2.2 Network meta-analysis Visual Analog Score Data from 8 studies 107, 112, 113, 115, 119, 139, 140, 144 were included in pooling of indirect comparisons of the VAS scores (see Table 2.6). Mean VAS scores measured at 4 to 24 weeks after receiving treatments were fitted as the dependent variable in a mixed linear regression model. The VAS score was lowest in the diacerein group with an overall mean of 3.28 (95% CI: 2.25, 4.30) followed by glucosamine (3.30, 95% CI: 2.61, 4.01), NSAIDs (3.31, 95% CI: 2.13, 4.50), and placebo groups (5.05, 95% CI: 3.79, 6.32). The regression analysis suggested that all active treatments resulted in a significant difference in VAS score when compared to placebo (see Table 2.7). Multiple comparisons suggested no difference in effects between active treatments (see Figure 2.2).
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Table 2.6 Sample Size, Mean, and SD between treatment groups for studies included in a Network Meta-analysis Author Treatments VAS pain score n Mean SD Pujalte, JM, (1980) Glucosamine sulfate 10 3.13 0.63 Placebo 10 5.9 1.98 Lopes VA, (1982) Glucosamine sulfate 18 2.7 1.6 NSAIDs 20 4 2 Qiu GX, (1998) Glucosamine sulfate 88 3.6 4.07 NSAIDs 90 4.18 2.81 Rindone JP, (2000) Glucosamine sulfate 49 4.9 2.8 Placebo 49 4.9 2.2 Mudhu D (2013) Glucosamine sulfate 30 2.93 2.06 Placebo 30 4.60 2.08 Brahmachari B, (2009) Diacerein 50 mg 28 3.39 1.19 Placebo 27 6.03 1.3 Zheng WJ, (2006) Diacerein 50 mg 106 2.86 1.97 NSAIDs 107 2.73 1.83 Nguyen M, (1994) Diacerein 50 mg 75 4 2.6 NSAIDs 75 3.8 2.7 Placebo 71 4.8 2.4 Houpt JB, (1999) Glucosamine sulfate 58 36.57 19.50 Placebo 60 38.57 19.30 Frestedt JL, (2008) Glucosamine sulfate 15 70.20 17.60 Placebo 16 54.8 22.7 Louthrenoo W, (2007) Diacerein 50 mg 82 16.67 17.76 NSAIDs 79 35.86 27.69 Pavelka K, (2007) Diacerein 50 mg 82 30.36 20.45 Placebo 83 39.4 21.87 Houpt JB, (1999) Glucosamine sulfate 58 7.14 4.01 Placebo 60 7.65 4.13 Clegg DO, (2006) Glucosamine sulfate 317 5.97 4.64 NSAIDs 318 5.43 4.33 Placebo 313 6.04 4.52
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Table 2.6 Sample Size, Mean, and SD between treatment groups for studies included in a Network Meta-analysis (Cont.)
Author Treatments Total WOMACscore n Mean SD Frestedt JL, (2008 Glucosamine sulfate 15 14.58 3.52 Placebo 16 10.58 4.28 Durmus D (2013) Glucosamine sulfate 18 0.55 0.7 Placebo 19 1.94 1.99 Louthrenoo W, (2007) Diacerein 50 mg 86 3.32 3.53 NSAIDs 85 8.05 3.53 Pavelka K, (2007) Diacerein 50 mg 82 4.36 1.49 Placebo 83 4.2 1.60 Houpt JP, (1999) Glucosamine sulfate 58 3.39 1.81 Placebo 60 3.73 1.76 Clegg DO, (2006) Glucosamine sulfate 317 2.82 2.09 NSAIDs 318 2.67 2.06 Placebo 313 2.82 1.95 Frestedt JL, (2008 Glucosamine sulfate 15 2.47 0.79 Placebo 16 1.85 1.01 Louthrenoo W, (2007) Diacerein 50 mg 86 1.44 1.49 NSAIDs 85 2.28 2.25 Pavelka K, (2007) Diacerein 50 mg 82 2.68 1.87 Placebo 83 3.52 2.06 Brahmachari B, (2009) Diacerein 50 mg 28 1.82 1.35 Placebo 27 2.06 2.31 Houpt JP, (1999) Glucosamine sulfate 58 25.98 14.7 Placebo 60 27.17 14.1 Clegg DO, (2006) Glucosamine sulfate 317 21.27 15.54 NSAIDs 318 20.00 15.31 Placebo 313 21.61 14.96 Frestedt JL, (2008) Glucosamine sulfate 15 48.08 12.51 Placebo 16 38.35 16.32 Durmus D (2013) Glucosamine sulfate 18 2.94 2.91 Placebo 19 9.89 1.13
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Table 2.6 Sample Size, Mean, and SD between treatment groups for studies included in a Network Meta-analysis (Cont.)
Author Treatments Function WOMAC score n Mean SD Louthrenoo W, (2007) Diacerein 50 mg 82 11.91 12.92 NSAIDs 79 25.56 20.66 Durmus D (2013) Glucosamine sulfate 18 2.94 2.91 Placebo 19 9.89 1.13 Louthrenoo W, (2007) Diacerein 50 mg 82 11.91 12.92 NSAIDs 79 25.56 20.66 Pavelka K, (2007) Diacerein 50 mg 82 21.76 14.64 Placebo 83 28.2 13.06 Brahmachari B, (2009) Diacerein 50 mg 28 24.51 13.47 Placebo 27 31.6 13.06 Muller FH, (1994) Glucosamine sulfate 94 9.6 5.82 NSAIDs 95 9.6 5.85 Noack W, (1994) Glucosamine sulfate 120 7.4 5.48 Placebo 121 8.4 4.4 Nguyen M, (1994) Diacerein 50 mg 75 7.7 4.6 NSAIDs 75 6.9 4.6 Placebo 71 8.4 4.1 Reginster JY, (2001) Glucosamine sulfate 106 -0.06 0.79 Placebo 106 0.31 0.95 Pavelka K, (2002) Glucosamine sulfate 101 0.04 0.1 Placebo 101 -0.19 0.51 Kawasaki T, (2008) Glucosamine sulfate 39 0 1 Placebo 32 -0.3 1 Rozendaal RM, (2008) Glucosamine sulfate 111 -0.094 0.32 Placebo 111 -0.057 0.32 Dougados M, (2001) Diacerein 50 mg 246 0.18 0.25 Placebo 247 0.23 0.23
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Table 2.7 Comparisons of treatment effects: a network meta-analysis Pain VAS score Treatment n Β P-value 95%CI Glucosamine 195 -1.75 0.034* -3.32, -0.17 NSAIDs 292 -1.74 0.047* -3.44, -0.03 Diacerein 209 -1.78 0.024* -3.24, -0.32 Placebo 187 0 - - Diacerein vs. glucosamine - -0.03 0.964 -1.58, 1.52 NSAIDs vs. glucosamine - 0.01 0.988 -1.52, 1.54 Diacerein vs. NSAIDs - -0.04 0.893 -0.72, 0.64 Total WOMAC score n Β P-value 95%CI Glucosamine 73 17.70 0.367 -35.46, 70.87 NSAIDs 79 -7.03 0.334 -26.51, 12.45 Diacerein 164 -6.2 0.597 -39.69, 27.29 Placebo 159 0 - - Diacerein vs. glucosamine - -23.90 0.218 -72.85, 25.06 NSAIDs vs. glucosamine - -24.74 0.180 -69.91, 20.44 Diacerein vs. NSAIDs - 0.84 0.899 -18.52, 20.20 Pain WOMAC score n Β P-value 95%CI Glucosamine 408 1.47 0.139 -0.74, 3.68 NSAIDs 164 -0.38 0.612 -2.31, 1.55 Diacerein 397 -0.75 0.521 -3.75, 2.24 Placebo 491 0 - - Diacerein vs. glucosamine - -2.22 0.078 -4.84, 0.39 NSAIDs vs. glucosamine - -1.85 0.065 -3.88, 0.18 Diacerein vs. NSAIDs - -0.376 0.643 -2.46, 1.71 Function WOMAC score n Β P-value 95%CI Glucosamine 408 -2.42 0.534 -11.18, 6.33 NSAIDs 503 1.53 0.463 -3.13, 6.20 Diacerein 189 1.89 0.392 -3.02, 6.81 Placebo 407 0 - - Diacerein vs. glucosamine - 4.32 0.436 -8.03, 16.67 NSAIDs vs. glucosamine - 3.96 0.438 -7.43, 15.34 Diacerein vs. NSAIDs - 0.36 0.913 -7.16, 7.89 Stiffness WOMAC score n Β P-value 95%CI Glucosamine 390 -0.15 0.480 -0.66, 0.36 NSAIDs 397 -0.77 0.207 -2.14, 0.60 Diacerein 196 -0.89 0.097 -2.01, 0.23 Placebo 499 0 - - Diacerein vs. glucosamine - -0.74 0.193 2.00, -0.52
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Table 2.7 Comparisons of treatment effects: a network meta-analysis (Cont.) Stiffness WOMAC score Treatment n Β P-value 95%CI NSAIDs vs. glucosamine - 0.62 0.205 -1.71, 0.47 Diacerein vs. NSAIDs - -0.12 0.788 -1.20, 0.96 Lequesne score change n Β P-value 95%CI Glucosamine 214 -1.12 0.063 -2.36, 0.12 Diacerein 75 0.03 0.970 -2.13, 2.18 Placebo 192 0 - - Diacerein vs. glucosamine - 1.15 0.331 -4.32, 2.01 Joint space width change n Β P-value 95%CI Glucosamine 357 -0.08 0.363 -0.31, 0.14 Diacerein 246 0.12 0.207 -0.10, 0.34 Placebo 597 0 - - Diacerein vs. glucosamine - -0.20 0.001* -0.27, -0.14 Adverse event n RR P-value 95%CI Glucosamine 1474 1.07 0.398 0.92, 1.23 NSAIDs 814 2.20 <0.001* 1.56, 3.11 Diacerein 381 1.91 <0.001* 1.36, 2.69 Placebo 1634 1 - - Diacerein vs. glucosamine - 1.80 0.001* 1.27, 2.55 NSAIDs vs. glucosamine - 2.07 <0.001* 1.47, 2.91 Diacerein vs. NSAIDs - 0.87 0.416 0.62, 1.22 Adverse event (GI) n RR P-value 95%CI Glucosamine 1850 0.84 0.103 0.68, 1.04 NSAIDs 899 1.33 0.038* 1.02, 1.77 Diacerein 1345 1.44 <0.001* 1.24, 1.68 Placebo 1917 1 - - Diacerein vs. glucosamine - 1.72 <0.001* 1.34, 2.22 NSAIDs vs. glucosamine - 1.60 0.004* 1.16, 2.19 Diacerein vs. NSAIDs - 1.08 0.576 0.98, 1.50 *statistically significant difference (P < 0.05)
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Total WOMAC score Data from 4 studies 103, 105, 143, 146 were included in pooling of indirect comparisons of the actual total WOMAC scores (Table 2.6). The mean total WOMAC scores were lower in diacerein and NSAIDs groups, but higher in glucosamine compared to placebo but this was not statistically significant (Figure 2.3, Table 2.7). Multiple comparisons suggested no difference in effects between active treatments.
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Pain WOMAC score Data from 6 studies 101, 102, 104, 120, 142, 145 were included in the network meta-analysis of pain WOMAC scores (see Table 2.6). Fitting the regression analysis using placebo as the reference suggested that pain WOMAC scores were lower in both diacerein and NSAIDs groups. In contrast, the pain score was higher in the glucosamine group compared with placebo, but this was not statistically significant (see Figure2.4, Table 2.7).
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Function WOMAC score Data from 8 studies 101, 102, 104, 120, 142-145 were included in pooling of indirect comparisons of WOMAC function scores (see Table 2.6). The regression analysis suggested that mean WOMAC function scores of diacerein, NSAIDs and glucosamine were lower than placebo; but these results were not statistically significant (see Figure 2.5, Table 2.7). Multiple comparisons indicated that diacerein and NSAIDs resulted in lower scores than glucosamine but these results also were not statistically significant.
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Stiffness WOMAC score Data from 6 studies 101, 102, 104, 142, 143, 145 were included in pooling of indirect comparisons of the WOMAC stiffness scores (see Table 2.6). The regression analysis suggested that mean WOMAC stiffness scores were lower in diacerein, NSAIDs, and glucosamine groups when compared to placebo (see Figure 2.6 and Table 2.7). There was no significant difference between the three active treatments. Lequesne Algofunctional score change Three studies 109, 110, 139 compared mean changes of Lequesne scores after receiving treatments at 4 to 24 weeks (see Table 2.6). The regression analysis suggested that mean Lequesne change in the glucosamine group was lower than the placebo group. There was no significant difference between the glucosamine and diacerein groups.
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Joint space width difference Data from 5 studies 106, 111, 114, 116, 141 were used for the network meta-analysis of joint space width change. Change of joint space width after receiving glucosamine and diacerein had no statistically significant difference when compared to placebo (see Table 2.7). Multiple comparisons indicated that diacerein was superior to glucosamine at -0.2(95% CI: -0.27, -0.14) mm. Adverse events Sixteen studies99-105, 108, 110-112, 114-116, 160, 161 reported overall adverse events between treatment groups (Table 2.8). Compared to glucosamine, NSAIDs was 2.07 (95%CI: 1.47, 2.91) times and diacerein was 1.80 (95%CI: 1.27, 2.55) times more likely to have adverse events (Figure 2.7). Diacerein had approximately 13% (RR = 0.87; 95%CI: 0.62, 1.22) lower risk than NSAIDs but this was not statistically significant (Table 2.7). Considering only GI adverse events showed similar results to overall adverse events.
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Table 2.8 Frequency of overall adverse events between Treatment groups Author Treatment All adverse event n Adverse No adverse event event Pujalte JM, (1980) Glucosamine sulfate 10 0 10 Placebo 10 1 9 Noack W, (1994) Glucosamine sulfate 126 8 118 Placebo 126 13 113 Lopes VA, (1982) Glucosamine sulfate 18 2 16 NSAIDs 20 5 15 Muller FH, (1994) Glucosamine sulfate 100 6 94 NSAIDs 99 35 64 Qiu GX, (1998) Glucosamine sulfate 88 5 83 NSAIDS 90 14 76 Houpt JB, (1999) Glucosamine sulfate 58 7 51 Placebo 60 7 53 Rindone J, (2000) Glucosamine sulfate 49 2 47 Placebo 49 4 45 Reginster JY, (2001) Glucosamine sulfate 106 101 5 Placebo 106 83 23 Hughes R, (2002) Glucosamine sulfate 39 23 16 Placebo 39 25 14 Pavelka K, (2002) Glucosamine sulfate 101 85 16 Placebo 101 69 32 Braham R, (2003) Glucosamine sulfate 24 11 13 Placebo 22 10 12 Cibere J, (2004) Glucosamine sulfate 71 0 71 Placebo 66 0 66 McAlindon T, (2004) Glucosamine sulfate 101 18 83 Placebo 104 14 90 Clegg DO, (2006) Glucosamine sulfate 317 9 308 NSAIDs 318 7 311 Placebo 313 11 302
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Table 2.8 Frequency of overall adverse events between Treatment groups (Cont.) Author Treatment All adverse event n Adverse No adverse event event Herrero-Beaumont G, Glucosamine sulfate 106 44 62 (2007) Placebo 104 35 69 Frestedt J, (2008) Glucosamine sulfate 19 12 7 Placebo 16 14 2 Rozendaal R, (2008) Glucosamine sulfate 111 57 54 Placebo 111 59 55 Chopra A (2013) Glucosamine sulfate 108 34 74 NSAIDs 105 34 71 Mudhu K (2013) Glucosamine sulfate 30 5 25 Placebo 30 2 28 Kwoh CK (2014) Glucosamine sulfate 98 3 95 Placebo 103 4 99 Kwoh CK (2014) Glucosamine sulfate 98 3 95 Placebo 103 4 99 Zheng WJ, (2006) Diacerein 100 mg 106 42 64 NSAIDs 107 50 57 Pavelka K, (2007) Diacerein 50 mg 82 36 46 Placebo 83 24 59 Brahmachari B, (2009) Diacerein 50 mg 28 27 1 Placebo 27 8 19 Nguyen M, (1994) Diacerein 50 mg 75 68 7 NSAIDs 75 30 45 Placebo 71 33 38 Pujalte J, (1980) Glucosamine sulfate 10 0 10 Placebo 10 0 10 Noack W, (1994) Glucosamine sulfate 126 5 121 Placebo 126 6 120 Lopes VA. (1982) Glucosamine sulfate 18 1 17 NSAIDs 20 2 18
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Table 2.8 Frequency of overall adverse events between Treatment groups (Cont.) Author Treatment All adverse event n Adverse No adverse event event Muller FH, (1994) Glucosamine sulfate 100 5 95 NSAIDs 99 29 70 Qiu GX, (1998) Glucosamine sulfate 88 3 85 NSAIDS 90 6 84 Houpt JB, (1999) Glucosamine sulfate 58 7 51 Placebo 60 7 53 Reginster JY, (2001) Glucosamine sulfate 106 27 79 Placebo 106 37 69 Hughes R, (2002) Glucosamine sulfate 39 0 39 Placebo 39 0 39 Pavelka K, (2002) Glucosamine sulfate 101 25 76 Placebo 101 28 73 Braham R, (2003) Glucosamine sulfate 24 4 20 Placebo 22 3 19 Cibere J, (2004) Glucosamine sulfate 71 0 71 Placebo 66 0 66 McAlindon T, (2004) Glucosamine sulfate 101 4 97 Placebo 104 6 98 Clegg J, (2006) Glucosamine sulfate 317 0 317 NSAIDs 318 0 318 Placebo 313 0 313 Herrero-Beaumont G, Glucosamine sulfate 106 11 95 (2007) Placebo 104 12 92 Frestedt J(2008) Glucosamine sulfate 19 5 14 Placebo 16 6 10 Rozendaal RM, (2008) Glucosamine sulfate 111 58 53 Placebo 111 46 65 Mudhu K (2014) Glucosamine sulfate 30 1 29 Placebo 30 1 29
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Table 2.8 Frequency of overall adverse events between Treatment groups (Cont.) Author Treatment All adverse event n Adverse No adverse event event Chopra A (2014) Glucosamine sulfate 108 34 74 NSAIDs 105 34 71 Pelletier J, (2000) Diacerein 100 mg 385 192 193 Placebo 125 32 93 Dougados M, (2001) Diacerein 100 mg 255 185 70 Placebo 252 115 137 Pham T, (2004) Diacerein 100 mg 85 25 60 Placebo 85 72 13 Zheng WJ, (2006) Diacerein 100 mg 106 29 77 NSAIDs 107 35 72 Pavelka K, (2007) Diacerein 50 mg 82 25 57 Placebo 83 14 69 Nguyen M, (1994) Diacerein 50 mg 75 60 15 NSAIDs 75 28 47 Placebo 71 24 47
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2.3.3 Discussion This review compared effects of glucosamine, diacerein, NSAIDs, and placebo for treatment of osteoarthritis of the knee. Relevant clinical outcomes that were pooled included VAS pain score, total and sub-WOMAC scores, joint space width and adverse events. The second line drugs for OA knee in the SYSADOA group include glucosamine sulfate, glucosamine hydrochloride, chondroitin sulfate, hyaluronic acid, ASU, and diacerein. This study included both glucosamine sulfate and glucosamine hydrochloride because the results of previous meta-analysis of both preparations show that they have no statistically significant difference125. Chondroitin sulfate162-164, hyaluronic acid 165 and ASU 166 were not included in this review because there were too few studies to pooled outcomes with network meta-analysis. The clinical results of our study were consistent to previous meta-analyses85, 98, 120, 146 in which glucosamine and diacerein statistically improved pain scores (VAS and WOMAC) and function scores (WOMAC) when compared to placebo. However, we have added more evidence of multiple active treatment comparisons. There were no statistically significant differences between the three groups in pain VAS, total
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WOMAC, sub-WOMAC scores and Lequesne functional scores. Although glucosamine showed greater improvement in joint space width when compared to diacerein, glucosamine and diacerein did not show a clinically relevant effect in joint space narrowing when compared to placebo. Both glucosamine and diacerein increased risk of adverse events when compared with placebo. However, glucosamine had a lower risk of adverse events when compared to diacerein. In the subgroup of gastrointestinal adverse events, patients who took diacerein had an approximately 86.9% and 99.6% increased risk of GI adverse events when compared to glucosamine and placebo respectively. Glucosamine and diacerein can reduce pain VAS and improved function (WOMAC). Glucosamine and diacerein showed no differences in adverse effects when compared to NSAIDs. In conclusion, this study demonstrated that either glucosamine or diacerein can be selected for treatment of pain associated with knee osteoarthritis. Diacerein has a higher risk of adverse GI events when compared to glucosamine. Both glucosamine and diacerein cannot decrease risk of adverse effects and they both do not have a clinically relevant effect in delaying progression of joint space narrowing in OA of the knee. The small number of studies that evaluated each particular pair of treatments limits performing a direct meta-analysis. A network meta-analysis circumvents this problem by creating indirect comparisons between active treatments that can identify the most effective therapy. In this case, diacerein was the best therapy for improvement of pain VAS scores. Glucosamine is the best therapy in terms of having less adverse effects when compared to diacerein but not when compared toplacebo controls. None of the RCTs had compared combined treatments with an active control. The strengths of this study were that a network meta-analysis was applied to increase the power of the tests and reduce type I errors153-155. We applied a regression model taking into account study effects to assess treatment effects. The network meta- analysis ‘borrows’ treatment information from other studies and increases the total sample size. As a result, treatment effects that could not be detected in direct meta- analysis could be identified. All possible treatment comparisons are mapped and displayed; and results are summarized in Table 2.9. Although our pooled estimates were heterogeneous, the regression model with cluster effect takes into account variations at the study level.
Table 2.9 Summarization all Treatment Effects for Osteoarthritis patients Fac. of Grad. Studies, Mahidol Univ.
Treatments Pain VAS WOMAC WOMAC pain WOMAC WOMAC Lequesne mean Joint space Adverse Adverse score total score function score stiffness score difference width event event (GI) score
Glu vs. Pla N D* D* D X D X D X
NSAIDs vs. Pla N X X X X - - N N
Dia vs. Plac D&N X X X D X X D&N N
Glu vs. Dia X X X X X X N N N
Glu vs. NSAIDs D X X X X - - N N
Diac vs. NSAIDs X X X D D - - X X Ph.D.(Clinical Epidemiology) /65
D=direct, N=network *Score change
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None of RCT compared dual therapy with mono-therapy of SYSADOA. In relation to the SYSADOA mechanism, diacerein inhibits IL-1b effects and reduces synthesis of cartilage specific macromolecules. In addition, diacerein also decreases IL- 1b stimulated secretion of metalloproteinases and aggrecanases, thereby preventing breakdown of cartilage by these enzymes129. Glucosamine, an amino sugar, is a building block of the glycosaminoglycan, which is a part of the cartilage structure. The SYSADOA group should be able to support effects of each other and may yield better clinical improvement than monotherapy. Further RCTs that compare dual vs mono- therapy SYSADOA are necessary to determine if this may enhance treatment effects. In conclusion, this investigation demonstrates the potency of diacerein and glucosamine in the treatment of osteoarthritis of the knee. Glucosamine shows significant improvements in pain score but does not decrease risk of adverse effects and does not have a clinically relevant effect in slowing progression of joint space narrowing in OA knee. Diacerein has a higher risk of adverse GI events when compared to glucosamine. Diacerein also does not decrease risk of adverse effects and has no clinically relevant effect in delaying progression of joint space narrowing in OA of the knee. When compared to diacerein, glucosamine is the better treatment choice for OA of the knee.
2.3.4 Acknowledgements The manuscript of this chapter was published in European Journal of Medical Research.2015; Mar13; 20(1):24.
2.3.5 Funding source: This study has no funding support.
2.4 Definition
Osteoarthritis Osteoarthritis is defined according to the American College of Rheumatology Criteria16 as having atleast three of the following 6 criteria: 50 years of
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 67 age or older, stiffness lasting less than 30 minutes, crepitus, bony tenderness, bony enlargement, no warmth to the touch
2.5 Drug mechanism
2.5.1 Diacerein, a drug of the anthraquinone class, has rhein as its active metabolite. In chondrocytes, this drug acts on the IL-1β system, reducing the level of this cytokine as well as downregulating the IL-1β-induced inflammatory pathways and cartilage breakdown in OA 167-170 (see Figure 2.8). On human subchondral bone osteoblasts, data showed that diacerein/rhein reduces osteocalcin, urokinase, and IL-6, factors that would contribute to curbing bone formation/resorption 83
Figure 2.8 Drug mechanism of action of Diacerein 2.5.2 Non-Steroidal Anti-Inflammatory Drug (NSAIDs) the mechanism of action was through their inhibition of prostaglandin biosynthesis 171
2.5.3 Glucosamine is a naturally occurring amino-monosaccharide found in high concentrations as a normal constituent in cartilage matrix and synovial fluid;
Jatupon Kongtharvonskul Literature Review / 68 most supplements are manufactured synthetically or are derived from shellfish shells. It can commonly be found in two forms: glucosamine sulphate and glucosamine hydrochloride. the mechanism of action of glucosamine (see Figure 2.9) in OA is unknown but it is hypothesised that the supply of glucosamine is a rate-limiting step in the formation of lubricating hyaluronic acid in connective tissue 82
Direct route Glucosamine Glucose Indirect route Glutamine Glucose 6P Glucosamine 6P AcCoA
SO4- n-Ac Glucosamine 6P NSAIDs Glucosamine ATP Mg2+ N-Ac Glucosamine 1P UTP 6-synthetase UDP N-Ac Glucosamine inhibitors PAPS NAD UDP N-Ac Galactosamine GLYCOSAMINOGLYCANS Glycosaminoglycan PROTEOGLYCANS Biosyntheticpathway
Figure 2.9 Drug mechanism of action of Glucosamine sulfate
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CHAPTER III METHODOLOGY
3.1 Study design The study design was a double-blind randomized placebo-controlled trial, which was conducted at the Orthopedics outpatient clinic, Ramathibodi Hospital, Bangkok, Thailand during August 2013– August 2014. Informed consent was obtained from all study participants. Approval for the study was given by the Committee on Human Rights Related to Research Involving Human subjects at the Faculty of Medicine, Ramathibodi Hospital, Mahidol University, and the protocol (ID 04-56-25) of the study was registered at ClinicalTrials.gov (NCT01906801).
3.2 Inclusion criteria Patients were eligible if they met all of the following criteria: - Diagnosed as having primary or secondary knee OA based on the ACR clinical criteria 16, i.e. having knee pain measured by VAS plus 3 of the following: Aged 50 years or older, bony tenderness, stiffness lasting less than 30 minutes, bony enlargement, crepitus, or warmth to touch. - Had not received glucosamine or diacerein within 6 months. - Radiographic evidence of OA with KL grade 2 or 3. - Willing to participate and provided consent.
3.3 Exclusion criteria Patients were excluded if they had any of the following: - Undergone knee replacement surgery. - Inflammatory arthritis (e.g. systemic lupus erythematosus, rheumatoid
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arthritis, gout). - Previous intra-articular treatment of the knee joint with any product (corticosteroids in the previous 2 months, or hyaluronic acid in the previous 6 months), - GI conditions (Gastro-esophageal reflux disorder, Inflammatory bowel syndrome, Peptic ulcer and Duodenal ulcer), renal disease, liver disease, or diabetes mellitus.
3.4 Treatment and blinding Eligible patients were randomly assigned to receive either of following treatments; - A sachet of glucosamine sulfate 1500 mg (Rottapharm, Monza, Italy) plus placebo once daily - Glucosamine sulfate 1500 mg plus diacerein 50 mg once daily (TRB Chemedica, International S.A., Geneva, Switzerland) for 6 months. Placebo capsules were prepared identically to diacerein by appearance, smell, and taste by TRB Chemedica. Patients, physicians, assessors, and research nurses did not know which one was active drug or placebo, see Figure 3.1.
Diacerien (Artrodar, TRB Placebo (identically to diacerein Chemedica, International S.A., by appearance, smell, and taste Geneva, Switzerland) by TRB Chemedica)
Figure 3.1 Placebo and diacerein preparation
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3.5 Randomization A block randomization with a ratio of 1:1 was applied to generate a randomization list, with varying block size of 4 to 8. This was prepared by biostatisticians (A.T) who was not involved in the patient’s recruitment or data collection. STATA version 13.0 software was used to generate the random sequence lists 172, which were then prepared using sequentially numbered drug packages and administered by a research nurse if patients met the inclusion criteria and had given informed consent. Patients might be prescribed other pain relief (acetaminophen (500 mg) or NSAIDs) depending on the physician’s judgement. The use of NSAIDs could be started with ibuprofen (400 mg) 1 tablet three times per day or naproxen (250 mg) 1 tablet two times per day if patients were allergic to ibuprofen. The patients were provided with a diary to record their daily pain medication intake.
3.6 Outcome measures The primary outcomes of interest were pain score measured using a VAS (ranging from 0-10 which the higher score indicate the greater pain)) and the Osteoarthritis index, measured using the (Thai version 173) WOMAC scores. The WOMAC index consists of 3 domains and 22 items, i.e., pain (5 items), function (15 items), and stiffness (2 items). Each item was graded from 0 to 10, with higher scores indicating more severe symptoms. Total and sub-domain scores were calculated by summation of scores for all items. The total scores range from 0 to 220, where higher scores refer to more severe OA. The secondary outcomes of interests were WOMAC sub-scores (i.e., pain, function and stiffness) and JSW. The WOMAC scores were measured using WOMAC questionnaires by a well-trained research assistant at baseline, and weeks 4, 8, 12, 16, 20 and 24 after treatment. Total sub-scores were ranged from 0-50, 0-150, 0-20 for pain, function and stiffness respectively. The JSW was assessed using weight-bearing metatarsophalangeal radiography 174 (see Figure 3.2) at baseline, 12 weeks, and 24 weeks, and determined by computer-generated measurements from digitized images. The JSW was defined as the
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distance from distal femoral condyle to the proximal tibia, and was measured by one Orthopedist (J.K.) at 3 months and 6 months after receiving treatment. In addition, adverse events including gastrointestinal effects (abdominal pain, stomach and intestinal symptoms) were also assessed at each visit after receiving treatments. Other co-variables including age, gender, underlying disease (i.e., diabetes, hypertension, malnutrition, cardiovascular disease, and obesity (body mass index; BMI ≥ 30 mg/m2)) and disease severity at baseline were also collected.
Figure 3.2 weight-bearing metatarsophalangeal radiography 174
3.7 Co-intervention 3.2.7.1 Lifestyle modification and health education - All patients were encouraged to participate in self- management educational programs and incorporate activity modifications into their lifestyle. They were instructed that they were walking instead of running; performing alternative activities, attempting weight loss, shoe modification, avoiding extreme flexion of the knee, and performing quadriceps exercises. - Regular contact to promote self-care for all patients at 0, 8, 16, 24 weeks
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- All patients, who were overweight (as defined by a BMI>25 mg/m2), were encouraged to lose weight (a minimum of five percent (5% mg/m2) of body weight) and maintain their weight at a lower level with an appropriate program of dietary modification and exercise. 3.2.7.2 Exercise (range of motion exercise [ROME], strengthening, aerobic) - All patients were encouraged to participate in low-impact aerobic fitness exercises. - Range of motion/flexibility exercises and quadriceps strengthening were encouraged for all patients. (Exercises were perform twice daily for 24 weeks. Furthermore patients were recommended to exercise at least 30 minutes a day)
3.8 Protocol violation Possible protocol violations could be non-compliance, co-intervention, or contamination. For compliance, a research assistant or the investigator called patients (say at 8, 16, and 20 weeks) to check whether patients have taken studied treatments as prescribed. Numbers of mentions were recorded for every visit. The numbers of pills given to the patient at each visit were recorded, and when the patient returns for follow up they were instructed to bring any remaining pills, as those remaining pills were counted to see how many doses the patient had missed. For co-intervention, use of pain killers including NSAIDs and paracetamol with and without prescriptions were asked and recorded. In addition, use of these drugs via over-counter without prescriptions were also asked and recorded. Furthermore, patients were asked at every visit whether they had taken other pills or supplement tablets (e.g. steroid, injection of other medicine) along with co-treatment (e.g. yoga, acupuncture, tapping knee and heel wedge) that might contain or having similar mechanisms as our studied drugs.
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Measure taken for protocol violation Failure to include all participants in the analysis may bias the trial results. However, most trials did not yield perfect data. Protocol violations may occur, such as when the patients did not completely receive the assigned intervention or the correct intervention or a few ineligible patients were randomly allocated in error. Despite the fact that this study was carefully planned, many problems can occur during the conduct of the study. The possible issues that could occur during a study were as follows: - Some of the study groups could be contaminated with interventions from other groups. - Patients dropped out from the study or had loss of follow up. - Some patients were not compliant or had poor adherence, meaning they did not take their medication as instructed.
Contamination From the follow up of all the patients it was found that there was contamination between the two groups. When there is contamination among the groups, the data is not analyzed by the as-treated analysis method,i.e.,comparing the subjects between the treatment regimens that they actually received. But instead the intention- to-treat (ITT) approach is used, which provides fair comparisons among the treatment groups because it avoids the bias associated with the non-random loss of the participants. The basic ITT principle is that participants in the trials should be analyzed in the groups to which they were randomized, regardless of whether they received or adhered to the allocated intervention.
Drop out or loss of follow up: handling of missing data The principal options for dealing with missing data are as following: - Analyzing only the available data i.e. ignoring the missing data. this option may be appropriate when data can be assumed to be missing at random. - Imputing the missing data with replacement values, and treating these as if they were observed (e.g. last observation carried forward, imputing an assumed outcome such as assuming all were poor outcomes, imputing the mean, imputing based on predicted values from a regression analysis).
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One method of handling missing data is simply to impute, or fill in, values based on existing data. A standard method to do this is the Last-Observation-Carried- Forward (LOCF) method. The LOCF method allows for the analysis of the data. However, recent research shows that this method gives a biased estimate of the treatment effect and underestimates the variability of the estimated result. As an example, assume that there are 8 weekly assessments after the baseline observation. If a patient drops out of the study after the third week, then this value is "carried forward" and assumed to be his or her score for the 5 missing data points. The assumption is that the patients improve gradually from the start of the study until the end, so that carrying forward an intermediate value is a conservative estimate of how well the person would have done had he or she remained in the study. The advantages to the LOCF approach are that: it minimizes the number of the subjects who are eliminated from the analysis, and it allows the analysis to examine the trends over time, rather than focusing simply on the endpoint 175. - Imputing the missing data and accounting for the fact that these were imputed with uncertainty (e.g. multiple imputation, simple imputation methods with adjustment to the standard error). - Using statistical models to allow for missing data, making assumptions about their relationships with the available data. The National Academy of Sciences advisory panel instead recommended methods that provide valid type I error rates under explicitly stated assumptions taking missing data status into account, and the use of multiple imputation methods based on all the data available in the model. It recommended more widespread use of Bootstrap and Generalized estimating equation methods whenever the assumptions underlying them, such as Missing at Random for GEE methods, can be justified. It advised collecting auxiliary data believed to be associated with dropouts to provide more robust and reliable models, collecting information about reason for drop-out; and, if possible, following up on drop-outs and obtaining efficacy outcome data. Finally, it recommended sensitivity analyses as part of clinical trial reporting to assess the sensitivity of the results to the assumptions about the missing data mechanism 175
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3.9 Data collection
3.9.1 Case record form Data were collected using standard case record forms (see appendix A), which consist of 4 parts, see appendix A. The Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital were prepared case record forms (CRF) and sent to orthopedic clinic in Ramathibodi Hospital
3.9.2 Training Out-patient department research assistant, nurses, residents, hip & knee fellows and orthopedic staffs who were associated in this study were trained about the research project in terms of informed, consent, and randomization process at the beginning of the project and retrained every 6 months.
3.9.3 Non-participation Demographic and clinical data (i.e., clinical signs and symptoms, type of intervention, and primary outcome) of non-participated patients were retrieved and compared with participated patients. This were ensuring that participated patients were well representative for the whole OA patients.
3.9.4 Data flow, queries, quality control, and project monitoring A flow of data collection was described in Figure 3.3. At the orthopedic out- patient clinic, patients were screened for eligibility and were asked to participate in the study by a nurse, orthopedic resident or orthopedic attending staff (or else will be assigned). Patient log sheets and informed consent with patients’ signatures were collected by the research assistant. Then, the opaque envelopes were opened by the OPD nurse to see what treatments (glucosamine plus diacerein or glucosamine plus placebo) those patients were allocated to. Patients will be then followed up at 4, 8, 12, 16, 20, 24 weeks by an orthopedic physician for assessment of all outcomes of interest. After out- patient clinic hours, data were then collected daily by a research assistant and then checked for completion. A second research assistant were then double checked the data for completion, then taken the data to the database administrator for compilation. The
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assistants were required to sign an attendance register daily to ensure daily collection of data. At the database administrator, the research assistants were input the information into the database as double entries to ensure accuracy. If the data was incongruent, then the original log sheets and CRFs were rechecked.
Figure 3.3 Flow of the patients along with the responsible personnel
3.9.5 Data interaction All CRFs were delivered to the DMU, Section for Clinical Epidemiology and Biostatistics for computerizations. All CRFs were checked and validated by JK before computerizing. Data queries were made to resolve any unclear data. The data manager was regularly checked data for the quality of the data and the progression of the study.
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3.9.6 Databases and data entry The databases were constructed based on the CRFs using EPIDATA version 3.1. These were consisted of enrollment, follow up, and outcome databases. Data quality control program were constructed for controlling data entry. CRFs were checked and data entries were done by principle investigator (JK). The data were double entered by two independent DMU staffs. The two data sets were then validated to detect typing errors. Cleaning and checking of data were done weekly. If there was any unclear answer, missing data, or non-sensible data, an enquiry from the DMU were made. Data were kept in a safe area. Only principal investigators (JK), supervisor (AT), and the data manager were able to access to the data.
3.10 Sample size estimation We used data from systematic review and meta-analysis in Chapter 2 for sample size estimations. Pooled means along with SDs (measured at the end of study ~3 months) were described according to outcome and treatments (Glu, Diac, and placebo groups). Mean and SD of VAS scores in Glucosamine were 4.78 and 1.9, respectively (Table 3.1). Type I error, power of test, and ratio of Glucosamine plus Diacerein vs Glucosamine plus placebo were set at 0.05, 0.80, and 1:1, respectively. The estimated sample size for detect mean difference of VAS of 1 (MCS see Table 3.1) was 59 and 59 for Glucosamine plus Diacerein and Glucosamine plus placebo group, respectively. Taking into account for loss follow up of 20% yields total of 148 patients to enroll. The expected numbers of patients with OA knee at Orthopedic OPD clinic was approximately 30-40 patients per month. Therefore, the length of data recruitment periods were 10-12 months and data collection were end around the end of 2014.
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Table 3.1 Minimal clinical significance (MCS) and SD of VAS scores, WOMAC total and sub scores of Glucosamine and diacerein from systematic review176.
Outcome Standard deviation (Type I error) (Type II error) (Differences) Pain VAS Minimal clinical significance glucosamine 1.923 0.05 0.01 1 diacerein 1.618
Total WOMAC 16% glucosamine 15.85 0.05 0.01 12 diacerein 18.379
Pain WOMAC 16% glucosamine 3.511 diacerein 3.219 0.05 0.01 3 Function 16% WOMAC glucosmine 12.516 diacerein 12.762 0.05 0.01 10 Stiff WOMAC 16% glucosamine 1.386 diacerein 1.685 0.05 0.01 1
3.11 Statistical analysis Data were described using frequency for categorical data, and mean (SD) or median (range) where appropriate for continuous data. The baseline characteristics of the patients and co-interventions for analgesic usage were compared between the two intervention groups using the Chi-square test (or exact test where appropriate) and t-test for categorical data and continuous data, respectively. Continuous outcomes including pain VAS, total and sub-WOMAC scores were compared between treatment groups using a mixed linear regression analysis with hierarchical approach, in which a subject-variation term was fitted in the model as a random effect and treatment was considered as a fixed effect. In addition, times at measurement were also included in the mixed model by adding interaction effect of treatment and time (i.e., treatment x time). Marginal treatment effects between treatments and times were then estimated and compared. Co-variables at baseline were included if they were unequally distributed between two groups. The normality of
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residuals of the mixed model was then checked using normality plots (i.e., quantile of normal distribution) and the Shapiro-Wilk test. Diagnostic measures were explored if the assumption of normality was violated. The continuous outcomes were then transformed where appropriate to meet the assumption. Dichotomous outcomes (i.e., a composite of adverse events and individual event) were compared between treatment groups using a mixed-effect Poisson regression analysis, in which a subject-variation was fitted in the model as a random effect, and the treatment was considered as a fixed effect. In addition, time at measurement was also included in the mixed model by treating it as a fixed effect. Incidence adverse events in both groups and a ratio of the incidence, i.e., a risk ratio (RR) between treatments and times were then estimated and compared. Co-variables at baseline were included if there was a significant difference between the two groups. An intention-to-treat analysis (ITT) approach was applied for all analyses if there was any evidence of a protocol violation. All analyses were performed using STATA version 13.0172. A p-value < 0.05 was considered as statistically significant.
3.12 Ethical considerations
3.12.1 Respect for human rights and autonomy The patient had rights to knowledge regarding the advantages and adverse effects of each of the medication, and any risk that was taken to take part in this study. Healthcare professionals have provided this information at the outpatient clinic. The patient has been able to ask for further information at their convenience. After the patient has made an educated decision, they were required to give informed consent to take part in the study. In the case that the patient declined to take part in the study, the patient was received treatment according to standard guidelines for treatment of OA. The patient was withdrawing their consent of participation at any time in the study.
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3.12.2 Confidentiality The information provided by the patients were kept confidential, as all of their personal information were recorded either by numeric code or hospital number. Only the conductors of the study were access information.
3.12.3 Beneficence Due to diacerein being an expensive medication that was not covered by any insurance, the patients receive full benefit as they were provided free access to the medication. Both groups received standard treatment and follow up according to OA guidelines.
3.12.4 Non-maleficence Each patient received payment of 200 THB for each follow up visit (once per month). If the patient was experiencing adverse effects, they withdraw from the study at any time.
3.12.5 Justice All patients received treatment according to standard guidelines for the treatment of OA, and all patients underwent the same treatment procedure and follow up.
3.13 Budget The budget has been shown in Table 3.2
3.14 Time frame The timeframe has been shown in Table 3.3
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Table 3.2 Budget
Responsible Level Items Cost/Unit Units Time Costs unit Study- Collaborator meeting - Steering level committee -Lunch & Breaks 200 20 3 12000 -Travel costs 500 20 3 30000 -Protocol development 40000 2 1 80000 Data collection training 1000 15 1 15000 - Steering committee Data management 100 400 6 240000 - DMU DSMB -DSMB -DSMB meeting 1500 3 2 9000 Publication 40000 2 1 80000 - Steering committee research assistant 14200 1 12 170400 DMU Subject- Medicine - Study sites level Glucosamine sulfate 30 148 180 799,200 Diacerein 16.5 74 180 219,780 Placebo 5 74 180 66,600 Subjects reimbursement 200 177 6 212400 - Study sites (Discount)
Table 3.3 Time frame Fac. of Grad. Studies, Mahidol Univ. 2012 2013 Activities Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct - Finalized proposal - CRF dictionary and
handout - First meeting - Apply Ethics Committee - data collection training - Enrollment - Monitoring and audit - Regular meeting and Ph.D.(Clinical Epidemiology) /83 problem solving - Data management
2013 2014 Activities Nov Dec Mar April May June July Aug Sept Oct Nov Dec - Data management - Final analysis - Writing & Publication-
Final report
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3.15 Trial organization The trial organization has been shown in Figure 3.2
Figure 3.4 Trial organization
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CHAPTER IV RESULTS
4.1 Patient characteristics Recruitment began in August 2013 at Ramathibodi hospital in Bangkok, Thailand. The study was completed in September 2014. A total of 148 patients were recruited and randomly allocated to treatment groups, see Figure 4.1. Of these, 1 patient was ineligible because his pain scores by VAS and WOMAC at baseline were 0, leaving 147 patients for assessing clinical outcomes. Baseline characteristics were described and compared between treatment groups, see Table 4.1. For the glucosamine plus diacerin group, the majority was female (83.1%), with a mean (±SD) age of 58.8 (±6.6) and BMI of 28.9 (±5.3) kg/m2. The corresponding characteristics in glucosamine plus placebo group were 61.2 (±7.3) years and 27.22 (±4.2) kg/mg2. Mean age and BMI were statistically significant different between groups (p = 0.038 and p = 0.033, respectively). Disease severity at baseline including pain, function, and stiffness scores were comparable between treatment groups. Patient’s compliance with the allocated treatments, measured by counting number of capsules at each visit, ranged from 88% to 100% and 79% to 100% in glucosamine plus diacerin and glucosamine plus placebo groups, respectively. Loss to follow up in these two corresponding groups ranged from 4.1% to 12.2% and 4.1% to 13.5%.
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Figure 4.1 study flow diagram
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Table 4.1 Baseline characteristics of patients between treatment groups
Characteristics Glucosamine sulfate Glucosamine sulfate P-Value plus diacerein plus placebo (n=74) (n=74) Age (year), mean(SD) 58.8 (6.6) 61.2 (7.3) 0.038 Sex (%) Male 11 (14.9) 14 (18.9) 0.510 Female 63 (85.1) 60 (81.1) Weight (Kg), mean(SD) 69.6 (13.7) 66.5 (11.7) 0.148 Height (cm.), mean(SD) 155.1 (7.8) 156.1 (6.0) 0.364 BMI (kg/m2), mean(SD) 28.9 (5.3) 27.2 (4.2) 0.033 Knee Symptom Warm(%) Yes 22 (30.14) 24 (32.43) 0.859 No 51 (69.86) 50 (67.57) Stiffness(%) Yes 39 (52.7) 33 (44.6) 0.411 No 35 (47.3) 41 (55.4) Time of symptom before enrolled 12 (2-120) 12 (2-120) 1.000 (months), median (range) Drug allergy (%) Yes 15 (20.3) 15 (20.3) 1.000 No 59 (79.7) 59 (79.7) Underlying disease Diabetes (%) Yes 8 (10.8) 13 (17.6) 0.346 No 65 (89.2) 61 (82.4) Hypertension (%) Yes 40 (54.1) 34 (45.9) 0.411 No 34 (45.9) 40 (54.1) Dyspepsia (%) Yes 8 (11.76) 7 (9.86) 0.780 No 60 (88.24) 64 (90.14) Other disease (%) Yes 34 (45.9) 32 (43.2) 0.869 No 40 (54.1) 42 (56.8)
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Table 4.1 Baseline characteristics of patients between treatment groups (Cont.)
Characteristics Glucosamine sulfate Glucosamine sulfate P-Value plus diacerein plus placebo (n=74) (n=74) Defecation (%) Normal 59 (79.7) 54 (73) 0.351 Abnormal 15 (20.3) 20 (27) Smoking (%) Yes 1 (1.4) 3 (4) 0.620 No 73 (98.6) 71 (96) Alcohol drinking (%) Yes 7 (9.5) 3 (4) 0.327 No 67 (90.5) 71 (96) Family history of OA knee (%) Yes 25 (33.8) 31 (41.9) 0.397 No 49 (66.2) 43 (58.1) Quadricep exercises (%) Yes 46 (62.2) 48 (64.9) 0.733 No 28 (37.8) 26 (35.1) Frequency (%) Daily 26 (57.78) 32 (71.11) 0.20 Weekly 19 (42.22) 12 (26.67) Kellgren and Lawrence grade 2, 81.1 76.4 0.448 number (%) Pain VAS score, mean (SD) 5.01 (2.55) 5.05 (2.61) 0.939 WOMAC questionnaire, mean (SD) 82.3 (47.3) 81.4 (44.1) 0.904 pain WOMAC, mean (SD) 21.3 (11.8) 21.1 (12.3) 0.919 Stiffness WOMAC , median (range) 6.5 (0-20) 4.5 (0-20) 0.204 Function WOMAC, mean (SD) 54.2 (32.7) 54.4 (29.3) 0.971 Medial minimal joint space width 2.98. (0.82) 2.82 (0.84) 0.242 (right), mean (SD) Lateral minimal joint space width 4.25 (1.28) 4.32 (1.12) 0.748 (right), mean (SD) Medial minimal joint space width 2.83 (0.84) 2.90 (0.78) 0.590 (left), mean (SD) Lateral minimal joint space width 4.35 (1.10) 4.28 (1.15) 0.691 (left), mean (SD)
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4.2 Pain VAS Mean VAS was plotted by treatment and time, which indicated declining VAS after receiving treatment in both groups, see Figure 4.2. The mean VAS scores in the glucosamine plus diacerin group at 1, 2, 3, 4, 5, and 6 months were 4.07, 3.58, 3.61, 3.35, 3.32, and 3.16 respectively; the corresponding values in the glucosamine and placebo group were 4.72, 4.19, 3.74, 3.48, 3.29, and 2.77. Applying the mixed-effect regression model indicated no significant difference between the two groups at each distinct time, see Table 4.2. Comparing within treatment group effects for glucosamine plus diacerein indicated that the VAS was approximately 0.72 to 0.91 units lower at 4 to 6 months compared to 1 month after receiving treatments, see Table 4.3. A similar trend was observed within the glucosamine plus placebo group but the change of VAS score was 0.98 to 1.95 units lower at 3 to 6 months compared to 1 month after treatment. This implies that both groups showed similar and statistically significant improvement over time. Sub-group analysis was performed in patients whose pain VAS scores at baseline were 5 or higher. The overall mean VAS scores were respectively 6.72±1.69 and 6.92±1.56 in the combined treatments and mono-therapy groups, but there was no statistically significant difference (P-value = 0.607). Age and BMI between two groups were statistically significant; they were therefore adjusted in a mixed linear regression model (see Table 4.4). Coefficient of age and BMI were 0.02 (P-valve=0.338) and 0.12 (P-value<0.001) this implied that if age increase 1 year then VAS will increase 0.02 unit, and if BMI increase 1 unit then VAS will increase 0.12 unit. After adjusted age and BMI, the VAS was approximately 0.81 units lower in glucosamine plus diacerein when compared to glucosamine alone.
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Figure 2. Mean VAS by treatment groups and time 6 5 4.72
4.19 4 4.07 3.72 3.48 3.32 3.58 3.61 3.35 3.16 3.29 3 Linear Prediction, Fixed Portion 2.77 2
1m 2m 3m 4m 5m 6m Time (months)
Glucosamine plus diacerein Glucosamine
Figure 4.2 Mean VAS by treatment groups and time
4.3 WOMAC score
4.3.1 WOMAC total scores mean WOMAC total scores were plotted by treatment and time, which indicated declining WOMAC scores in both treatment groups, see Figure 4.3A and Table 4.2. Applying the mixed-effect regression model indicated no significant difference between the two groups at each distinct time. Comparing within treatment group effects for glucosamine plus diacerein indicated that the WOMAC total scores were approximately 13.01 to 18.32 units lower at 4 to 6 months compared to 1 month after receiving treatment, see Table 4.3. A similar trend was observed within the glucosamine plus placebo group but the change in WOMAC total scores was 10.77 to 25.27 units lower at 3 to 6 months compared to 1 month after treatment. Age and BMI between two groups were statistically significant; they were adjusted in a mixed linear regression model (see Table 4.4). Coefficient of age and BMI Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 91
were 0.26 (P-valve=0.560) and 2.41 (P-value<0.001) unit this implied that if age increase 1 year then WOMAC total scores will increase 0.26 unit and if BMI increase 1 unit then WOMAC will increase 2.41 unit. After adjusted age and BMI, the VAS was approximately 2.29 units lower in glucosamine plus diacerein when compared to glucosamine alone.
4.3.2 WOMAC pain scores mean WOMAC pain scores were plotted by treatment and time, which indicated declining WOMAC scores in both treatment groups, see Figure 4.3B and Table 4.2. Comparing within treatment group effects for glucosamine plus diacerin indicated that the WOMAC pain scores were approximately 2.37 to 3.80 units lower at 4 to 6 months compared to 1 month after receiving treatment, see Table 4.3. A similar trend was observed within the glucosamine plus placebo group but the change in WOMAC pain scores was 2.07 to 6.19 lower at 3 to 6 months compared to 1 month after treatment. Age and BMI between two groups were statistically significant; they were adjusted in a mixed linear regression model (see Table 4.4). Coefficient of age and BMI were 0.07 (P-valve=0.489) and 0.61 (P-value<0.001) unit this implied that if age increase 1 year then WOMAC pain scores will increase 0.07 unit and if BMI increase 1 unit then WOMAC pain scores will increase 0.61 unit. After adjusted age and BMI, the VAS was approximately 1.07 units lower in glucosamine plus diacerein when compared to glucosamine alone.
4.3.3 WOMAC stiffness scores mean WOMAC stiffness scores were plotted by treatments and time, which indicated declining WOMAC scores in both treatment groups, see Figure 4.3C and Table 4.2. Applying the mixed-effect regression model indicated no significant difference between the two groups at each distinct time. For within treatment group comparison, the WOMAC stiffness score was approximately 1.23 to 1.91 units lower at 4 to 6 months compared to 1 month after receiving glucosamine plus diacerein, see Table 4.3. For glucosamine plus placebo group, the change in WOMAC stiffness scores at 4 to 6 months were 0.77 to 1.29, which was significantly decreased only at 6 months when compared to 1 month. Jatupon Kongtharvonskul Results / 92
Age and BMI between two groups were statistically significant; they were adjusted in a mixed linear regression model (Table 4.4). Coefficient of age and BMI were -0.02 (P-valve=0.669) and 0.18 (P-value=0.005) unit this implied that if age increase 1 year then WOMAC stiffness scores will decrease 0.02 unit and if BMI increase 1 unit then WOMAC stiffness scores will increase 0.18 unit. After adjusted age and BMI, the VAS was approximately 0.57 units higher in glucosamine plus diacerein when compared to glucosamine alone.
4.3.4 WOMAC function scores mean WOMAC function scores decreased over time for both treatments see Figure 4.3D and Table 4.2. Applying the mixed-effect regression model indicated no significant difference between the two groups at each distinct time. Within-group comparisons for the glucosamine plus diacerein group, showed a change in WOMAC function scores of approximately 9.4 to 12.63 units lower at 4 to 6 months compared to 1 month after receiving treatment, see Table 4.3. A similar trend was observed within the glucosamine plus placebo group but the change in WOMAC function scores was 7.56 to 17.77 units lower at 3 to 6 months compared to 1 month after treatment. Age and BMI between two groups were statistically significant; they were adjusted in a mixed linear regression model (see Table 4.4). Coefficient of age and BMI were 0.21 (P-valve=0.502) and 1.62 (P-value<0.001) unit this implied that if age increase 1 year then WOMAC function scores will increase 0.21 unit and if BMI increase 1 unit then WOMAC function scores will increase 1.62 unit. After adjusted age and BMI, the VAS was approximately 1.78 units lower in glucosamine plus diacerein when compared to glucosamine alone.
Fac. of Grad. Studies, Mahidol Univ.
A. Mean WOMAC total with 95% CIs in both groups in difference time B. Mean WOMAC pain with 95% CIs in both groups in difference time 20 80 71.02 17.14 16.01 70 67.09 63.44 14.88 15.08 69.81 58.01 16.94 15 13.54 64.12 55.80 60 15.27 59.04 14.14 14.57 13.14 52.69 59.09 13.40 50 55.07
10 10.95 44.53 40 Linear Prediction, FixedPortion Linear Prediction, FixedPortion 30 5
1m 2m 3m 4m 5m 6m 1m 2m 3m 4m 5m 6m Time (months) Time (months)
Glucosamine plus diacerein Glucosamine Glucosamine plus diacerein Glucosamine
C. Mean WOMAC stiffness with 95% CIs in both groups in different time D. Mean WOMAC function with 95% CIs of both groups in difference time Ph.D.(Clinical Epidemiology) /93 60 7
6.06 48.02 6 5.89 50 45.51 43.42 5.11 47.54 4.84 38.62 5 43.90
40 38.02 5.12 4.94 39.98 4.93 4.22 39.64 35.38 37.39
4 4.35 4.15 4.21 30 29.76 3.83 Linear Prediction, FixedPortion Linear Prediction, FixedPortion 3 20
1m 2m 3m 4m 5m 6m 1m 2m 3m 4m 5m 6m Time (months) Time (months)
Glucosamime plus diacerein Glucosamine Glucoamine plus diacerein Glucosamine
Figure 4.3 Mean total and sub-WOMAC scores by treatment groups and time
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4.4 Minimal Joint Space Width (JSW) Comparing the JSWs between the two treatments groups showed no statistically significant differences with mean differences at 3 and 6 months of 0.06 (95% CI: -0.35, 0.24) and 0.04 (95% CI: -0.33, 0.26), see Table 4.2 and Figure 4.4. Comparing within treatment group of the glucosamine plus diacerein group indicated that the JSW was only 0.04 mm lower at 6 months when compared to 3 month; a similar trend was observed within the glucosamine plus placebo group with only 0.04 mm of change, see Table 4.3. 2.8
2.64
2.60 2.6
2.59 2.56 Linear Prediction, Fixed Portion 2.4
3m 6m Follow up times
Glucosamine plus diacerein Glucosamine
Figure 4.4 Mean difference of JSW between glucosamine plus diacerein group and glucosamine and placebo group at 3 and 6 months follow-up
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 95
Table 4.2 Mean of VAS, WOMAC total, WOMAC sub-score and Joint space width compared between two groups at 1 month to 6 months follow up VAS Treatment Mean differences 95%CI P-value Follow up time Glucosamine Glucosamine between groups plus diacerein plus placebo 1 month 4.07 4.72 -0.65 -0.12, 1.43 0.098 2 months 3.58 4.19 -0.61 -1.39, 0.16 0.119 3 months 3.61 3.74 -0.13 -0.9, 0.65 0.750 4 months 3.35 3.48 -0.13 -0.66, -0.92 0.745 5 months 3.32 3.29 0.03 -0.76, 0.82 0.944 6 months 3.16 2.77 0.38 -0.38, 1.14 0.324 WOMAC total Treatment Mean differences 95%CI P-value Follow up time Glucosamine Glucosamine between groups plus diacerein plus placebo 1 month 71.02 69.81 1.21 -12.64, 15.07 0.864 2 months 67.09 64.12 2.97 -10.85, 16.78 0.674 3 months 63.44 59.04 4.41 -9.45, 18.26 0.533 4 months 58.01 59.09 -1.08 -15.08, 12,.92 0.879 5 months 55.07 55.80 -0.73 -14.74, 13.27 0.918 6 months 52.69 44.53 8.16 -5.52, 21.84 0.332 WOMAC pain Treatment Mean differences 95%CI P-value Follow up time Glucosamine Glucosamine between groups plus diacerein plus placebo 1 month 16.94 17.14 0.20 -3.20, 3.61 0.907 2 months 16.01 15.27 -0.74 -4.13, 2.66 0.670 3 months 14.88 14.14 -0.73 -4.14, 2.67 0.674 4 months 14.57 15.08 0.51 -2.94, 3.95 0.772 5 months 13.40 13.54 0.14 -3.31, 3.58 0.938 6 months 13.14 10.95 -2.19 - 5.55, 1.16 0.200
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Table 4.2 Mean of VAS, WOMAC total, WOMAC sub-score and Joint space width compared between two groups at 1 month to 6 months follow up (Cont.)
WOMAC Treatment Mean differences 95%CI P-value stiffness between groups Follow up time Glucosamine Glucosamine plus diacerein plus placebo 1 month 6.06 5.12 0.94 -0.57, 2.44 0.221 2 months 5.89 4.94 0.65 -0.85, 2.14 0.399 3 months 5.11 4.93 0.19 -1.32, 1.69 0.809 4 months 4.84 4.35 0.49 -1.04, 2.01 0.534 5 months 4.22 4.21 0.01 -1.52, 1.54 0.990 6 months 4.15 3.83 0.32 -1.16, 1.79 0.675 WOMC function Treatment Mean differences 95%CI P-value Follow up time between groups Glucosamine Glucosamine plus diacerein plus placebo 1 month 48.02 47.54 0.49 -9.08, 10.05 0.921 2 months 45.51 43.90 1.61 -7.93, 11.15 0.741 3 months 43.42 39.98 3.45 -6.12, 13.02 0.480 WOMC function Treatment Mean differences 95%CI P-value Follow up time between groups Glucosamine Glucosamine plus diacerein plus placebo 4 months 38.62 39.64 -1.02 -10.69, 8.65 0.836 5 months 37.39 38.02 -0.63 -10.31, 9.04 0.898 6 months 35.38 29.76 5.62 -3.83, 15.06 0.244 Joint Space Treatment Mean differences 95%CI P-value Width between groups Follow up time Glucosamine Glucosamine plus diacerein plus placebo 3 months 2.64 2.59 0.06 -0.35, 0.24 0.707 6 months 2.60 2.56 0.04 -0.33, 0.26 0.807
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Table 4.3 Mean of VAS, WOMAC total, sub-score and Joint space width comparing within group at time compared to 1 to 6 month follow up VAS Glucosamine plus diacerein Glucosamine plus placebo Time Mean Within group P-value Mean Within group P-value differences differences 1 month 4.07 - - 4.72 - - 2 months 3.58 0.49 0.081 4.19 0.53 0.059 3 months 3.61 0.46 0.107 3.74 0.98 <0.001 4 months 3.35 0.72 0.013 3.48 1.24 <0.001 5 months 3.32 0.75 0.009 3.29 1.43 <0.001 6 months 3.16 0.91 0.001 2.77 1.95 <0.001 WOMAC Glucosamine plus diacerein Glucosamine plus placebo total Mean Within group P-value Mean Within group P-value Time differences differences 1 month 71.02 - - 69.81 - - 2 months 67.09 3.93 0.325 64.12 5.69 0.154 3 months 63.44 7.58 0.060 59.04 10.77 0.007 4 months 58.01 13.01 0.001 59.09 10.72 0.008 5 months 55.07 15.96 <0.001 55.80 14.01 0.001 6 months 52.69 18.32 <0.001 44.53 25.27 <0.001 WOMAC Glucosamine plus diacerein Glucosamine plus placebo pain Mean Within group P-value Mean Within group P-value Time differences differences 1 month 16.94 - - 17.14 - - 2 months 16.01 0.93 0.378 15.27 1.87 0.076 3 months 14.88 2.06 0.053 14.14 3.00 0.005 4 months 14.57 2.37 0.029 15.08 2.07 0.054 5 months 13.40 3.54 0.001 13.54 3.61 0.001 6 months 13.14 3.80 <0.001 10.95 6.19 <0.001
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Table 4.3 Mean of VAS, WOMAC total, sub-score and Joint space width comparing within group at time compared to 1 to 6 month follow up (Cont.)
WOMAC Glucosamine plus diacerein Glucosamine plus placebo stifness Mean Within group P-value Mean Within group P-value Time differences differences 1 month 6.06 - - 5.12 - - 2 months 5.89 0.47 0.378 4.94 0.18 0.738 3 months 5.11 0.95 0.078 4.93 0.20 0.715 4 months 4.84 1.23 0.025 4.35 0.77 0.153 5 months 4.22 1.84 0.001 4.21 0.91 0.920 6 months 4.15 1.91 <0.001 3.83 1.29 0.015 WOMAC Glucosamine plus diacerein Glucosamine plus placebo function Mean Within group P-value Mean Within group P-value Time differences differences 1 month 48.02 - - 47.54 - - 2 months 45.51 2.51 0.365 43.90 3.63 0.189 3 months 43.42 4.60 0.099 39.98 7.56 0.006 4 months 38.62 9.40 0.001 39.64 7.89 0.005 5 months 37.39 10.63 <0.001 38.02 9.51 0.001 6 months 35.38 12.63 <0.001 29.76 17.77 <0.001 Minimal Glucosamine plus diacerein Glucosamine plus placebo JSW Mean Within group P-value Mean Within group P-value Time differences differences 3 months 2.64 - - 2.59 - - 6months 2.60 0.04 0.586 2.56 0.02 0.765
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Table 4.4: Mean of VAS, WOMAC total, sub-score and adverse event (diarrhea and dyspepsia) compared between two groups with or without co-variable (age and BMI) adjusted Outcome un-adjusted model Age and BMI adjusted model Mean difference P-value Mean difference P-value
VAS -0.65 0.098 -0 .81 0.039 WOMAC total -1.21 0.864 -2.29 0.742 WOMAC pain 0.20 0.907 -1.07 0.529 WOMAC stiffness -0.94 0.221 0.57 0.453 WOMAC function -0.49 0.921 -1.78 0.711 Adverse event RR P-value RR P-value Diarrhea 1.06 0.901 1.03 0.951 Dyspepsia 1.00 0.993 1.01 0.962
4.5 Adverse events The incidence of diarrhea and dyspepsia after receiving treatments ranged from 0.06 to 0.1 vs 0.05 to 0.1 and 0.02 to 0.06 vs 0.01 to 0.05 in the glucosamine plus diacerein and glucosamine plus placebo groups, respectively, see Table 4.5. The estimated RR of having diarrhea in the glucosamine plus diacerein group compared with the glucosamine plus placebo group at 1, 2, 3, 4, 5, and 6 months were 1.06, 1.14, 0.75, 0.67, 1.43 and 1.68 respectively, however none were statistically significant (P-value = 0.901, 0.775, 0.546, 0.456, 0.514 and 0.296). The estimated RRs of having dyspepsia in the glucosamine plus diacerein group compared with the glucosamine plus placebo group at 1, 2, 3, 4, 5, and 6 months were 1.10, 0.54, 1.61, 1.15, 1.70 and 1.02 respectively, however none were statistically significant (P-value = 0.860, 0.419, 0.461, 0.893, 0.537 and 0.976). Hence, the risk of having diarrhea and dyspepsia did not differ between the two groups during 6 months of treatment. Table 4.5 shows the frequency of the most common adverse events. The most common adverse event was abnormal urine (red or orange color), seen in 87.7% of patients receiving glucosamine plus diacerein and in 66.2% of the patients receiving glucosamine plus placebo. For approximately one third of the patients, the adverse
Jatupon Kongtharvonskul Results / 100
events were related to the gastrointestinal system (diarrhea, gastritis, constipation and nausea) however there were no significant differences between groups. Approximately 10% of patients in both groups reported skin reactions. No adverse events led to the dropout of any patient or discontinuation of any medication. No deaths occurred in this study. Parameters determined from vital signs and physical examinations were similar in both groups. The consumption of rescue medication in this study, i.e. other pain medication, was low and similar between the two groups.
Table 4.5 Incidence and risk ratio of adverse events between treatment groups Diarrhea Treatment RR 95%CI P-value Follow up Glucosamine plus Glucosamine plus time diacerein placebo 1 month 0.10 0.09 1.06 0.43, 2.62 0.901 2 months 0.10 0.09 1.14 0.45, 2.79 0.775 3 months 0.08 0.10 0.75 0.29, 1.91 0.546 4 months 0.06 0.09 0.67 0.46, 1.92 0.456 5 months 0.08 0.05 1.43 0.49, 4.21 0.514 6 months 0.10 0.06 1.68 0.64, 4.42 0.296 Dyspepsia Treatment RR 95%CI P-value Follow up Glucosamine plus Glucosamine plus time diacerein placebo 1 month 0.06 0.05 1.10 0.37, 3.34 0.860 2 months 0.02 0.04 0.54 0.12, 2.38 0.419 3 months 0.05 0.03 1.61 0.46, 5.65 0.461 4 months 0.02 0.01 1.15 0.15, 8.73 0.893 5 months 0.02 0.01 1.70 0.28, 11.60 0.537 6 months 0.03 0.03 1.02 0.23, 4.51 0.976
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Table 4.6 Proportion of patients in each group reporting adverse events and co- intervention Adverse Event Glucosamine plus diacerein Glucosamine plus placebo (N=74) (N=74) Diarrhea 33 (44.6%) 26 (35.1%) Dyspepsia 19 (25.7%) 16 (21.6%) Urine abnormal 65 (87.8%) 49 (66.2%) Gastritis 31 (41.9%) 28 (37.8%) Constipation 33 (44.6%) 39 (52.7%) Nausea 24 (32.4%) 23 (31.1%) Hypertension 42 (56.8%) 47 (63.5%) Edema 30 (40.5%) 28 (37.8%) Dizziness 27 (36.5%) 29 (39.2%) Skin reaction 15 (20.3%) 14 (18.9%) Co-intervention 13 (17.6%) 16(21.6%) (analgesic used)
Jatupon Kongtharvonskul Discussion and conclusion / 102
CHAPTER V DISCUSSION
5.1 Our findings We conducted a double-blind RCT to compare the efficacy of the combination of glucosamine plus diacerein to glucosamine plus placebo in the treatment of knee OA. Our findings suggest that combined treatment does not reduce pain VAS, WOMAC total score, or WOMAC sub-scores when compared to glucosamine monotherapy in patients with mild-to-moderate knee OA. Although the efficacy for both treatment groups did not differ, clinical signs and symptoms were improved in both treatment groups at 3 to 6 months, and this was particularly evident in the glucosamine plus placebo group. Glucosamine, an essential component of the proteoglycans in normal cartilage, is found naturally in the knee joint of human body. With its possible anabolic effect, it is used for inhibition of metalloproteinase activity, prostaglandin E2 release, nitric oxide production, degradation of glycosaminoglycans, and stimulating the synthesis of hyaluronic acid in the joint82, 177. It has a slow onset of response and provides long-lasting pain relief, functional improvement, and delays progression of the joint space narrowing111, 114 in OA of the knee82, 109, 142. Diacerein may be beneficial for treatment of OA as it inhibits interleukin-1, controls lymphocytes, increases the number of bone marrow cells, reducing degeneration of the bone joint83. As a result, diacerein is also claimed to improve pain and function in OA of the knee 140, 142, 145, 178. A recent animal study found chondroprotective effects with both diacerein and glucosamine but a better range of motion of the knee joint was found with diacerein use than with glucosamine179. No animal study or clinical trial explored the combination effect of glucosamine and diacerein in OA knee. This study has demonstrated neither an additive nor synergistic effect from combined glucosamine and diacerein treatment. An explanation for this is that glucosamine may reach its ceiling anabolic effect already without the catabolic effect from diacerein, as in the study it was found that there were Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 103 no differences clinical outcomes in OA patients who were treated with different doses of glucosamine 99 or diacerein 140. Our findings are similar to a previous study that compared combined glucosamine sulfate plus chondroitin sulfate with glucosamine sulfate or chondroitin sulfate alone in patients with OA of the knee Kellgren and Lawrence grade 2 to 331. This study was later combined in a network meta-analysis 98, which showed similar results. Although the potential synergistic effects from a pharmacologic study of glucosamine and diacerein 177 looked promising, our findings indicate that combined treatments do not provide any benefit over monotherapy.
5.2 Measures taken for protocol violation Despite the fact that this study was carefully planned, many problems (non- compliance, co-intervention, or contamination) could occur during the conducting of this study. For co-intervention and contamination, all patients received personal log books and were closely checked for whether or not patients had adhered to the assigned treatment. The number of remaining pills and pain-killers used, including NSAIDs and paracetamol, were recorded at every visit. Furthermore, patients were asked at every visit whether they had taken other pills or supplementary tablets (e.g. steroid, injection of other medicine) along with co-treatment (e.g. yoga, acupuncture, arthrocentesis of the knee and use of heel wedges) that might contain or have similar mechanisms as our studied drugs. There were no reports of use of non-protocol medication or other co- treatments, which meant co-intervention or contamination between the groups was less likely. However, the data was analyzed by the ITT method. As for compliance, the follow-up period of our study was scheduled at 6 months, and some patients did not come at the exact time of follow-up. The method in which we dealt with this matter was by arranging new groups into time periods rather than using the exact number of weeks of follow-up, such as within 1.5 months rather than exactly 6 weeks. If the patient came for follow-up at later than 9 months (which was the latest date that we collected follow-up data), we grouped that patient’s data with Jatupon Kongtharvonskul Discussion and conclusion / 104 the follow-up data at the last follow-up session for all patients. The group that came after the last scheduled follow-up consisted of about 10% of all patients. After the groups had been rearranged, we calculated the difference of the outcomes using the following statistics and parameters. These include the continuous outcomes of pain VAS score, total and sub-WOMAC scores compared between treatment groups using a mixed linear regression analysis with a hierarchical approach. Dichotomous outcomes (i.e., a composite of adverse events and individual events) were compared between treatment groups using a mixed-effect Poisson regression analysis.
5.3 Strengths and limitations To the best of our knowledge, this is the first double-blind RCT to assess the effects of combined glucosamine plus diacerein vs monotherapy glucosamine with 6 months follow-up. The active treatments, which consisted of both capsules and sachets, were identical in appearance, and were administered to patients using coded drug packs so that the patients, investigators and outcome assessors were truly blinded. We have considered most relevant outcomes including subjective (i.e., pain VAS, WOMAC total and sub-scores) and objective measures (i.e., minimal tibio-femoral JSW). In addition, all possible adverse effects were also collected. Drug compliance was reasonably high and ranged from 88% to 100% and 79% to 100% in combined treatment and monotherapy groups respectively, (p-value = 0.133). Co-intervention with additional pain medications was also similar at 17.6% vs 21.6% in combined treatments and monotherapy groups (p-value = 0.534). We applied an intention to treat analysis by considering all patients in the groups to which they were originally randomly allocated, thus minimizing bias. We pooled mostly OA knee patients with mild to moderate pain scores at baseline, which might have made it difficult to detect the benefits of combined treatment. Moreover, in this study the follow-up was restricted to 6 months. This study has some limitations. First of all, the results can be referred in treated only mild to moderate OA knee but not in severe cases. Secondly, a factorial design (i.e., glucosamine, diacerein plus placebo, glucosamine plus diacerein and placebo plus placebo) should be conducted but we could not because of high budget. Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 105
Third, the endpoint of all outcomes were assessed within 6 months due to the high cost of running RCTs with two expensive medications (glucosamine and diacerein). Fourth, the most objective outcome of this study was radiographic JSW, which strongly depends on adequate positioning when taking the X-ray. It is also not specific to cartilage loss. Magnetic Resonance Images (MRI) provide somewhat superior sensitivity to change when compared to the commonly used radiographs, and has recently provided non- location-dependent measures of cartilage thickness loss and gain, which are potentially more sensitive in detecting SYSADOA effects than radiographic JSW. However, the cost of MRI is much more expensive than radiographs, costing about 20 times as much. Therefore we have used radiographic JSW with strict positioning in order to obtain the highest quality of this outcome.
5.4 What we have learned from this study The complementary pharmacologic treatment for OA knee according to EULAR recommendations suggest that the SYSADOA groups (glucosamine sulfate, chondroitin sulfate, ASU, diacerein, and hyaluronic acid) have symptomatic effects and may modify structure of the knee. Systematic review and network meta-analysis of glucosamine diacerein when compared to placebo in treatment of OA knee suggested that in diacerein significant differences in pain and functional scores were seen when compared with placebo. At higher doses, a significant number of adverse events was seen. On the other hand, glucosamine shows significant improvements in pain score but does not decrease risk of adverse effects and does not have a clinically relevant effect in slowing progression of joint space narrowing in OA knee. Diacerein has a higher risk of adverse GI events when compared to glucosamine. When compared to diacerein, glucosamine is the better treatment choice for OA of the knee. This study is the first study that explored the efficacy of combination of glucosamine and diacerein with aim to increase anabolic (glucosamine) and decrease catabolic (diacerein) effect to knee joint but the results indicate that combined treatments did not provide any benefit over monotherapy. Jatupon Kongtharvonskul Discussion and conclusion / 106
In summary, there is evidence to support the efficacy of glucosamine sulfate and diacerein in the management of knee OA both for pain reduction and functional improvement. However, in term of adverse events, diacerein has the highest risk compared to the others. There were no benefits of giving a combination of glucosamine sulfate with diacerein or chondroitin sulfate from the current evidence in treatment of mild to moderate OA knee (KL I-III). We recommend glucosamine sulfate or chondroitin sulfate as the first line drugs for the treatment of moderate OA knee (KL I- III) with diacerein as a second line drug. A combination of either glucosamine sulfate with chondroitin sulfate or glucosamine and diacerein is not recommended for treatment.
5.5 Suggestion for further studies From a review of the current literature and the results of this study, a combination of glucosamine and two other SYSADOA drugs (chondroitin or diacerein) in mild to moderated OA knee are considered. However, there are still uncertainties regarding the treatment of severe OA knee (higher pain scores or KL grade III-IV), particularly in specific patient groups (low BMI). This study measured outcomes at 6 months due to time restrictions on the study, making it a short-term assessment. However, according to previous studies of both drugs there have been long-term effects at 1 year (longest effect was 3 years). There are also sustained effects at longer than 3 months, therefore when assessing stratified OA knee patients in a subgroup with longer follow up times a sustained effect could be considered to detect the benefits of combined treatment. Replication in a larger sample due to repeated measurement might show greater difference of all possible outcomes over time, which can more properly address the treatment effects. Moreover, the results from this study have been based on plain radiographs, which may not be enough to assess knee cartilage, the major component that responds to both drugs (based on the joint space width of the knee joint). Magnetic resonance image (MRI) may better facilitate the assessment of cartilage change in the knee joint in the next study as MRI is much more sensitive than plain radiography. Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 107
Finally, there are various generic preparations of glucosamine that approximately were 5 times cheaper than the original ones. Bioequivalence trial between original and generic glucosamine should be conducted.
5.6 Conclusions This study demonstrated that adding diacerein with glucosamine sulfate does not improve clinical outcomes over monotherapy of glucosamine sulfate in mild to moderate osteoarthritis knees with Kellgren Lawrence grade 2-3. Both combined and mono-therapy can significantly reduce pain VAS and WOMAC function after 3 months to 6 months when compared to baseline.
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141.Dougados M, Nguyen M, Berdah L, Mazieres B, Vignon E, Lequesne M. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum. 2001;44(11):2539-47. 142.Pavelka K, Trc T, Karpas K, Vitek P, Sedlackova M, Vlasakova V, et al. The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled study with primary end points at two months after the end of a three-month treatment period. Arthritis Rheum. 2007;56(12):4055-64. 143.Brahmachari B, Chatterjee S, Ghosh A. Efficacy and safety of diacerein in early knee osteoarthritis: a randomized placebo-controlled trial. Clin Rheumatol. 2009;28(10):1193-8. 144.Zheng WJ, Tang FL, Li J, Zhang FC, Li ZG, Su Y, et al. Evaluation of efficacy and safety of diacerein in knee osteoarthritis in Chinese patients. Chin Med Sci J. 2006;21(2):75-80. 145.Louthrenoo W, Nilganuwong S, Aksaranugraha S, Asavatanabodee P, Saengnipanthkul S. The efficacy, safety and carry-over effect of diacerein in the treatment of painful knee osteoarthritis: a randomised, double-blind, NSAID-controlled study. Osteoarthritis Cartilage. 2007;15(6):605-14. 146.Bartels EM, Bliddal H, Schondorff PK, Altman RD, Zhang W, Christensen R. Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials. Osteoarthritis Cartilage. 2010;18(3):289-96. 147.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. 148.Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15(12):1833-40. Jatupon Kongtharvonskul Reference / 122
149.Lequesne MG. The algofunctional indices for hip and knee osteoarthritis. J Rheumatol. 1997;24(4):779-81. 150.Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ. 2003;326(7382):219. 151.Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta- analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol. 2008;61(10):991-6. 152.Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-34. 153.Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ. 2003;326(7387):472. 154.Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004;23(20):3105-24. 155.Song F, Harvey I, Lilford R. Adjusted indirect comparison may be less biased than direct comparison for evaluating new pharmaceutical interventions. J Clin Epidemiol. 2008;61(5):455-63. 156.Stata/SE 11.0 for windows [32bit]. 13 july 2009 [updated 13 july 2009; cited]. 13 july 2009. 157.Pham T, Le Henanff A, Ravaud P, Dieppe P, Paolozzi L, Dougados M. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis. 2004;63(12):1611-7. 158.Durmus D, Alayli G, Bayrak IK, Canturk F. Assessment of the effect of glucosamine sulfate and exercise on knee cartilage using magnetic resonance imaging in patients with knee osteoarthritis: a randomized controlled clinical trial. J Back Musculoskelet Rehabil. 2012;25(4):275-84. 159.Kwoh CK, Roemer FW, Hannon MJ, Moore CE, Jakicic JM, Guermazi A, et al. Effect of oral glucosamine on joint structure in individuals with chronic knee pain: a randomized, placebo-controlled clinical trial. Arthritis Rheumatol. 2014;66(4):930-9. Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical epidemiology) / 123
160.Madhu K, Chanda K, Saji MJ. Safety and efficacy of Curcuma longa extract in the treatment of painful knee osteoarthritis: a randomized placebo-controlled trial. Inflammopharmacology. 2013;21(2):129-36. 161.Chopra A, Saluja M, Tillu G, Sarmukkaddam S, Venugopalan A, Narsimulu G, et al. Ayurvedic medicine offers a good alternative to glucosamine and celecoxib in the treatment of symptomatic knee osteoarthritis: a randomized, double-blind, controlled equivalence drug trial. Rheumatology (Oxford, England). 2013;52(8):1408-17. 162.Michel BA, Stucki G, Frey D, De Vathaire F, Vignon E, Bruehlmann P, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum. 2005;52(3):779-86. 163.Mazieres B, Hucher M, Zaim M, Garnero P. Effect of chondroitin sulphate in symptomatic knee osteoarthritis: a multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2007;66(5):639-45. 164.Kahan A, Uebelhart D, De Vathaire F, Delmas PD, Reginster JY. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2009;60(2):524-33. 165.Tashiro T, Seino S, Sato T, Matsuoka R, Masuda Y, Fukui N. Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: a double-blind, placebo-controlled study over a 12-month period. TheScientificWorldJournal. 2012;2012:167928. 166.Appelboom T, Schuermans J, Verbruggen G, Henrotin Y, Reginster JY. Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double blind, prospective, placebo-controlled study. Scand J Rheumatol. 2001;30(4):242-7. 167.Pelletier JP, Lajeunesse D, Reboul P, Mineau F, Fernandes JC, Sabouret P, et al. Diacerein reduces the excess synthesis of bone remodeling factors by human osteoblast cells from osteoarthritic subchondral bone. J Rheumatol. 2001;28(4):814-24. 168.Pelletier JP, Mineau F, Fernandes JC, Duval N, Martel-Pelletier J. Diacerhein and rhein reduce the interleukin 1beta stimulated inducible nitric oxide synthesis Jatupon Kongtharvonskul Reference / 124
level and activity while stimulating cyclooxygenase-2 synthesis in human osteoarthritic chondrocytes. J Rheumatol. 1998;25(12):2417-24. 169.Tamura T, Ohmori K. Rhein, an active metabolite of diacerein, suppresses the interleukin-1alpha-induced proteoglycan degradation in cultured rabbit articular chondrocytes. Jpn J Pharmacol. 2001;85(1):101-4. 170.Yaron M, Shirazi I, Yaron I. Anti-interleukin-1 effects of diacerein and rhein in human osteoarthritic synovial tissue and cartilage cultures. Osteoarthritis Cartilage. 1999;7(3):272-80. 171.Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin- like drugs. Nat New Biol. 1971;231(25):232-5. 172.Leung KS, Chen CM, So WS, Sato K, Lai CH, Machaisavariya B, et al. Multicenter trial of modified Gamma nail in East Asia. Clin Orthop Relat Res. 1996(323):146-54. 173.Kuptniratsaikul V, Rattanachaiyanont M. Validation of a modified Thai version of the Western Ontario and McMaster (WOMAC) osteoarthritis index for knee osteoarthritis. Clin Rheumatol. 2007;26(10):1641-5. 174.Buckland-Wright JC, Ward RJ, Peterfy C, Mojcik CF, Leff RL. Reproducibility of the semiflexed (metatarsophalangeal) radiographic knee position and automated measurements of medial tibiofemoral joint space width in a multicenter clinical trial of knee osteoarthritis. J Rheumatol. 2004;31(8):1588-97. 175.The Prevention and Treatment of Missing Data in Clinical Trials. Washington DC: 2010 by the National Academy of Sciences; 2010. 176.Kongtharvonskul J, Anothaisintawee T, McEvoy M, Attia J, Woratanarat P, Thakkinstian A. Efficacy and safety of glucosamine, diacerein, and NSAIDs in osteoarthritis knee: A systematic review and network meta-analysis. Eur J Med Res. 2015;20(1). 177.Calamia V, Mateos J, Fernandez-Puente P, Lourido L, Rocha B, Fernandez-Costa C, et al. A pharmacoproteomic study confirms the synergistic effect of chondroitin sulfate and glucosamine. Sci Rep. 2014;4:5069. Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical epidemiology) / 125
178.Lequesne M, Berdah L, Gerentes I. [Efficacy and tolerance of diacerhein in the treatment of gonarthrosis and coxarthrosis]. Rev Prat. 1998;48(17 Suppl):S31-5. 179.Toegel S, Huang W, Piana C, Unger FM, Wirth M, Goldring MB, et al. Selection of reliable reference genes for qPCR studies on chondroprotective action. BMC Mol Biol. 2007;8:13.
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APPENDICES
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APPENDIX A META-ANALYSIS
Search Strategies #1 Osteoarthritis or Degenerative arthritis #2 adult #3 elderly #4 #1 AND #2 AND #3 #5 “SYmptomatic Slow Acting Drug for OsteoArthritis” #6 SYSADOA #7 glucosamine #8 diacerein #9 #5 OR #6 OR #7 OR #8 #10 Pain #11 Functions #12 score #13 grade #14 WOMAC #15 KSS #16 motion #17 radiographic grading #18 x-ray #19 MRI #20 KellgrenLawrance #21 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 #22 clinical trial OR RCT OR randomize controlled trial #23 #4 AND #9 AND #21 AND # 22
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APPENDIX B
โครงการศึกษา เปรียบเทยบผลการรี ักษาโรคข้อเข่าเสื่อมด้วยยากลูโคซามนี หรือกลูโคซามนคี ู่กบไดอะซั ีรีน และ เปรียบเทยบอาการปวดเขี ่า ดชนั ีความเสื่อมของเข่า และ ช่องว่างของข้อเข่าในเอกซเรย์ รวมถึงผลข้างเคยงของี ยา ในช่วงเวลา 6 เดอนื Form 1: Eligible data
วนั /เดือน/ปี (พศ..) // ผกรอกขู้ อม้ ูล HN ……………………………………. กรุณาทาเครํ ื่องหมายกากบาทหนาเกณฑ้ การค์ ดเลั ือกถาผ้ ปู้ ่วยผานเกณฑ่ ค์ ดเลั ือกขอน้ ้นั ผปู้ ่วยที่เขาร้ ่วมการวจิ ยั
ตองผ้ านเกณฑ่ เข์ าร้ ่วมการวจิ ยครบทั ุกขอ้ ดงตั อไปน่ ้ี
ไดร้ ับการวนิ ิจฉยวั าเป่ ็นโรคขอเข้ าเส่ ื่อมระยะเร่ิมตน้ มีอายมากกวุ า่ 50 ปี ไม่มีการผดริ ูปเกิน K&L II หรือแผลผาต่ ดบรั ิเวณเขา่ สามารถอาน่ และสื่อสารภาษาไทยได ้ ไม่ไดร้ ับประทานยาในกลุมสเตอรอยด่ ์ เช่น prednisolone หรือ ยาในกลุม่ SYSADOA เช่น กรูโค ซามีน หรือ (glucosamine) ไดอะซีรีน (diacerein) ในช่วงเวลาก่อนการศึกษาเป็นเวลา 6 เดือน ไม่เคยมีประวตั ิโรคประจาตํ วทั ี่ไม่สามารถรับยาไดเช้ ่น Renal insufficiency, Hepatic disease, Metabolic disease, Persistent diarrhea or laxative use severe, Severe parenchymal organ disease, Anaemia (haemoglobin< 10.0 g/ dl or haematocrit < 30%). ไม่เคยไดร้ ับการวินิจฉยวั าเป่ ็นขอเข้ าเส่ ื่อมจากสาเหตุอื่น - เป็นผปู้ ่วยโรคขอร้ ูมาตอยด ์ หรือ SLE - ไม่เคยมีประวตั ิกระดูกหกเขั าข้ อเข้ า่ - ไม่มีภาวะอวนผ้ ิดปกติ (BMI > 40 kg/m2) ในกรณีที่ผปู้ ่วยผานเกณฑ่ เข์ าร้ ่วมวจิ ยครบทั ุกขอ้ ใหข้ อม้ ูลผปู้ ่วยเกี่ยวเนื่องกบการวั จิ ยั (Information process and consent form) Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 129
ยนดิ ีที่จะเขาร้ ่วมการวจิ ยั และ เซ็น inform consent ยนดิ ี (participants) Participants ID ไม่ยนดิ ี (non-participants) Non-participants ID
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โครงการศึกษา เปรียบเทยบผลการรี ักษาโรคข้อเข่าเสื่อมด้วยยากลูโคซามนี หรือกลูโคซามนคี ู่กบไดอะซั ีรีน และ เปรียบเทยบอาการปวดเขี ่า ดชนั ีความเสื่อมของเข่า และ ช่องว่างของข้อเข่าในเอกซเรย์ รวมถึงผลข้างเคยงของี ยา ในช่วงเวลา 6 เดอนื Form 2: Patient’s log sheet HN Participants ID
ขอม้ ูลผปู้ ่วย ชื่อ ...... นามสกลุ ...... วนั /เดือน/ปี เกิด (.ศ.พ) // ที่อย ู่ บานเลขท้ ี่ ...... ซอย...... หมู่...... หมู่บาน้ ...... ถนน...... แขวง ...... จงหวั ดั ...... รหสไปรษณั ีย...... ์ เบอร์โทรศพทั บ์ าน้ ...... เบอร์โทรศพทั เคล์ ื่อนที่ ...... ญาติที่สามารถติดต่อไดช้ ื่อ ...... เบอร์โทรศพทั เคล์ ื่อนที่......
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โครงการศึกษา เปรียบเทยบผลการรี ักษาโรคข้อเข่าเสื่อมด้วยยากลูโคซามนี หรือกลูโคซามนคี ู่กบไดอะซั ีรีน และ เปรียบเทยบอาการปวดเขี ่า ดชนั ีความเสื่อมของเข่า และ ช่องว่างของข้อเข่าในเอกซเรย์ รวมถึงผลข้างเคยงของี ยา ในช่วงเวลา 6 เดอนื
Form 3: Baseline data วนั (.ศ.พ)ปี/เดือน/// ID A) Baseline data and Chief complaint ผกรอกขู้ อม้ ูล ...... กรุณาตอบคาถามในขํ อต้ างๆด่ านล้ างโดยกาเคร่ ื่องหมายกากบาท × ลงในช่องสี่เหลี่ยม 1.อาย ุ กปี 2. เพศ 1. ชาย 3. น้าหนํ กั )kg( 4. ความสูง )cm( 2. หญิง 5. อาการสาคํ ญั (chief complaint) 1.ปวดเข่า 2. อื่นๆ ระบุ ...... 6. อาการร่วม 6.1เขาบวมอ่ ุน่ 1. ตลอดเวลา 2. เดือนละคร้ัง 3.ปีละคร้ัง 3. อื่นๆ ...... 6.2 เขาต่ ิด 1. ตลอดเวลา 2. เดือนละคร้ัง 3.ปีละคร้ัง 3. อื่นๆ ...... 7. ระยะเวลาเร่ิมมีอาการปวดเขา่ เดือนก่อนมาโรงพยาบาล 8.โรดกระเพาะ 1. มี 2. ไม่มี 9. ถายเหลว่ 1. มี 2. ไม่มี 10. แพยา้ 1. มี 2. ไม่มี 11. โรคประจาตํ วั (Underlying disease) 12. สูบบุหรี่ 1. สูบ 2. ไม่สูบ; ประมาณ 11.1 เบาหวาน 1. เป็น 2. ไม่เป็น มวน...... /วนั 11.2 ความดนโลหั ิตสูง 1. เป็น 2. ไม่เป็น 13. ดื่มสุรา 1. ดื่ม 2. ไม่ดื่ม; ประมาณ 11.3 โรคประจาตํ วอั ื่นๆ 1. เป็น 2. ไม่เป็น ขวด...... /วนั ระบุ ...... 14. ประวตั ิโรคขอเข้ าเส่ ื่อมในครอบครัว (Family History) 1. มี 2. ไม่ 15. ประวตั ิการรับประทานยาเดิม หรือการ รักษาพยาบาลในอดีต 1. มี 2.ไม่มี ถาม้ ี ......
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B) Physical examination Crepitus test 1. Yes 2.No Ballottement test 1. Yes 2.No Grinding test 1. Yes 2.No Gliding test 1. Yes 2.No Range of motion 1. 0-90 degree 2. 90-120 degree 3. More than 120 degree Other
C) Radiologic results Kellgran Lawrance 1. Grade I 2. Grade II 3. Grade III
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โครงการศึกษา เปรียบเทยบผลการรี ักษาโรคข้อเข่าเสื่อมด้วยยากลูโคซามนี หรือกลูโคซามนคี ู่กบไดอะซั ีรีน และ เปรียบเทยบอาการปวดเขี ่า ดชนั ีความเสื่อมของเข่า และ ช่องว่างของข้อเข่าในเอกซเรย์ รวมถึงผลข้างเคยงของี ยา ในช่วงเวลา 6 เดอนื Form 3: First visit form Participants ID date / / A) Pain assessment
B) WOMAC questionnaire ระดบความปวดั ( 0 – 10) โดย 0 หมายถึงไม่ปวดเลย และ 10 หมายถึงปวดมากจนทนไม่ได ้ 1. ปวดขณะเดิน
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้ 2. ปวดขณะข้ึนลงบนไดั
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้ 3. ปวดขอตอนกลางค้ ืน
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้ 4. ปวดขอขณะอย้ เฉยๆู่
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้
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5. ปวดขอขณะย้ นลงนื ้าหนํ กั (ขาขางน้ ้นรั ับน้าหนํ กตั วั )
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้ ระดบอาการขั ้อฝื ด,ข้อยดึ (0–10 ) โดย 0 หมายถึงไม่มีอาการฝืดเลย และ 10 หมายถึง มีอาการฝืดมากที่สุด 1. ขอฝ้ ืดช่วงเชา้ (ขณะตื่นนอน)
0 1 2 3 4 5 6 7 8 9 10 ไม่ฝืดเลย ฝืดมากที่สุด 2. ขอฝ้ ืดในช่วงระหวางว่ นั
0 1 2 3 4 5 6 7 8 9 10 ไม่ฝืดเลย ฝืดมากที่สุด ระดบความสามารถในการใชั ้งานข้อ (0 – 10)โดย 0 หมายถึงไม่มีอาการฝืดเลย และ 10 หมายถึง ไม่สามารถทากํ ิจกรรมน้นๆไดั ้ 1. การลงบนไดั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 2. การข้ึนบนไดั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 3. การลุกยนจากทื ่านง่ั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 4. การยนื
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 5. การเดินบนพ้ืนราบ
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 6. การข้ึนลงรถยนต ์ Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 135
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 7. การไปซ้ือของนอกบาน้ หรือการไปจ่ายตลาด
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 8. การใส่กางเกง
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 9. การลุกจากเตียง
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 10. การถอดกางเกง
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 11. การเขาออกจากห้ องอาบน้ ้าํ
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 12. การนง่ั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 13. การรเขา้ -ออกจากส้วม
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้
14. การทางานบํ านหน้ กๆั
Jatupon Kongtharvonskul Appendices / 136
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 15. การทางานบํ านเบาๆ้
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ C) ความกว้างระหว่างช่องข้อเข่าจากเอกซเรย์ (มลลิ เมตริ ) 1. Yes; . Millimeters 2. Not perform If yes at date / /
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 137
โครงการศึกษา เปรียบเทยบผลการรี ักษาโรคข้อเข่าเสื่อมด้วยยากลูโคซามนี หรือกลูโคซามนคี ู่กบไดอะซั ีรีน และ เปรียบเทยบอาการปวดเขี ่า ดชนั ีความเสื่อมของเข่า และ ช่องว่างของข้อเข่าในเอกซเรย์ รวมถึงผลข้างเคยงของี ยา ในช่วงเวลา 6 เดอนื Form 4: Follow up form มา Follow up 1.Yes 2. No Participants ID Follow up date (dd/mm/yyyy) / / A) Pain assessment
- Use of analgesic drug as required yes No if yes, Paracetamol…………….tablets/months, NSAIDs…………….tablets/month B) WOMAC questionnaire ระดบความปวดั ( 0 – 10) โดย 0 หมายถึงไม่ปวดเลย และ 10 หมายถึงปวดมากจนทนไม่ได ้ 1. ปวดขณะเดิน
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้ 2. ปวดขณะข้ึนลงบนไดั
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้ 3. ปวดขอตอนกลางค้ ืน
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้ 4. ปวดขอขณะอย้ เฉยๆู่
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้
Jatupon Kongtharvonskul Appendices / 138
5. ปวดขอขณะย้ นลงนื ้าหนํ กั (ขาขางน้ ้นรั ับน้าหนํ กตั วั )
0 1 2 3 4 5 6 7 8 9 10 ไม่ปวดเลย ปวดมากจนทนไม่ได ้ ระดบอาการขั ้อฝื ด,ข้อยดึ (0–10 ) โดย 0 หมายถึงไม่มีอาการฝืดเลย และ 10 หมายถึง มีอาการฝืดมากที่สุด
1. ขอฝ้ ืดช่วงเชา้ (ขณะตื่นนอน)
0 1 2 3 4 5 6 7 8 9 10 ไม่ฝืดเลย ฝืดมากที่สุด 2. ขอฝ้ ืดในช่วงระหวางว่ นั
0 1 2 3 4 5 6 7 8 9 10 ไม่ฝืดเลย ฝืดมากที่สุด ระดบความสามารถในการใชั ้งานข้อ (0 – 10)โดย 0 หมายถึงไม่มีอาการฝืดเลย และ 10 หมายถึง ไม่สามารถทากํ ิจกรรมน้นๆไดั ้ 1. การลงบนไดั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 2. การข้ึนบนไดั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 3. การลุกยนจากทื ่านง่ั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 4. การยนื
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 139
5. การเดินบนพ้ืนราบ
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้
6. การข้ึนลงรถยนต ์
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้
7. การไปซ้ือของนอกบาน้ หรือการไปจ่ายตลาด
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้
8. การใส่กางเกง
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 9. การลุกจากเตียง
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้
10. การถอดกางเกง
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้
11. การเขาออกจากห้ องอาบน้ ้าํ
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 12. การนง่ั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ Jatupon Kongtharvonskul Appendices / 140
13. การเขา้ -ออกจากส้วม
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 14. การทางานบํ านหน้ กๆั
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ 15. การทางานบํ านเบาๆ้
0 1 2 3 4 5 6 7 8 9 10 ทาไดํ ด้ ีมาก เป็นปัญหามากที่สุด (ไม่สามารถทาไดํ )้ C) ความกว้างระหว่างช่องข้อเข่าจากเอกซเรย์ (มลลิ เมตริ ) 1. Yes. Millimeters 2. Not perform If yes at date / / D) ผลข้างเคยงจากยาี (Adverse effect) ช่วงเดอนทื ี่ Urinary system disorders 1. มี 2. ไม่มี Urine abnormal 1. มี 2. ไม่มี Respiratory system disorders 1. มี 2. ไม่มี Upper respiratory tract infection 1. มี 2. ไม่มี Gastro-intestinal system disorders 1. มี 2. ไม่มี Gastritis 1. มี 2. ไม่มี GI hemorrhage 1. มี 2. ไม่มี Dyspepsia 1. มี 2. ไม่มี Diarrhea 1. มี 2. ไม่มี Abdominal pain 1. มี 2. ไม่มี Bowel motility disorders 1. มี 2. ไม่มี Constipation 1. มี 2. ไม่มี Nausea 1. มี 2. ไม่มี Cardiovascular disorders, general 1. มี 2. ไม่มี Hypertension 1. มี 2. ไม่มี Musculo-skeletal system disorders 1. มี 2. ไม่มี Myalgia 1. มี 2. ไม่มี Arthropathy 1. มี 2. ไม่มี Edema 1. มี 2. ไม่มี Body as a whole e general disorders 1. มี 2. ไม่มี Central and peripheral nervous system disorders 1. มี 2. ไม่มี Dizziness 1. มี 2. ไม่มี Dermatological 1. มี 2. ไม่มี Other
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 141
APPENDIX C DUMMY TABLE
Dummy table 1 Baseline characteristics of the patient Variables Group 1 Group 2 Value labels/Legal (glus) (glus&diac) range Age, year, mean (SD) BMI (kg/m2), mean (SD) Height, cm, mean (SD) Weight, kg, mean (SD) Sex Male Female Criteria for diagnosis Knee pain Yes No Swelling Yes No Stiffness Yes No Physical Examination Crepitus Yes No Ballottement Yes No Gliding test Yes NO Grinding test Yes No Jatupon Kongtharvonskul Appendices / 142
Radiographic Examination Kellgrane-Lawrance grade Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Underlying disease Gastrointestinal disease Yes No Peptic ulcer Yes No Duodenal ulcer Yes No Renal disease Yes No Secondary osteoarthritis Yes No History of medication Antiplatelets or anticoagulant Yes No Intra-articular injection (e.g. steroid) Yes No Previous Surgery Yes No
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 143
Dummy table 2 Primary and secondary outcomes of two treatment groups Pain score (0-100) Intervention Time Group 1 (glus) Group 2 (glus&diac)
Day 0 Month 1 Month 2 Month 3 Month 4 Month 5 Month 6
WOMAC score Intervention (0-96) Time Group 1 (glus) Group 2 (glus&diac) Day 0 Month 1 Month 2 Month 3 Month 4 Month 5 Month 6
Jiont space width (mm) Intervention Time Group 1 (glus) Group 2 (glus&diac) Day 0 Month 1 Month 2 Month 3 Month 4 Month 5 Month 6
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Dummy table 3 Adverse effect of two treatment groups Adverse event Interventions Time Group 1 (glus) Group 2 (glus&diac) Yes No Yes No Day 0 Month 1 Month 2 Month 3 Month 4 Month 5 Month 6
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 145
Dummy table 4 Intervention effects after adjusting unbalanced co-variable Group 2 Group 1 (glus) Outcomes (glus&diac) P value β 95% CI n = n = Pain score
WOMAC score Joint space width Adverse effect Yes No Age <50 >50 Sex male female BMI <25 >25 Kellgren Lawrance Grade I Grade II GRADE III Underlying disease Yes No History of Medication Yes No Analgesic use Paracetamol Yes No NSAIDs Yes No Paracetamol&NSAID Yes No Other co-variable Yes No
Jatupon Kongtharvonskul Appendices / 146
Dummy table 5 Comparisons of pain score, WOMAC score, joint space width and adverse effect of two groups. A mixed model linear regression analysis 5.1 Pain score Factors Coefficient SE P value F-test 95% CI Intervention Glucosamine Glucosamine and diacerein Subjects Other unbalanced co- variables Yes No
5.2 WOMAC score Factors Coefficient SE P value F-test 95% CI Intervention Glucosamine Glucosamine and diacerein Subjects Other unbalanced co- variables Yes No
5.3 Joint space width Factors Coefficient SE P value F-test 95% CI Intervention Glucosamine Glucosamine and diacerein Subjects Other unbalanced co- variables Yes No
Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 147
5.4 Adverse effect Factors Coefficient RR P value F-test 95% CI Intervention Glucosamine Glucosamine and diacerein Subjects Other unbalanced co- variables Yes No
Jatupon Kongtharvonskul Appendices / 148
APPENDIX D INFORMATION SHEET & CONSENT FORM
Information sheet Project title: Pain and Osteoarthritis index at 6 months of mild degree OA patients treated with Diacerein combined with Glucosamine, as compared to the treatment with glucosamine alone: A randomized controlled trial.
Principle investigator Jatupon Kongtharvonskul Address Section for Clinical Epidemiology and Biostatistics, Ramathibodi Hospital, Mahidol University, Bangkok. Telephone 02-2011284 The aim of this research is to compare the results of medical treatment of osteoarthritis with glucosamine and a combination of glucosamine and diacerein. The results of knee pain are also considered using the Osteoarthritis index, joint space width (from plain radiography) as well as side effects of the said medication within 6 months of receiving the treatment. The current treatment of patients with osteoarthritis includes medical therapy that prevents future deterioration of the joint. This includes medical treatment with glucosamine and diacerein, in which previously there have been no studies done to show which treatment is more effective. There are also no studies that show concurrent use of both of these medications. Both of these medications have different advantages and disadvantages associated with their use. Both can reduce pain and deterioration of the joint, and increase function of the joint. However, both of them have side effects. Glucosamine may cause dyspepsia or severe adverse drug reactions, whereas diacerein may cause abdominal discomfort or diarrhea. There have been no studies showing the results and side effects of using both medications concurrently, but when their pathophysiology is taken into account, use of both these medications at the same time may provide better results. The researcher invites you to take part in this study, as you are an eligible patient whom in which early osteoarthritis is suspected, providing that in plain radiography your affected joint shows appropriate signs of osteoarthritis. You will be randomly selected for treatment with either glucosamine or glucosamine in addition to diacerein. The selection randomization Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 149 reduces the bias of the study. Complications that may occur after receiving these medications include a drug allergy reaction. Symptoms that the patient should beware of include swelling at the face, numbness of the lips, or a generalized rash at the body, which may eventually lead to anaphylactic shock. These adverse drug reactions may be treated by ceasing use of the causative drug, or receiving oral or intravenous antihistamines. The common side effects of diacerein seen after taking the medication include abdominal discomfort and diarrhea. If the symptoms persist for longer than three months or the patient cannot tolerate the symptoms, after cessation of taking the medication the symptoms will improve without causing any long-term side effects in the future. These side effects are not life- threatening. If you have any of these symptoms, it is recommended that you seek medical attention before the scheduled follow up appointment, or you may contact Dr. Jatupon Kongthavornskul, M.D. at the provided telephone number. The researcher guarantees that all patients in the study will receive fair and equal treatment. The patients will receive advice regarding lifestyle modification such as weight loss, exercise, and behavioral changes. The patients will also receive medication to control pain symptom, anti-inflammatory drugs. In all patients in all study groups all treatment provided by the physician will be equal. You have the right to decline participation in this study, or to withdraw consent of participation at any time. Withdrawal of participation in the study will have no effect on the physician’s treatment of the disease. The researcher guarantees that all personal information regarding each patient will be kept confidential. This study has been approved by the ethics committee of the Faculty of Medicine, Ramathibodi Hospital, and is also funded by the Faculty of Medicine, Ramathibodi Hospital. You will receive monetary compensation for your time in coming to six follow up appointments at a rate of 100 THB per follow up visit. The research panel thanks you for your cooperation and participation in this study.
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คาแนะนํ ําผู้ป่ วย (Information Sheet) โครงการศึกษา เปรียบเทยบผลการรี ักษาโรคข้อเข่าเสื่อมด้วยยากลูโคซามนี หรือกลูโคซามีนคู่กบไดอะซั ีรีน และ เปรียบเทยบอาการปวดเขี ่า ดชนั ีความเสื่อมของเข่า และ ช่องว่างของข้อเข่าในเอกซเรย์ รวมถึงผลข้างเคยงของยาี ในช่วงเวลา 6 เดอนื ผรู้ ับผดชอบโครงการิ นพ.จตุพล คงถาวรสกลุ สถานที่ติดตอ่ หน่วยระบาดวทยาคลิ ินิก คณะแพทยศาสตร์โรงพยาบาลรามาธิบดี มหาวทยาลิ ยั มหิดล 270 ถ. พระราม 6 แขวง พญาไท เขต ราชเทวี 10400 หมายเลขโทรศพทั ์ 02-2011284 การวจิ ยนั ้ีมีวตถั ุประสงคเพ์ ื่อศึกษาเปรียบเทียบผลการรักษาโรคขอเข้ าเส่ ื่อมดวยยากล้ โคซามู ีน หรือกลโคู ซามีนคูก่ บไดอะซั ีรีน และเปรียบเทียบอาการปวดเขา่ ดชนั ีความเสื่อมของเขา่ และ ช่องวางของข่ อเข้ าในเอกซเรย่ ์ รวมถึงผลขางเค้ ียงของยา ในช่วงเวลา 6 เดือน การรักษาผปู้ ่วยโรคขอเข้ าเส่ ื่อมปัจจุบนมั ีการรักษาดวยยาหลายชน้ ิดเพื่อป้ องกนและชะลอความเสั ื่อมท่ีจะเกิดข้ึน ในอนาคต กลโคซามู ิน และไดอะซีรินเป็นยาในกลุมท่ ี่ใชในการป้ ้ องกนและชะลอความเสั ื่อมรักษา ซ่ึงผลการวจิ ยทั ี่ ผานมาย่ งไมั ่สามรถสามารถสรุปไดว้ าว่ ธิ ีไหนดีกวาก่ นรวมถั ึงยงไมั ่มีการศึกษาผลการรักษาดวยยาท้ ้งสองชนั ิด พร้อมกนั โดยยาแตละชน่ ิดมีขอด้ ีขอเส้ ียที่แตกต่างกนไปั กลาวค่ ือ กลโคซามู ิน และ ไดอะซีรีน สามารถลดอาการ ปวดและเพ่ิมการใชงานข้ อเข้ ารวมถ่ ึงสามารถลดการสึกกร่อนของของขอเข้ า่ แตอย่ างไรก่ ตามยาท็ ้งสองชนั ิด ยาแต่ ละตวยั งมั ีผลขางเค้ ียงเช่นในกลโคซามู ีนอาจเกิดโรคกระเพาะหรือแพยาได้ ้ ในขณะที่ไดอะซีรีนอาจเกิดอาการมวน ทอง้ หรือทองเส้ ียได ้ ส่วนการรับประทานยาท้งสองตั วยั งไมั ่เคยมีการศึกษาถึงผลดีและผลขางเค้ ียงของยา แตจาก่ กลไกการทางานของยาทํ ้งสองชนั ิดอาจใหผลการร้ ักษาร่วมถึงผลขางเค้ ียงเมื่อใชยาร้ ่วมกนไดั ด้ ีข้ึน ผวู้ จิ ยขอเชั ิญท่านเขาร้ ่วมการศึกษาน้ี ถาหากท้ ่านยนดิ ีเขาร้ ่วมการศึกษาน้ี ท่านจะถกเลู ือกอยางส่ ุ่ม ใหได้ ร้ ับยาอยาง่ ใดอยางหน่ ่ึง ระหวางกล่ โคซามู ิน หรือ กลโคซามู ินและไดอะซีรีน ซ่ึงวธิ ีการเลือกอยางส่ ุ่มน้ี จะช่วยลดความลาเอํ ียง ที่อาจมีผลตอการว่ จิ ยั ภาวะแทรกซอนท้ ี่อาจเกิดข้ึนหลงไดั ร้ ับยาท้งั 3 วธิ ีคือ อาจมีอาการแพยา้ อาการที่ตองส้ ังเกต คือ มีอาการหนาบวม้ ริมฝีปากชา มีผื่นข้ึนตามตวั อาการแพยาน้ ้ีสามารถรักษาไดด้ วยการหย้ ดยาุ และ ฉีดยาหรือ รับประทานยาแกแพ้ ้ นอกจากน้ีอาจมีอาการมวนทองหร้ ือถายเหลวซ่ ่ึงเป็นผลขางเค้ ียงในช่วงแรกของยาไดอะซีรีน หากพบวาอาการเป่ ็นนานเกิน 3 เดือนหรือผปู้ ่วยไม่สามารถทนตออาการด่ งกลั าวได่ ้ หลงจากหยั ดยาุ 3 ถึง 5 วนั อาการจะดีข้ึนโดยไม่ก่อใหเก้ ิดผลระยะยาวตอในอนาคต่ ภาวะแทรกซอนน้ ้ีไม่มีอนตรายตั อช่ ีวิต คาใช่ จ้ ่ายในการ รักษาน้นสามารถเบั ิกไดตามส้ ิทธ์ิการรักษา ถาท้ ่านมีอาการผดปกติ ิดงกลั ่าว ใหมาพบแพทย้ ท์ นทั ี่โดยไม่ตองรอว้ นั นดั หรือติดตอนพ่ จตุพล ไดตามเบอร้ ์โทรศพทั ท์ ี่ใหไว้ ้ ผวู้ จิ ยขอรั ับรองวา่ ท่านจะไดร้ ับการดูแลรักษา และปฏิบตั ิที่เท่าเทียมกนั ไดร้ ับความรู้เกี่ยวกบการดั ูแล ตวเองั ลดน้าหนํ กั ออกกาลํ งกายั ปรับเปลี่ยนพฤติกรรม ยาแกปวด้ ลดอกเสบั ตลอดการดูแลรักษาอื่นๆ จะเท่าเทียม กนไมั ่วาท่ ่านจะถกสู ุ่มใหได้ ร้ ับการรักษาดวยยากล้ ุมไหนก่ ตาม็ ท่านมีอิสระในการตดสั ินใจเขาร้ ่วมโครงการ ท่าน มีสิทธ์ิที่จะปฏิเสธไม่เขาร้ ่วมโครงการวจิ ยไดั ้ หรือเมื่อเขาโครงการแล้ วก้ สามารถท็ ี่จะถอนตวจากโครงการตั อมาได่ ้ ทุกเมื่อ โดยการปฏิเสธ หรือการถอนตวนั ้ี จะไม่มีผลตอการร่ ักษาพยาบาลใดๆท้งสั ิ้น นอกจากน้ี ผวู้ จิ ยขอยั นยื นวั า่ ชื่อ-นามสกลุ ตลอดจนขอม้ ูลการรักษาท้งหมดของทั ่าน จะถกเกู บเป็ ็นความลบั งานวจิ ยนั ้ีไดร้ ับความเห็นชอบจาก คณะกรรมการจริยธรรมการวจิ ยในมนั ุษย ์ จากคณะแพทยศาสตร์โรงพยาบาลรามาธิบดี ไดร้ ับแหลงท่ ุนสนบสนั ุน Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 151
จากคณะกรรมการวจิ ยจากคณะแพทยศาสตรั ์โรงพยาบาลรามาธิบดี ท่านจะไดร้ ับคาทดแทนการเส่ ียเวลา สาหรํ ับ มาตรวจตามนดครั ้ังละ 100 บาทจานวนํ 6 คร้ัง คณะผวู้ จิ ยั ขอขอบคุณในความร่วมมือของท่าน ที่จะทาใหํ งานว้ ิจยครั ้ังน้ีดาเนํ ินลุลวงไปได่ ด้ วยด้ ี
Jatupon Kongtharvonskul Appendices / 152
Consent form Research project “Pain and Osteoarthritis index at 6 months of mild degree OA patients treated with Diacerein combined with Glucosamine, as compared to the treatment with glucosamine: A randomized controlled trial.” Date (dd/mm/yy) ...... /……./…………… Prior to consenting to participation in this study, a full and detailed explanation regarding the aims, objectives, methodology, benefits and risks associated with this study has been provided, ensuring that I have a complete understanding and all my questions regarding the study have been adequately answered without omitting any important information or neglecting to provide necessary details so that I provide my full informed consent in participation of this study. I reserve the right to withdraw my participation at any point in the study without losing the right of continuous treatment in osteoarthritis. The researcher provides guarantee and assurance that all of my personal data will be kept confidential and the only data that will be publicly available will be a summary of clinical outcomes. Divulgement of my data will only be provided to exclusive personnel in departments that are directly related to the study, and all imparting of data must be given my documented approval. As part of the study, all participants will initially receive a thorough orthopedic physical examination and plain radiography of the affected joints, which will not cause any pain or harm to the patient. The researcher guarantees that if the participants experience any adverse effects from use of the medication, he will provide attentive treatment and care. I consent to the director of the study, the examiner, and the research safety board and ethics committee of this study having access to my medical records for verification of research methodology of the study without infringement of my rights of confidentiality as permitted by law. I hereby have read and have a full understanding all of the above, and am willing to provide signed informed consent. Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 153
If I am not able to read the above on my own, a designated agent will have read this entire consent form to me until full understanding is achieved so that I am willing to provide signed informed consent. I can contact the researcher at the Department of Clinical Epidemiology and Biostatistics, Ramathibodi Hospital, Mahidol University, Bangkok. The responsible person is Dr. Jatupon Kongtharvonskul, M.D. Contact no. 02-2011284
Sign ………………………………… (...... ) Sign………………………………Witness (...... ) Sign ………………………………Witness (...... )
Jatupon Kongtharvonskul Appendices / 154
ใบยนยอมของอาสาสมิ ครั (Consent form)
โครงการวจิ ยเรั ื่องการศึกษา เปรียบเทียบผลการรักษาโรคขอเข้ าเส่ ื่อมดวยยากร้ ูโคซามีน หรือกลูโคซามีนคูก่ บั ไดอะซีรีน และเปรียบเทียบอาการปวดเขา่ ดชนั ีความเสื่อมของเข่า และ ช่องวางของข่ อเข้ าในภาพร่ ังสี รวมถึง ผลขางเค้ ียงของยา ในช่วงเวลา 6 เดือน วนทั ี่ใหค้ ายํ นยอมิ วนทั ี่ ………………เดือน ……………………พ.ศ………………………
ก่อนที่จะลงนามในใบยนยอมใหิ ท้ าการวํ จิ ยนั ้ี ขาพเจ้ าได้ ร้ ับการอธิบายจากผวู้ จิ ยถั ึงวตถั ุประสงคของการ์ วจิ ยั วธิ ีการวจิ ยั อนตรายหรั ืออาการที่อาจเกิดข้ึนจากการวจิ ยั รวมท้งประโยชนั ์ที่จะเกิดข้ึนจากการวจิ ยอยั าง่ ละเอียด และมีความเขาใจด้ ีแลว้ ซ่ึงผวู้ จิ ยไดั ตอบค้ าถามตํ ่างๆที่ขาพเจ้ าสงส้ ัยดวยความเต้ มใจ็ ไม่ปิดบงั ซ่อนเร้น จนขาพเจ้ าพอใจ้ และเขาร้ ่วมโครงการน้ีโดยสมครใจั
ขาพเจ้ าม้ ีสิทธ์ิที่จะบอกเลิกการเขาร้ ่วมการวจิ ยนั ้ีเมื่อใดกได็ ้ ถาข้ าพเจ้ าปรารถนาโดยไม้ ่เสียสิทธิในการ รักษาพยาบาลที่จะเกิดข้ึนตามมาในโอกาสตอไป่
ผวู้ จิ ยรั ับรองวาจะเก่ บข็ อม้ ูล เฉพาะเกี่ยวกบตั วขั าพเจ้ าเป้ ็นความลบและจะเปั ิดเผยไดเฉพาะในร้ ูปที่เป็น สรุปผลการวจิ ยั
การเปิดเผยขอม้ ูลเกี่ยวกบตั วขั าพเจ้ าต้ อหน่ ่วยงานตางๆ่ ที่เกี่ยวของกระท้ าไดํ เฉพาะกรณ้ ีจาเปํ ็นดวย้ เหตุผลทางวชาการเทิ ่าน้นและจะตั องได้ ร้ ับคายํ นยอมจากขิ าพเจ้ าเป้ ็นลายลกษณั ์อกษรั
ในการวจิ ยครั ้ังน้ีผปู้ ่วยจะไดร้ ับการตรวจร่างกายและเอกซเรยก์ ่อนเขาร้ ่วมงานวจิ ยั ซ่ึงจะไม่ก่อหเก้ ิด ความเจบปวดแต็ อย่ างใด่ ผวู้ จิ ยรั ับรองวาหากเก่ ิดภาวะแทรกซอนใดๆ้ ที่มีสาเหตุจากการวิจยดั งกลั ่าว ขาพเจ้ าจะได้ ร้ ับการ รักษาพยาบาลอยางใกล่ ช้ ิด ขาพเจ้ าย้ นยอมใหิ ผ้ กู้ ากํ บดั ูแลการวจิ ยั ผตรวจสอบู้ คณะกรรมการจริยธรรมการวจิ ยในคนั และ คณะกรรมการที่เกี่ยวของก้ บการควบคั ุมยา สามารถเขาไปตรวจสอบบ้ นทั ึกขอม้ ูลทางการแพทยของข์ าพเจ้ า้ เพื่อ เป็นการยนยื นถั ึงข้นตอนโครงการวั จิ ยทางคลั ินิก โดยไม่ลวงละเม่ ิดเอกสิทธ์ิ ในการปิดบงขั อม้ ูลของการสมครตามั กรอบที่กฎหมายและกฏระเบียบไดอน้ ุญาตไว ้
ขาพเจ้ าได้ อ้ านข่ อความข้ างต้ นแล้ ว้ และมีความเขาใจด้ ีทุกประการ และไดลงนามในใบย้ นยอมนิ ้ีดวย้ ความเตมใจ็
ในกรณีที่ขาพเจ้ าไม้ ่สามารถอ่านหนงสั ือได ้ ผวู้ จิ ยไดั อ้ านข่ อความในใบย้ นยอมนิ ้ีใหข้ าพเจ้ าฟ้ ังจนเขาใจ้ ดีแลว้ ขาพเจ้ าจ้ ึงลงนามในใบยนยอมนิ ้ีดวยความเต้ มใจ็ Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 155
ขาพเจ้ าสามารถต้ ิดตอผ่ วู้ จิ ยไดั ท้ ี่ หน่วยระบาดวิทยาคลินิก คณะแพทยศาสตร์โรงพยาบาลรามาธิบดี มหาวทยาลิ ยั มหิดล 270 ถ.พระราม 6 แขวง พญาไท เขต ราชเทวี 10400 หมายเลขโทรศพทั ์ 02-2011284 ในเวลาราชการ และ โทรศพทั เคล์ ื่อนที่ 089-667-5440
ลงนาม…………………………………ผยู้ นยอมิ (...... )
ลงนาม…………………………………พยาน
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ลงนาม…………………………………พยาน
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Log Book สมุดพกประจําตวผั ู้ร่วมวจิ ัยในแต่ละคนสําหรับ รายงานการรับประทานยารายวันในแต่ละเดอนื Jatupon Kongtharvonskul Appendices / 156
รายงานการรับประทานยารายวนั ( เดือนกรกฎาคม ) วนทั ี่ ยา พาราเซต็ ยาแก้อกเสบั ยาชง ยาแคปซูล ตามอล (ยาซอง) (ขาวเขียว) 15 เช้า กลางวนั เย็น 16 เช้า กลางวนั เย็น 17 เช้า กลางวนั เย็น 18 เช้า กลางวนั เย็น 19 เช้า กลางวนั เย็น 20 เช้า กลางวนั เย็น Fac. of Grad. Studies, Mahidol Univ. Ph.D.(Clinical Epidemiology) / 157
BIOGRAPHY
NAME Mr. Jatupon Kongtharvonskul DATE OF BIRTH 29 May 1979 PLACE OF BIRTH Bangkok, Thailand INSTITUTIONS ATTENDED Mahidol University, (1996-2002) Doctor of Medicine Srinakarin Hospital, (2003-2007) Thai Board of Orthopedic Medicine Police general hospital (2008-2009) Follow hip & knee arthroplasty Mahidol University, (2009-2015) Doctor of Philosophy (Clinical Epidemiology) SCHOLARSHIP - RESEARCH GRANT Mahidol University Grant for Goal-oriented Research Project, Thailand Faculty of Ramathibodi hospital POSITION & OFFICE Orthopedic Department Police General Hospital, Bangkok, Thailand HOME ADDRESS 99/92 the Palazzo Sathorn, Kalaprapruk Road, bangkontein, Bangkok, Thailand PHONE Mobile: (6689) 6675440 E-MAIL [email protected]