key: cord-0980502-b9fhie4l authors: Gohir, Sameer Akram; Eek, Frida; Kelly, Anthony; Abhishek, Abhishek; Valdes, Ana M. title: Effectiveness of Internet-Based Exercises Aimed at Treating Knee Osteoarthritis: The iBEAT-OA Randomized Clinical Trial date: 2021-02-23 journal: JAMA Netw Open DOI: 10.1001/jamanetworkopen.2021.0012 sha: 1940e9e24873042d226a6a71cfe049775ef0eb78 doc_id: 980502 cord_uid: b9fhie4l IMPORTANCE: Osteoarthritis is a prevalent, debilitating, and costly chronic disease for which recommended first-line treatment is underused. OBJECTIVE: To compare the effect of an internet-based treatment for knee osteoarthritis vs routine self-management (ie, usual care). DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted from October 2018 to March 2020. Participants included individuals aged 45 years or older with a diagnosis of knee osteoarthritis recruited from an existing primary care database or from social media advertisements were invited. Data were analyzed April to July 2020. INTERVENTIONS: The intervention and control group conformed to first-line knee osteoarthritis treatment. For the intervention group, treatment was delivered via a smartphone application. The control group received routine self-management care. MAIN OUTCOMES AND MEASURES: The primary outcome was change from baseline to 6 weeks in self-reported pain during the last 7 days, reported on a numerical rating scale (NRS; range, 0-10, with 0 indicating no pain and 10, worst pain imaginable), compared between groups. Secondary outcomes included 2 physical functioning scores, hamstring and quadriceps muscle strength, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and quantitative sensory testing. RESULTS: Among a total of 551 participants screened for eligibility, 146 were randomized and 105 were analyzed (mean [SD] age, 66.7 [9.2] years, 71 [67.1%] women), including 48 participants in the intervention group and 57 participants in the control group. There were no significant differences in baseline characteristics between the groups. At the 6-week follow-up, the intervention group showed a greater NRS pain score reduction than the control group (between-group difference, −1.5 [95% CI, −2.2 to −0.8]; P < .001). Similarly, the intervention group had better improvements in the 30-second sit-to-stand test (between-group difference, 3.4 [95% CI, 2.2 to 4.5]; P < .001) and Timed Up-and-Go test (between-group difference, −1.8 [95% CI, −3.0 to −0.5] seconds; P = .007), as well as the WOMAC subscales for pain (between-group difference, −1.1 [95% CI, −2.0 to −0.2]; P = .02), stiffness (between-group difference, −1.0 [95% CI, −1.5 to −0.5]; P < .001), and physical function (between-group difference, −3.4 [95% CI, −6.2 to −0.7]; P = .02). The magnitude of within-group changes in pain (d = 0.83) and function outcomes (30 second sit-to-stand test d = 1.24; Timed Up-and-Go test d = 0.76) in the intervention group corresponded to medium to very strong effects. No adverse events were reported. CONCLUSIONS AND RELEVANCE: These findings suggest that this internet-delivered, evidence-based, first-line osteoarthritis treatment was superior to routine self-managed usual care and could be provided without harm to people with osteoarthritis. Effect sizes observed in the intervention group corresponded to clinically important improvements. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03545048 Effects of web-based exercises on the population with knee arthritis Short title Knee arthritis and exercises Objectives [1] To test whether internet-based exercises reduce the pain in knee OA [2] To check whether internet-based exercises improve the physical activity in the patients with knee OA. [3] To explore the correlation between sleep, knee inflammation (effusion, synovial hypertrophy or/and synovial hyper vascularity) and biomarkers of insulin resistance and knee pain. Setting Primary care Sample size estimate Control and interventional arms each consisting of 67 individuals with predicted dropout rate of 10-12% A sample size of n=60 per group is necessary to achieve 75% stat power. The estimated dropout rate for exercise interventions is 12%. Therefore, a sample of 67 per arm will be recruited to produce at least 75% power. Number of participants 67 in each group and 134 in total Eligibility criteria • Arthritis in at least one knee with at least score of grade 1 or above osteoarthritis on Kellgren and Lawrence classification • Age group > 45 years • Able to use internet • Able to read and write the English language Description of interventions 20-30 minutes of gentle exercises on a daily basis for six weeks (interventional group) Control group will continue with their routine practiceadvice/support given by GP. Osteoarthritis is the most common cause of disability in the elderly population and most individuals suffering from osteoarthritis is managed in the primary care setting (1) . Knee osteoarthritis is a most common form of arthritis in the world (2) . The rate of knee arthritis is as high as that of cardiac disease and is the most common problem in the individuals over the age of 65 (3) . In the United Kingdom, 10% of 65-74-year-old individuals consult their general practitioners about osteoarthritis per year (4) . 4% population attend their general practitioners as a result of knee osteoarthritis and half of them (2%) consult their general practitioner for the first time or with the acute flare of knee arthritis (1). According to national and international guidelines, the first line treatment for osteoarthritis pain (OA) is non-surgical; exercise, information and, in relevant cases, weight loss (5-9). There is enough evidence for the effectiveness of exercises in the management of knee osteoarthritis and to improve the functional capacity of these individuals to cope better with the activities of daily living (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) . In fact, one study reported a slowdown of progressive radiographic changes of knee OA as a result of strengthening exercises (25) .There is a significant disparity on the effectiveness of different types of exercises for the knee osteoarthritis, and a combination of open and closed isotonic exercises are recommended knee osteoarthritis (26) with the exception to those individuals who find these exercises difficult and painful. In such groups, isometric exercises of knee muscles should be considered (26) . In an attempt to manage the knee osteoarthritis, one can exacerbate the symptoms of knee arthritis by following ineffective or unsafe exercises leading to poor prognosis and poor adherence to these exercises (27) , hence one should choose the exercises carefully. As knee arthritis is a significant issue in the elderly population, therefore, the less expensive community-based approach will be beneficial for these patients. There are previous studies which have assessed the efficacy of home-based exercises and reported good results (12, 14, 28) however there are only a few studies which looked at the web-based exercises on the knee arthritis (29-33). Unfortunately, most of these studies recruited patients with knee pain, and radiographic evidence of knee osteoarthritis was undermined except one study (31) . It infers that these web-based exercises can be used for knee pain which may include cases of soft tissue injuries, arthritic knee or any other reason for knee pain. However, generalising these results on the group of patients with knee osteoarthritis warrants a risk of increasing their pain just in case that those exercises are strenuous or more demanding. The aim of this study is to explore the benefits of web-based exercises in the patients with knee osteoarthritis to establish if their pain decreases after six weeks. Being a web-based set of activities, it makes it more accessible to the patients living in rural areas and should make it more cost-effective requiring no travelling time. Our study is different from the other studies as there is not a single study (to our knowledge) which has studied web-based intervention on United Kingdom population of knee osteoartsurgerhritis. Furthermore, we will endeavour to recruit only those individuals who have radiographic evidence of knee osteoarthritis. Therefore, this study will produce recommendations for the clinical setups where most of the symptomatic patients have radiographic evidence of knee osteoarthritis. We will be using a web-based exercises platform known as Joint Academy (JA) as recent pilot studies (32, 33) demonstrated promising results for this platform. This programme is based on Swedish face to face selfmanagement program known as 'Artrosskolan' (The Osteoarthritis School) which provides structured information and exercises for knee arthritis to the relevant population suffering from knee arthritis. The efficacy of it is covered elsewhere (34). The company that produced the Joint Academy platform has given consent to use their web based platform to conduct this study. We will recruit 134 individuals with the clinical evidence of radiographic knee arthritis, and these will be randomised into a control group and an interventional group (67 individuals in each group). The interventional group will get the login details for the Joint Academy (JA), and Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 they will follow the strengthening exercises for six weeks with educational material online relevant to knee osteoarthritis. They will record their pain levels on the Numerical rating scale (NRS) at baseline and at the end of the trial. The validity and sensitivity of NRS have been established numerous times (35) (36) (37) (38) (39) . Other than determining the subjective pain levels, we will use standardised quantitative sensory testing (QST) such as pressure pain threshold (PPT), temporal summation (TS) and conditioned pain modulation (CPM). Pressure Pain threshold (PPT) has been used in previous studies done on the knee arthritis and deemed to be a valid and reliable method to establish tenderness around the knee joint (40) (41) (42) (43) (44) (45) . Similarly, temporal summation (TS) has been used in previous studies (40, 43, 44, 46) to establish whether individuals have an element of central sensitisation thus amplifying their localised knee pains. Conditioned pain paradigms are commonly used to assess the function of endogenous pain inhibitory pathways in humans. In this technique, a painful test stimulus is evaluated in the absence and in the presence of a second painful (conditioning) stimulus applied to a remote region of the body. In a typically functioning nociceptive system, the amount of pain experienced with the primary test stimulus will be reduced during the presentation of the secondary conditioning stimulus (47) (48) (49) . Decreased inhibition of experimental pain is found in many patients with idiopathic pain syndromes (50) (51) (52) (53) (54) (55) (56) (57) (58) . It predicts the tendency to develop future chronic pain (59, 60) . The purpose of using QST is to establish objective data as to whether these exercises reduce the localised tenderness or global central sensitisation. We will use the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) which is widely utilised in the evaluation of Hip and Knee Osteoarthritis. It is a selfadministered questionnaire made of 24 items and consists of three subscales covering pain, stiffness and physical function. It has been used extensively and deemed to be a valid and reliable tool (61) (62) (63) (64) (65) . For the quality of life, stiffness, generalised well-being, difficulty with sleeping and understanding of the diagnosis and treatment, we will use patient-reported outcome measure 'The Arthritis Research UK Musculoskeletal Health Questionnaire' (MSK-HQ). MSK-HQ covers a broad aspect of musculoskeletal conditions, and recent studies have shown it to be reliable and valid (66, 67) . Both the 30-second sit to stand test (30CST) and the 'time up and go' (TUG) test will be used to see if patients have improved their lower limb fitness levels. 30CST has shown excellent reliability and validity (65, 68, 69) . TUG has been widely used in clinical setups and is a valid tool to assess necessary functional mobility (70) (71) (72) (73) (74) (75) (76) . In this study, we aim to assess the sleeping pattern of individuals suffering from degenerative changes of the knee and purpose is to determine whether sleeping patterns improve when the exercises for knee osteoarthritis are introduced. Disturbed sleep is a frequent complaint of people experiencing chronic pain such as those with knee osteoarthritis (OA) (77) (78) (79) (80) (81) (82) (83) . The resultant changes in sleep architecture can affect health even in the presence of apparently adequate sleep duration. For example, an insufficient amount of slow wave sleep associates with hypertension, type 2 diabetes mellitus, poor cognition and obesity (84) (85) (86) (87) (88) (89) .Sleep disturbances are present in 67-88% of people with chronic pain and ≥50% individuals with insomnia have chronic pain (85, 90) . Actigraphy will be used to assess the sleeping data which has been used widely and deemed as a valid method (91) (92) (93) (94) (95) (96) .We will also use Pittsburgh sleep quality index (PSQI) which has been used in multiple studies and validated to measure sleep disturbances (97) (98) (99) (100) (101) . We will also endeavour to assess the isokinetic strength of quadriceps to establish if these exercises improve the dynamic strength of knee extensors. Quadriceps muscles strength deficits are associated with knee osteoarthritis (102) . Isometric testing will be done at 60 and 180 degrees of flexion as done in a previous study (103) . We will also extract the blood samples at baseline and after six weeks to assess the biomarkers and to establish insulin resistance (104, 105) . A urine sample will be taken as well. Studying these parameters will help us to understand the traits of osteoarthritis, their correlation to each other and potential detrimental effects of them on the health of knee joint. This study will help us to establish whether web-based intervention can replicate the results which it has produced in Swedish population and if it does, then next target will be to assess the socio-economic benefits of this programme over the standard treatment for knee arthritis provided in the community set up in the United Kingdom. All the methods which have been mentioned above are safe, and procedures have been done previously safely at Academic Rheumatology. The purpose of this study is to establish the benefits of web-based exercises in the community-based participants with knee osteoarthritis to see if their pain decreases after six weeks. This will be undertaken primarily by randomised controlled trial in a hospital setup. 1. Carry out an exercise intervention in the individuals with osteoarthritis pain to assess the effect on sleep, central and peripheral pain measures 1. To link the changes in pain, sleep and physical activity to muscle mass, biomarkers of insulin resistance, inflammation and pain. 2. To test individualised web (or app) based delivery of exercise intervention designed specifically for OA pain in the United Kingdom population. The key advantages of the system are costs savings for the health provider and increased long-term compliance. We will be using web-based exercises platform known as Joint Academy (JA), and recent pilot studies (32, 33) demonstrated promising results. This programme is based on Swedish face to face self-management program known as 'Artrosskolan' (The Osteoarthritis School) which provides structured information and exercises for knee arthritis to the relevant population suffering from knee arthritis. The efficacy of it is covered elsewhere (34). Increased knee, hip or low back pain and one reported case of increased hypertension (106) . A multi-centre randomised controlled trial in primary care setting A single-centred randomised controlled trial in the primary care setting with participants suffering from the knee arthritis, 1:1 randomised to web based exercises or usual care. Participants will undergo computer-generated stratified randomisation by a statistician at Academic Rheumatology using the https://sealedenvelope.com/ software. Generation of a randomisation schedule will include obtaining the random numbers and assigning random numbers to each subject under the specific treatment conditions. Participants will be equally allocated between treatment arms with at least n=67 per arm. Masking: Not applicable, the study is not double-blinded as participants will find out their allocated group, however, the examiner will be blinded to the intervention. As per cohort multiple randomised controlled trial design mentioned by another study (107) , individuals will have an assessment to establish their suitability for this study and once, that has been established we will randomise them in to control group and interventional group. At this occasion, individuals will find out that they belong to one group or the other and hence blinding is not possible. As the online system will be used for randomisation, therefore, code break will be kept online, and the research manager will be responsible for keeping a track if it. The study will be managed in Academic Rheumatology, Clinical Sciences Building by the Research Manager under the supervision of the Chief Investigator who has overall responsibility for the study and shall oversee all study management. The study management group will meet regularly and have documented quarterly meetings from the start of the study. The group will also monitor and supervise the progress of the study and advice on recruitment rate and unforeseen logistical issues to ensure that its objectives are achieved. The data custodian will be CI who will also have overall responsibility for the study and shall oversee all study management. The trial is expected to start in spring 2018 (May -June 2018), and enrolment will end in in the late summer of 2020. After about two months from the end of recruitment, all data will be collected. Data analysis will be performed by a PhD student supervised by CI. Six-Eight weeks including any induction period. The end of the trial will be on the last participant visit. A selection of eligible people for the study will be invited from existing databases held at Academic Rheumatology of participants with knee pain who have agreed to be contacted for future studies. Any shortfall in the recruitment will be compensated by sending study leaflet to GP surgeries. Potentially eligible people are all men and women, aged between 45 years and older, registered with the GP surgery. The screening of existing records can be done by members of their direct healthcare team for those who had x-rays and osteoarthritis of the knee had been established. The GPs will exclude anyone with a known terminal illness, severe psychiatric illness or dementia, or with any other condition or circumstance that makes them unsuitable for the study. All those individuals who are suitable for the study will be sent the study information sheet so they can have some time to think about the research and what is involved in this study. The study team in Academic Rheumatology will invite interested participants to start the study and this will be considered as the first session. The purpose of the visit will be to establish suitability by proceeding with radiographs for those who have not had x-rays in last 12 months. Those who had x-rays in previous 12 months and qualified for this study will be an exception from x-rays, and they would proceed with the assessment after signing the consent form. The research team will seek consent from the individuals who have not had X-rays, and they will go through the x-rays of a painful knee. If their x-rays demonstrate radiographic evidence of osteoarthritis (K/L= 1 or above), will be included in the study. Those individuals, where their K/L score <1, will be considered as screening failure and will be excluded from the study. All qualifying individuals will be randomised to interventional and control group. Participants will be free to leave the study at any time without giving any reason. Participants who indicate in their questionnaire that they are willing to receive information about future OA studies may withdraw this indication at any time, and this will be altered appropriately on the Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 study database. Participants will be made aware via the questionnaire that all data will remain confidential and will be anonymised before use in further analysis. It will be explained to the potential participant that entry into the trial is entirely voluntary and that their treatment and care will not be affected by their decision. It will also be explained that they can withdraw at any time, but attempts will be made to avoid this occurrence. In the event of their withdrawal, it will be explained that their data collected so far cannot be erased, and we will seek consent to use the data in the final analyses where appropriate (via the information sheet and consent form). Those who withdraw from the study will be made aware that this will not in any way affect their future care. Clinical diagnosis of knee arthritis with complaints of knee pain for 3 or more months, early morning stiffness <30 minutes, crepitus, bony tenderness, and no palpable warmth and radiographically established osteoarthritis (at least score 1 on K/L scale) Able to read and write English Able to use/access computer or tablet and have access to internet Exclusion criteria: Inability to give informed consent -(capacity levels are already established under GP care) Terminal or mental illness Neurological conditions, inflammatory joint diseases including rheumatoid arthritis, gout or calcium pyrophosphate deposition disease (CPPD), and dementia Participants with sleep apnea Acute soft tissue injury to the knee within last 3 months before recruiting Unstable heart condition or rapid fluctuations in hypertension BMI>50 All participants will provide written informed consent. The Informed Consent Form will be signed and dated by the participant before they enter the trial. The Investigator will explain the details of the trial and provide a Participant Information Sheet, ensuring that the participant has sufficient time to consider participating or not. The Investigator will answer any questions that the participant has concerning study participation. Informed consent will be collected from each participant before they undergo any interventions (including physical examination and history taking) related to the study. One copy of this will be kept by the participant, one will be kept by the Investigator, and a third will be retained in the participant's hospital records. Should there be any subsequent amendment to the final protocol, which might affect a participant's participation in the study at any part, continuing consent will be obtained using an amended Consent form which will be signed by the participant. Participants will be asked to indicate on the questionnaire whether they are willing for their contact details to be stored on a secure database in Academic Rheumatology, to enable them to be informed of future studies relating to knee pain and OA undertaken by Academic Rheumatology and the Pain Centre for which they might be suitable. Participant data will be kept up-to-date in accordance with Data Protection Act, 1998. The consent form includes an Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 optional clause asking participants to confirm whether they are happy for their personal details to be retained for this purpose -if not their contact details will be destroyed at the end of this study after it is no longer necessary to contact them. Participants seeking care for osteoarthritis will be informed of the study both orally and in writing. Those who qualify for the study will sign the informed consent and the participants will be randomised to interventional group and control group. The exception applies to those Participants who have not had knee X-rays in last 12 months. These individuals will be called to the hospital. After gaining a valid consent, knee radiographs will be taken, and their X-rays will be verified by experienced staff. Once, a definite eligibility criterion (K/L score at least 1 or above) is established in such cases, the potential participants will be randomised to interventional group and control group like the other individuals. Blinding such interventional studies are difficult to achieve as participants will establish as to in which group they are in however study will be blinded to the examining clinician. Controlled and interventional groups individuals will be recruited for this study. Interventional groups will have an assessment session with the experienced staff and NRS, QST, WOMAC, MSK-HQ, 30CST, TUG, PSQI, MSK-USS, urine and blood samples will be taken at baseline. Interventional group will shortly after that receive a link via email, which will be used to log-in to Joint Academy online portal. After log-in has been achieved, the intervention starts. It consist of a 6-week internet-based physical therapy program that provides information, exercises, contact details of a personal physiotherapist, education about lifestyle and behavioural changes. This intervention can be accessed using a smartphone, a tablet or a computer. The program encourages the physical activity by sending email prompts on a regular basis to help participants to continue during the whole treatment. Initially, participants will answer an online-questionnaire covering areas such as joint pain intensity, health-related quality of life, physical function as well as being instructed in and performing a physical test assessing lower limb strength / physical function. This questionnaire will form a part of online baseline assessment. Exercises itself consistent of knee and hip exercises along with some functional activities such as sit to stand and stairs climbing. Interventional group will be given actigraphy device (a device to monitor sleeping pattern) which is CE marked. Therefore, their sleeping pattern can be recorded quantitatively. Once exercises programme is finished in six weeks, the participants will fill in the same questionnaire and perform the physical tests, to enable evaluation. There are two face-toface meetings between participants and physiotherapist/nurse, at enrolment and after six weeks. The physiotherapist is also available via asynchronous online chat or over the phone during the 6-week study period. After six weeks, participants can continue with sustainprogram for self-management, mainly focusing on the continuation of treatment, performing the exercises regularly. Control group will continue with their routine self-management which is offered in the community setup. They will be assessed on NRS, QST, WOMAC, MSK-HQ, PSQI, 30CST, TUG, isokinetic muscles strengthen of quadriceps, urine and blood samples at baseline. Control group will also get the actigraphy to monitor sleeping pattern of that group. They will be re-assessed after six weeks on the primary objective measures to see if they have made any difference by following self-management strategies in the community. Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 The suggested study utilises a pragmatic approach, where all participants with clinical knee OA that would have been eligible for a face-to-face program are included if they can handle a computer, tablet or smartphone. To summarise, the total study duration, including recruitment and the two assessment visits, will be 12-15 months. The key stages are detailed below; • Individuals who agree to attend for a clinical assessment will participate for two appointments. This appointment will last approximately 2-3 hours. • They will be seen at the Academic Rheumatology Unit, Clinical Sciences Building, Nottingham City Hospital and will be asked to come between 8.00am and 10.00am without having had breakfast or any drink other than water. • Transport (taxi) will be arranged if required and any travel expense will be reimbursed. Our Research Nurses will get a 15ml blood sample from the participant and also ask the participant to provide a urine sample. Once blood and urine samples have been collected participants will be offered a light breakfast and drink refreshment before a brief assessment to confirm medical history and current medications. Questionnaires such as WOMAC, MSK-HQ and Numeric Rating Scale will be collected. Physiological measurements such as 30 seconds sit to stand (30CST), time up and go (TUG) and Muscle strength assessment will be taken at this point. Quantitative sensory testing to test the sensitivity to mechanical pressure and pain. Participants will be asked if they wish to donate a faecal sample and if they agree they will be given a collection kit to take home, which will be shipped back by post. Participants will be shown how to wear actigraphy device and will be familiarised with the equipment. Each participant will take one device with them, therefore, their sleeping pattern can be assessed. Participant will be expected to login to online exercises portal on daily basis and complete the exercises which consist of 30 minutes of exercises and some educational videos. A sequence of three physiological measures will be undertaken: Time up and Go: The participant will start in a seated position. The participant will stand up upon therapist's command, walk 3 meters, turn around, walk back to the chair and sits down. The time will stop when the participant is seated. The subject can use an assistive device. If the assistive device is used, it will be documented. NOTE: A practice trial will be completed before the timed trial slightly in front of the other to help maintain balance. Arms are crossed at the wrists and held against the chest. Demonstrate the task both slowly and quickly. Have the participant practice a repetition or 2 before completing the test. If a participant must use their arms to complete the test, they are scored 0. The participant is encouraged to complete as many full stands as possible within 30 seconds. The participant is instructed to fully sit between each stand. While monitoring the participant's performance to ensure proper form, the tester silently counts the completion of each correct stand. The score is the total number of stands within 30 seconds (more than halfway up at the end of 30 seconds counts as a full stand). Incorrectly executed stands are not counted. The 30-second chair stand involves recording the number of stands a person can complete in 30 seconds rather than the amount of time it takes to complete a pre-determined number of repetitions. Muscle strength Assessment: Isokinetic testing will be done at 60 and 180 degrees of flexion as done in previous study (103) and participant will be in sitting position with hips and knees strapped to keep the position standardised. PPT is a non-invasive test during which the sensitivities of the nerves are assessed by recording the smallest force applied to the skin. When this force by the surface area of the skin is applied (pressure), this will be felt as mild, temporary pain and recorded. The pressure probe used consists of a rod with an end the size of a 5p piece, mounted in a handheld device connected to a computer. The force with which the probe is pressed onto the skin is gradually increased until the participant indicates (by pressing a button) that the sensation has changed from pressure to pain. The probe is then automatically immediately taken off the skin. The probe will be used on knees, and proximal shins using a standardised protocol used in other studies within the Pain Centre. Each region will be tested three times with short rest periods between. The participants will be familiarised with the test before it is administered so that they know what to expect and how to respond. CPM will be done along with PPT testing. The reference point for PPT testing will be 3cm medial to patella on the most painful knee. Verbal instructions will be given to the participant. The Numerical Rating Scale (NRS) target will be ≥4 out of 10 from the cuff pressure. Staff/ clinician will wrap 7.5cm wide tourniquet cuff around the contralateral arm to the knee being tested. The lower rim of tourniquet cuff will be kept 3cm proximal to cubital fossa. Systolic pressure will be set to 270mmHg. After target pressure is achieved, the participant will be asked to rate sensation in the arm from 0-10. The participant will be asked to make hand grip ≥10 times until NRS of 4 will be reached. NRS rating will be asked every five hand grips. Once NRS of 4 will be achieved, the probe of algometer will be applied in the same manner as before to knee test site (during PPT testing). Once the participant presses the button, the probe will be withdrawn, and cuff will be released from the elbow. Participants will be advised to wait until cuff evoked pain subsides before re-test, and a minimum of 1 minute should be spared. PPT test will be repeated again (without the cuff now). Their difference in PPT score (with conditioningwithout conditioning) will establish the CPM effects. Positive value predicts efficient and negative value predicts in-effective CPM. The mechanical temporal summation is a non-invasive test during which repetitive mechanical stimulation is applied over a short period to get their augmented response. Increased pain response to a repeated mechanical stimulus may indicate enhanced central sensitisation. The test site will be a suprapatellar region (5 cm proximal from the central part of patella). A 256mN weighted pinprick stimulator will be used and applied perpendicular to the skin of suprapatellar region of affected knee (5cm proximal from the centre of patella). The participant Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 will be asked to rate the pain or sharpness they experience from 0-100 where 0 indicates no pain or sharpness and 100 indicates the most intense pain or sharpness imaginable. Numerical Rating Scale (NRS) with verbal descriptors will be used. The response of the participant will be recorded. The same stimulator at the same site will be applied ten times repeatedly at a rate of 1/second. The size of the site would be kept approximately 1 cm square. At the end of the series of 10 pinpricks, the participant will be asked to rate the pain or sharpness which they experience averaged over the whole series of 10 stimuli using the same NRS. The mechanical temporal summation reading will be calculated as the difference between two ratings which is second rating minus the first rating. Compliance will be judged by the online participation of individuals to follow their exercises and by the attendance of two face to face sessions. E-mail prompts are routinely sent out reminding individuals of their exercises. Furthermore, individuals will be given a contact number to contact us as to if they have any query. As the study involves two assessments only and does not involve investigational medicinal products or medical devices it is not envisaged that circumstances will arise that require termination of this study. Tibiofemoral and patellofemoral radiographs will be taken using a standardised protocol (standing posterior-anterior (PA) and skyline views) and will be scored by a single experienced observer. A Perspex Rosenberg template with lead beads is used for the standing PA view to standardising the degree of knee flexion, foot rotation and magnification (108) . PA radiographs are taken with the participant facing the x-ray tube while standing on the Rosenberg jig and leaning forwards with their thighs touching the anterior aspect of the jig, the x-ray beams passing from the posterior aspect through to the anterior aspect of the knee. Variable jigs are used for the skyline view to obtaining 30 0 of knee flexion with the participant lying in a reclined supine position on a couch Grading of radiographs for changes of OA will be based on the Kellgren and Lawrence (K/L) score (109, 110) . This study involves exposure to a very small amount of additional radiation. As part of everyday living, everyone is exposed to naturally occurring background radiation. The effective dose for this study has been estimated to be roughly equivalent to half a day of average background radiation in the UK. At this dose level, no harmful effects of radiation have been demonstrated as any effect would be too small to measure. The risk is believed to be minimal. If a participant received the highest doses, then this would give ≈1.6μSV for all exposures. Bearing in mind that practice varies between sites, other dose data suggests that doses may vary by a factor of two. Therefore we could assume a maximum of 3μSV per participant from research exposures. The sample will be stored at the premises which belongs to University of Nottingham. Whole blood (5ml) samples will be stored in a refrigerator (at -20°C). Remaining blood (10ml) will be centrifuged as soon after venesection as possible and the serum stored, with the urine, at -80C within freezers in University of Nottingham premises at the Clinical Sciences Building (CSB), City Hospital for future metabolomic studies. Excess samples (serum, urine and faeces) that remain after the study analyses have been undertaken will remain stored within the CSB for possible future research studies related to OA and/or pain provided that participants are agreeable and sign the optional clause on the consent form. These CSB facilities come within the remit of the Research Tissue Bank (DI Dr William Dunn-Licence Number 12265) where participants do not agree to the future use of the samples they will be destroyed in accordance with the Human Tissue Act, 2004. Samples will be stored in the linked anonymised format in the CSB and labelled using a randomly generated unique participant identifier to permit accurate linkage to clinical data and the consent form. The master database will be held by the CI in an encrypted password file. Whole blood may be sent to a specialist company for processing using standard protocols. Bacterial DNA will be extracted from faecal samples to identify bacterial lineages associated with pain and inflammation in OA. Faecal samples will be stored till we have all the samples (as this is optional) and then we will send it to the laboratory. Similarly, biochemical analyses may be undertaken by other academic or commercial groups. Such investigations will be undertaken on anonymised samples under usual Material Transfer Agreement arrangements. Storage of these tissues will be managed, transported and handled according to SOP HTMG 004. Companies which will be used for the analysis should process the samples within seven days upon receipt or companies with HTA licence will be considered. Associate Professor Dr Ana Valdes will oversee the statistical analyses. The data will be entered into MS Access and analysed using SPSS (Statistical Packages for Social Scientists, version 19) . The results of the study will be available to the study management group. All data will be stored in Academic Rheumatology and will be backed up on the University of Nottingham servers. Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 We are anticipating at least 60 individuals in each study arm at the closure of the study. A recent systematic review of 44 high-quality exercise trials for knee OA pain (3537 participants) (106) found an average effect of 12/100 VAS points corresponding to 0.49 standard deviations. A sample size of n=60 per group is necessary to achieve 75% stat power. The estimated dropout rate for exercise interventions is 12%, therefore, a sample of 67 per arm will be recruited to achieve at least 75% power. Increase in the knee, hip or back pain are possible adverse effects (106) . One case of raised hypertension has been reported by a previous study (111) . Participants will be asked to contact the study site immediately in the event of any serious adverse event. Any adverse event will be recorded and closely monitored until resolution, stabilisation or until it has been shown that the study treatment / intervention is not the cause. Participants can contact physiotherapists (SG) if there is any adverse event. The CI shall be informed immediately of any serious adverse events and shall determine seriousness and causality in conjunction with any treating medical practitioners. Any serious adverse event (s) related to this study will be recorded and reported to the REC as part of annual reports. Unexpected serious adverse events will be reported within timeframes to the REC and CI will be responsible for all adverse event reporting. Participant's GPs will not be informed that their patient has agreed to participate in the study. The study will not be initiated before the protocol, consent forms and participant information sheets have received approval / favourable opinion from the Research Ethics Committee (REC), and the respective National Health Service (NHS) Research & Development (R&D) department. Should a protocol amendment be made, that requires REC approval, the changes in the protocol will not be instituted until the amendment and revised informed consent forms, and participant and GP information sheets (if appropriate) have been reviewed and received approval / favourable opinion from the REC and R&D departments. A protocol amendment intended to eliminate an apparent immediate hazard to participants may be implemented immediately notifying the REC as soon as possible and approval is requested. Minor protocol amendments only for logistical or administrative changes may be implemented immediately, and the REC will be informed. The process for obtaining participant informed consent will be in accordance with the REC guidance, and Good Clinical Practice (GCP) and any other regulatory requirements that might be introduced. The investigator or their nominee and the participant shall both sign and date the Consent Form before the person can participate in the study. The participant will receive a copy of the signed, and dated forms and the original will be retained in the Study records. The decision regarding participation in the study is entirely voluntary. The investigator or their nominee shall emphasize to them that consent regarding study participation may be withdrawn at any time without penalty or affecting the quality or quantity of their future medical care, or loss of benefits to which the participant is otherwise entitled. No study-specific interventions will be done before informed consent has been obtained. The investigator will inform the participant of any relevant information that becomes available during the course of the study and will discuss with them, whether they wish to continue with the study. If applicable, they will be asked to sign revised consent forms. If the Consent Form is amended during the study, the investigator shall follow all applicable regulatory requirements pertaining to approval of the amended Consent Form by the REC and use of the amended form (including for ongoing participants). Each participant will be assigned a study identity code number, and this will be used on the study forms as well as other trial documents and the electronic database. This will be a randomly generated unique participant identifier. An additional identifier will be sued to allow validation of participants ID and prevent number being transposed. This additional identifier will consistent of participant's initials at the end of unique participant identifier number. Study forms will be treated as confidential documents and held securely in accordance with regulations. The investigator will make a separate confidential record of the participant's name, date of birth, local hospital number or NHS number, and Participant Study Number, to permit identification of all participants enrolled in the trial, in accordance with regulatory requirements and for follow-up as required. Study forms shall be restricted to those personnel approved by the Chief or local Principal Investigator and recorded in a Study Personnel Log. All paper forms shall be filled in using a black ballpoint pen. Errors shall be lined out but not obliterated by using correction fluid and the correction inserted, initialled and dated. The Chief or local Principal Investigator shall sign a declaration ensuring the accuracy of data recorded in the study form. Each participant will be assigned a unique study identification code number for use on the samples, consent forms and other study documents and the electronic database. Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 Source documents shall be filed at the investigator's site and may include but are not limited to, consent forms, study records, field notes, interview transcriptions and audio records. A study form may also completely serve as its own source data. The study form and all source documents, including progress notes and copies of laboratory and medical test results, shall be made be available at all times for review by the Chief Investigator, Sponsor's designee and inspection by relevant regulatory authorities. All trial staff and investigators will endeavour to protect the rights of the trial's participants to privacy and informed consent and will adhere to the Data Protection Act, 1998. The study forms will only collect the minimum required information for the purposes of the trial. Study forms will be held securely, in a locked room, or locked cupboard or cabinet. Access to the information will be limited to the trial staff and investigators and relevant regulatory authorities (see above). The computer held data including the trial database will be held securely and password protected. All data will be stored on a secure dedicated web server. Access will be restricted by user identifiers and passwords (encrypted using a one-way encryption method). Information about the trial in the participant's medical records / hospital notes will be treated confidentially in the same way as all other confidential medical information. Electronic data will be backed up every 24 hours to both local and remote media in encrypted format Insurance and indemnity for clinical study participants and study staff are covered within the NHS Indemnity Arrangements for clinical negligence claims in the NHS, issued under cover of HSG (96)48. There are no special compensation arrangements, but study participants may have recourse through the NHS complaints procedures. The University of Nottingham as research sponsor indemnifies its staff, research participants and research protocols with both public liability insurance and clinical trials insurance. These policies include provision for indemnity in the event of a successful litigious claim for proven non-negligent harm. Study conduct will be subject to systems audit for inclusion of essential documents; permissions to conduct the study; CVs of study staff and training received; local document control procedures; consent procedures and recruitment logs; adherence to procedures defined in the protocol (e.g. inclusion / exclusion criteria, random selection of suitable participants for Phase II and Phase III, timeliness of visits); accountability of study materials and equipment calibration logs. Monitoring of study data shall include confirmation of informed consent; source data verification; data storage and data transfer procedures; local quality control checks and Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 procedures, back-up and disaster recovery of any local databases and validation of data manipulation. This will be managed by the direct study team. Entries on study forms will be verified by inspection against the source data. A sample of the forms (10%) will be checked on a regular basis for verification of all entries made. In addition, the subsequent capture of the data on the study database will be checked. Where corrections are required these will carry a full audit trail and justification. Study data and evidence of monitoring and systems audits will be made available for inspection by the REC as required. In compliance with the ICH/GCP guidelines, regulations and in accordance with the University of Nottingham Code of Research Conduct and Research Ethics, the Chief or local Principal Investigator will maintain all records and documents regarding the conduct of the study. These will be retained for at least seven years or for longer if required. If the responsible investigator is no longer able to maintain the study records, a second person will be nominated to take over this responsibility. The study master file held by the Chief Investigator on behalf of the Sponsor shall be finally archived at secure archive facilities at the University of Nottingham. This archive shall include study databases and associated meta-data encryption codes. The Sponsor reserves the right to discontinue this study at any time for failure to meet expected enrolment goals, for safety or any other administrative reasons. The Sponsor shall take advice as appropriate in making this decision. Individual participant medical or personal information obtained as a result of this study are considered confidential, and disclosure to third parties is prohibited. Participant confidentiality will be further ensured by utilising identification code numbers to correspond to treatment data in the computer files. Data generated as a result of this study will be available for inspection on request by the participating physicians, the University of Nottingham representatives, the REC, local R&D Departments and the regulatory authorities. The study results will be submitted to Arthritis Research UK, regulatory authorities, and peerreviewed journals for publication. In addition, the results will be presented at national and international conferences. Study participants' identity will not be disclosed when publishing the results. Study participants will also be informed of the results if requested. actigraphy as a good non-invasive alternative to polysomnography and saw no problem with using the device for 6 weeks. On 17/05/2017 6 representatives from the PPI MSK group were asked about exercise interventions and were all supportive of this. They were also asked about the extraction of synovial fluid from their joints. Five out of six said they would not have a problem with this if it was performed by a specialist using ultrasound to guide the needle, which is why this is an optional part of the protocol. The latest versions of the participant facing documentation (PIS, consent form, invitation letter and flyer) has all been forwarded to three PPI representatives who have reviewed and commented on it. Osteoarthritis is the most common cause of disability in the elderly population and most individuals suffering from osteoarthritis is managed in the primary care setting (1). Knee osteoarthritis is the most common form of arthritis in the world (2) . The rate of knee arthritis is as high as that of cardiac disease and is the most common problem in the individuals over the age of 65 (3) . In the United Kingdom, 10% of individuals between the ages of 65 and 74 consult their general practitioners about osteoarthritis every year (4). 4% of general population see their general practitioners as a result of knee osteoarthritis, and half of them (2%) consult their general practitioner for the first time or with an acute flare of knee arthritis (1). According to national and international guidelines, the first line of treatment for osteoarthritis pain (OA) is non-surgical; exercise, information and, in relevant cases, weight loss (5) (6) (7) (8) (9) . There is sufficient evidence for the effectiveness of exercises in the management of knee osteoarthritis and to improve the functional capacity of these individuals to cope better with the activities of daily living (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) . In fact, one study reported a slow-down of progressive radiographic changes of knee OA as a result of Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 strengthening exercises (25) . There is a significant disparity on the effectiveness of different types of exercises for the knee osteoarthritis, and a combination of open and closed isotonic exercises are recommended knee osteoarthritis (26) with the exception to those individuals who find these exercises difficult and painful. In such groups, isometric exercises of knee muscles should be considered (26) . In an attempt to manage the knee osteoarthritis, one can exacerbate the symptoms of knee arthritis by following ineffective or unsafe exercises leading to poor prognosis and poor adherence to these exercises (27) , hence the need to choose the exercises carefully. There are no standardised exercise programs for knee OA in the United Kingdom. Arthritis Research UK (ARUK) recommend knee exercises for knee pain which is a generic term and covers soft tissue injuries (28) . These exercises are normally recommended by the general practitioners as the first line of protocol when they consult someone with the knee pain. If these exercises fail to make remarkable progress, individuals with knee OA are referred to the Physiotherapy department. As there is no standardised protocol, therefore various exercises are given by the physiotherapists which vary in term of contents, intensity and duration. These exercises may help some individuals and may not help others. One example is that a patient may get recommended generic knee exercises which may help individuals with knee OA, however, may flare up the pain in the individuals with the patellofemoral joint syndrome or vice versa. Therefore, there is a need for standardised exercises to address knee OA pain which can ideally be accessed online. The exercise programme which we will use is a part of the web-based exercises which is derived from the Supported Osteoarthritis Self-Management Programme (SOASP) developed in Sweden. In the SOASP, scientific evidence for information and exercise in conjunction with osteoarthritis was put into clinical practice. From 2008 until January 2017, around 75,000 patients had participated the SOASP, 2339 physiotherapists and occupational therapists were educated to hold the Supported Osteoarthritis Self-Management Programme, and today SOASP is offered in 700 units all over Sweden (https://boa.registercentrum.se/boa-in-english/better-management-of-patients-withosteoarthritis-boa/p/By_o8GxVg). This intervention has been rated as good or as very good by 94% of patients and has an excellent safety profile and acceptability (29). Because of the high prevalence of knee arthritis, strategies to deliver exercise interventions that are both efficacious and cost-effective becomes a priority. Some of the issues relating to the delivery of exercise interventions for knee OA include compliance, accessibility to clinics for people with mobility problems and cost of delivery of such services. There are previous studies which have assessed the efficacy of home-based exercises and reported good results (12, 14, 30 ) however very few studies looked at a web-based delivery of exercises on the knee arthritis (31) (32) (33) (34) (35) . Unfortunately, most of these studies recruited patients with knee pain, and radiographic evidence of knee osteoarthritis was only assessed in a single study (33) . Some of these exercises can be used for non-specific knee pain including cases of soft tissue injuries, arthritic knees, patellofemoral syndrome or any other reason for knee pain. However, generalising these results on the group of patients with knee osteoarthritis warrants a risk of increasing their pain just in case that those exercises are strenuous or more demanding. Therefore, there is a need for an exercise programme which is specific for osteoarthritis and economical so individuals can access them in their own homes. Most individuals lose interest in exercising regularly after they finish with their physiotherapy intervention. There are various reasons for this including adjusting lifestyle to include these exercises, pain during the exercises, lack of motivation and lack of professional to monitor the progress (36) (37) (38) . So, there is a need for the Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 intervention which keeps them motivated and improves the compliance and that actually encourages forming a habit of regular exercising. Knee OA pain is accompanied by a number of additional disturbances that influence the individual's health which we also propose to study in conjunction with pain relief due to exercise. There is well known link between sleep disturbances and chronic pain and both epidemiological studies (39) (40) (41) and experimental studies (42) (43) (44) (45) (46) have established a link between disturbed sleep and knee OA. These studies confirmed that individuals with OA have the higher suffering from sleep disturbances. Sleep disturbances have been recognised as an important factor in determining the perception of pain in individuals (46) . A relationship between sleep disturbances and pain severity in knee OA patients is usually explored, and sleep disturbances such as shortened sleep duration and fragmented sleep (39) have been associated with increased sensitivity to pain in OA patients and consequently with decreased quality of life (41) . Therefore, studying the sleeping pattern is highly relevant if we are discussing a successful online exercise programme for knee OA. Recent epidemiological and clinical studies have also underlined that metabolic syndrome (MetS) has the most significant impact on the initiation and severity of OA (47) (48) (49) (50) (51) . Metabolic triggered inflammation, also known as meta-inflammation (52) can be a result of abnormalities in body composition, adipokines, cytokines, lipids and vitamin D and has been associated with the pathogenesis of OA (50) . However, the intricate links between exercises, sleep, pain, metabolic syndrome and OA are not fully understood. To date, the relationship between improvements in pain due to exercise for pain relief and other changes related to health parameters that have been linked to OA or chronic pain has not been explored. Specifically, the effects of exercise for knee pain relief on sleep, biomarkers of inflammation and insulin resistance is unknown. We aim to study these parameters and establish the link between exercises for knee OA and these parameters. This study aims to explore the benefits of internet-based exercises in the patients with knee osteoarthritis to establish if their pain decreases after six weeks. Being a web-based set of activities, it makes it more accessible to the patients living in rural areas or who have difficulty assessing a clinic and should make it more cost-effective and by cutting down the traveling time and freeing up the time of the physiotherapists. Another reason is to establish if we can have a standardised intervention for knee OA which keeps the individuals motivated, and they can manage their pain. Lastly, we will endeavour to explore the complicated relationship between chronic pain, sleep, biomarkers of inflammation and knee osteoarthritis. Our study is different from the other studies as there is not a single study (to our knowledge) which has studied web-based intervention on United Kingdom population of knee osteoarthritis. Furthermore, we will endeavour to recruit only those individuals who have radiographic evidence of knee osteoarthritis. The purpose of these inclusion criteria is to rule out other causes of knee pain such as soft tissue injuries or patellofemoral syndrome and to establish the efficacy of this programme specifically in individuals with knee OA. Therefore, this study can help in generation of recommendations for the clinical setups where most of the symptomatic patients have radiographic evidence of knee osteoarthritis. Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 The primary aim of the study is to test the effect of an internet-based exercise treatment program on pain, measured on a Numerical Rating Scale (NRS), in knee OA. Secondary aims of the study are to test the effect of an internet-based exercise treatment program on the following outcomes: 1. Sleep 2. Pain (Pressure pain threshold -PPT, Temporal summation -TS, and conditional pain modulation -CPM) 3. Inflammatory markers on ultrasound (Synovial fluid, synovial hypertrophy and hyper vascularity) (MSK-USS) 4. Muscle Thickness Assessment (MTA) of Vastus Lateralis Oblique (VLO) using MSK-USS 5. Maximum Voluntary Contraction (MVC)-isokinetic contraction of Quadriceps muscle 6. Biomarkers of insulin resistance 7. Physical functioning (Timed up and go test, 30-second sit to stand test) 8. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) 9. Pittsburgh Sleep Quality Index (PSQI) 10. General health questionnaire (MSK-HQ) The iBEAT-OA study is a randomised controlled trial in the primary care setting at Nottingham with participants suffering from knee osteoarthritis, 1:1 randomised to web-based exercises or 'usual care'. The study has been approved by the sponsor, Research Ethical committee (REC) and Health Research Authority (HRA). Participants will undergo computer-generated stratified randomisation by a statistician at Academic Rheumatology using the https://sealedenvelope.com/ software. Generation of a randomisation schedule will include obtaining the random numbers and assigning random numbers to each subject under the specific treatment conditions. Participants will be equally allocated between treatment arms with at least n=67 per arm. As the online system will be used for randomisation, therefore, code break will be kept online, and the research manager will be responsible for keeping a track of it. As per cohort multiple randomised controlled trial design mentioned by another study (54) , individuals will have an assessment to establish their suitability for this study and once that has been established, we will randomise them into control group and interventional group. At this occasion, individuals will find out that they belong to one group or the other and hence blinding is not possible. Because the lack of masking might affect the motivation of participants randomised into the control arm, individuals in the control arm will be offered access to the web-based exercise programme after the six weeks of the study, if they wish to use it to avoid a nocebo effect in this group. Blinding such interventional studies are difficult to achieve as participants will establish as to in which group they are in, however, the examiner will be blinded to the intervention. Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 The sample size calculation is based on a standardised effect size of 0.49, corresponding to a group difference in primary outcome VAS pain of 12 points on a scale of 0-100 (corresponding to a mean difference of 1,2 points on a 1-10 NRS scale). This difference was found in a recent systematic review of 44 high-quality exercise trials for knee OA pain (3537 participants) (56) . With this estimated effect, 60 participants in each group is required to achieve 75% power to reject the null hypothesis, with alpha level set to 0.05. We hypothesise that i-BEAT OA is superior to "usual care" in primary care setup, in order to decrease pain reported by OA patients. No interim analysis was planned or performed. As there was no adverse event expected, the trial was not planned to be stopped early. The final analyses will be performed once the trial has stopped and all follow up data has been collected. All outcome variables were collected at baseline, and at follow-up (6 weeks post baseline) in both arms. However, trial was stopped on 19 th March 2020 due to the COVID-19 pandemic resulting in having only 105 eligible participants completing both visits. Alpha level will be set to 0.05. 95% confidence intervals will be presented (if data allows for parametric analyses). Adjustments for multiplicity will not be performed. However, primary outcome is defined and will be the main focus for the results interpretation. Remaining analyses will be considered exploratory, and interpreted in light of the general pattern of effects rather than solely based on individual p-values. Adherence to the i-BEAT OA will be defined as percentage patient completed activities of those distributed by the platform per week. Number of non-compliant participants will be reported. Analyses will be based on the Intention to treat (ITT) population. Since there are no risks associated with i-BEAT OA, safety analyses will not be performed. Screening Data A selection of eligible people for the study will be invited from existing databases held at Academic Rheumatology, City Hospital Nottingham of participants with knee pain who have agreed to be contacted for future studies. Any shortfall in the recruitment will be compensated by sending study leaflet to GP surgeries. Exercise intervention for knee arthritis Final Version 1.0 26 th Apr 2018 between group comparisons, Mann-Whitney test will be applied and for the within group comparison, Wilcoxon signed rank test will be used. Results will be presented as median scores (IQR) and p-values. No adjustment for baseline scores will be performed, as the non-parametric tests do not allow for this. Missing data will be handled by group mean imputation. No risks are associated with the intervention; however we will record any serious adverse event or harms and will report in publications. The data will be analysed using StatsDirect V3.2.10, SigmaXL 8.15 and SPSS v24 Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care Weight and osteoarthritis. The American journal of clinical nutrition The effects of specific medical conditions on the functional limitations of elders in the Framingham Study Office of Population C, et al. 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The Journal of bone and joint surgery American volume Radiological Assessment of Osteo-Arthrosis Classifications in Brief: Kellgren-Lawrence Classification of Osteoarthritis Does hydrotherapy improve strength and physical function in patients with osteoarthritis-a randomised controlled trial comparing a gym based and a hydrotherapy based strengthening programme Exercise intervention for knee arthritis Final Version 1 Exercise intervention for knee arthritis Final Version 1 Age and BMI will be presented as mean (SD). KL score will be presented as median, mean (SD), and proportion A single device was given to each participant during baselines assessment session and was collected back during the follow-up session Pain sensitivity (Pressure pain thresholds -PPT, Temporal summation -TS, and conditional pain modulation -CPM) Inflammatory markers on ultrasound (Synovial fluid, synovial hypertrophy and hyper vascularity Muscle Thickness Assessment (MTA) of Vastus Lateralis Oblique (VLO) using MSK-USS. This was dropped from the study due to lack of Panoramic view on Toshiba Aplio SSA-770A machine as the machine did not allow to find the midportion of the VLO to have valid and repeatable measurements Maximum Voluntary Contraction (MVC)-isokinetic contraction of Quadriceps and hamstring muscles using Computer Sports Medicine, Inc (CSMI) HUMAC / NORM Testing and Rehabilitation System Physical functioning (Time up and go test, 30-second sit to stand test) General health questionnaire Potentially eligible people will be all men and women, aged between 45 years and older, registered with the GP surgery. The screening of existing records can be done by members of their direct healthcare team for those who had x-rays and osteoarthritis of the knee had been established. The GPs will follow the inclusion and exclusion criteria. Recruitment will be presented as CONSORT flow diagram. This will be presented in the article as per CONSORT guidelines. Loss to follow up will be presented as proportion of participants in each group not responding to the 6 week follow up survey. Descriptive baseline characteristics regarding age, sex, Body Mass Index (BMI) and Kellgren-Lawrence (KL) score will be presented for each group. INCLUSION The distribution for each difference score will be evaluated. If the score follows an approximately normal distribution with no apparent outliers, between group differences will be analysed through ANOVA with adjustment for baseline scores (ANCOVA). Due to the randomisation, no systematic differences between groups are expected and hence no control for further "confounding" will be performed. Results for the between group comparison will be presented as "difference in mean difference" with accompanying 95% confidence intervals.Within group differences from baseline to follow up will be evaluated through pre-post mean difference with accompanying 95% CI. Differences/changes with confidence intervals not covering "0" will be considered statistically significant. Standardised effect sizes (Cohen's D) will be computed (mean difference/baseline SD).If the difference scores clearly deviate from a normal/symmetric distribution, the comparisons will instead be performed through non-parametric analyses. For the