A total of subjects with inflammatory and erosive hand OA, according to the classification criteria of the American College of Rheumatology ACR , with recent X-ray will be recruited across outpatient sites, hospitals and universities in Germany. Both groups receive standard therapy non-steroidal anti-inflammatory drugs [NSAID], coxibs for OA treatment, taken steadily two weeks before enrollment and continued further afterwards.
The co-primary radiographic endpoint is the radiographic progression from baseline to week A multiple endpoint test and analysis of covariance will be used to compare changes between groups. All analyses will be conducted on an intention-to-treat basis. Osteoarthritis OA is a heterogeneous group of conditions with defective integrity of articular cartilage and changes in the underlying bone.
The pathogenesis is multifactorial and involves a complex interplay of genetic, metabolic, biochemical, and biomechanical factors with variable components of inflammation. Subsets of patients with OA develop an inflammatory and erosive form of the disease. As one of the most prevalent musculoskeletal diseases, the condition leads to pain in and around the affected joints and to swelling, stiffness, deformity, and gradual loss of function [ 1 , 2 ].
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This disease not only affects older people, but also the younger working population. The pathologic mechanisms and its triggers are still not known. Treatment options are limited to symptomatic therapy and rarely surgical intervention. Compared to the research results of hip OA and knee OA, there are very few basic research activities in the field of hand OA. Nevertheless, effective treatments for OA are limited, since many treatments have only small symptom-relieving effects. Most of these randomized controlled trials RCTs used a broad range of outcome measures, some of them poorly standardized.
Differences in disease definition between studies make it hard to generalize the results for clinical practice. Many studies were underpowered or planned as pilot studies [ 3 , 4 ]. HCQ has been used since the s for the treatment of various rheumatic and dermatologic diseases. Current research has further enhanced our understanding of the pharmacologic mechanisms of these drugs, involving inhibition of endosomal toll-like receptor TLR signaling, which inhibits B cell and dendritic cell activation [ 5 ].
With this understanding, the use of these medications in rheumatology is broadening. This study was an open retrospective study [ 7 ]. To summarize, the review of published data on hand OA raises more questions than it answers with regard to the evaluation of therapeutic agents in hand OA. Moreover, the few RCTs that have been performed were in small patient populations and lack standardized outcome assessments [ 4 ]. Despite initial evidence for good efficacy of HCQ, there has not been a randomized, double-blind, and placebo-controlled trial in a larger patient group.
The evidence of HCQ in hand OA has never been investigated in controlled randomized studies, although there are clinical indications for good effectiveness in daily rheumatologic practice. Until now, HCQ is only used for hand OA in daily practice once all other available therapies have failed. HCQ treatment of patients with other rheumatic diseases shows that the drug is very well tolerated if management for the prevention of possible side effects e.
HCQ acts as prostaglandin antagonist by inhibition of phospholipase A2 [ 16 ]. Rheumatoid arthritis RA and inflammatory OA synovial tissue have a similar pro-inflammatory and anti-inflammatory cytokine profile. Moreover, HCQ potentiates Fas-mediated apoptosis of synoviocytes [ 18 ]. This background and the knowledge of the effectiveness in RA patients raise the question of whether this drug may also be effective in hand OA.
When compared with other immunomodulatory agents, antimalarial drugs have a favorable safety profile. Our understanding of the toxicities and modes of action of these drugs may suggest new applications and modified treatment regimes in hand OA where there is huge unmet clinical need. On the other hand, more studies are needed to further explore the relationship between self-reported and radiographic outcomes and the relationship with other domains such as biomarkers and other imaging modalities [ 10 , 19 — 21 ].
The co-primary hypotheses are that patients receiving HCQ have a lower Australian-Canadian OA Index AUSCAN score in the dimensions for pain and hand disability at week 52 and that they have a lower rate of radiographic progression from baseline to week 52 compared to patients receiving placebo. The trial is based on a call of investigator initiated trial funding by the German Ministry of Education and Research Bundesministerium für Bildung und Forschung [BMBF] and is carried out with German rheumatologic and statistical stakeholders with experience of treating hand OA.
All selected centers are very experienced in trial performance and approved by the local ethic committees EC in their quality management as a clinical trial center. Patients with hand OA according to the classification criteria of the American College of Rheumatology ACR with recent X-ray of the hands [ 22 ], dating from less than six months and showing radiological signs of digital erosive OA as defined by grades 2 or higher, per the Kellgren and Lawrence scale in one or more joints [ 23 ].
Participants must meet the inclusion and exclusion criteria in order to participate. These will be assessed at the screening visit. A total of patients with erosive and inflammatory hand OA will be recruited and randomly allocated to either the treatment or placebo group. Recruitment methods will include advertisements through the local media and community groups, invitations to previous study participants who have given their consent to be contacted regarding future research projects and liaisons with general practitioners, rheumatologists, orthopedists, and German patients associations for example, Rheumaliga.
Group II receives capsules as an oral placebo application from day 1 up to the end of week Ongoing physiotherapy or occupational therapy before screening can be continued unchanged, but must not be commenced after enrollment. The patient-centered self-administered AUSCAN Index is a valid, responsive and feasible tri-dimensional pain, stiffness, and function index developed specially for hand osteoarthritis studies [ 24 — 26 ].
The HAQ-DI assesses the degree of difficulty experienced in eight categories of daily living activity using 20 questions. This questionnaire has been validated for rheumatoid arthritis RA ; there is no experience in OA hand trials. The SACRAH includes visual analog scales covering the extent of hand function, stiffness and level of pain from 0 to [ 27 ].
The SF v. It measures eight general concepts: physical functioning, physical role, bodily pain, general health, vitality social functioning, emotional role and mental health. This questionnaire should be completed by the subject prior to any procedures being performed at the visit, if possible.
To date, there is no experience in OA hand trials. Examples of health-related quality instruments include the SF [ 28 ]. For these reasons, we aim to detect an effect size ES of 0. An ES of 0. Randomization will be undertaken during normal working hours Monday to Friday from to by the German Rheumatologic Research Center Deutsches Rheumatologisches Forschungszentrum, DRFZ of participating centers upon receipt of a randomization request form and after blinded review of X-rays of both hands. Identical HCQ and placebo capsules will be produced to ensure allocation concealment.
Upon production, study medication will be packed into numbered bottles according to a randomization schedule.
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This will be prepared by the DRFZ using a computerized random number generator, thereby guaranteeing full allocation concealment. Participants in each site will be randomly assigned to the intervention arm or the placebo arm in a ratio of and the randomization will be double-blind. The blind will be maintained at all times until all data has been collected and the study database locked. Participants will be randomized centrally by computer generated random numbers stratified by center.
Patients and investigators are blind to the treatment allocation. This envelope may be opened in the case of emergency. Unopened envelopes will be returned to the sponsor at the end of the study. The possible influence of these drugs on the outcome will be discussed. Radiographs will be read in a concealed time order by two readers blinded to treatment assignment. All patients who received at least one dose of the study medication will be included in the statistical analysis of the efficacy and safety of HCQ modified intention-to-treat mITT population.
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Using this test the outcome in the AUSCAN scales pain and hand function at week 52 is compared between the treatment groups. In the case of a significant difference of the first primary hypothesis, the second primary hypothesis radiographic outcome at week 52 will be tested by means of an analysis of covariance ANCOVA based on ranks nonparametric ANCOVA.
To estimate whether any imbalance in the use might have influenced the outcome in pain and function the suggestions by Dougados et al. All subject data obtained during the study will be recorded using pseudonyms. Every patient will be clearly identified by a registration number and a pseudonym, which will be assigned during the registration process.
Access to this list is only provided to the local study personal and the study monitor. The original source files and medical records directly related to the study can be accessed by study monitors, auditors or inspectors from regulatory authorities. All data collection of pseudonomized data will be done on standardized case report forms CRFs , which will be completed by site staff, verified by the principal investigator, and returned to the clinical trials unit for double data entry.
The sponsor will maintain a list of personnel authorized to enter data into the database. Validation of correct data entry will be ensured by the named data managers to check for discrepancies and to ensure consistency of the data. Validated data will be entered into an electronic trial database.
Any addition, change or correction to the entered data must be approved by the investigator and will be recorded. Records of correction will be kept together with the case report form. Regular backups of the electronic data will be performed. When all data have been recorded and validated after termination of the study the database will be closed. This process will be recorded. The sponsor maintains a list of personnel authorized to access the data. The monitor has the responsibility to familiarize the investigator s and the entire center staff involved in the study with all study procedures including the administration of the study drug.
The sponsor must provide a trained monitor to assist the investigator s in conducting the clinical study.
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The monitor must visit the clinical study center on a regular basis and at least once before the first subject has been enrolled, once during the course of the study, and finally at study completion. The monitor has the responsibility of reviewing the ongoing study with the investigator s to verify adherence to the protocol and to deal with any problems that arise. At all times the sponsor must maintain the confidentiality of the study documents. The trial monitoring requires a high degree of professional expertise of the monitor.
We have a variety of very specific outcome criteria, which are new to the involved trial sites. The focus of monitoring will be on developing, checking and adjusting the trial procedures, and on providing training, mentoring and support to study staff in response to the issues identified. In addition to the on-site monitoring, the following activities are planned: central monitoring of fax data and data management, training of and information on trial staff, and specific support of trial sites information and download website and investigators investigator meetings.
Independent audits will also take place in the course of study.
A screening visit and six monitor visits per trial site are planned. The DSMB will review the blinded safety data, including adverse events reports. The main tasks of the DSMB are to review relevant information about the trial; to ensure adherence to protocol; to advise whether to continue, modify or stop a trial; and to provide the funding organizations with information and advice.
A UAR includes any event that may be symptomatically and pathophysiologically related to an event listed in the labelling, but differs from the labelled event because of greater severity or specificity. Suspected unexpected serious adverse reactions SUSARs are serious events that are not listed in the IB or SmPC and that the investigator identifies as related to the investigational product or procedure. For both serious and non-serious AEs, the investigator must determine both the intensity of the event and the relationship of the event to study drug administration.