Effectiveness of an Ayurveda treatment approach in knee osteoarthritis – a randomized controlled trial

Accepted Manuscript Effectiveness of an Ayurveda Treatment Approach in Knee Osteoarthritis – a Randomized Controlled Trial Christian S. Kessler, MD, MA, Kartar S. Dhiman, Professor, Abhimanyu Kumar, Professor, Thomas Ostermann, Professor, Shivenarain Gupta, Professor, Antonio Morandi, MD, Martin Mittwede, Professor, Elmar Stapelfeldt, MA, Michaela Spoo, MD, Katja Icke, Andreas Michalsen, Professor, Claudia M. Witt, Professor PII:

S1063-4584(18)30082-7

DOI:

10.1016/j.joca.2018.01.022

Reference:

YJOCA 4160

To appear in:

Osteoarthritis and Cartilage

Received Date: 3 August 2017 Revised Date:

19 January 2018

Accepted Date: 30 January 2018

Please cite this article as: Kessler CS, Dhiman KS, Kumar A, Ostermann T, Gupta S, Morandi A, Mittwede M, Stapelfeldt E, Spoo M, Icke K, Michalsen A, Witt CM, Effectiveness of an Ayurveda Treatment Approach in Knee Osteoarthritis – a Randomized Controlled Trial, Osteoarthritis and Cartilage (2018), doi: 10.1016/j.joca.2018.01.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Effectiveness of an Ayurveda Treatment Approach in Knee

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Osteoarthritis – a Randomized Controlled Trial

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Running Head: Ayurveda and Knee Osteoarthritis

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Christian S Kessler (MD, MA)1,2, Kartar S Dhiman (Professor)3,4, Abhimanyu Kumar

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(Professor)3,5,Thomas Ostermann (Professor)6, Shivenarain Gupta (Professor)7,8,

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Antonio Morandi (MD)9, Martin Mittwede (Professor)7,10, Elmar Stapelfeldt (MA)2,

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Michaela Spoo (MD)2, Katja Icke1, Andreas Michalsen (Professor)1,2* Claudia M Witt

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(Professor)1,11,12*

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Berlin, Luisenstr. 57, 10117 Berlin, Germany

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Germany

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No.61-65, Institutional Area, Janakpuri, New Delhi 110058, India

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Straße 50, Witten, Germany

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Nadiad 387001, India

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Germany

Institute for Social Medicine, Epidemiology and Health Economics, Charité – Universitätsmedizin

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Immanuel Hospital Berlin, Department for Complementary Medicine, Königstr. 63, 14109 Berlin,

Ministry of AYUSH, AYUSH Bhawan, B Block, GPO Complex, INA, New Delhi 110023, India

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Central Council for Research in Ayurvedic Sciences (CCRAS), Jawahar Lal Nehru Bhavan

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All India Institute of Ayurveda, Mathura Road, Gautampuri, Sarita Vihar, New Delhi 110076, India University of Witten Herdecke, Department of Psychology and Psychotherapy, Alfred-Herrhausen-

European Academy of Ayurveda, Forsthausstr. 6, 63633 Birstein, Germany Department of Kaya Cikitsa, J.S. Ayurveda College & P.D. Patel Ayurveda Hospital, College Road,

Ayurvedic Point, School of Ayurvedic Medicine, Corso Sempione 63, 20149 Milan, Italy University of Frankfurt, Department of Religious Sciences, Grüneburgplatz 1, 60323 Frankfurt,

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Rämistrasse 100, 8091 Zurich, Switzerland

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East Hall, Baltimore, MD 21201, USA

Institute of Complementary and Integrative Medicine, University Hospital and University of Zurich,

University of Maryland School of Medicine, Center for Integrative Medicine, 520 W. Lombard Street

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Corresponding author and reprint requests

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Prof. Dr. med. Andreas Michalsen

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Head of Department

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Immanuel Hospital Berlin, Department for Complementary Medicine

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Königstr. 63

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14109 Berlin

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Germany

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[email protected]

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Phone +49 (0) 30 80505 691

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Fax +49 (0) 30 80505 692

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ABSTRACT

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Objective: Ayurveda is commonly used in South Asia to treat knee osteoarthritis

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(OA). We aimed to evaluate the effectiveness of Ayurvedic treatment compared to

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conventional conservative care in patients with knee OA.

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Method: According to American College of Rheumatology (ACR) criteria knee OA

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patients were included in a multicenter randomized, controlled, open-label trial and

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treated in 2 hospital clinics and 2 private outpatient clinics in Germany. Participants

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received either a multi-modal Ayurvedic treatment or multi-modal conventional care

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with 15 treatments over 12 weeks respectively. Primary outcome was the change on

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the Western Ontario and McMaster University Osteoarthritis (WOMAC) Index after 12

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weeks. Secondary outcomes included WOMAC subscales; the pain disability index

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and a pain experience scale, numeric rating scales for pain and sleep quality, quality-

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of-life and mood, rescue medication use, and safety issues.

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Results One hundred fifty-one participants (Ayurveda n=77, conventional care n=74)

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were included. Changes of the WOMAC Index from baseline to 12 weeks were more

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pronounced in the Ayurveda group (mean difference 61.0 [95%CI: 52.4;69.6]) than in

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the conventional group (32.0 [95%CI: 21.4;42.6]) resulting in a significant between-

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group difference (p<0.001) and a clinically relevant effect size (Cohen’s d 0.68 [95%

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CI:0.35;1.01]). Similar trends were observed for all secondary outcomes at week 12.

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Effects were sustained at follow-ups after 6 and 12 months.

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Conclusion: Results suggest that Ayurvedic treatment is beneficial in reducing knee

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OA symptoms. Further studies should be conducted to confirm the magnitude of the

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effect and to clarify the role of different treatment components and non-specific

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effects.

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Registration at clinicaltrials.gov (NCT01225133; initial release 10/06/2010).

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Funding: Ministry of AYUSH, Government of India.

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Keywords: Ayurveda, Knee Osteoarthritis, Complementary Medicine, Integrative

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Medicine

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INTRODUCTION

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Osteoarthritis (OA) is of global relevance with up to 250 million people being affected

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from knee OA worldwide 1-4. Despite progress in conventional knee OA management

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many patients continue to be affected from pain and disability and there is a need for

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further effective treatment approaches 5-7. In India and South Asia traditional

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Ayurvedic medicine is also commonly used as a treatment approach in knee OA and

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the World Health Organization (WHO) recommends to include traditional systems of

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medicine in global health care 8,9.

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In India Ayurveda is recognized and regulated by an independent ministry (AYUSH)

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such as manual therapies, nutritional therapy and herbs, lifestyle counseling and

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yoga-based exercise 12 (Appendix 1).

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A review of 33 Ayurveda studies showed that most trials (91%) evaluated herbal

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preparations as single interventions 13. No clinical trial evaluated Ayurveda treatment

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with its multi-modal components for knee OA so far 14.

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In western countries, knee OA is treated by conventional multi-modal interventions

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combining pharmacological and non-pharmacological interventions 7,15,16. Ayurveda

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also uses a multi-modal intervention approach for the treatment of knee OA.

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Comparisons of the effectiveness of conventional and Ayurveda interventions for the

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treatment of knee OA would be a feasible research question.

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. Ayurveda uses individualized treatments consisting of multi-modal components

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METHOD

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Study design

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Protocol details have been published previously. We designed a multicenter open-

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label trial and randomized participants to 12 weeks of Ayurveda or conventional

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guideline-based care (Appendix 2) 14,17. Outcomes were assessed at baseline, 6

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weeks, 12 weeks, 6 months and 1 year. Participants received 15 treatment sessions

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within 12 weeks. Long-term effects were evaluated after 6 and 12 months (Figure 1).

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We used an equal block-randomization with variable block size and stratified for

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study site. An independent statistician generated a randomization list with SAS

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(version 9.1, SAS Inc, Cary, NC). The data manager transferred the randomization

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list into a secure database (Microsoft Office Access 2007), where the randomization

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list was not accessible to anyone else. Each participant could be registered and

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randomized only once and the database did not allow deleting participants´ data.

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Statisticians, data entry personnel and the funding source were blinded to treatment

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assignment throughout the study.

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The trial was registered at clinicaltrials.gov under NCT01225133 and was approved

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by the university ethics committee (Charité Medical University, EA1/124/10). It

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followed the Declaration of Helsinki and Good Clinical Practice guidelines for trial

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conduct. Participants provided written informed consent before taking part and were

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not reimbursed for participation. Due to changes in ethical regulations during the trial

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one amendment has been made regarding the provision of nutritional supplements.

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Thereafter, the remaining 24 study participants from the Ayurveda group did not

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receive nutritional supplements but were advised to increase the food intake of the

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previously supplemented nutrients as much as feasible.

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Participants

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Seventy percent of participants were recruited via newspaper advertisements. The

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remaining participants were recruited by physicians from the trial center clinics or

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contacted the centers themselves, because they had heard about the trial.

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Participants were pre-screened over the phone and if suitable scheduled to an

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enrolment visit (Figure 2).

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Inclusion criteria: male or female, 40 to 70 years of age; knee OA pre-diagnosed by

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an orthopedic surgeon or radiologist according to ACR criteria 18,19; radiologic

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changes in X-ray (Kellgren-Lawrence ≥ 2 20,21 or an MRI Recht grading score ≥ 2(a)

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visual analogue scale (VAS) over 7 days preceding enrollment, written informed

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consent.

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Exclusion criteria: knee pain caused by congenital dysplasia, rheumatoid arthritis,

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autoimmune diseases, malignancies, knee surgery or knee-arthroscopy;

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administration of chondroprotective drugs, intra-articular injections into the knee joint

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or systemic corticosteroid medication during the 3 months preceding enrollment; start

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of any new treatment for knee OA during the 4 weeks preceding enrollment including

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treatment with paracetamol, OTC NSAIDs and any CAM treatments; pregnancy or

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breastfeeding; acute mental disorders; serious acute organic diseases; serious

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chronic co-morbidity; obesity ≥ WHO grade II; blood coagulation disorders; intake of

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coagulation-inhibiting medication other than acetylsalicylic acid and clopidogrel;

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; mean baseline pain intensity in the affected knee of ≥ 40 mm on a 100 mm

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invasive measures at the affected joint during the 12 weeks preceding enrollment or

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planned for the 12 months following enrollment; and being in the process of applying

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for pension/disability benefits.

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Interventions

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The interventions were developed in an international consensus process with

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Ayurveda and orthopedic experts from three countries (India, Germany and Italy)

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using a Delphi approach 24. Ayurvedic literature (Ayurveda group) 12,25, and current

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guidelines (conventional group) were used 16,26,27. Ayurveda was provided by

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conventionally trained physicians with additional Ayurveda training, who had

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undergone either a university program for Ayurveda in India (Bachelor of Ayurveda

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Medicine and Surgery [B.A.M.S.] Indian expert) or had ≥ 500 hours of academic

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training in Ayurveda plus ≥ 2 years of continuous clinical experience with Ayurveda

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(European experts). Other involved Ayurvedic therapists were required to have ≥ 2

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years of continuous clinical experience in their fields (manual therapies, nutritional

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advice, lifestyle advice, yoga therapy). To assure treatment quality, line of treatment

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for the first 30 participants was discussed by 4 Ayurveda doctors until consent was

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achieved. In the conventional group interventions were prescribed by board certified

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medical doctors (MDs) specialized in orthopedics or orthopedic surgery. All other

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conventional therapists (physiotherapy, occupational therapy) required a completed

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licensed training in their field and a minimum of ≥ 2 years of continuous clinical

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experience. In total 5 specialized physicians (2 Ayurveda, 3 conventional MDs) and

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20 specialized therapists (12 Ayurveda [8 for manual therapies, 2 for yoga, 2 for

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nutrition and lifestyle], 8 conventional [6 for physiotherapy, 2 for nutrition and

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occupational therapy]) treated participants in 2 public hospital outpatient clinics and 2

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hospital affiliated private outpatient clinics for Ayurveda, orthopedics, orthopedic

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surgery, physiotherapy and occupational therapy in Berlin, Germany. Treatments in

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both groups were administered in 15 sessions over 12 weeks (2 sessions/week in the

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first 3 weeks and 1 session/week in weeks 4 to 12), with treatment time between 45

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and 50 minutes (conventional) and 60-90 minutes (Ayurveda) per session. Treatment

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time between groups was not further equalized as a treatment time >50 minutes per

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session for physiotherapy/exercise would have largely exceeded existing treatment

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standards for knee OA patients.

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The multi-modal Ayurveda intervention was individualized and followed the treatment

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principles of Ayurveda. Individualized treatment included specific manual treatments

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and massages; Ayurvedic diet counseling including specific consideration of selected

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food items, adapted to local food items commonly available in German grocery

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stores; two nutritional Ayurvedic supplements typically used for painful conditions of

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the musculoskeletal system, Ashvagandha (Withania somnifera Dunal. Linn) and

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Yogaraja Guggulu (compound supplement, main ingredient Commiphora mukul

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Hook. ex Stocks); general and specific Ayurvedic lifestyle advice; knee specific yoga

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posture advice; and daily self-applied knee massage.

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Conventional group participants received multi-modal and individualized conventional

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care for knee OA according to current guidelines; this included quadriceps muscle

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strengthening exercises, knee specific physiotherapy including manual therapy,

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occupational therapy, advice for individual home knee exercises, dietary advice for

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weight loss for overweight participants, and, if necessary, administration of long-term

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pain medication according to current guidelines 16,26,27 (Appendix 2 f).

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In both groups rescue medication with a maximum of 3g paracetamol per day could

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be used. In case of intolerance or non-response to paracetamol, topical or oral

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NSAIDs could be used (e.g. diclofenac-sodium ointment 3 time per day or oral

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ibuprofen up to a maximum dose of 800mg per day or equivalent) after having

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consulted a study physician. The use of other pain medication was discouraged.

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Participants were instructed to document the use of pain medication in diaries during

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the intervention period.

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Outcome Measures

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Primary outcome measure was the change in the WOMAC Index between baseline

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and 12 weeks 28,29. The WOMAC has three subscales that measure pain (range 0-

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50), stiffness (range 0-20), and function (range 0-170) and can be summarized as

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Index ; the validated German version was used 29. Secondary outcomes were

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WOMAC subscales (pain, stiffness and function separately), a Pain Disability Index

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(PDI) 30, Numeric Rating Scales (NRS, 0 to 10) for additional questions on pain and

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quality of sleep (instead of Visual Analogue Scales (VAS) as written in the protocol

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publication), a Pain Experience Scale (SES) 31, health-related quality of life (Short

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Form-36 Health Survey, SF-36 32), Profile of Mood States (POMS) 33, a 7-point Likert

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Scale for general health-related participant satisfaction, a participant diary for rescue

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medication use, and safety (adverse events and serious adverse events). Outcomes

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were assessed using participant questionnaires. All outcomes were assessed at

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baseline, 6 and 12 weeks, and 6 and 12 months. Study nurses handed out

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questionnaires and diaries at baseline (before randomization), week 6 and week 12,

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and asked participants to complete them and to return them in sealed envelopes.

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The 6-months and 12-months questionnaires and participants´ diaries were mailed by

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the study office. Adverse events were assessed by trial personnel in a standardized

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way at each visit and were also documented by the participants at the end of week 6

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and week 12. Participants documented their expectations for treatment outcome at

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baseline (Figure 1).

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Statistical Analyses

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This study was designed to have 80% power to detect a difference of 10 points

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improvement (change to baseline) on the WOMAC Index after 12 weeks between

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both groups (pooled standard deviation=20, two sided t-test α=0.05). To achieve this,

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64 participants per group were needed. By taking drop outs into account, we planned

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to include 74 participants per group. The primary analysis population was the

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intention-to-treat (ITT) population including all randomized participants, who provided

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baseline data for the primary outcome. The primary outcome was the change of the

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WOMAC Index after 12 weeks. Missing data were multiply imputed by maximum-

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likelihood based regression methods. Overall, 20 complete data sets were generated

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and combined adequately. Generalized Linear Mixed Models (GLM) were fitted to the

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data sets, including the treatment group as a fixed factor. Results are presented as

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adjusted WOMAC means per group with 95% confidence intervals and the two-sided

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p-value for the treatment group comparison. For sensitivity analysis ANCOVA models

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for WOMAC Index and WOMAC subscales were used after 12 weeks as independent

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variables. Treatment group and gender as fixed factors, baseline values and

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participants´ expectations as linear covariates were applied to the data. The

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magnitude of effect sizes between and within groups for the primary endpoint was

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calculated using Cohen's d and its confidence intervals with d > 0.5 defining clinically

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relevant effect sizes 34. Partial η2, another measure of effect size, was used to

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measure the proportion of the total variance in the variable “WOMAC Index after 12

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weeks” attributable to a particular independent variable (e.g. treatment group or

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expectation). Finally, within-group changes in both primary and secondary outcomes

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were assessed using univariate t-test statistics. Treatment responder analyses were

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performed using Chi-Square tests. We defined a decrease of at least 12 points as a

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treatment response for the main outcome parameter representing slightly stricter

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common response criteria 35. All statistical analyses were carried out blind and prior

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to breaking the randomization code. Analyses were conducted using SPSS (release

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23.0; IBM, Armonk, NY, USA, 2015).

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RESULTS

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Between October 2010 and January 2014, 329 individuals were contacted by

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telephone, 197 were assessed for eligibility, and 151 were randomly assigned (77 to

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the Ayurveda group, 74 to the conventional group). Participants were treated

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between November 2010 and January 2015 and included into the primary analyses

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(Figure 2). Four participants had missing values for all outcomes at 6 and 12 weeks,

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five participants at 6 months and six participants at 12 months; missing values were

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multiply imputed.

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Overall, baseline characteristics were comparable between the groups (Table 1).

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Participants in the Ayurveda group started with slightly lower mean WOMAC Index

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values. Participants and physicians had higher expectations for Ayurveda than for

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conventional care (Table 1), which was considered in the sensitivity analyses.

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The average number of treatment sessions was 13.5 ± 1.7 for Ayurveda participants

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and 14.0 ± 2.7 for conventional participants. Mean treatment duration time was 67.8

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± 4.1 minutes (90.2 ± 5.8 minutes in the Ayurveda group and 45.3 ± 2.5 minutes in

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the conventional group).

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Primary outcome

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Changes of the WOMAC Index from baseline to 12 weeks were more pronounced in

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the Ayurveda group (mean difference 61.0 [95% CI: 52.4;69.6]) than in the

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conventional group (mean difference 32.0 [95% CI: 21.4;42.6]) resulting in a

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significant group difference (p<0.001) and a clinically relevant effect size (Cohen’s d

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0.68 [95% CI: 0.35;1.01] respectively partial η2=0.212) (Table 2). The between-group

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difference for the WOMAC Index persisted in similar magnitude up to the 12-month

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follow-up (Table 2, Figure 3).

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The proportion of treatment responders was 93.5 % for Ayurveda, and 60.8% for

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conventional guideline care (Chi-Square: 21.24; p<0.001).

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Secondary outcomes

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Changes within each subscale of WOMAC and all other secondary outcomes were

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also more prominent in the Ayurveda group at week 12. Similar findings were

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observed at months 6 and 12, with the exception of POMS scales and the mental

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component subscale of the SF-36 (Tables 2 and 3).

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In the first 12 weeks, the proportion of participants that used rescue pain medication

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was 18.9 % in the Ayurveda group, and 81.1% in the conventional group (Table 4).

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Sensitivity analyses

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The results were significantly sensitive to participant expectations and WOMAC

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baseline values. For all WOMAC subscales baseline values revealed a statistically

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significant influence (p<0.001) on the primary outcome. Moreover, participant

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expectation significantly influenced the WOMAC subscales “function” (p=0.038) and

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“stiffness” (p=0.034) while no significant influence of participant expectation was

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observed for the subscale “pain” (p=0.149). Respectively, for the global WOMAC

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index a significant influence of participant expectation (p<0.044) was given. However,

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findings were very robust for sensitivity analyses (ANCOVA-modeled): the same

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significant differences between the two randomized groups (p<0.001) for both the

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WOMAC Index (composite score of three WOMAC subscales) and for each single

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WOMAC subscale were observed in the treatment expectation-adjusted model.

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Expectation with respect to Ayurveda accounted for 2.6% and with respect to

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conventional care for 1.6% of the total variance in the adjusted model (see Table 5

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for details).

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Safety

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There were 137 adverse events throughout the intervention period in 73 participants

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(59.7 % of participants [n=46] in the Ayurveda group and 36.5 % [n=27] in the

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conventional group had ≥ 1 adverse events). Ayurveda participants had a mean of

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1.2 ± 1.3 adverse events (range 0-6), conventional participants 0.6 ± 1.0 adverse

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events (range 0-5). Both the difference in proportion (p=0.004) as well as in the

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amount of adverse events (p=0.002) were statistically higher in the Ayurveda group.

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Adverse events were related to the locomotor system (n=88), the skin (n=9) or to

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other reasons (n=40). None of the intervention-related adverse events led to clinically

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relevant disease or required hospital treatment. A total of 4 serious adverse events

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occurred among 4 participants (fracture of radius, cholecystectomy, major depression

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episode, erysipelas; Ayurveda n=3, conventional n=1); none of the serious adverse

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events were classified as intervention-related.

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DISCUSSION

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With this clinical trial we aimed to evaluate the effectiveness of an Ayurveda-

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medicine treatment approach in knee OA. After 12 weeks Ayurveda treatment led to

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a significantly greater and clinically relevant improvement of knee OA related

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complaints compared to the conventional guideline-based care with group

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differences maintained over 12 months.

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This RCT is the first to evaluate the effectiveness of a complex multi-modal

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Ayurveda-medicine approach. We performed a head-to-head comparison with multi-

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modal complex conventional care. The Ayurvedic treatment approach and the

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conventional care were carefully designed with the aim of best practice for each

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group and including an individual diagnosis as basis for the treatment in the

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Ayurveda study arm. The multi-modal Ayurveda treatment was developed in a Delphi

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procedure before being put into practice 24. As this trial was implemented in

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Germany, Western standards of care and the availability of Ayurvedic interventions in

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Europe were considered, including cultural, infrastructural and legal aspects into the

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trial methodology. To ensure comparable individualized conventional treatments, the

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conventional intervention was guideline-based and developed in an evidence-based

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consensus procedure by the study team and two board-certified external orthopedic

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surgeons15,16,26,27.

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Notably, in the Ayurveda group physical and mental outcomes improved during the

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intervention, whereas afterwards mental improvements decreased again, but physical

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improvements maintained. Ayurveda represents a rather new therapy in Western

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countries. This was an open label study in which both care providers and participants

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were aware of the treatment being given, and participants had higher expectations for

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Ayurveda treatment compared to conventional care. Expectation is discussed as a

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prominent aspect of the placebo effect 36,37. Research on a relatively Ayurvedic-naïve

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German population may introduce expectation bias; however, we controlled for

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expectations in the sensitivity analyses for this reason. While the unblinded nature

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formally remains a weak spot, blinding would have been not feasible, given the

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characteristics of the complex multi-modality Ayurvedic interventions.

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Nevertheless, one might argue that the main part of the difference between groups

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might be solely due to non-specific effects in the Ayurveda group. Complementary

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medicine methods are well known to have non-specific effects of relevant size; as

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expectation is the main mechanism of the placebo effect, results of this study have

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been controlled for expectation in the analyses 38. Furthermore, when comparing OA

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with other pain conditions it seems to be less sensitive to placebo effects as

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responder analyzes from sham-controlled acupuncture trials suggest 39. To

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summarize, we believe that the open-label design introduced some non-specific

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effects; however, this does not appear to explain the magnitude of the effects that we

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observed.

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Also, compared to data from other studies on the effectiveness of non-surgical

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approaches our conventional group showed similar effect sizes, while our Ayurveda

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group had larger effects 40,41. 16

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It is interesting to see that while the intervention lasted 12 weeks only, beneficial

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effects persisted up to 12 months. In the Ayurveda group this might have been

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particularly due to the integration of elements of active self-care into the

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individualized therapeutic schemes, including self-empowerment via nutritional

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advice, lifestyle counseling and knee yoga postures, outlasting the 12-week

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intervention period.

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A number of limitations apply to this study. One of them is the exclusion of individuals

391

with obesity ≥ WHO grade II; however this played a minor role, since less than 5

392

individuals were excluded due to this criterion during the screening process.

393

Moreover, no comparison with intra-articular corticosteroids was done, since in

394

Germany many patients refuse this treatment; being aware that our approach thus

395

reduces generalizability to other countries, we excluded them with the aim of

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reducing selection bias 14. Furthermore, the medication dosage was adapted to

397

reduce the risk of side effects such as gastrointestinal bleeding.

398

The consultation duration differed between the groups. However, this reflects the

399

usual care setting of both systems: reducing time in the Ayurveda group would not

400

have allowed adequate treatment while increasing conventional treatment time would

401

have introduced artificial settings 14.

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In conventional care, patients not responding well to treatment often become

403

interested in complementary and alternative medicine. This could have introduced

404

bias towards Ayurveda. One method to reduce this bias could have been to recruit

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only incident cases of knee OA. However, in turn this also would have introduced an

406

artificial setting, since Ayurveda is not seen as first line treatment.

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For ethical reasons Ayurveda participants were allowed to take conventional rescue

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medication. Because of this we decided to follow a superiority and not a non-

409

inferiority or equivalence hypothesis. However, only 19% in the Ayurveda group

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compared to 81% in the conventional group used pain medication, suggesting that

411

Ayurveda might be an option to reduce pain medication.

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In this study the botanical/herbal medical options of Ayurveda medicine suggested for

413

treatment of osteoarthritis could not be fully explored due to legal restrictions in

414

Germany, while Ayurvedic safety aspects remain controversial 42. Despite this, the

415

inclusion of a full-fledged botanical treatment could have led to even more

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pronounced effects; In a preceding review and meta-analysis we identified 33 trials

417

evaluating the use of Ayurveda for OA 13, most of them had methodological

418

limitations. In contrast to our study 14, no previous trial used multi-modal treatment,

419

although such an approach reflects routine practice in Ayurvedic care. Most trials

420

evaluated standardized interventions with single botanicals. A recent RCT on

421

rheumatoid arthritis demonstrated that individualizing Ayurvedic botanicals can be

422

incorporated in RCTs 43.

423

Also, the authors were limited in providing information to the readers on how

424

Ayurvedic treatment was individualized for participants with varying severity of knee

425

osteoarthritis and body constitution. The authors realize that this information is of

426

importance in replicating the results of the study to some extent. However, the

427

authors plan to provide additional information on how treatments were individualized

428

in a separate case-publication with teachable cases from this RCT.

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The study design could serve as a blueprint for future trials on whole medical

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systems. Since several questions remain unanswered, particularly related to cultural

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transmigration of Ayurveda and economic aspects of complex Ayurveda 18

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interventions, future research should address qualitative analyses, health economic

434

aspects and interdisciplinary approaches in addition to well planned RCTs in order to

435

further prove the effectiveness of Ayurvedic medicine.

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CONCLUSIONS

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Results showed that Ayurveda led to significant and clinically relevant improvements

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in disease-specific symptom-reduction after 12 weeks of treatment compared with

441

conventional care with most effects lasting over 12 months. However, further studies

442

should be conducted to confirm the magnitude of the effect and to clarify the role of

443

the different treatment components and of non-specific effects. The individualized

444

Ayurvedic approach might contribute to more integrative and personalized OA care.

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DECLARATIONS

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Acknowledgements

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We want to thank the Ministry of AYUSH and the Central Council for Research in

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Ayurvedic Sciences (CCRAS) for funding the trial; thanks in particular to Secretary S.

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Jalaja, Secretary Nilanjan Sanyal, Dr. Gandhidas Lavekar, Dr. Ramesh Babu, Dr.

453

M.M. Padhi, Dr. Dinesh Katoch, and Dr. Syed Hissar. We also thank the European

454

Academy of Ayurveda in Birstein, particularly Mark Rosenberg, for the fruitful

455

collaboration. Thanks to Dr. Manfred Wischnewsky for his valuable statistical advice.

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We are very grateful for the work of the participating medical personnel (Grit Bartsch,

457

Eva Maack, Ottmar Karl, Amrita Ronniger, Chrissa Kiosse, Andrea Schultze, Michael

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Ehm, Stephanie Riecker, Binita Chakraborty, Dr. Ileni Donachie, Alexander Peters

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and his team at Sonne und Mond, Dr. Günter Niessen, Frank Ruppenthal, Barbara

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Ellguth, Marion Prüßing and her team, Dr. Kai Bauwens, Dr. Laif Bröcker, Dr.

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Matthias Müller, Dr. Ludwig Kronpaß and Dr. Uwe Kehnscherper). Special thanks

462

also to Dr. Kalapi Patel, Dr. Manish Patel, Markus Ludwig and Karin Bachmaier for

463

their guidance regarding treatment aspects. We are also grateful for the work of all

464

secretaries, study nurses, students and other helpers involved in this project, in

465

particular to Gunda Loibl, Sabine Saalfeld, Christa Müller-Aziz, Sabine Leisching,

466

Miriam Rösner, Kathrin Otto, Karl-Heinz Krüger, Dr. Michael Jeitler, Kenneth Spiteri

467

and Dania Schumann. Dr. Rainer Lüdtke and Stephanie Roll gave valuable statistical

468

advice. Thanks also to Jutta Maier, Gayatri Puranik, Bruno Zimmer, Ranjit Puranik,

469

Dr. Hedwig Gupta, Dr. Bernhard Uehleke and Dr. Harsha Gramminger for their

470

advice and support related to massage oils and nutritional supplements. Carina

471

Bühner entered the data from the embedded diagnostic study. Thanks also to Roy

472

Noack, Björn Teuteberg, Dr. Stefan Willich and Dr. Benno Brinkhaus and Iris Bartsch

473

for facilitating administrative processes at Charité University and Immanuel Hospital.

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Last but not least we would like thank all participants for participating in this trial.

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Transparency declaration

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A. Michalsen and C.M. Witt had full access to all of the data in the study and take full

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responsibility for the integrity of the data and the accuracy of the data analysis. They

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affirm that the manuscript is an honest, accurate, and transparent account of the

481

study being reported; that no important aspects of the study have been omitted; and

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that any discrepancies from the study as planned have been explained.

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Funding statement and role of the funding source

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The study was supported by a grant from the Ministry of AYUSH, Government of

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India, Central Council for Research in Ayurvedic Sciences (CCRAS), Delhi, India,

489

that had suggested a randomized trial including a conventional control group for knee

490

OA. (Memorandum of understanding dated February 2, 2010); no other funding

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sources were used. All other decisions on design; data collection, analysis, and

492

interpretation; and publication were completely independent of the funding source.

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Competing interests

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Dr. Kessler reports personal fees from Bruno Zimmer, Germany, outside the

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submitted work. All other authors declare that they have no conflicts of interest: no

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support from any organization for the submitted work; no financial relationships with

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any organizations that might have an interest in the submitted work in the previous

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three years; no other relationships or activities that could appear to have influenced

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the submitted work.

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Author contributions

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CW, AM, AntM, SG and CK conceptualized the research project, developed the

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methodology and the trial protocol. CW, AM, AntM took part in the acquisition of the

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financial support for the project leading to this publication. CW and AM conducted the

508

investigation process; CK and AM coordinated the research activity planning and

509

execution. CK, CW and AM wrote the initial draft of the manuscript. TO performed the

510

formal statistical analysis. KD, AK, MM and ES took part in the development of the 21

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Ayurvedic treatment protocol and participated in writing and editing the manuscript.

512

KI was responsible for the trial database software; KI and MS performed data entry

513

and data curation and also took part in editing the manuscript.

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Data sharing

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The study protocol has been published 14, the German version is available on

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request. Statistical code: Available from T. Ostermann (e-mail:

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[email protected]). Data set: Certain portions of the analytic data set

520

are available to approved individuals through written agreements with the authors.

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Figure legends

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Figure 1: Study design

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Figure 2: Study flow diagram

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Figure 3: WOMAC Index progression: baseline - 12 months

527

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28

Characteristic

Ayurveda (n=77)

61.2 (6.6)

60.9 (6.5)

35 (23.2) 116 (76.8) 26.1 (3.9) 81 (54.4) 9.4 (8.1)

18 (23.4) 59 (76.6) 25.8 (3.7) 42 (56.0) 9.7 (9.1)

87 (57.6) 150 (99.3) 68 (45.0) 128 (84.8) 10 (6.6) 31 (20.5) 140 (92.7) 4.3 (2.5) 27 (17.9) 48 (31.8) 65 (43.0) 73 (48.3) 139.4 (16.8) 85.6 (9.4) 57.7 (11.7)

Conventional (n=74)

P-value

61.5 (6.6)

0.562 0.554

17 (23.0) 57 (77.0) 26.4 (4.2) 39 (52.7) 9.0 (7.0)

0.353 0.949 0.598 0.938

47 (61.0) 77 (100) 32 (41.6) 67 (87.0) 7 (9.1) 17 (22.1) 71 (92.2) 4.4 (2.6) 13 (16.9) 22 (28.6) 36 (46.8) 34 (44.2) 137.3 (16.1) 84.1 (9.6) 56.9 (11.7)

40 (54.1) 73 (98.6) 36 (48.6) 61 (82.4) 3 (4.1) 14 (18.9) 69 (93.2) 4.1 (2.4) 14 (18.9) 26 (35.1) 29 (39.2) 39 (52.7) 141.5 (17.3) 87.1 (9.1) 58.6 (11.7)

92.6 (42.2) 19.3 (8.5) 9.9 (4.7) 63.4 (31.8) 23.8 (11.4)

91.1 (40.3) 19.0 (8.1) 9.8 (4.7) 62.3 (30.6) 22.6 (10.6)

94.2 (44.4) 19.6 (9.0) 10.1 (4.7) 64.5 (33.1) 25.1 (12.1)

0.647 0.651 0.734 0.662 0.192

27.1 (8.2) 18.2 (5.7)

27.3 (8.8) 18.3 (5.6)

26.9 (7.6) 18.1 (5.8)

0.743 0.824

1.5 (0.9)

1.5 (1.0)

1.4 (0.9)

0.842

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Mean age (SD), years Gender, n (%) Male Female 2 Mean Body mass index (SD), kg/m > 10 years of school, n (%) Mean duration of knee pain (SD), years Consulting physicians due to knee OA, n (%)* General practitioner Orthopedic surgeon Other surgeon Radiologist Neurologist Other physicians Participants with concomitant diagnoses (CD), n (%) Mean number of CD (SD) Participants with 1-2 CD, n (%) Participants with 3-4 CD, n (%) Participants with ≥ 5 CD, n (%) Medication intake for knee OA Mean systolic blood pressure (SD), mmHg Mean diastolic blood pressure (SD), mmHg Mean VAS score for knee pain (SD), mm WOMAC, mean (SD) Index Pain subscale Stiffness subscale Function subscale PDI, mean (SD) SES, mean (SD) Affective Sensory POMS, mean (SD) Depression factor

All participants (n=151)

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Table 1: Baseline Characteristics

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0.943 0.463 0.917 0.240 0.124 0.047 0.373

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1.8 (0.9) 2.0 (0.7) 1.7 (0.8)

0.888 0.989 0.309

33.2 (7.7) 51.3 (11.3)

33.4 (7.4) 50.4 (12.1)

33.0 (8.1) 52.3 (10.5)

0.752 0.300

3.4 (2.3) 5.6 (1.9) 5.3 (2.0) 5.6 (2.5)

3.4 (2.3) 5.4 (2.0) 5.1 (2.1) 5.2 (2.5)

3.4 (2.3) 5.9 (1.7) 5.6 (1.9) 6.0 (2.5)

0.970 0.051 0.194 0.067

4.8 (1.1) 4.7 (1.2) 4.6 (1.3)

4.8 (1.1) 4.6 (1.2) 4.6 (1.3)

4.8 (1.0) 4.9 (1.1) 4.6 (1.3)

0.667 0.111 0.862

3.7 (1.3) 3.4 (1.1) 4.0 (1.3)

3.9 (1.4) 4.0 (1.2) 4.2 (1.4)

0.364 0.002 0.363

5.1 (1.0) 4.5 (1.0) 4.7 (1.1)

5.0 (1.0) 4.5 (0.9) 4.7 (1.0)

0.613 1.000 1.000

3.4 (1.0) 3.0 (0.9) 3.7 (1.1)

3.5 (0.8) 3.0 (0.8) 3.8 (1.1)

0.500 1.000 0.577 0.933

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5.0 (1.0) 4.5 (0.9) 4.7 (1.1) 3.5 (0.9) 3.0 (0.9) 3.8 (1.1)

121 (80.1) 30 (19.9)

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3.8 (1.3) 3.7 (1.2) 4.1 (1.4)

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1.8 (0.9) 2.0 (0.6) 1.8 (0.9)

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*multiple answers possible

1.8 (0.9) 2.0 (0.7) 1.7 (0.9)

61 (40.4) 16 (10.6)

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Fatigue factor Vigor factor Anger factor SF-36, mean (SD) Physical component summary Mental component summary NRS (11-point 0-10), mean (SD) Pain at rest Pain during movement Everyday bothersomeness through pain Sleep quality Likert scales (7-point, 0-6), mean (SD) Participant´s expectations of Ayurveda therapy Reduction of OA complaints Overall effectiveness Comprehensibility Participant´s expectations of conventional therapy Reduction of OA complaints Overall effectiveness Comprehensibleness Physician´s expectations of Ayurveda therapy Reduction of OA complaints Overall effectiveness Comprehensibility Physician´s expectations of conventional therapy Reduction of OA complaints Overall effectiveness Comprehensibility Study center, n (%) Study center 1 Study center 2

60 (39.7) 14 (9.3)

Abbreviations: SD = standard deviation; CD = concomitant disease; OA = osteoarthritis; WOMAC = Western Ontario and McMaster University Osteoarthritis Index; PDI = Pain disability index; SES = Pain experience scale; POMS = Profile of mood states; SF-36 = Short form 36; NRS = Numeric rating scale

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Table 2: WOMAC Index and WOMAC Subscales Time Point

Week 12 Mean (95% CI)

Month 6 Mean (95% CI)

Month 12 Mean (95% CI)

∆ Mean (95% CI)

49.6 (41.9; 57.3) 74.5 (65.7; 83.3)

30.0 (24.0; 36.1) 62.2 (52.4; 72.0)

36.3 (28.1; 44.4) 66.3 (56.9; 75.7)

43.0 (34.3; 51.7) 69.6 (59.9;79.2)

61.0 (52.4; 69.6) 32.0 (21.4; 42.6)

1.78 [1.41;2.16] 0.73 [0.46;1.00]

<0.001 <0.001

0.68 [0.35;1.01]

<0.001

10.4 (8.8; 12.0) 15.9 (14.0; 17.9)

6.2 (4.8; 7.6) 13.0 (10.7; 15.2)

7.2 (5.4; 8.9) 13.7 (11.6; 15.8)

7.9 (6.3; 9.6) 14.0 (11.9;16.1)

12.8 (10.8; 14.8) 6.7 (4.4; 8.9)

1.77 [1.37;2.17] 0.70 [0.44;0.97]

<0.001 <0.001

0.64 [0.32;0.97]

<0.001

5.4 (4.4; 6.4) 7.4 (6.4; 8.4)

3.6 (2.8;4.4) 6.7 (5.7;7.7)

4.1 (3.2; 4.9) 6.8 (5.8; 7.8)

4.8 (3.8.; 5.8) 7.1 (6.0; 8.1)

6.2 (5.2; 7.2) 3.4 (2.3; 4.4)

1.51 [1.17;1.84] 0.74 [0.47;1.00]

<0.001 <0.001

0.63 [0.30;0.95]

<0.001

33.8 (28.2; 39.5) 51.2 (44.9; 57.5)

20.2 (16.0;24.5) 42.6 (35.6; 49.5)

25.0 (19.2; 30.8) 45.8 (39.1; 52.5)

30.3 (23.8; 36.8) 48.5 (41.5; 55.5)

42.0 (35.7; 48.4) 22.0 (14.3; 29.7)

1.65 [1.29;2.00] 0.69 [0.42;0.96]

<0.001 <0.001

0.64 [0.32;0.97]

<0.001

675 676 677

SC

EP

674

Effect Size [CI]

P-Value

Abbreviations: WOMAC = Western Ontario and McMaster University Osteoarthritis Index; CI = Confidence Interval; Ayur. = Ayurveda Group; Conv. = Conventional Group

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673

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671 672

Between Group Differences (Baseline-week 12) Effect Size P-Value [CI]

Week 6 Mean (95% CI)

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WOMAC Index Ayur. Conv. Pain Ayur. Conv. Stiffness Ayur. Conv. Function Ayur. Conv.

Within Group Differences (Baseline-week 12)

RI PT

670

678

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Table 3: Secondary Outcomes

Week 6

681 682 683

8.2 (6.7; 9.7)

Week 6

Week 12

Month 6

Month 12

9.8 (7.8; 11.9)

11.8 (9,4; 14,2)

20.3 (17.7; 22.9)

16.4 (13.9; 18.9)

17.2 (15.1; 19.4)

18.2 (15.6; 20.9)

Month 6

21.9 (20.1; 23.7) 15.7 (14.7; 16.7)

18.3 (16.9; 19.8) 13.5 (12.4; 14.5)

18.7 (17.1; 20.4) 13.6 (12.5; 14.8)

19.0 (17.7; 20.3) 14.2 (13.0; 15.4)

23.9 (22.3; 25.5) 15.8 (14.8; 16.9)

21.5 (19.8; 23.2) 15.0 (14.0; 16.1)

21.8 (20.2; 23.3) 15.2 (14.2; 16.2)

21.2 (19.8; 22.6) 15.3 (14.3; 16.3)

3.6 (1.0; 6.2) 1.8 (-0.1; 3.7)

0.007 0.060

1.1 (1.0; 1.3) 1.6 (1.4; 1.8) 1.8 (1.7; 2.0) 1.6 (1.5; 1.8)

1.1 (0.9; 1.3) 1.5 (1.3; 1.7) 1.8 (1.7; 2.0) 1.5 (1.4; 1.7)

1.3 (1.1; 1.6) 1.7 (1.5; 1.9) 1.9 (1.8; 2.1) 1.7 (1.5; 2.0)

1.5 (1.2; 1.7) 1.9 (1.6; 2.1) 2.0 (1.9; 2.2) 1.7 (1.5; 1.9)

1.4 (1.1; 1.6) 1.9 (1.7; 2.1) 1.9 (1.8; 2.1) 1.5 (1.3; 1.7)

1.2 (1.0; 1.4) 1.7 (1.5; 1.9) 1.9 (1.8; 2.0) 1.6 (1.4; 1.7)

1.4 (1.2; 1.6) 1.8 (1.6; 2.0) 1.9 (1.7; 2.0) 1.6 (1.5; 1.8)

1.3 (1.1; 1.5) 1.8 (1.6; 2.0) 2.0 (1.8; 2.1) 1.7 (1.5; 1.9)

0.2 (-0.1; 0.4) 0.2 (0.0; 0.5) 0.1 (-0.1; 0.3) 0.2 (-0.1; 0.4)

0.190 0.089 0.502 0. 217

39.5 (37.7; 41.4) 52.8 (50.5; 55.0)

44.9 (43.1; 46.7) 53.7 (51.7; 55.7)

43.0 (40.9; 45,2) 53.0 (51,1; 55,0)

41.7 (39.5; 44.0) 52.5 (50.5; 54.4)

36.1 (34.1; 38.1) 52.7 (50.1; 55.3)

37.9 (35.7; 40.1) 53.9 (51.7; 56.1)

37.1 (35.0; 39.2) 54.1 (52.0; 56.1)

37.1 (35.0; 39.1) 54.0 (51.7; 56.2)

-6.6 (-9.3; -3.9) -1.7 (-5.1; 1.6)

<0.001 0.308

1.7 (1.3; 2.1) 3.4 (3.0; 3.9) 3.2 (2.8; 3.7) 6.0 (5.5; 6.6)

1.0 (0.7; 1.3) 2.5 (2.0; 2.9) 2.0 (1.6; 2.3) 6.4 (5.8; 7.0)

1.2 (0.8; 1.5) 2.6 (2.1; 3.0) 2.4 (1.9; 2.8) 6.4 (5.8; 7.0)

1.3 (1.0; 1.7) 2.7 (2.2; 3.2) 2.5 (2.0; 3.0) 6.0 (5.4; 6.5)

2.5 (2.1; 2.9) 4.7 (4.2; 5.1) 4.5 (4.0; 5.0) 5.8 (5.2; 6.3)

2.3 (1.7; 2.8) 3.9 (3.4; 4.5) 3.8 (3.2; 4.4) 6.5 (6.0; 7.1)

2.2 (1.7; 2.6) 4.0 (3.5; 4.5) 3.8 (3.3; 4.3) 5.8 (5.2; 6.3)

2.1 (1.7; 2.5) 4.2 (3.7; 4.7) 4.1 (3.6; 4.7) 6.0 (5.4; 6.6)

1.3 (0.5; 2.0) 0.9 (0.2; 1.6) 1.4 (0.7;2.1) -0.6 (-1.5;0.2)

0.001 0.018 <0.001 0.146

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Abbreviations: CI = Confidence Interval; PDI = Pain disability index; SES = Pain experience scale; POMS = Profile of mood states; SF-36 = Short form 36; NRS = Numeric rating scale

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680

14.1 (12.2; 16.1)

Month 12

Between Groups Baseline-Week 12 P-Value Mean ∆ (95% CI) 5.8 (2.1; 9.5) 0.002

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PDI SES Affective Sensory POMS Depress. Fatigue Vigor Anger SF-36 Subscales PCS MCS NRS (11-p) Pain Rest Pain Mov. Pain Both. Sleep

Week 12

Conventional Group (95% CI)

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Ayurveda Group (95% CI)

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679

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684

Table 4: Rescue medication use during the 12-week intervention period

685

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Number of RM intakes in the conventional group 585 1 8 60 654 (81.1%)

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Rescue medication (RM) category Total number of RM intakes Number of RM intakes in the Ayurveda group Category 1: NSAIDs oral 676 91 Category 2: NSAIDs topical 32 30 Category 3: other oral analgetics 32 24 Category 4: Paracetamol oral 67 7 806 (100%) 152 (18.9%)

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EP

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686 687 688 689

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WOMAC Stiffness WOMAC Function F p-value F p-value

Corrected Model

14.835

<0.001

11.434

<0.001

15.088

<0.001

14.999

<0.001

Intercept*

8.225

0.005

5.115

0.025

7.937

0.006

8.890

0.003

Participant Expectation

4.139

0.044

2.104

0.149

4.589

0.034

4.370

0.038

Baseline Value

29.884

<0.001

21.734

<0.001

38.010

<0.001

31.881

<0.001

Group

23.859

<0.001

22.083

<0.001

17.104

<0.001

22.548

<0.001

Gender

1.387

0.241

2.214

0.139

0.441

0.507

1.113

0.293

Group * Gender

0.061

0.805

0.615

0.434

0.015

0.903

0.011

0.917

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WOMAC Pain F p-value

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692 693

WOMAC-Index F p-value

*: the value of the dependent variable if all other explanatory variables hypothetically took on the value zero

EP

691

Table 5: ANCOVA Interaction Analyses

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690

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Appendix 1: Basic Information on Ayurveda

2 Ayurveda is the largest and most important traditional system of medicine in

4

India. Notwithstanding its ancient roots it is still very popular in South Asia. Its

5

popularity has recently been increasing also in the West due to its person-

6

centered and constitutional approach, its approach to treating chronic

7

diseases as well as aging-related ailments, and for its inclusive and dynamic

8

conceptualization of health1-3.

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In India Ayurveda is regulated by an independent ministry (AYUSH), it is

11

legalized equally to conventional medicine, and guidelines for education,

12

research, pharmacovigilance and medical practice are already established4-9.

13

According to the World Health Organization Ayurveda is a suitable and cost-

14

effective option for certain diseases8. Also outside of its country of origin,

15

particularly in the US and Europe, professional associations are trying to set

16

standards for Ayurveda practice and education, but national licensing for

17

Ayurveda is still pending10-12.

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Health, according to Ayurveda, comprises of physiological, psychological,

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social and spiritual dimensions and derives from a harmonious equilibrium of

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their functions13. This balance, which is considered as the natural state of the

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individual, is described as an interplay of three principles known as doshas,

23

named vata, pitta, and kapha. These principles regulate all life functions at the

24

body and mind levels and broadly refer to principles of 1. movement (vata) -

25

i.e. locomotor system, circulation, elimination, breathing, sensory perceptions;

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ACCEPTED MANUSCRIPT 2. metabolism (pitta) - i.e. temperature, digestion, intellectual discrimination,

27

rationale thinking; and 3. cohesion (kapha) - i.e. structure, physical shape,

28

maintenance of cell adhesion and networking, memory, mental stability.

29

Another essential factor for the maintenance of health is the balance between

30

food intake, its transformation and waste elimination, which is controlled by

31

the agni-principle, a factor which rules the transformation of heterologous

32

elements into homologous elements14.

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According to their relative proportions, the three principles determine the

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individual constitution, or prakriti that differs in physical, physiological,

35

psychological as well as behavioral traits. Several studies have shed light on

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relationships between the concept of prakriti and current omic-debates15-22.

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A diseased state is a condition of unbalanced functions of dosha and agni

39

which is expressed differently according to the individual constitution.

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Since the definition of the individual constitution allows the identification of

41

predisposition to diseases as well as forecasting responses to treatments and

42

therapies, it constitutes a necessary step of Ayurvedic diagnosis and

43

prescription processes. The centrality of the individual constitutional paradigm

44

in Ayurveda prioritizes the person who bears a specific illness as the

45

therapeutic target, rather than the illness per se. Individualized Ayurvedic

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treatment usually consists of several tailored components (for example

47

nutritional therapy, botanical therapy, manual therapy, lifestyle counseling,

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cleansing measures, leech-application, meditation and yoga elements).

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49 50

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ACCEPTED MANUSCRIPT REFERENCES

52 53

1.

Chaturvedi S, Patwardhan B. Building bridges for integrative medicine. Lancet Psychiatry. 2016 Aug;3(8):705–6.

54 55 56

2.

Morandi A, Nambi AN. An Integrated View of Health and Well-being [Internet]. Springer; 2014 [cited 2018 Jan 11]. Available from: http://link.springer.com/content/pdf/10.1007/978-94-007-6689-1.pdf

57 58 59 60

3.

Witt CM, Michalsen A, Roll S, Morandi A, Gupta S, Rosenberg M, et al. Comparative effectiveness of a complex Ayurvedic treatment and conventional standard care in osteoarthritis of the knee--study protocol for a randomized controlled trial. Trials. 2013;14:149.

61 62 63 64

4.

WHO. Benchmarks for Training in Ayurveda [Internet]. 2010 [cited 2018 Jan 11]. Available from: http://www.who.int/medicines/areas/traditional/BenchmarksforTraininginA yurveda.pdf

65 66 67

5.

Central Council for Research in Ayurvedic Sciences. Central Council for Research in Ayurvedic Sciences. [Internet]. 2015 [cited 2018 Jan 11]. Available from: http://www.ccras.nic.in/

68 69 70 71

6.

India Ministry of Health & Family Welfare. Protocol for National Pharmacovigilance Programme for Ayurveda, Siddha and Unani (ASU) Drugs, 2008. In collaboration with WHO Country Office for India. New Delhi; 2008.

72 73 74

7.

World Health Organization. Legal Status of Traditional medicine and Complementary/Alternative Medicine: a Worldwide Review. Geneva: World Health Organization; 2001.

75 76 77

8.

World Health Organization. WHO traditional medicine strategy: 20142023. [Internet]. 2013 [cited 2018 Jan 11]. Available from: http://apps.who.int/iris/bitstream/10665/92455/1/9789241506090_eng.pdf

78 79 80 81

9.

World Health Organization. Guidelines on Developing Consumer Information on Proper Use of Traditional, Complementary and Alternative Medicine. [Internet]. 2004 [cited 2018 Jan 11]. Available from: http://apps.who.int/medicinedocs/pdf/s5525e/s5525e.pdf

82 83 84

10. National Ayurvedic Medical Association. National Ayurvedic Medical Association [Internet]. 2015 [cited 2018 Jan 11]. Available from: http://www.ayurvedanama.org/

85 86 87

11. Association of Ayurvedic, Professionals of North America. Association of Ayurvedic Professionals of North America [Internet]. 2015 [cited 2018 Jan 11]. Available from: www.aapna.org

88 89

12. Baghel MS. Ayurvedic education in foreign countries. Globalization of Ayurveda. [Internet]. [cited 2018 Jan 11]. Available from: http://iaf-

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ngo.org/pdf/Ayurvedic%20education%20in%20foreign%20countries%20%20GLOBALISATION%20OF%20AYURVEDA%20(No.%207).pdf 13. Sharma PV (transl.). Sushruta Samhita. English translation. Reprint 2010. Sutrasthana (Su.) 15.41. Varanasi: Chaukhambha Visvabharati; 2010.

95 96 97 98

14. Caraka, Agnivesa, Cakrapanidatta, Sarma RK, Dash B. Agnivesa’s Caraka samhita: text with English translation & critical exposition based on Cakrapani Datta’s Ayurveda dipika. Vimanasthana VIII.14. Chowkhamba Sanskrit series office; 2002.

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92 93 94

15. Rotti H, Raval R, Anchan S, Bellampalli R, Bhale S, Bharadwaj R, et al. Determinants of prakriti, the human constitution types of Indian traditional medicine and its correlation with contemporary science. J Ayurveda Integr Med. 2014 Jul;5(3):167–75.

103 104 105 106

16. Rotti H, Raval R, Anchan S, Bellampalli R, Bhale S, Bharadwaj R, et al. Determinants of prakriti, the human constitution types of Indian traditional medicine and its correlation with contemporary science. J Ayurveda Integr Med. 2014 Jul;5(3):167–75.

107 108 109

17. Govindaraj P, Nizamuddin S, Sharath A, Jyothi V, Rotti H, Raval R, et al. Genome-wide analysis correlates Ayurveda Prakriti. Sci Rep. 2015;5:15786.

110 111 112

18. Patwardhan B, Bodeker G. Ayurvedic genomics: establishing a genetic basis for mind-body typologies. J Altern Complement Med N Y N. 2008 Jun;14(5):571–6.

113 114 115

19. Prasher B, Gibson G, Mukerji M. Genomic insights into ayurvedic and western approaches to personalized medicine. J Genet. 2016 Mar;95(1):209–28.

116 117 118 119

20. Aggarwal S, Negi S, Jha P, Singh PK, Stobdan T, Pasha MAQ, et al. EGLN1 involvement in high-altitude adaptation revealed through genetic analysis of extreme constitution types defined in Ayurveda. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18961–6.

120 121 122

21. Juyal RC, Negi S, Wakhode P, Bhat S, Bhat B, Thelma BK. Potential of ayurgenomics approach in complex trait research: leads from a pilot study on rheumatoid arthritis. PloS One. 2012;7(9):e45752.

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22. Ghodke Y, Joshi K, Patwardhan B. Traditional Medicine to Modern Pharmacogenomics: Ayurveda Prakriti Type and CYP2C19 Gene Polymorphism Associated with the Metabolic Variability. Evid-Based Complement Altern Med ECAM. 2011;2011:249528.

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Appendix 2: Intervention Details

2 3

Ayurveda-Intervention

4 The Ayurveda intervention reflected Ayurvedic treatment for knee OA, trying to be accurate

6

with the epistemology notwithstanding the ethnographic differences as well as

7

German/European Union bureaucratic limitations. Treatment was individualized for each

8

participant and adapted to the traditional Ayurveda diagnosis only (appendix 1). Ayurvedic

9

treatment consisted of maximum 15 sessions of individualized treatments with a maximum

11

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duration of 90 minutes: •

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Manual treatments / body massages (abhyanga) using classical Ayurvedic massage practices and knee poultices/ specific local applications (lepas, janu-bastis, kati-

13

bastis) with emphasis on the affected knee(s) and knee associated structures.

14

Ayurvedic oils / fats freely available in Germany were used after having been selected

15

by the physician according to the individual expression of the disease according to

16

the constitution of the participant (appendix 1). The most commonly used oil was

17

mahanarayan, alternative oils were dhanvanataram, shulahara, kshirabala and

18

murivenna). •

20

Sudation treatment (svedana, induction of sweating, for instance by placing the

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participant in a traditional Ayurvedic steam-box or by locally applying steam or hot-

21

wet cloths on body parts) during and/or following massage treatments), using local

22

knee sudation and generalized sudation measures according to the individual

23

expression of the disease according to the constitution as per time and intensity stay

24 25

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in sweatbox; application of wet and hot cloth on affected knees, pinda-sveda). •

Individualized nutritional counseling according to the principles of Ayurvedic dietetic

26

treatment including standardized diet-sheets. Focus on vata reducing, agni enhancing

27

measures and vegetarian nutrition.

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•

29 30

Individualized lifestyle counseling according to the individual constitution, including standardized handout material. Focus on vata reducing lifestyle measures.

•

Individualized knee Yoga posture counseling (asana) according to the individual constitution as well as to the individual expression of the disease and instruction for

32

regular domestic implementation: Knees to chest pose, bridge pose, downward facing

33

dogpose, half chair pose, hero pose, upside down pose (Sanskrit: apanasana,

34

dvipada pitham, adhomukhasvanasana, ardha utkatasana, virabhadrasana, viparita

35

karani). •

Administration of Ayurvedic dietary supplements customarily used and available in

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German pharmacies. (1) ashvagandha (botanical name: Withania somnifera Dunal.

38

Linn.) maximum 3 grams twice daily preferably with milk, and (2) yogaraja-guggulu

39

(compound supplement with the main ingredient Commiphora mukul Hook. ex Stocks

40

maximum 1.5 gram 3 x daily. •

42 43

Instruction for self-applied local knee massage (sva-abhyanga) to be done by the participant once daily at home.

•

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General information about Ayurveda and Ayurvedic treatment options in vataconditions (e.g. oily enemas, mild purgation, Sanskrit: anuvasana-basti, mrdu-

45

virecana) through bibliography handouts and print material.

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Conventional Intervention

50 Participants enrolled in the control group received conventional standard care for knee

52

osteoarthritis to according to current guidelines. Treatment was individualized for each

53

participant and based on the conventional diagnosis only. Conventional treatment consisted

54

of maximum 15 sessions of individualized treatments with a maximum duration of 45-50

55

minutes:

56

•

Individualized instruction for sequences of quadriceps muscle strengthening

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57

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51

exercises. •

Local physiotherapy including e.g. manual therapy techniques.

59

•

Occupational therapy.

60

•

Counseling for individual knee exercise (knee school).

61

•

Individualized nutritional counseling in case of obesity.

62

•

Prescription of pharmacological treatment options for acute medication (oral

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Paracetamol up to 3 g daily and/or topical NSAIDs, e.g. Diclofenac-Sodium ointment

64

or equivalent up to 3 x daily, and, in case of intolerance or non-response to these

65

substances, an alternative acute medication with oral NSAIDs, e.g. Ibuprofen up to

66

800 mg daily or equivalent. Moreover, the option of a regular administration of oral

67

Paracetamol up to a maximum of 3 g daily or topical NSAIDs and in case of

69

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intolerance or non-response to these substances an alternative medication with oral NSAIDs was given.

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Table: Number of treatment sessions for Ayurveda and conventional groups

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N of treatment sessions: Ayurveda group 12-13

N of treatment sessions: conventional group n/a

1-2 1-2

n/a n/a

n/a

12-15

n/a n/a

maximum 1-2 maximum 1-2, if applicable maximum 1, if applicable

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Therapeutic category

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Ayurvedic manual therapies, steamtherapies, instructions for selfmassage Knee-Yoga Ayurvedic nutritional and lifestyle counselling, nutritional supplements Conventional physiotherapy, quadriceps exercise, knee school Conventional occupational therapy Conventional nutritional advice if overweight Conventional pain medication

4

n/a

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Study Design

Randomization 1:1

Follow-up

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Ayurveda treatment (15 sessions)

Follow-up

0

6

12

Patient enrollment Study Intervention

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All other secondary outcomes (WOMAC subscales, SF-36, POMS, PDI, SES, NRS, Likertscales)

6

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Main outcome WOMAC global RM use (PD)

months

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weeks

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Conventional treatment (15 sessions)

October 2010 – January 2014 November 2010 – January 2015

WOMAC = Western Ontario and McMaster University Osteoarthritis Index; RM: Rescue Medication; PD: Participant Diary; SF-36 = Short Form-36 Health Survey; NRS= Numeric Rating Scales; POMS = Profile of mood states; PDI = Pain Disability Index; SES= Pain Experience Scale indicate time points for the assessment of outcomes

12

ACCEPTED MANUSCRIPT Study flow diagram.

Excluded (n = 132) Did not meet inclusion criteria: 83 Declined to participate: 31 Other reasons: 18

Patients assessed for eligibility (n = 197 )

Excluded (n = 46 ) Did not meet inclusion criteria: 35 Declined to participate: 5 Other reasons: 6

Visited at 6 weeks (n = 76) Personal reasons: 1

Visited at 6 weeks (n = 71) No reasons given:2 Personal reasons: 1

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Followed up at 6 month (n = 76) Personal reasons: 1

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Follow-up

Visited at 12 weeks (n = 76) Personal reasons: 1

Analyses

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Allocated to Conventional Care (n = 74 )

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Allocated to Ayurveda (n = 77)

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Allocation

Randomly assigned (n = 151)

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Enrollment

Patients contacted (n = 329 )

Visited at 12 weeks (n = 71) No reasons given:2 Personal reasons: 1

Followed up at 6 month (n = 70) No reasons given: 3 Personal reasons: 1

Followed up at 12 month (n = 76) Personal reasons: 1

Followed up at 12 month (n = 69) No reasons given: 3 Personal reasons: 2

Included in the main analyses (n = 77 )

Included in the main analyses (n = 74 )

Note: All participants with availabe baseline data were incuded in the analyses. Missing outcomes were imputed on the basis of baseline values. No participant was excluded because of missing outcome values

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