Osteoarthritis and Cartilage 23 (2015) 761e771

Review

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hip osteoarthritis N.E. Lane y *, M.C. Hochberg z, M.C. Nevitt x, L.S. Simon k, A.E. Nelson ¶, M. Doherty #, Y. Herontin yy, K. Flechsenhar zz y University of California at Davis School of Medicine, Sacramento, CA 95817, USA z University of Maryland, School of Medicine, Baltimore, MD 21201, USA x University of California at San Francisco, San Francisco, CA 94143, USA k SDG LLC, Cambridge, MA 02138, USA ¶ University of North Carolina, Chapel Hill, NC 27599, USA # University of Nottingham, School of Medicine, Nottingham, UK yy Bone and Cartilage Research Unit, Department of Physical Therapy and Rehabilitation, Marche-en-Famenne, Belgium zz Sanofi, Research and Development, Bio Innovation, Frankfurt, Germany

a r t i c l e i n f o

s u m m a r y

Article history: Received 9 January 2015 Received in revised form 6 March 2015 Accepted 9 March 2015

The ability to assess the efficacy and effectiveness of an intervention for the treatment of hip osteoarthritis (OA) requires strong clinical trial methodology. This consensus paper provides recommendations based on a narrative literature review and best judgment of the members of the committee for clinical trials of hip OA. We provide recommendations on clinical trial design, outcome measures, including structural (radiography), and patient and physician global assessments, performance based measures, molecular markers and experimental endpoints including MRI imaging. This information can be utilized by sponsors of trials for new therapeutic agents for hip OA. © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Keywords: Clinical trial Osteoarthritis Hip

Introduction Over the past decade, there have been important advances in the understanding of the pathophysiology of osteoarthritis (OA), including OA of the hip. In addition, there are a number of novel therapeutic agents that are being evaluated for the treatment of hip OA. Since hip OA can affect up to 10% of the elderly population, there is a significant need to develop strong methodology for clinical trials of hip OA1. The Osteoarthritis Research Society International (OARSI) established a Task Force to address the issue of clinical trial guidelines for OA in 20122. The intent of the Task Force was to bring together the ideas of academic and clinical physicians, epidemiologists, researchers in the pharmaceutical industry and other interested experts on the conduct of clinical trials generated by the relevant active working groups, and to add sufficient detail to be of help to any party involved in the design of clinical trials2. This paper serves to update the recommendations for clinical trials in patients with hip OA published in 19962 by providing recommendations on clinical trial design, outcome measures, and an assessment of * Address correspondence and reprint requests to: N.E. Lane, University of California at Davis School of Medicine, Sacramento, CA 95817, USA. E-mail address: [email protected] (N.E. Lane).

symptom modifying medications trials. Issues regarding imaging are considered both herein as well as in an accompanying article on hip OA imaging in this issue. The methodology that the group utilized to develop these recommendations is now described. Initially our group had one group meeting. This was followed by a series of teleconferences. All group members reviewed both the individual sections of the recommendations and the entire manuscript and provided feedback. Many of the recommendations are evidence-based and supported by the published literature; the remainder are based on best judgment of the members of the committee.

Different trial objectives for hip OA Osteoarthritis of the hip is a significant problem in the U.S. and Europe, with nearly 7e15% of elderly subjects with radiographic and clinical manifestations of the disease. Patients with hip OA are at increased risk for pain on movement, weight bearing pain as well as nighttime pain. This commonly leads to loss of function, increased isolation and with decreased activity an increased risk of hypertension, cardiovascular disease and death. Patients are more likely to seek medical care in the setting of symptoms as well as

http://dx.doi.org/10.1016/j.joca.2015.03.006 1063-4584/© 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

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activity and/or functional limitation1. The complexities of measuring the importance of pain and how it relates to functional status is a critical component of the outcomes to be measured in clinical trials of interventions to treat symptomatic hip OA3. Standard trial designs Standard trial designs for measurement of these outcomes include parallel-group, randomized controlled trials (RCTs) comparing study intervention with placebo or standard of care (SOC) and can be designed as superiority or non-inferiority trials. Randomized withdrawal trials in which an active intervention is compared to a group of subjects that were randomly withdrawn from the intervention have also been used. . Open-label experiences may be informative, but the importance of randomization and blinding cannot be overemphasized. Furthermore, good study conduct is crucial for an understandable outcome. It is critical to minimize missing data; an intention to treat analysis is usually required, particularly for drug or device regulatory approvals, and for applying instruments for measured outcomes, which are validated and well understood. For clinical trials to be used for pivotal approval for drugs to treat the signs and symptoms of hip OA, regulatory agencies prefer assessment of pain, function and patient assessment of global impact, and all three must be significantly superior as compared to SOC or placebo4. However, in the US, drugs may be approved for the treatment of OA pain by demonstrating a clinically meaningful and statistically significant pain response while the functional assessment and patient global need not be statistically significantly better, but they cannot worsen5,95. For device approvals, the importance of efficacy is secondary to the safety of the device from the regulatory agency perspective; however, to determine efficacy in terms of pain relief and functional improvement, a numerical rating scale (NRS) for pain, the Western Ontario and McMasters Universities (WOMAC) pain and function measures as well as the Hip Disability and Osteoarthritis Outcome Score (HOOS) outcome instrument have been used6. These instruments are described in more detail in Section D. Study subject requirements: entering patients in hip OA clinical trials This section addresses several aspects of the study design, including the protocol, admission criteria, and selection of the study population and the definition of what is to be studied. Overview of the protocol The study protocol should be divided into sections that encompass background information, rationale for the study, the question(s) being asked, size and site(s) of the study, method of patient selection (including inclusion and exclusion criteria), the study methods including clearly defined primary and secondary outcome variables, specific measures to be performed at each visit, drug dispensing format, method of reporting adverse events, statistical analysis and regulatory issues (including drug accountability, institutional requirements, etc.). The protocol (Table I) should carefully define the investigators, their study sites, the method of randomization, patient monitoring procedures, technical aspects of imaging techniques, laboratory tests, methods of documenting adverse events, methods of blinding, method of documenting medication intake for each patient (active drug, placebo, rescue analgesia), and the method of maintaining the medication log for each participating center.

Table I Recommended requirements for the study protocol Definition of the Investigators and their roles in the study Study Sites Method of Randomization Patient monitoring procedures Technical aspects of Imaging Techniques Laboratory tests Methods to Document Adverse Events Method of Blinding Documentation of Medication Intake Method of Maintaining the Medication Log for each Participating Center

Demographics Subject characteristics and other demographic information recorded should include age (date of birth), weight, height, and body mass index (BMI), gender, race/ethnicity, co-morbid medical conditions, medication history, marital status, type of insurance and years of formal education, history of participation in elite, extreme or professional sports should be elicited. Diagnosis Criteria for diagnosis of hip OA should be clearly stated. Patients should fulfill criteria for the classification of OA, such as those published by the American College of Rheumatology (ACR)7. The disease should be classified as idiopathic (primary) or secondary. Study populations should be as homogenous as possible with regard to the presence of idiopathic (primary) or secondary OA1,7. If patients with secondary OA are studied, the underlying condition should be specified and should be the same in all patients (e.g., post-traumatic OA, femoroacetabular impingement [FAI]). It is suggested that in studies of patients with idiopathic OA, exclusions should include not only inflammatory arthropathies but also secondary OA of the study joint. Baseline information about the index joint helps to characterize the study population and provides reference data for assessing how variables of interest have changed during the course of treatment. This should include measurement of pain and self-reported function using a reliable, valid and responsive instrument such as the WOMAC8 OA index or Hip Osteoarthritis Outcome Score (HOOS)12. See Section D for further description of outcome instruments. Radiographs The radiographic severity of OA in each patient should be quantified and documented using either a valid radiographic scale (e.g., Kellgren and Lawrence grade9 or Croft scale10) or grading of specific individual radiographic features (e.g., OARSI Atlas11). The radiographic entry criteria should also be appropriate for the specific study design. For example, a cohort that included advanced severity might be appropriate in studies of a symptom modifying drug while a cohort limited to minimal severity would be more appropriate for studies of a structure modifying drug intended to slow progression. Study population Inclusion criteria should be clearly defined and should specify the population to be studied by age, clinical diagnosis and classification criteria, severity of symptoms, and radiographic grade (vide supra). Exclusion criteria should similarly be clearly defined with regard to concomitant diseases, concomitant medications, and secondary OA.

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As with any investigational drug, women of childbearing potential should be screened for pregnancy, and if pregnant, should be excluded from the trial. Symptom modifying treatments For studies of symptomatic response, the level of symptoms at baseline should be of sufficient severity to permit detection of change (e.g., a minimum pain score of 4 on a 0e10 NRS). Inclusion criteria for symptomatic response should include the following:  Pain of at least moderate intensity: e.g., visual analog scale (VAS) recording of 40 mm (0e100 mm); or NRS of 4 (0e10 units);  Definite radiographic changes of OA, using an established scale and atlas, e.g., KellgreneLawrence grade 2 or modified Croft scale 210e12.

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Pain Pain in the index hip should be assessed, most commonly using some type of visual analog scale (100 mm VAS, 5-point Likert scale, or 11-point NRS14,15). Pain can be assessed in general, over a given time frame (e.g., 48 h, 1 week), and/or with specific activities such as weight bearing [standing or walking], stair climbing, and rest. Reliable, valid and responsive measures, such as the pain subscales of the Western Ontario and McMaster Osteoarthritis Index (WOMAC), HOOS Oxford hip score (OHS) or Harris Hip Score (HHS), can provide additional, more detailed information relevant to a given study8,15e18. The measure of Intermittent and Constant Osteoarthritis Pain (ICOAP) is a measure developed specifically to separately assess intermittent and constant aspects of OA pain12. The psychometric properties of the ICOAP, HOOS, WOMAC, and NRS are comparable18. Function

Structure modifying treatments For studies of structure modifying drugs, enriching for special subpopulations of subjects who are at high risk for development or progression of OA within the window of opportunity for measurement (usually not more than 2 years) of a clinical trial may be advantageous. In addition, the following should be considered: Kellgren and Lawrence radiographic entry criteria: prevention studies: grades 0 or 1 (i.e., absence of both a definite osteophyte and definite joint space narrowing (JSN)); structure modification studies: grades 2 or 3 (i.e., sufficient remaining interbone distance to permit detection of worsening/progression). Current pain in the index joint is essential, as improvement in clinically relevant symptoms is presently required as a co-primary endpoint by regulatory bodies in both US and Europe for approval of a disease modifying OA drug (DMOAD), i.e., for both structure and symptom modification. Physical examination A general physical examination should be performed at the onset of the study and again at the end of the study. Examination of the hip joint itself, with assessment of such parameters as range of motion (ROM) and pain on palpation or ROM, or examination for clinical signs of FAI may be useful, and when standardized have adequate reliability for research purposes7. For clinical trials of hip OA, the parameters of internal and external rotation may be the most affected by the disease and these movements can elicit pain such that they may be used for the diagnosis and assessment of intervention efficacy and effectiveness. Also, advanced radiographic hip OA can be accompanied by a flexion contracture, and notation of this abnormality is important, as a medical intervention would most likely not influence this parameter. Palpation of the greater trochanter and trochanteric bursa should be performed and noted if pain was elicited. Informed consent Guidelines for information to be contained in the Informed Consent statement should be in accordance with the Declaration of Helsinki13. Patient participation requires understanding, and completion of an informed consent document that has been approved by the appropriate institutional review boards.

There are several available instruments to assess self-reported functional status in hip OA patients. The most commonly used valid and reliable measures are the WOMAC and the HOOS. The HHS and OHS also assess function and activities of daily living but may not be as well suited for research purposes18. Assessment of performancebased function should also be considered (see Section D5). Patient and physician global assessments Determination of the global status of the index joint can be made from the patient and the physician perspective, and can be assessed using a VAS or Likert scale. The optimal method by which this should be measured is not well established. However, a standard patient assessment question such as “Considering all the ways your hip OA affects you, how are you doing over the past (specify time frame)?” can be used. The regulatory expectation is for limiting the amount of recall built into the question. Thus a 24 or 48-h question would be more reliably answered than a 7-day question. The physician can assess using a question such as: “Considering all information, how is the patient's hip OA today?1,7 Quality of life Quality of life assessments are important components of treatment effectiveness in hip OA. The HOOS, mentioned above for pain and function, also contains subscales focused on quality of life as well as sports and recreational activities18. The Osteoarthritis Knee and Hip Quality of Life (OAKHQOL) was specifically designed for this purpose and shows good psychometric properties19,20. Other general measures of quality of life commonly used in arthritis studies include the Medical Outcomes Study 36 question short form (SF-36)21e23, the Euroquol (EQ-5D)24,25, and the Assessment of Quality of Life (AQol)26. Psychosocial outcomes, such as pain coping Pain Coping Inventory27, self-efficacy (Arthritis Self-Efficacy Scale30), fear of movement (Brief Fear of Movement Scale for Osteoarthritis28), and symptoms of depression and anxiety (Center for Epidemiologic Studies-Depression scale29,30, Hospital Anxiety Depression Scale29,31,34), may also be relevant in some trials, particularly for symptom-modifying therapies and for studies that examine mechanistic aspects of patient response and predictors of treatment response32.

Outcome measures Performance-based functional measures All of the following outcome measures are best expressed as a change from baseline values. This allows for heterogeneity of the patient population at baseline.

OARSI has published recommendations for performance-based tests to assess function in persons with hip (and knee) OA. The

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core set includes 3 measures: 30 s chair stand test, 40 m fast-paced walk test, and a stair climb test. Additional measures that may be of interest to include the timed up and go test and the 6-min walk test32e34.

whose responsiveness to therapeutic intervention would be reasonably likely to predict a response in a relevant clinical outcome. An example of this would be blood pressure, where hypertension and its response to therapies mimic the alteration in risk for stroke and myocardial infarction as well as death.

Response criteria Biomarkers and hip OA Some measures have defined minimum clinically important differences (MCIDs). For the WOMAC, a change from baseline measure of approximately 10 mm on the 100 mm normalized VAS form was detectable to patients35. In addition, validated measures such as the OMERACT-OARSI responder criteria36 categorize individuals as responders (50% or greater improvement in pain or function and absolute change of at least 20 points, OR at least 20% and at least 10 point improvements in 2 of 3 [pain, function, patient global]) or non-responders. This can be used to calculate numbers needed to treat, which can be useful in economic evaluations. The concept of percentage of patients who achieve a clinically relevant improvement threshold measured by a responder analysis has long been acceptable by regulatory bodies both in Europe and the US. Molecular biomarkers Definition of a biomarker The US National Institutes of Health (NIH) defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. This section focuses on the so-called “soluble” or “wet” biomarkers, usually measured in body fluids such as serum, plasma, urine or synovial fluids and usually reflecting variation of an endogenous substance (proteins, protein fragments, metabolites, carbohydrate or genomic biomarkers (RNA or DNA) in these fluids Ideally, soluble biomarkers should be specific for one single joint tissue and/or one particular pathogenic process and should reflect metabolic changes occurring in this particular tissue37. In theory, these existing biomarkers can be categorized according to the OA process targeted such as markers of cartilage degradation/synthesis, bone remodeling, and synovial tissue degradation/activity. A system called BIPEDS classifies the major types of biomarkers according to their clinical information into six categories: Burden of disease, Investigational, Prognostic, Efficacy of intervention, Diagnostic and Safety biomarkers38. The three biomarker categories of prognostic, efficacy of intervention and safety are the highest development priorities for OA clinical trials; this is due to the fact that, at present, the diagnosis of OA for meeting enrollment criteria is based on established anatomic abnormalities identified by an imaging technique such as plain radiography or magnetic resonance imaging (MRI)39 It is conceivable that, in the future, OA trials will be conducted on patients at earlier stages of disease development that might require diagnostic biomarkers, including serum, urine, synovial or genetic biomarkers to identify the appropriate patient population and verify a diagnosis of early OA that would not yet be possible by an existing imaging technique. OARSI/FDA biomarker classification More recently, the OARSI/FDA Osteoarthritis Biomarkers Working Group has classified biomarkers into four categories (exploration, demonstration, characterization and surrogacy levels) according to their current level of qualification for drug development40. At this time, no biomarkers are considered as surrogate biomarkers of radiographic features in the development of drugs40e42. By US FDA criteria, a surrogate biomarker would be a measureable biomarker

Until now, soluble biomarkers have been mainly investigated in knee OA, and our knowledge of applicability of biochemical markers in hip OA is limited. In 2010, a systematic review of the literature scoring biochemical markers according the BIPEDS criteria, found that only 23% concerned hip OA41. There is a need for clinical trials and cohorts investigating specifically hip OA. Recently, a large scale meta-analysis of urinary and serum biomarkers including 3583 individuals from the Rotterdam study, the genetics of osteoarthritis and Progression (GARP) study, the Chingford Study and the Twins UK cohort concluded that after adjustment for multiple comparison only urinary C-terminal telopeptide of type II collagen (CTX-II) was associated with hip OA risk, but not hip OA severity, while no association was found for serum COMP or another type II collagen epitope C2M42. However, these data need to be interpreted with caution since it was demonstrated that uCTX-II was the only cartilage biomarker correlated with the bone biomarkers suggesting that uCTX-II more likely reflects bone turnover rather than cartilage metabolism43. Specificity of a biomarker or a cluster of biomarkers for one particular tissue, one particular joint and/or one particular pathogenic process are key elements for the interpretation of soluble marker value. In this way, post-translational modified forms of matrix proteins, such as Coll2-1NO2 and D-COMP, have been proposed as joint and/or disease specific biomarkers. Coll2-1NO2 is the nitrated form of Coll2-1, a denaturation epitope located in the helicoidal part of type II collagen44. In serum, Coll2-1NO2, but not Coll2-1, is correlated with the level of C-reactive protein in both OA and RA population indicating that Coll2-1NO2 could be used as a specific marker of the inflammatory reaction occurring in joint45. In a study of patients undergoing joint replacement, serum deamidated COMP (D-COMP), but not total COMP, declined significantly after joint replacement demonstrating a joint tissue source for DCOMP. In analyses of 450 participants from the Johnston County Osteoarthritis Project, D-COMP was associated with radiographic hip OA but not knee OA severity. In contrast, total COMP was associated with radiographic knee but not hip OA severity. D-COMP is the first biomarker to show some specificity to a particular joint site46. Recently, a few studies have reported changes in both serum and synovial cytokines and other markers of inflammation in subjects with hip OA or FAI compared to control subjects47e50. We recommend that there should be standardized protocols for fluid handling, storage, and analysis of the biomarkers to ensure the data are both reliable and valid. Additional information regarding recommendations for biomarkers for clinical trials of OA is covered in ARTICLE X in this special issue. Evaluation of structural endpoints in SMOAD trials Radiography [see also Chapter X for additional information on radiographic protocols and measurements for hip OA] Plain radiography is widely used to establish the diagnosis and to evaluate structural outcome in longitudinal DMOAD trials in persons with hip OA. It is widely available, less complex, although requiring consistent positioning from study to study and over time, and less costly than MRI and other modalities, and there is an extensive literature evaluating its performance. Joint space width

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(JSW) on radiographs provides an estimate of cartilage thickness, and is currently the only outcome measure recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in Europe and Therapeutic Good Administration (TGA) in Australia for use in osteoarthritis research trials51. In the hip, JSN over time may be more directly related to cartilage damage and loss than in the knee, where in the opinion of the authors, a large component of the apparent JSW reflects the integrity and position of the meniscus52. Radiographic endpoint (see also Chapter X for additional information on radiographic protocols and measurements for hip OA) Change in quantitative JSW obtained from conventional AP radiographs of the pelvis is the most commonly recommended53, used and studied measure of hip OA structural outcome. Quantitative JSW, and categorical measurements derived there from, have superior reliability and responsiveness compared to other metrics of hip OA radiographic progression, such as KellgreneLawrence grades and semi quantitative JSN grades54. Protocol for AP hip radiograph A weight-bearing AP view of the pelvis (both hips) with the beam centered on the superior aspect of the symphysis pubis is the preferred protocol for obtaining a measure of JSW at the critical points on superior locations of the joint56. The AP pelvis view is also suitable for assessing the presence and severity of radiographic OA for determining study eligibility using KellgreneLawrence or semi quantitative JSN grades53e56. Alternative radiography protocols (e.g., oblique, frog leg) can evaluate JSN in locations other than the superior aspect of the joint and when combined with an AP view may increase sensitivity to detection of JSN and change in JSW57. Unilateral AP views centered on the hip joint space are sometimes used in clinical studies and comparative data suggest that reliability and responsiveness for JSW are comparable to an AP pelvis57,58. However, these alternative protocols are far less practical since positioning is more complex and requires fluoroscopy. Several variations in the AP hip acquisition protocol have been compared for JSW measurement performance, but the data are generally not conclusive as to which approaches are superior. Regardless of the specific protocol used, the most important consideration for obtaining high quality structural outcome data is to ensure that all aspects of the acquisition are carefully standardized and are identical at all time-points in an individual study participant. In theory, weight-bearing helps ensure that the JSW most closely reflects cartilage thickness in the plane of measurement in the hip. The limited data available tend to support weight-bearing JSW as more accurate and sensitive for superior JSN in OA hips with at least moderate OA59,60, but data demonstrating greater reliability and responsiveness of weight-bearing are not conclusive61. Supine positioning may have advantages for obese subjects by reducing interference from abdominal soft tissue. If acquired standing in obese subjects, it may be necessary to move the panniculus away from the field of view (e.g., using waist bands). Since morbid obesity is a less frequent comorbidity in patients with hip OA, as compared to knee OA, weight bearing will be suitable for most study subjects in a treatment trial, with supine positioning at all measurement time points as an alternative when needed in obese subjects. Whether standing or supine, internal rotation should be standardized at a selected point somewhere between 10 and 20 for both feet and replicated precisely over time, since internal rotation can affect JSW by generating force on the superior articular surfaces62,63 and failure to standardize will increase measurement

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variability64. Other positional variations, including hip abduction, adduction and flexion can affect JSW, but may have a greater influence on fixed location than on the minimum JSW (mJSW)65. A positioning device to standardize internal rotation of the femur at 10e20 as well as other aspects of positioning between subjects and over time is preferred, although foot maps have also been used to replicate internal rotation within subjects over time59. Most trials and longitudinal studies have imaged both hips together in a pelvis view with the beam centered on the superior aspect of the symphysis pubis. Since centering higher on the abdomen tends to show a larger JSW64,65, care in determining this landmark should be emphasized. JSW measurement: reliability, validity, responsiveness and progression Quantitative JSW is assessed in a superior region of the hip joint as the distance between the femoral head bone edge and the apparent articulating bone edge of superior acetabular, defined by the bright line, or acetabular sourcil, using either manual or computer-assisted methods. The mJSW, or the point of maximal narrowing in the superior region of the joint, has been recommended as the preferred primary structural endpoint in hip OA DMOAD trials51,53. Most studies evaluating the performance of different acquisition protocols and measurement techniques have used mJSW as the standard51,53. Therefore, data on reliability, validity, responsiveness and comparative performance apply largely to mJSW and may not be applicable to other measurement techniques, such as JSW in a fixed location or another area of the joint space. It follows from this that while the performance of mSJW is the best characterized, there are insufficient data to definitively support a claim that it is the most reliable or responsive JSW parameter. Further studies are needed comparing mJSW with other metrics. Cross-sectional reliability of measurement methods of hip JSW is generally good, but shows a wide range across studies, with interclass correlation coefficients (ICCs) for a measurement on radiographs from single acquisition ranging from 0.78 to 0.98 for inter-rater and 0.77 to 0.98 for intra-rater57,58,67e70. Intra-rater is usually better than inter-rater reliability, suggesting that for methods relying on some degree of observer judgment (including computer-assisted, semi-automated needing observer intervention), a single well-trained and experienced observer will provide the highest measurement precision. Only a few studies have assessed reliability for measurements of change in mJSW, and as expected reliability is less, sometimes substantially so, than for cross-sectional measurements58,59. Moreover, there are no data examining reliability of the entire measurement system for hip JSW, including repeat radiographs with repositioning at multiple time points and repeat measurement at each timepoint. In the absence of this real world data on ability to reliably measure change, trial planning can be based on data from longitudinal studies of the mean, and standard deviation (SD), for rates of change and the derived responsiveness. The mean rate of decline in mJSW in hips with OA varies widely across studies, from 25% of subregion, and 4 ¼ several large full thickness defects or single full thickness defect >25% of subregional area affected. BMLs of the subchondral bone of the acetabulum (n ¼ 6, with scoring range of 0e18) and femur (n ¼ 9, with scoring range of 0e27) are assessed in 15 subregions. Coronal and sagittal PD-weighted fat-saturated MR images are used to evaluate BMLs, and subchondral cysts are graded according to the volume of the region affected with 1  33% of region, 2 ¼ 33e66% of region, and 3  66% of region. Coronal and axial T1-weighted fat suppressed contrast-enhanced MR images are used to evaluate the presence of synovitis. Synovitis is scored in four different locations and the severity is based on the thickness of the synovium with 0 or

Table II Semi-quantitative assessment of hip OA HOAMS

SHOMRI

HIMRISS

14 articular features Cartilage evaluated 9 subregions (range 0e4)

8 features Articular cartilage evaluated in 10 subregions, femur (n ¼ 4), acetabulum (n ¼ 6) Bone Marrow Lesions

3 features of Active Lesions

Bone Marrow Lesion of acetabulum (range 0e18) and femur (range 0e27)

Subchondral cysts (range 0e3) based on region affected Synovitis scored in 4 locations based on thickness of synovium (0e4)

Bone Marrow Lesions Femur scored with 5 center (range 0e45), 5 anterior (range 0e20), and 5 posterior slices (range 0e20) for total score 0e65 Acetabulum BMLs e 5 central, 5 anterior, 5 posterior with range 0e43. Total range per subject 0e100.

Subchondral cysts Joint effusions

Joint Effusions scored (0e2)

Loose bodies Abnormalities of Ligamenous teres Sinusitis scored (0e2)

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physiologic 4 mm ¼ Grade 2. The presence of MRI detected lesions that were moderate to severe including cartilage damage, synovitis, joint effusion, etc. by HOAMS were found to be closely associated with the severity of radiographic hip OA as measured by Kellgren and Lawrence grades88. The investigators reported a non-significant association with MRI features of BMLs and synovitis obtained by HOAMS and hip pain. The reliability assessment in the research group that developed the HOAMS system was very good, with an intra-reader and interreader reliability for 15 random cases reported weighted kappas values of 0.18e0.85 and 0.15e0.85. A second semi-quantitative scoring systems available for assessing hip OA with MRI is the Scoring Hip OA with MRI (SHOMRI). SHOMRI scores 8 features that include the articular cartilage (acetabulum and femoral head combined), BMLs, subchondral cysts, labral abnormalities, loose bodies, joint effusion and abnormalities of the ligamentous teres. Ten subregions (6 in the femur and four in the acetabulum) are used to score the articular cartilage bone marrow edema patterns, and subchondral cysts88,89. Initial intra-reader and inter-reader reliability of this new scoring method was assessed by two radiologists, with intra-class correlation coefficients greater than 90%; Cohen's kappa values and percent agreement ranged from 0.55 to 0.79 and 66e99%, respectively. The research group also reported significant correlations with the SHOMRI scores and both radiographic scoring and clinical outcomes89. Hip Inflammation MRI Scoring System (HIMRISS) A third MRI based scoring system is the HIMRISS that focuses only on what is described as active lesions, including BMLs and synovitis or effusions. A BML is defined as an increase in signal within the bone on STIR sequences, and does not include bone cysts. The contralateral hip is the normal reference signal for this assessment using a bladder signal and T1 images to assist with identification of subchondral cysts. The nearest normal bone marrow is used if the contralateral hip is abnormal or a THR is present. The femoral BML is scored in five central (range 0e45), five anterior (range 0e20) and five posterior slices (range 0e20), with a total range of the femoral BML of 0e65. The acetabular BMLs are also scored in five central slices, five anterior and five posterior with a range of 0e43, and a BML scoring range per subject of 0e100. Effusion and synovitis are scored together with a 0e2 grading on the same central, anterior and posterior slices, with a total score ranging from 0 to 3090. Currently there are no randomized clinical trials that have used these MRI scoring systems. However a reliability study was completed with HOAMS and HIMRISS. Twenty MRIs of the hip were read by six readers. HIMRISS ICCs ranged from 0.52, 0.61, 0.70, and 0.58 for femoral BMLs, acetabular BMLs, effusion and total scores. For HOAMS summed BMLs and synovitis the ICCs were 0.52 and 0.4692. In another study, the MRI of the hip from 18 subjects enrolled in an RCT were assessed at 2 timepoints and inter-observer change scores were 0.81 and 0.71 for HIMRISS femoral and HOAMAS summed BMLs93. Based on these data, the authors concluded that both HIMRISS and HOAMS scoring systems are feasible and reliable however further validation is required. In summary, two semi-quantitative MRI scoring systems are available for assessing hip OA in clinical trials, and another method, HIMRISS, is useful for assessing active lesions, including BMLs and synovitis (Table II). While initial studies of the investigators that developed the scoring methods for hip OA assessed by MRI demonstrate very good reliability for these MRI endpoints, additional work is still required. For example, prior to the introduction of these scoring methods into clinical trials, detailed teaching atlases should be developed and both the number of MRI scans and

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readers being tested for reliability should be increased. In addition, a training set of MRI scans read by highly trained assessors, could be available and used by new assessors to efficiently learn how best to score the scan abnormalities and to calibrate themselves to the trained assessors. The introduction of hip MRI into clinical trials as an imaging endpoint will provide useful information on both the national history of hip OA and how interventions may change the tissues within the hip. The interval to assess changes in joint structures such as volume of the articular cartilage may be shorter with MRI than with radiographs, although the exact interval in which meaningful change can reliability be determined will require additional investigation. Assessment of symptom modifying drugs and devices The primary objective of symptom-modifying drugs or devices in clinical trials for hip OA should be improvement of symptoms from baseline. The duration of the clinical trials should depend upon the target product profile of the drug or device whose efficacy is explored in those studies. For drugs or devices with a fast onset of action, the length of the trial may be as short as 1 week, whereas in terms of safety follow-up periods of up to 1 year are mandatory. The efficacy of symptom-modifying drugs or devices should ideally be compared against placebo. A positive outcome of a trial is based on the demonstration of a statistically significant and clinically important difference between the scores for improvement of active treatment and placebo groups. Substantiating efficacy of a symptom-modifying drug or device may be thwarted by a high placebo effect, which is well known in OA trials94. For the conduct of clinical trials and the correct assessment of symptoms, it is essential that patients should refrain from taking rescue analgesic medication at least 24e48 h prior to their follow-up-visits. Given the problems of missing data, use of rescue analgesic medications and the use of subjective outcomes, it is critical for the RCTs used for regulatory approval to be carefully constructed with “a priori” definitions of the primary outcome(s), analysis of multiple co-primary and secondary outcome measures, rescue analgesic use, and missing data. In both the US and Europe, the regulatory agencies consider symptom modifying drugs in OA to be chronic therapies; thus pivotal double-blind RCTs should be at least 12 weeks in duration. Proof of concept studies, however, might be shorter. Disease modifying drugs According to the guidelines of health authorities (EMA and the FDA), the efficacy of structure-modifying drugs needs to be determined with measurement of JSW on X-ray. Measurement of JSW in the hip appears more correlated with the actual cartilage thickness as the hip is devoid of a meniscus. However, due to the slow progression of cartilage loss in OA and small changes in JSW observed over time and the SD being much higher than the changes of the mean, in clinical trials for hip OA, follow-up-periods of at least 2 years appear warranted. An example of a study in which JSW was used as the primary endpoints was performed by Falgarone and Dougados72. These investigators carried out a study with 446 patients with hip OA in which study participants were randomized 1:1. In 269 patients who had completed the study (n ¼ 131 (diacerein), n ¼ 138 (placebo)), they detected a statistically significant difference (p ¼ 0.042) in the progression of JSW (0.18 ± 0.25 mm vs 0.23 ± 0.23 mm), thus suggesting structure-modifying effects in terms of slowing progression of hip. According to regulatory guidelines, measurement of JSW appears warranted to demonstrate structure-modifying properties of a disease-modifying agent for the treatment of hip OA. MRI may be

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a more sensitive and a more promising tool as it helps to visualize changes in both cartilage and bone morphology that are both pathophysiologically relevant for the genesis and for the progression of hip OA.

3.

Summary 4. There has been a dramatic increase in activity related to the improvement of clinical trials in hip OA in the past 20 years since the publication of the initial OARSI recommendations2. We have presented updated recommendations on study design, inclusion and exclusion criteria, validated radiographic, MRI and clinical outcome measure for clinical trials that focus on hip OA. In addition, we have provided updated information on potential biomarkers for clinical trials. This information can be utilized by sponsors of trials for new therapeutic agents for hip OA.

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Author contributions Conception and Design: NEL, MCH, MCN, LSS, AEN, MD, YH, KF. Analysis and Interpretation of Data: NEL, MCH, MCN, LSS, AEN, MD, YH, KF. Drafting of the Article: NEL, MCH, MCN, LSS, AEN, MD, YH, KF. Critical Revision of the Article for Important Intellectual Content: NEL, MCH, MCN, LSS, AEN, MD, YH, KF. Final Approval of the Article: NEL, MCH, MCN, LSS, AEN, MD, YH, KF. Collection and Assembly of Data: NEL, MCH, MCN, LSS, AEN, MD, YH, KF. Obtaining funding: NEL, MCH, MCN. Role of the funding source This work results has received a partial funding from the European Union Seventh Framework Programme (FP7/2007e2013) under grant agreement n 305815 (YH), National Institutes of Health grants AR048841, AR052000, AR060752, and AR063043 to NEL. Conflicts of interest Yves Henrotin e YH received honoraria from Artialis, Bioiberica, Danone, Expanscience, Ibsa, Merck, Pierre Fabre, Synolyne Pharma, Tilman. YH is the founder and owner of Artialis SA a biomarker manufacturerand Synolyne Pharma, two spin-off companies of the ge. YH also received unrestricted educational grant University of Lie from Bioiberica, Expanscience, Royal canin, Artialis, and Nestle”.

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14. Disclosure No other authors have anything to disclose regarding the information in this manuscript.

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Acknowledgments

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Elizabeth Lincoln for her editorial assistance. OARSI gratefully acknowledges support to defer in part the cost of printing of the Clinical Trial Recommendations from Abbvie, BioClinica, Boston Imaging Core Lab, and Flexion. The funding sources for printing had no role in the outcome of this manuscript.

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