Conducting clinical trials in osteoarthritis: OMERACT III

Various rheumatology and non-rheumatology organizations (e.g. EULAR, FDA, SADOA, ORS) have published guidelines for the design of osteoarthritis trials. Currently, the most widely used guidelines are the Outcome Measures in Arthritis Clinical Trials (OMERAC III) and the Osteoarthritis Research Society (ORS) guidelines for the design and conduct of clinical trials in osteoarthritis.

Recommendations for the design of clinical trials in osteoarthritis (according to Bellamy N., 1995)

Recommendations	Indicator
EULAR 1	Osteoarthritis Severity Index of the Knee and Hip Joints (Lekena) General assessment of the patient's condition by the researcher Pain according to YOU General assessment of the patient's condition by the patient himself Time to cover a certain distance (in case of gonarthrosis - time to climb one flight of stairs)
FDA 2	Swelling Redness of the skin over the joint Pain on palpation Pain at rest or with movement Range of motion The time it takes to walk a certain distance or climb one flight of stairs Assessment of the patient's condition by the researcher on the day of the visit Patient's assessment of his condition on the day of the visit
SADOA 3	YOUR Functional index (W0MAC or Lequesne) Doyle Index Decreased joint mobility The time it takes to walk a certain distance or climb one flight of stairs Consumption of analgesics and/or NSAIDs Number of exacerbations over a given period of time (especially the presence of effusion in the knee joint) Overall assessment of the effectiveness of treatment by patients Overall assessment of treatment effectiveness by the investigator Quality of life

Note. ¹ EULAR - European League Against Rheumatism. ² FDA - Food and Drug Administration. ³ SADOA - Slow Acting Drug in Osteoarthritis.

The main result of the first OMERACT conference (OMERACT I), which took place in 1992, was the development of recommendations for conducting clinical trials in rheumatoid arthritis. These recommendations formed the basis for the criteria for improving rheumatoid arthritis that appeared later. During the next conference, OMERACT II, issues of measuring the toxicity of drugs used in the treatment of rheumatic diseases, assessing the quality of life of patients with a rheumatic profile, and issues of pharmacoeconomics were considered. The third OMERACT conference (1996) resulted in the development of recommendations for conducting clinical trials in osteoarthrosis and osteoporosis.

From all of the above, it is clear that the OMERACT movement has expanded beyond the study of rheumatoid arthritis, which was originally reflected in its name. Therefore, it was proposed to rename it to OMR (Outcome Measures in Rheumatology), and after the inclusion of osteoporosis - to OMMSCT (Outcome Measures in Musculoskeletal Clinical Trials). Mainly because of the euphoniousness of the first abbreviation, it was decided to keep the name OMERACT.

Even before the conference, participants were asked to fill out questionnaires to determine the parameters that could potentially serve as performance criteria in clinical trials of osteoarthrosis. Then another questionnaire was offered, in which participants were asked to rank the parameters by importance depending on the localization of osteoarthrosis (knee, hip, hand joints and generalized osteoarthrosis), the class of drugs being studied (symptomatic or modifying the structure of cartilage), and the class of parameters (clinical, instrumental and biological markers). The second task turned out to be difficult, since only 15 completed questionnaires were returned to the conference secretariat.

Already during OMERACT III, conference participants had to propose a list of indicators for inclusion in:

• the main list of effectiveness criteria (mandatory for phase III clinical trials of patients with osteoarthritis of the knee, hip, and hand joints);
• an additional list of performance criteria (i.e. those that may be included in the main one in the future);
• a list of criteria that will not be included in either the main or additional criteria.

After the voting results were announced, several important issues arose that needed to be addressed:

1. Is generalized osteoarthritis a separate object from other forms of the disease for clinical research? (Resolution - generalized osteoarthritis is not to be considered as an object for clinical research in the future).
2. Does the time of onset of action of the drug under investigation determine the need for different efficacy criteria? (Resolution - time of onset of action determines when to test rather than what to test.)
3. Do studies of the effectiveness of "simple" analgesics and NSAIDs require different criteria? (Resolution - the groups of criteria are the same, but the methods for determining them may vary).
4. Should the efficacy criteria be different for symptom modifying drugs and structure modifying drugs? (Resolution - the groups of indicators included in the core list should be the same).
5. It is expected that biological markers will be an important part of the clinical trial protocol for osteoarthritis in the future, but at present there is insufficient convincing data on the importance of biological markers in assessing the effectiveness of treatment in patients, as well as their prognostic value for osteoarthritis.
6. It was recognized that none of the existing methods for assessing quality of life demonstrated advantages over others. The importance of assessing quality of life in conducting clinical trials in osteoarthrosis was noted. (Resolution - not to include quality of life assessment in the main list of effectiveness criteria, but to recommend its use in conducting phase III trials lasting at least 6 months; in the next 3 - 5 years, determine the role of the quality of life indicator in conducting clinical trials).
7. It was noted that the use in the future of criteria that were not included in the main and additional lists when studying the effectiveness of newly created drugs cannot be ruled out.
8. Should the symptom of stiffness be included in any of the lists of performance criteria; do pain and stiffness belong to the same group of indicators; do patients with osteoarthritis understand the concept of stiffness; to what extent are existing methods able to assess stiffness? (Resolution - WOMAC or Lequesne index should be used to assess stiffness in patients with osteoarthritis of the knee or hip).
9. The issue of the informativeness of the “physician’s overall assessment” indicator in clinical trials in patients with osteoarthritis was discussed (a similar issue was discussed during OMERACT I in relation to rheumatoid arthritis); despite the fact that only 52% of conference participants spoke in favor of including it in the core list of effectiveness criteria, the indicator was not excluded.

OMERACT III Participants' Preferences for Efficacy Criteria for Phase III Clinical Trials in Patients with Gonarthrosis, Coxarthrosis, and Osteoarthritis of the Hand Joints (according to Bellamy N. et al., 1997)

Indicator	Number of people who voted "for" inclusion, %		Number of people who voted "against" inclusion in both lists, %	Total number of voters
	To the main list	To the additional list
Pain	100	0	0	75
Physical function	97	1	1	76
Visualization*	92	7	1	76
Overall assessment by the patient	91	1	1	75
Overall assessment by the physician	52	21	27	73
Quality of life	36	58	6	69
Morning stiffness	14	61	25	72
Other**	13	69	19	16
Inflammation	8	70	22	74

Notes: "standard radiography; after demonstrating advantages over radiography - other methods (MRI, ultrasound, etc.). "For example, pain on palpation, active and passive movements; number of exacerbations, biological markers.

When compiling the list of criteria, it was decided to include not the indicators themselves, but their groups, leaving the final choice of the evaluation method to the researcher. More than 90% of the OMERACT III conference participants spoke in favor of including the following indicators (or their groups) in the main list:

• pain,
• physical function,
• general assessment of the patient,
• visualization methods (for studies lasting 1 year or more as a criterion for the effectiveness and safety of drugs that
  modify cartilage structure).

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