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

  • C.S. Kessler
    Affiliations
    Charité́ – Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany

    Immanuel Hospital Berlin, Department for Complementary Medicine, Königstr. 63, 14109 Berlin, Germany
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  • K.S. Dhiman
    Affiliations
    Ministry of AYUSH, AYUSH Bhawan, B Block, GPO Complex, INA, New Delhi 110023, India

    Central Council for Research in Ayurvedic Sciences (CCRAS), Jawahar Lal Nehru Bhavan, No.61-65, Institutional Area, Janakpuri, New Delhi 110058, India
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  • A. Kumar
    Affiliations
    Ministry of AYUSH, AYUSH Bhawan, B Block, GPO Complex, INA, New Delhi 110023, India

    All India Institute of Ayurveda, Mathura Road, Gautampuri, Sarita Vihar, New Delhi 110076, India
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  • T. Ostermann
    Affiliations
    University of Witten Herdecke, Department of Psychology and Psychotherapy, Alfred-Herrhausen-Straße 50, Witten, Germany
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  • S. Gupta
    Affiliations
    European Academy of Ayurveda, Forsthausstr. 6, 63633 Birstein, Germany

    Department of Kaya Cikitsa, J.S. Ayurveda College & P.D. Patel Ayurveda Hospital, College Road, Nadiad 387001, India
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  • A. Morandi
    Affiliations
    Ayurvedic Point, School of Ayurvedic Medicine, Corso Sempione 63, 20149 Milan, Italy
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  • M. Mittwede
    Affiliations
    European Academy of Ayurveda, Forsthausstr. 6, 63633 Birstein, Germany

    University of Frankfurt, Department of Religious Sciences, Grüneburgplatz 1, 60323 Frankfurt, Germany
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  • E. Stapelfeldt
    Affiliations
    Immanuel Hospital Berlin, Department for Complementary Medicine, Königstr. 63, 14109 Berlin, Germany
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  • M. Spoo
    Affiliations
    Immanuel Hospital Berlin, Department for Complementary Medicine, Königstr. 63, 14109 Berlin, Germany
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  • K. Icke
    Affiliations
    Charité́ – Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany
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  • Author Footnotes
    a Contributed equally.
    A. Michalsen
    Correspondence
    Address correspondence and reprint requests to: A. Michalsen, Head of Department Immanuel Hospital Berlin, Department for Complementary Medicine, Königstr. 63, 14109 Berlin, Germany. Tel.: 49-(0)-30-80505-691; Fax: 49-(0)-30-80505-692.
    Footnotes
    a Contributed equally.
    Affiliations
    Charité́ – Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany

    Immanuel Hospital Berlin, Department for Complementary Medicine, Königstr. 63, 14109 Berlin, Germany
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  • Author Footnotes
    a Contributed equally.
    C.M. Witt
    Footnotes
    a Contributed equally.
    Affiliations
    Charité́ – Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany

    Institute of Complementary and Integrative Medicine, University Hospital and University of Zurich, Rämistrasse 100, 8091 Zurich, Switzerland

    University of Maryland School of Medicine, Center for Integrative Medicine, 520 W. Lombard Street, East Hall, Baltimore, MD 21201, USA
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  • Author Footnotes
    a Contributed equally.
Open AccessPublished:February 06, 2018DOI:https://doi.org/10.1016/j.joca.2018.01.022

      Summary

      Objective

      Ayurveda is commonly used in South Asia to treat knee osteoarthritis (OA). We aimed to evaluate the effectiveness of Ayurvedic treatment compared to conventional conservative care in patients with knee OA.

      Method

      According to American College of Rheumatology (ACR) criteria knee OA patients were included in a multicenter randomized, controlled, open-label trial and treated in 2 hospital clinics and 2 private outpatient clinics in Germany. Participants received either a multi-modal Ayurvedic treatment or multi-modal conventional care with 15 treatments over 12 weeks respectively. Primary outcome was the change on the Western Ontario and McMaster University Osteoarthritis (WOMAC) Index after 12 weeks. Secondary outcomes included WOMAC subscales; the pain disability index and a pain experience scale, numeric rating scales for pain and sleep quality, quality-of-life and mood, rescue medication use, and safety issues.

      Results

      One hundred fifty-one participants (Ayurveda n = 77, conventional care n = 74) were included. Changes of the WOMAC Index from baseline to 12 weeks were more pronounced in the Ayurveda group (mean difference 61.0 [95%CI: 52.4;69.6]) than in the conventional group (32.0 [95%CI: 21.4;42.6]) resulting in a significant between-group difference (p < 0.001) and a clinically relevant effect size (Cohen's d 0.68 [95% CI:0.35;1.01]). Similar trends were observed for all secondary outcomes at week 12. Effects were sustained at follow-ups after 6 and 12 months.

      Conclusion

      Results suggest that Ayurvedic treatment is beneficial in reducing knee OA symptoms. Further studies should be conducted to confirm the magnitude of the effect and to clarify the role of different treatment components and non-specific effects.

      Registration

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

      Keywords

      Introduction

      Osteoarthritis (OA) is of global relevance with up to 250 million people being affected from knee OA worldwide
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      Knee osteoarthritis has doubled in prevalence since the mid-20th century.
      . Despite progress in conventional knee OA management many patients continue to be affected from pain and disability and there is a need for further effective treatment approaches
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      • et al.
      OARSI guidelines for the non-surgical management of knee osteoarthritis.
      . In India and South Asia traditional Ayurvedic medicine is also commonly used as a treatment approach in knee OA and the World Health Organization (WHO) recommends to include traditional systems of medicine in global health care
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      WHO Traditional Medicine Strategy: 2014-2023.
      .
      In India Ayurveda is recognized and regulated by an independent ministry (AYUSH)
      • World Health Organization
      WHO Traditional Medicine Strategy: 2014-2023.

      WHO. Benchmarks for Training in Ayurveda [Internet]. 2010 [cited 2017 Nov 27]. Available from: http://www.who.int/medicines/areas/traditional/BenchmarksforTraininginAyurveda.pdf.

      • India Ministry of Health & Family Welfare
      Protocol for national pharmacovigilance programme for Ayurveda, Siddha and Unani (ASU) drugs, 2008.
      . Ayurveda uses individualized treatments consisting of multi-modal components such as manual therapies, nutritional therapy and herbs, lifestyle counseling and yoga-based exercise
      (Appendix 1).
      A review of 33 Ayurveda studies showed that most trials (91%) evaluated herbal preparations as single interventions
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      . No clinical trial evaluated Ayurveda treatment with its multi-modal components for knee OA so far
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      • 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.
      .
      In western countries, knee OA is treated by conventional multi-modal interventions combining pharmacological and non-pharmacological interventions
      • McAlindon T.E.
      • Bannuru R.R.
      • Sullivan M.C.
      • Arden N.K.
      • Berenbaum F.
      • Bierma-Zeinstra S.M.
      • et al.
      OARSI guidelines for the non-surgical management of knee osteoarthritis.
      • National Clinical Guideline Centre (UK)
      Osteoarthritis: Care and Management in Adults.
      • American Academy of Othopaedic Surgeons
      Treatment of Osteoarthritis of the Knee. Evidence-based Guideline and 2nd Edition.
      . Ayurveda also uses a multi-modal intervention approach for the treatment of knee OA. Comparisons of the effectiveness of conventional and Ayurveda interventions for the treatment of knee OA would be a feasible research question.

      Method

      Study design

      Protocol details have been published previously. We designed a multicenter open-label trial and randomized participants to 12 weeks of Ayurveda or conventional guideline-based care (Appendix 2)
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      • Michalsen A.
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      • 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.
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      • Gagnier J.J.
      • Altman D.G.
      • Tunis S.
      • Haynes B.
      • et al.
      Improving the reporting of pragmatic trials: an extension of the CONSORT statement.
      . Outcomes were assessed at baseline, 6 weeks, 12 weeks, 6 months and 1 year. Participants received 15 treatment sessions within 12 weeks. Long-term effects were evaluated after 6 and 12 months (Fig. 1).
      We used an equal block-randomization with variable block size and stratified for study site. An independent statistician generated a randomization list with SAS (version 9.1, SAS Inc, Cary, NC). The data manager transferred the randomization list into a secure database (Microsoft Office Access 2007), where the randomization list was not accessible to anyone else. Each participant could be registered and randomized only once and the database did not allow deleting participants' data. Statisticians, data entry personnel and the funding source were blinded to treatment assignment throughout the study.
      The trial was registered at clinicaltrials.gov under NCT01225133 and was approved by the university ethics committee (Charité Medical University, EA1/124/10). It followed the Declaration of Helsinki and Good Clinical Practice guidelines for trial conduct. Participants provided written informed consent before taking part and were not reimbursed for participation. Due to changes in ethical regulations during the trial one amendment has been made regarding the provision of nutritional supplements. Thereafter, the remaining 24 study participants from the Ayurveda group did not receive nutritional supplements but were advised to increase the food intake of the previously supplemented nutrients as much as feasible.

      Participants

      Seventy percent of participants were recruited via newspaper advertisements. The remaining participants were recruited by physicians from the trial center clinics or contacted the centers themselves, because they had heard about the trial. Participants were pre-screened over the phone and if suitable scheduled to an enrolment visit (Fig. 2).
      Inclusion criteria: male or female, 40–70 years of age; knee OA pre-diagnosed by an orthopedic surgeon or radiologist according to American College of Rheumatology (ACR) criteria
      • Hochberg M.C.
      • Altman R.D.
      • April K.T.
      • Benkhalti M.
      • Guyatt G.
      • McGowan J.
      • et al.
      American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee.
      • Altman R.
      • Asch E.
      • Bloch D.
      • Bole G.
      • Borenstein D.
      • Brandt K.
      • et al.
      Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the American rheumatism association.
      ; radiologic changes in X-ray (Kellgren–Lawrence ≥ 2
      • Kellgren J.H.
      • Lawrence J.S.
      Radiological assessment of osteo-arthrosis.
      • Kellgren J.H.
      • Moore R.
      Generalized osteoarthritis and Heberden's nodes.
      or an MRI Recht grading score ≥ 2(a)
      • Recht M.P.
      • Resnick D.
      Magnetic resonance imaging of articular cartilage: an overview.
      • Recht M.
      • Bobic V.
      • Burstein D.
      • Disler D.
      • Gold G.
      • Gray M.
      • et al.
      Magnetic resonance imaging of articular cartilage.
      ; mean baseline pain intensity in the affected knee of ≥40 mm on a 100 mm visual analogue scale (VAS) over 7 days preceding enrollment, written informed consent.
      Exclusion criteria: knee pain caused by congenital dysplasia, rheumatoid arthritis, autoimmune diseases, malignancies, knee surgery or knee-arthroscopy; administration of chondroprotective drugs, intra-articular injections into the knee joint or systemic corticosteroid medication during the 3 months preceding enrollment; start of any new treatment for knee OA during the 4 weeks preceding enrollment including treatment with paracetamol, OTC NSAIDs and any CAM treatments; pregnancy or breastfeeding; acute mental disorders; serious acute organic diseases; serious chronic co-morbidity; obesity ≥ WHO grade II; blood coagulation disorders; intake of coagulation-inhibiting medication other than acetylsalicylic acid and clopidogrel; invasive measures at the affected joint during the 12 weeks preceding enrollment or planned for the 12 months following enrollment; and being in the process of applying for pension/disability benefits.

      Interventions

      The interventions were developed in an international consensus process with Ayurveda and orthopedic experts from three countries (India, Germany and Italy) using a Delphi approach
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      • et al.
      Delphi-derived development of a common core for measuring complementary and alternative medicine prevalence.
      . Ayurvedic literature (Ayurveda group)
      , and current guidelines (conventional group) were used
      • American Academy of Othopaedic Surgeons
      Treatment of Osteoarthritis of the Knee. Evidence-based Guideline and 2nd Edition.
      • Jordan K.M.
      • Arden N.K.
      • Doherty M.
      • Bannwarth B.
      • Bijlsma J.W.J.
      • Dieppe P.
      • et al.
      EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT).
      . Ayurveda was provided by conventionally trained physicians with additional Ayurveda training, who had undergone either a university program for Ayurveda in India (Bachelor of Ayurveda Medicine and Surgery [B.A.M.S.] Indian expert) or had ≥ 500 hours of academic training in Ayurveda plus ≥ 2 years of continuous clinical experience with Ayurveda (European experts). Other involved Ayurvedic therapists were required to have ≥2 years of continuous clinical experience in their fields (manual therapies, nutritional advice, lifestyle advice, yoga therapy). To assure treatment quality, line of treatment for the first 30 participants was discussed by 4 Ayurveda doctors until consent was achieved. In the conventional group interventions were prescribed by board certified medical doctors (MDs) specialized in orthopedics or orthopedic surgery. All other conventional therapists (physiotherapy, occupational therapy) required a completed licensed training in their field and a minimum of ≥2 years of continuous clinical experience. In total 5 specialized physicians (2 Ayurveda, 3 conventional MDs) and 20 specialized therapists (12 Ayurveda [8 for manual therapies, 2 for yoga, 2 for nutrition and lifestyle], 8 conventional [6 for physiotherapy, 2 for nutrition and occupational therapy]) treated participants in 2 public hospital outpatient clinics and 2 hospital affiliated private outpatient clinics for Ayurveda, orthopedics, orthopedic surgery, physiotherapy and occupational therapy in Berlin, Germany. Treatments in both groups were administered in 15 sessions over 12 weeks (2 sessions/week in the first 3 weeks and 1 session/week in weeks 4–12), with treatment time between 45 and 50 min (conventional) and 60–90 min (Ayurveda) per session. Treatment time between groups was not further equalized as a treatment time >50 min per session for physiotherapy/exercise would have largely exceeded existing treatment standards for knee OA patients.
      The multi-modal Ayurveda intervention was individualized and followed the treatment principles of Ayurveda. Individualized treatment included specific manual treatments and massages; Ayurvedic diet counseling including specific consideration of selected food items, adapted to local food items commonly available in German grocery stores; two nutritional Ayurvedic supplements typically used for painful conditions of the musculoskeletal system, Ashvagandha (Withania somnifera Dunal. Linn) and Yogaraja Guggulu (compound supplement, main ingredient Commiphora mukul Hook. ex Stocks); general and specific Ayurvedic lifestyle advice; knee specific yoga posture advice; and daily self-applied knee massage.
      Conventional group participants received multi-modal and individualized conventional care for knee OA according to current guidelines; this included quadriceps muscle strengthening exercises, knee specific physiotherapy including manual therapy, occupational therapy, advice for individual home knee exercises, dietary advice for weight loss for overweight participants, and, if necessary, administration of long-term pain medication according to current guidelines
      • American Academy of Othopaedic Surgeons
      Treatment of Osteoarthritis of the Knee. Evidence-based Guideline and 2nd Edition.
      • Jordan K.M.
      • Arden N.K.
      • Doherty M.
      • Bannwarth B.
      • Bijlsma J.W.J.
      • Dieppe P.
      • et al.
      EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT).
      (Appendix 2f).
      In both groups rescue medication with a maximum of 3 g paracetamol per day could be used. In case of intolerance or non-response to paracetamol, topical or oral NSAIDs could be used (e.g., diclofenac-sodium ointment 3 time per day or oral ibuprofen up to a maximum dose of 800 mg per day or equivalent) after having consulted a study physician. The use of other pain medication was discouraged. Participants were instructed to document the use of pain medication in diaries during the intervention period.

      Outcome measures

      Primary outcome measure was the change in the WOMAC Index between baseline and 12 weeks
      • Bellamy N.
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      . The WOMAC has three subscales that measure pain (range 0–50), stiffness (range 0–20), and function (range 0–170) and can be summarized as Index; the validated German version was used
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      Evaluation of a German version of WOMAC (Western Ontario and McMaster Universities) arthrosis index.
      . Secondary outcomes were WOMAC subscales (pain, stiffness and function separately), a Pain Disability Index (PDI)
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      , Numeric Rating Scales (NRS, 0 to 10) for additional questions on pain and quality of sleep (instead of Visual Analogue Scales (VAS) as written in the protocol publication), a Pain Experience Scale (SES)
      • Geissner E.
      Die Schmerzempfindungsskala–SES (unter Mitarbeit von A. Schulte).
      , health-related quality of life (Short Form-36 Health Survey, SF-36
      • Morfeld M.
      • Bullinger M.
      • Kirchberger I.
      Fragebogen zum Gesundheitszustand: SF-36; deutsche Version des Short form-36 health survey.
      ), Profile of Mood States (POMS)
      • Grulke N.
      • Bailer H.
      • Schmutzer G.
      • Brähler E.
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      • et al.
      [Standardization of the German short version of “profile of mood states” (POMS) in a representative sample–short communication].
      , a 7-point Likert Scale for general health-related participant satisfaction, a participant diary for rescue medication use, and safety (adverse events and serious adverse events). Outcomes were assessed using participant questionnaires. All outcomes were assessed at baseline, 6 and 12 weeks, and 6 and 12 months. Study nurses handed out questionnaires and diaries at baseline (before randomization), week 6 and week 12, and asked participants to complete them and to return them in sealed envelopes. The 6-months and 12-months questionnaires and participants' diaries were mailed by the study office. Adverse events were assessed by trial personnel in a standardized way at each visit and were also documented by the participants at the end of week 6 and week 12. Participants documented their expectations for treatment outcome at baseline (Fig. 1).

      Statistical analyses

      This study was designed to have 80% power to detect a difference of 10 points improvement (change to baseline) on the WOMAC Index after 12 weeks between both groups (pooled standard deviation = 20, two sided t-test α = 0.05). To achieve this, 64 participants per group were needed. By taking drop outs into account, we planned to include 74 participants per group. The primary analysis population was the intention-to-treat (ITT) population including all randomized participants, who provided baseline data for the primary outcome. The primary outcome was the change of the WOMAC Index after 12 weeks. Missing data were multiply imputed by maximum-likelihood based regression methods. Overall, 20 complete data sets were generated and combined adequately. Generalized Linear Mixed Models (GLM) were fitted to the data sets, including the treatment group as a fixed factor. Results are presented as adjusted WOMAC means per group with 95% confidence intervals and the two-sided p-value for the treatment group comparison. For sensitivity analysis ANCOVA models for WOMAC Index and WOMAC subscales were used after 12 weeks as independent variables. Treatment group and gender as fixed factors, baseline values and participants' expectations as linear covariates were applied to the data. The magnitude of effect sizes between and within groups for the primary endpoint was calculated using Cohen's d and its confidence intervals with d > 0.5 defining clinically relevant effect sizes
      • Cohen J.
      Statistical Power Analysis for the Behavioral Sciences Lawrence Earlbaum Associates.
      . Partial η2, another measure of effect size, was used to measure the proportion of the total variance in the variable “WOMAC Index after 12 weeks” attributable to a particular independent variable (e.g., treatment group or expectation). Finally, within-group changes in both primary and secondary outcomes were assessed using univariate t-test statistics. Treatment responder analyses were performed using Chi–Square tests. We defined a decrease of at least 12 points as a treatment response for the main outcome parameter representing slightly stricter common response criteria
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      • van der Heijde D.
      • Altman R.D.
      • Anderson J.J.
      • Bellamy N.
      • Hochberg M.
      • et al.
      OMERACT-OARSI initiative: osteoarthritis research society international set of responder criteria for osteoarthritis clinical trials revisited.
      . All statistical analyses were carried out blind and prior to breaking the randomization code. Analyses were conducted using SPSS (release 23.0; IBM, Armonk, NY, USA, 2015).

      Results

      Between October 2010 and January 2014, 329 individuals were contacted by telephone, 197 were assessed for eligibility, and 151 were randomly assigned (77 to the Ayurveda group, 74 to the conventional group). Participants were treated between November 2010 and January 2015 and included into the primary analyses (Fig. 2). Four participants had missing values for all outcomes at 6 and 12 weeks, five participants at 6 months and six participants at 12 months; missing values were multiply imputed.
      Overall, baseline characteristics were comparable between the groups (Table I). Participants in the Ayurveda group started with slightly lower mean WOMAC Index values. Participants and physicians had higher expectations for Ayurveda than for conventional care (Table I), which was considered in the sensitivity analyses.
      Table IBaseline characteristics
      CharacteristicAll participants (n = 151)Ayurveda (n = 77)Conventional (n = 74)P-value
      Mean age (SD), years61.2 (6.6)60.9 (6.5)61.5 (6.6)0.562
      Gender, n (%)0.554
       Male35 (23.2)18 (23.4)17 (23.0)
       Female116 (76.8)59 (76.6)57 (77.0)
      Mean body mass index (SD), kg/m226.1 (3.9)25.8 (3.7)26.4 (4.2)0.353
      >10 years of school, n (%)81 (54.4)42 (56.0)39 (52.7)0.949
      Mean duration of knee pain (SD), years9.4 (8.1)9.7 (9.1)9.0 (7.0)0.598
      Consulting physicians due to knee OA, n (%)
      Multiple answers possible.
      0.938
       General practitioner87 (57.6)47 (61.0)40 (54.1)
       Orthopedic surgeon150 (99.3)77 (100)73 (98.6)
       Other surgeon68 (45.0)32 (41.6)36 (48.6)
       Radiologist128 (84.8)67 (87.0)61 (82.4)
       Neurologist10 (6.6)7 (9.1)3 (4.1)
       Other physicians31 (20.5)17 (22.1)14 (18.9)
      Participants with concomitant diagnoses (CD), n (%)140 (92.7)71 (92.2)69 (93.2)0.943
       Mean number of CD (SD)4.3 (2.5)4.4 (2.6)4.1 (2.4)0.463
       Participants with 1–2 CD, n (%)27 (17.9)13 (16.9)14 (18.9)
       Participants with 3–4 CD, n (%)48 (31.8)22 (28.6)26 (35.1)0.917
       Participants with ≥5 CD, n (%)65 (43.0)36 (46.8)29 (39.2)
      Medication intake for knee OA73 (48.3)34 (44.2)39 (52.7)0.240
      Mean systolic blood pressure (SD), mm Hg139.4 (16.8)137.3 (16.1)141.5 (17.3)0.124
      Mean diastolic blood pressure (SD), mm Hg85.6 (9.4)84.1 (9.6)87.1 (9.1)0.047
      Mean VAS score for knee pain (SD), mm57.7 (11.7)56.9 (11.7)58.6 (11.7)0.373
      WOMAC, mean (SD)
       Index92.6 (42.2)91.1 (40.3)94.2 (44.4)0.647
       Pain subscale19.3 (8.5)19.0 (8.1)19.6 (9.0)0.651
       Stiffness subscale9.9 (4.7)9.8 (4.7)10.1 (4.7)0.734
       Function subscale63.4 (31.8)62.3 (30.6)64.5 (33.1)0.662
      PDI, mean (SD)23.8 (11.4)22.6 (10.6)25.1 (12.1)0.192
      SES, mean (SD)
       Affective27.1 (8.2)27.3 (8.8)26.9 (7.6)0.743
       Sensory18.2 (5.7)18.3 (5.6)18.1 (5.8)0.824
      POMS, mean (SD)
       Depression factor1.5 (0.9)1.5 (1.0)1.4 (0.9)0.842
       Fatigue factor1.8 (0.9)1.8 (0.9)1.8 (0.9)0.888
       Vigor factor2.0 (0.7)2.0 (0.6)2.0 (0.7)0.989
       Anger factor1.7 (0.9)1.8 (0.9)1.7 (0.8)0.309
      SF-36, mean (SD)
       Physical component summary33.2 (7.7)33.4 (7.4)33.0 (8.1)0.752
       Mental component summary51.3 (11.3)50.4 (12.1)52.3 (10.5)0.300
      NRS (11-point 0–10), mean (SD)
       Pain at rest3.4 (2.3)3.4 (2.3)3.4 (2.3)0.970
       Pain during movement5.6 (1.9)5.4 (2.0)5.9 (1.7)0.051
       Everyday bothersomeness through pain5.3 (2.0)5.1 (2.1)5.6 (1.9)0.194
       Sleep quality5.6 (2.5)5.2 (2.5)6.0 (2.5)0.067
      Likert scales (7-point, 0–6), mean (SD)

      Participant's expectations of Ayurveda therapy
       Reduction of OA complaints4.8 (1.1)4.8 (1.1)4.8 (1.0)0.667
       Overall effectiveness4.7 (1.2)4.6 (1.2)4.9 (1.1)0.111
       Comprehensibility4.6 (1.3)4.6 (1.3)4.6 (1.3)0.862
      Participant's expectations of conventional therapy
       Reduction of OA complaints3.8 (1.3)3.7 (1.3)3.9 (1.4)0.364
       Overall effectiveness3.7 (1.2)3.4 (1.1)4.0 (1.2)0.002
       Comprehensibleness4.1 (1.4)4.0 (1.3)4.2 (1.4)0.363
      Physician's expectations of Ayurveda therapy
       Reduction of OA complaints5.0 (1.0)5.1 (1.0)5.0 (1.0)0.613
       Overall effectiveness4.5 (0.9)4.5 (1.0)4.5 (0.9)1.000
       Comprehensibility4.7 (1.1)4.7 (1.1)4.7 (1.0)1.000
      Physician's expectations of conventional therapy
       Reduction of OA complaints3.5 (0.9)3.4 (1.0)3.5 (0.8)0.500
       Overall effectiveness3.0 (0.9)3.0 (0.9)3.0 (0.8)1.000
       Comprehensibility3.8 (1.1)3.7 (1.1)3.8 (1.1)0.577
      Study center, n (%)0.933
       Study center 1121 (80.1)61 (40.4)0 (39.7)
       Study center 230 (19.9)16 (10.6)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.
      Multiple answers possible.
      The average number of treatment sessions was 13.5 ± 1.7 for Ayurveda participants and 14.0 ± 2.7 for conventional participants. Mean treatment duration time was 67.8 ± 4.1 min (90.2 ± 5.8 min in the Ayurveda group and 45.3 ± 2.5 min in the conventional group).

      Primary outcome

      Changes of the WOMAC Index from baseline to 12 weeks were more pronounced in the Ayurveda group (mean difference 61.0 [95% CI: 52.4;69.6]) than in the conventional group (mean difference 32.0 [95% CI: 21.4;42.6]) resulting in a significant group difference (p < 0.001) and a clinically relevant effect size (Cohen's d 0.68 [95% CI: 0.35;1.01] respectively partial η2 = 0.212) (Table II). The between-group difference for the WOMAC Index persisted in similar magnitude up to the 12-month follow-up (Table II, Fig. 3).
      Table IIWOMAC index and WOMAC subscales
      Time PointWithin group differences (Baseline-week 12)Between group differences (Baseline-week 12)
      Week 6 mean (95% CI)Week 12 mean (95% CI)Month 6 mean (95% CI)Month 12 mean (95% CI)Δ mean (95% CI)Effect Size [CI]P-ValueEffect size [CI]P-Value
      WOMAC
      Index
       Ayur.49.6 (41.9; 57.3)30.0 (24.0; 36.1)36.3 (28.1; 44.4)43.0 (34.3; 51.7)61.0 (52.4; 69.6)1.78 [1.41;2.16]<0.0010.68 [0.35;1.01]<0.001
       Conv.74.5 (65.7; 83.3)62.2 (52.4; 72.0)66.3 (56.9; 75.7)69.6 (59.9;79.2)32.0 (21.4; 42.6)0.73 [0.46;1.00]<0.001
      Pain
       Ayur.10.4 (8.8; 12.0)6.2 (4.8; 7.6)7.2 (5.4; 8.9)7.9 (6.3; 9.6)12.8 (10.8; 14.8)1.77 [1.37;2.17]<0.0010.64 [0.32;0.97]<0.001
       Conv.15.9 (14.0; 17.9)13.0 (10.7; 15.2)13.7 (11.6; 15.8)14.0 (11.9;16.1)6.7 (4.4; 8.9)0.70 [0.44;0.97]<0.001
      Stiffness
       Ayur.5.4 (4.4; 6.4)3.6 (2.8;4.4)4.1 (3.2; 4.9)4.8 (3.8.; 5.8)6.2 (5.2; 7.2)1.51 [1.17;1.84]<0.0010.63 [0.30;0.95]<0.001
       Conv.7.4 (6.4; 8.4)6.7 (5.7;7.7)6.8 (5.8; 7.8)7.1 (6.0; 8.1)3.4 (2.3; 4.4)0.74 [0.47;1.00]<0.001
      Function
       Ayur.33.8 (28.2; 39.5)20.2 (16.0;24.5)25.0 (19.2; 30.8)30.3 (23.8; 36.8)42.0 (35.7; 48.4)1.65 [1.29;2.00]<0.0010.64 [0.32;0.97]<0.001
       Conv.51.2 (44.9; 57.5)42.6 (35.6; 49.5)45.8 (39.1; 52.5)48.5 (41.5; 55.5)22.0 (14.3; 29.7)0.69 [0.42;0.96]<0.001
      Abbreviations: WOMAC = Western Ontario and McMaster University Osteoarthritis Index; CI = Confidence Interval; Ayur. = Ayurveda Group; Conv. = Conventional Group.
      Figure thumbnail gr3
      Fig. 3WOMAC Index progression: baseline - 12 months.
      The proportion of treatment responders was 93.5 % for Ayurveda, and 60.8% for conventional guideline care (Chi–Square: 21.24; p < 0.001).

      Secondary outcomes

      Changes within each subscale of WOMAC and all other secondary outcomes were also more prominent in the Ayurveda group at week 12. Similar findings were observed at months 6 and 12, with the exception of POMS scales and the mental component subscale of the SF-36 (Table II, Table III).
      Table IIISecondary outcomes
      Ayurveda group (95% CI)Conventional group (95% CI)Between groups

      Baseline-week 12
      Week 6Week 12Month 6Month 12Week 6Week 12Month 6Month 12Mean Δ (95% CI)P-Value
      PDI14.1 (12.2; 16.1)8.2 (6.7; 9.7)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)5.8 (2.1; 9.5)0.002
      SES
      Affective21.9 (20.1; 23.7)18.3 (16.9; 19.8)18.7 (17.1; 20.4)19.0 (17.7; 20.3)23.9 (22.3; 25.5)21.5 (19.8; 23.2)21.8 (20.2; 23.3)21.2 (19.8; 22.6)3.6 (1.0; 6.2)0.007
      Sensory15.7 (14.7; 16.7)13.5 (12.4; 14.5)13.6 (12.5; 14.8)14.2 (13.0; 15.4)15.8 (14.8; 16.9)15.0 (14.0; 16.1)15.2 (14.2; 16.2)15.3 (14.3; 16.3)1.8 (−0.1; 3.7)0.060
      POMS
      Depress.1.1 (1.0; 1.3)1.1 (0.9; 1.3)1.3 (1.1; 1.6)1.5 (1.2; 1.7)1.4 (1.1; 1.6)1.2 (1.0; 1.4)1.4 (1.2; 1.6)1.3 (1.1; 1.5)0.2 (−0.1; 0.4)0.190
      Fatigue1.6 (1.4; 1.8)1.5 (1.3; 1.7)1.7 (1.5; 1.9)1.9 (1.6; 2.1)1.9 (1.7; 2.1)1.7 (1.5; 1.9)1.8 (1.6; 2.0)1.8 (1.6; 2.0)0.2 (0.0; 0.5)0.089
      Vigor1.8 (1.7; 2.0)1.8 (1.7; 2.0)1.9 (1.8; 2.1)2.0 (1.9; 2.2)1.9 (1.8; 2.1)1.9 (1.8; 2.0)1.9 (1.7; 2.0)2.0 (1.8; 2.1)0.1 (−0.1; 0.3)0.502
      Anger1.6 (1.5; 1.8)1.5 (1.4; 1.7)1.7 (1.5; 2.0)1.7 (1.5; 1.9)1.5 (1.3; 1.7)1.6 (1.4; 1.7)1.6 (1.5; 1.8)1.7 (1.5; 1.9)0.2 (−0.1; 0.4)0. 217
      SF-36
      Subscales
      PCS39.5 (37.7; 41.4)44.9 (43.1; 46.7)43.0 (40.9; 45,2)41.7 (39.5; 44.0)36.1 (34.1; 38.1)37.9 (35.7; 40.1)37.1 (35.0; 39.2)37.1 (35.0; 39.1)−6.6 (−9.3; −3.9)<0.001
      MCS52.8 (50.5; 55.0)53.7 (51.7; 55.7)53.0 (51,1; 55,0)52.5 (50.5; 54.4)52.7 (50.1; 55.3)53.9 (51.7; 56.1)54.1 (52.0; 56.1)54.0 (51.7; 56.2)−1.7 (−5.1; 1.6)0.308
      NRS (11-p)
      Pain rest1.7 (1.3; 2.1)1.0 (0.7; 1.3)1.2 (0.8; 1.5)1.3 (1.0; 1.7)2.5 (2.1; 2.9)2.3 (1.7; 2.8)2.2 (1.7; 2.6)2.1 (1.7; 2.5)1.3 (0.5; 2.0)0.001
      Pain mov.3.4 (3.0; 3.9)2.5 (2.0; 2.9)2.6 (2.1; 3.0)2.7 (2.2; 3.2)4.7 (4.2; 5.1)3.9 (3.4; 4.5)4.0 (3.5; 4.5)4.2 (3.7; 4.7)0.9 (0.2; 1.6)0.018
      Pain both.3.2 (2.8; 3.7)2.0 (1.6; 2.3)2.4 (1.9; 2.8)2.5 (2.0; 3.0)4.5 (4.0; 5.0)3.8 (3.2; 4.4)3.8 (3.3; 4.3)4.1 (3.6; 4.7)1.4 (0.7;2.1)<0.001
      Sleep6.0 (5.5; 6.6)6.4 (5.8; 7.0)6.4 (5.8; 7.0)6.0 (5.4; 6.5)5.8 (5.2; 6.3)6.5 (6.0; 7.1)5.8 (5.2; 6.3)6.0 (5.4; 6.6)−0.6 (−1.5;0.2)0.146
      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.
      In the first 12 weeks, the proportion of participants that used rescue pain medication was 18.9 % in the Ayurveda group, and 81.1% in the conventional group (Table IV).
      Table IVRescue medication use during the 12-week intervention period
      Rescue medication (RM) categoryTotal number of RM intakesNumber of RM intakes in the Ayurveda groupNumber of RM intakes in the conventional group
      Category 1: NSAIDs oral67691585
      Category 2: NSAIDs topical32301
      Category 3: other oral analgetics32248
      Category 4: Paracetamol oral67760
      806 (100%)152 (18.9%)654 (81.1%)

      Sensitivity analyses

      The results were significantly sensitive to participant expectations and WOMAC baseline values. For all WOMAC subscales baseline values revealed a statistically significant influence (p < 0.001) on the primary outcome. Moreover, participant expectation significantly influenced the WOMAC subscales “function” (p = 0.038) and “stiffness” (p = 0.034) while no significant influence of participant expectation was observed for the subscale “pain” (p = 0.149). Respectively, for the global WOMAC index a significant influence of participant expectation (p < 0.044) was given. However, findings were very robust for sensitivity analyses (ANCOVA-modeled): the same significant differences between the two randomized groups (p < 0.001) for both the WOMAC Index (composite score of three WOMAC subscales) and for each single WOMAC subscale were observed in the treatment expectation-adjusted model. Expectation with respect to Ayurveda accounted for 2.6% and with respect to conventional care for 1.6% of the total variance in the adjusted model (see Table V for details).
      Table VANCOVA interaction analyses
      WOMAC-IndexWOMAC PainWOMAC StiffnessWOMAC Function
      FP-valueFP-valueFP-valueFP-value
      Corrected Model14.835<0.00111.434<0.00115.088<0.00114.999<0.001
      Intercept
      The value of the dependent variable if all other explanatory variables hypothetically took on the value zero.
      8.2250.0055.1150.0257.9370.0068.8900.003
      Participant expectation4.1390.0442.1040.1494.5890.0344.3700.038
      Baseline value29.884<0.00121.734<0.00138.010<0.00131.881<0.001
      Group23.859<0.00122.083<0.00117.104<0.00122.548<0.001
      Gender1.3870.2412.2140.1390.4410.5071.1130.293
      Group
      The value of the dependent variable if all other explanatory variables hypothetically took on the value zero.


      Gender
      0.0610.8050.6150.4340.0150.9030.0110.917
      The value of the dependent variable if all other explanatory variables hypothetically took on the value zero.

      Safety

      There were 137 adverse events throughout the intervention period in 73 participants (59.7 % of participants [n = 46] in the Ayurveda group and 36.5 % [n = 27] in the conventional group had ≥ 1 adverse events). Ayurveda participants had a mean of 1.2 ± 1.3 adverse events (range 0–6), conventional participants 0.6 ± 1.0 adverse events (range 0–5). Both the difference in proportion (p = 0.004) as well as in the amount of adverse events (p = 0.002) were statistically higher in the Ayurveda group. Adverse events were related to the locomotor system (n = 88), the skin (n = 9) or to other reasons (n = 40). None of the intervention-related adverse events led to clinically relevant disease or required hospital treatment. A total of 4 serious adverse events occurred among 4 participants (fracture of radius, cholecystectomy, major depression episode, erysipelas; Ayurveda n = 3, conventional n = 1); none of the serious adverse events were classified as intervention-related.

      Discussion

      With this clinical trial we aimed to evaluate the effectiveness of an Ayurveda-medicine treatment approach in knee OA. After 12 weeks Ayurveda treatment led to a significantly greater and clinically relevant improvement of knee OA related complaints compared to the conventional guideline-based care with group differences maintained over 12 months.
      This RCT is the first to evaluate the effectiveness of a complex multi-modal Ayurveda-medicine approach. We performed a head-to-head comparison with multi-modal complex conventional care. The Ayurvedic treatment approach and the conventional care were carefully designed with the aim of best practice for each group and including an individual diagnosis as basis for the treatment in the Ayurveda study arm. The multi-modal Ayurveda treatment was developed in a Delphi procedure before being put into practice
      • Lachance L.L.
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      . As this trial was implemented in Germany, Western standards of care and the availability of Ayurvedic interventions in Europe were considered, including cultural, infrastructural and legal aspects into the trial methodology. To ensure comparable individualized conventional treatments, the conventional intervention was guideline-based and developed in an evidence-based consensus procedure by the study team and two board-certified external orthopedic surgeons
      • National Clinical Guideline Centre (UK)
      Osteoarthritis: Care and Management in Adults.
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      Treatment of Osteoarthritis of the Knee. Evidence-based Guideline and 2nd Edition.
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      .
      Notably, in the Ayurveda group physical and mental outcomes improved during the intervention, whereas afterwards mental improvements decreased again, but physical improvements maintained. Ayurveda represents a rather new therapy in Western countries. This was an open label study in which both care providers and participants were aware of the treatment being given, and participants had higher expectations for Ayurveda treatment compared to conventional care. Expectation is discussed as a prominent aspect of the placebo effect
      • Enck P.
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      Does how you do depend on how you think you’ll do? A systematic review of the evidence for a relation between patients' recovery expectations and health outcomes.
      . Research on a relatively Ayurvedic-naïve German population may introduce expectation bias; however, we controlled for expectations in the sensitivity analyses for this reason. While the unblinded nature formally remains a weak spot, blinding would have been not feasible, given the characteristics of the complex multi-modality Ayurvedic interventions.
      Nevertheless, one might argue that the main part of the difference between groups might be solely due to non-specific effects in the Ayurveda group. Complementary medicine methods are well known to have non-specific effects of relevant size; as expectation is the main mechanism of the placebo effect, results of this study have been controlled for expectation in the analyses
      • Linde K.
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      . Furthermore, when comparing OA with other pain conditions it seems to be less sensitive to placebo effects as responder analyzes from sham-controlled acupuncture trials suggest
      • Cummings M.
      Modellvorhaben Akupunktur–a summary of the ART, ARC and GERAC trials.
      . To summarize, we believe that the open-label design introduced some non-specific effects; however, this does not appear to explain the magnitude of the effects that we observed.
      Also, compared to data from other studies on the effectiveness of non-surgical approaches our conventional group showed similar effect sizes, while our Ayurveda group had larger effects
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      Surgery versus physical therapy for a meniscal tear and osteoarthritis.
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      .
      It is interesting to see that while the intervention lasted 12 weeks only, beneficial effects persisted up to 12 months. In the Ayurveda group this might have been particularly due to the integration of elements of active self-care into the individualized therapeutic schemes, including self-empowerment via nutritional advice, lifestyle counseling and knee yoga postures, outlasting the 12-week intervention period.
      A number of limitations apply to this study. One of them is the exclusion of individuals with obesity ≥ WHO grade II; however this played a minor role, since less than 5 individuals were excluded due to this criterion during the screening process.
      Moreover, no comparison with intra-articular corticosteroids was done, since in Germany many patients refuse this treatment; being aware that our approach thus reduces generalizability to other countries, we excluded them with the aim of reducing selection bias
      • Witt C.M.
      • Michalsen A.
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      • Morandi A.
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      • 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.
      . Furthermore, the medication dosage was adapted to reduce the risk of side effects such as gastrointestinal bleeding.
      The consultation duration differed between the groups. However, this reflects the usual care setting of both systems: reducing time in the Ayurveda group would not have allowed adequate treatment while increasing conventional treatment time would have introduced artificial settings
      • Witt C.M.
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      • Roll S.
      • Morandi A.
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      • 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.
      .
      In conventional care, patients not responding well to treatment often become interested in complementary and alternative medicine. This could have introduced bias towards Ayurveda. One method to reduce this bias could have been to recruit only incident cases of knee OA. However, in turn this also would have introduced an artificial setting, since Ayurveda is not seen as first line treatment.
      For ethical reasons Ayurveda participants were allowed to take conventional rescue medication. Because of this we decided to follow a superiority and not a non-inferiority or equivalence hypothesis. However, only 19% in the Ayurveda group compared to 81% in the conventional group used pain medication, suggesting that Ayurveda might be an option to reduce pain medication.
      In this study the botanical/herbal medical options of Ayurveda medicine suggested for treatment of osteoarthritis could not be fully explored due to legal restrictions in Germany, while Ayurvedic safety aspects remain controversial
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      Lead, mercury, and arsenic in US- and Indian-manufactured Ayurvedic medicines sold via the Internet.
      . Despite this, the inclusion of a full-fledged botanical treatment could have led to even more pronounced effects; In a preceding review and meta-analysis we identified 33 trials evaluating the use of Ayurveda for OA
      • Kessler C.S.
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      • Michalsen A.
      • Cramer H.
      Ayurvedic interventions for osteoarthritis: a systematic review and meta-analysis.
      , most of them had methodological limitations. In contrast to our study
      • Witt C.M.
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      • 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.
      , no previous trial used multi-modal treatment, although such an approach reflects routine practice in Ayurvedic care. Most trials evaluated standardized interventions with single botanicals. A RCT on rheumatoid arthritis demonstrated that individualizing Ayurvedic botanicals can be incorporated in RCTs
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      Double-blind, randomized, controlled, pilot study comparing classic ayurvedic medicine, methotrexate, and their combination in rheumatoid arthritis.
      .
      Also, the authors were limited in providing information to the readers on how Ayurvedic treatment was individualized for participants with varying severity of knee osteoarthritis and body constitution. The authors realize that this information is of importance in replicating the results of the study to some extent. However, the authors plan to provide additional information on how treatments were individualized in a separate case-publication with teachable cases from this RCT.
      The study design could serve as a blueprint for future trials on whole medical systems. Since several questions remain unanswered, particularly related to cultural transmigration of Ayurveda and economic aspects of complex Ayurveda interventions, future research should address qualitative analyses, health economic aspects and interdisciplinary approaches in addition to well planned RCTs in order to further prove the effectiveness of Ayurvedic medicine.

      Conclusions

      Results showed that Ayurveda led to significant and clinically relevant improvements in disease-specific symptom-reduction after 12 weeks of treatment compared with conventional care with most effects lasting over 12 months. However, further studies should be conducted to confirm the magnitude of the effect and to clarify the role of the different treatment components and of non-specific effects. The individualized Ayurvedic approach might contribute to more integrative and personalized OA care.

      Author contributions

      CW, AM, AntM, SG and CK conceptualized the research project, developed the methodology and the trial protocol. CW, AM, AntM took part in the acquisition of the financial support for the project leading to this publication. CW and AM conducted the investigation process; CK and AM coordinated the research activity planning and execution. CK, CW and AM wrote the initial draft of the manuscript. TO performed the formal statistical analysis. KD, AK, MM and ES took part in the development of the Ayurvedic treatment protocol and participated in writing and editing the manuscript. KI was responsible for the trial database software; KI and MS performed data entry and data curation and also took part in editing the manuscript.

      Competing interests

      Dr. Kessler reports personal fees from Bruno Zimmer, Germany, outside the submitted work. All other authors declare that they have no conflicts of interest: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

      Funding

      Ministry of AYUSH, Government of India.

      Transparency declaration

      A. Michalsen and C.M. Witt had full access to all of the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. They affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

      Funding statement and role of the funding source

      The study was supported by a grant from the Ministry of AYUSH, Government of India, Central Council for Research in Ayurvedic Sciences (CCRAS), Delhi, India, that had suggested a randomized trial including a conventional control group for knee OA. (Memorandum of understanding dated February 2, 2010); no other funding sources were used. All other decisions on design; data collection, analysis, and interpretation; and publication were completely independent of the funding source.

      Data sharing

      The study protocol has been published
      • Witt C.M.
      • 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.
      , the German version is available on request. Statistical code: Available from T. Ostermann (e-mail: [email protected]). Data set: Certain portions of the analytic data set are available to approved individuals through written agreements with the authors.

      Acknowledgements

      We want to thank the Ministry of AYUSH and the Central Council for Research in Ayurvedic Sciences (CCRAS) for funding the trial; thanks in particular to Secretary S. Jalaja, Secretary Nilanjan Sanyal, Dr. Gandhidas Lavekar, Dr. Ramesh Babu, Dr. M.M. Padhi, Dr. Dinesh Katoch, and Dr. Syed Hissar. We also thank the European Academy of Ayurveda in Birstein, particularly Mark Rosenberg, for the fruitful collaboration. Thanks to Dr. Manfred Wischnewsky for his valuable statistical advice. We are very grateful for the work of the participating medical personnel (Grit Bartsch, Eva Maack, Ottmar Karl, Amrita Ronniger, Chrissa Kiosse, Andrea Schultze, Michael Ehm, Stephanie Riecker, Binita Chakraborty, Dr. Ileni Donachie, Alexander Peters and his team at Sonne und Mond, Dr. Günter Niessen, Frank Ruppenthal, Barbara Ellguth, Marion Prüßing and her team, Dr. Kai Bauwens, Dr. Laif Bröcker, Dr. Matthias Müller, Dr. Ludwig Kronpaß and Dr. Uwe Kehnscherper). Special thanks also to Dr. Kalapi Patel, Dr. Manish Patel, Markus Ludwig and Karin Bachmaier for their guidance regarding treatment aspects. We are also grateful for the work of all secretaries, study nurses, students and other helpers involved in this project, in particular to Gunda Loibl, Sabine Saalfeld, Christa Müller-Aziz, Sabine Leisching, Miriam Rösner, Kathrin Otto, Karl-Heinz Krüger, Dr. Michael Jeitler, Kenneth Spiteri and Dania Schumann. Dr. Rainer Lüdtke and Stephanie Roll gave valuable statistical advice. Thanks also to Jutta Maier, Gayatri Puranik, Bruno Zimmer, Ranjit Puranik, Dr. Hedwig Gupta, Dr. Bernhard Uehleke and Dr. Harsha Gramminger for their advice and support related to massage oils and nutritional supplements. Carina Bühner entered the data from the embedded diagnostic study. Thanks also to Roy Noack, Björn Teuteberg, Dr. Stefan Willich and Dr. Benno Brinkhaus and Iris Bartsch for facilitating administrative processes at Charité University and Immanuel Hospital. Last but not least we would like thank all participants for participating in this trial.

      Appendix A. Supplementary data

      The following are the supplementary data related to this article:

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