Levels of clinical studies of osteoarthritis

In the course of preclinical studies, a potential mechanism of action and therapeutic latitude (effective - toxic dose) of the drug are studied.

The results of preclinical research can shorten the duration of a clinical trial of a potential drug that modifies the structure of the cartilage.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]

Phase I of clinical trials of osteoarthritis

Study the pharmacokinetics and safety of the drug, sometimes in addition - the dose of the drug. Depending on the tasks assigned, the subjects of the study usually are healthy volunteers or patients with osteoarthritis without concomitant pathology. Optimal for studying the safety of the test drug in phase I is a double-blind, placebo-controlled study with one or more doses of the drug. Evaluation of the effectiveness of treatment can act as a secondary task.

Phase II of clinical trials of osteoarthritis

The purpose of Phase II is to determine the ideal therapeutic latitude and dosage regimens for the study drug. The duration of the study and the number of patients depend on the mechanism of action of the drug, the duration of its action, the effectiveness criteria to be used in the study protocol, the variability of the parameters studied, and the patient population. In this and subsequent studies, it is necessary to determine the minimum effective and maximum tolerated dose of the drug, as well as the profile of the effects of these doses in patients with osteoarthritis.

The study of symptomatic drug phase II should be placebo-controlled randomized and double-blind. The effectiveness of the drugs can be demonstrated within a few days of testing. A longer study (within a few weeks) may be required to demonstrate the slow onset of the drug or the duration of the effect. To study the safety of the drug, an even longer study may be needed. When performing long-term trials of symptomatic drugs, it may be necessary to prescribe pain medication. For this purpose, short-acting analgesics should be prescribed after a suitable washout period.

Phase III of clinical trials of osteoarthritis

The purpose of Phase III clinical trials is to demonstrate convincingly the efficacy and safety of the optimal doses of the study drug and dosage regimens. In the course of the study, only one joint is evaluated (usually the knee joint, with bilateral osteoarthritis - the most affected). In this phase of clinical trials, it is necessary to finally determine the dose and dosage regimen that will be recommended for use in clinical practice, continue to study its toxicity, and compare the test drug with reference and / or placebo. The volume and duration of the study should be planned in such a way that after a necessary period of time to determine the clinically and statistically significant difference in the parameters of the effectiveness of the drug between the main and control groups of patients. The necessary number of patients and the duration of the drug safety study are calculated based on recommendations for chronic diseases Guidelines for Industry.

The duration of phase III clinical trials of the effectiveness of high-speed symptomatic drugs should be no more than 4 weeks (sometimes significantly less). To objectify the study, an adequate "washout" period is needed. For a deeper study of the safety of a high-speed symptomatic agent, a short double-blind study can be followed by a longer double-blind or open trial. To demonstrate the effectiveness of slow-acting symptomatic drugs will require a longer period, as well as additional anesthesia.

The amount of research needed to demonstrate the effectiveness of drugs that modify the structure of cartilage is not defined. The duration of such a test should not be less than 1 year. The main or primary efficacy criteria should be structural changes in the joints affected by osteoarthritis. The number of the studied population should be calculated based on the results of phase II.

IV phase of clinical trials of osteoarthritis

IV phase of clinical trials is carried out after the relevant authorities approve the clinical use of the drug. Phase IV studies are conducted in order to better understand the data of clinical observations, as a result of which the list of indications is expanding. In addition, the study studies rare side effects, as well as the effectiveness of long-term treatment with the drug being tested. Some phase IV studies may be open.

Inclusion of patients in the study

To study the symptomatic effect of the test agent, the initial level of symptom severity is important, which will allow to assess their dynamics. Thus, the mandatory criteria for including patients in the study of the effectiveness of symptomatic drugs are the following:

• the severity of the pain syndrome according to the VAS of at least 2.5 cm or on the 5-point Likert scale - not less than 1 point;
• the presence of certain radiographic criteria for osteoarthrosis, for example, stage II (or higher) according to Kellgren and Lawrence for the tibial tfo (ie, the presence of certain RPs) or stage II (or higher) according to the modified Croft scale for hip joints.

Among the criteria for including in the study the effectiveness of drugs that modify the structure of cartilage, the following are mandatory:

• to study the ability to prevent the development of changes characteristic of osteoarthritis of stage 0 or I on X-ray patterns according to Kellgren and Lawrence (ie, the absence of certain osteophytes); to study the ability to slow the pathological process of II or III stage or to prevent its progression according to Kellgren and Lawrence, in which the degree of narrowing of the joint gap allows assessing the progression of the disease;
• the presence of pain in the joints being examined at the moment of inclusion or in the anamnesis is not necessary; the dynamics of the pain syndrome can be studied as a secondary (complementary) criterion of effectiveness.

In studies of drugs that modify the structure of cartilage, it is important to select a subpopulation of patients at high risk of rapid progression of osteoarthritis. To determine such a subpopulation, it is possible to use some biological markers capable of predicting the progression of changes on the roentgenograms of the affected joints.

In addition, among the inclusion criteria, it is necessary to indicate the age and sex of the patients being studied, which diagnostic criteria will be used, which joints affected by osteoarthritis will be studied (eg, knee or hip).

The exclusion criteria should also be clearly delineated; they must include the following:

• severity of symptoms of osteoarthritis;
• degree of radiographic changes;
• concomitant diseases;
• the presence of a peptic ulcer in an anamnesis (if the toxicity of the drug is expected in relation to the mucosa of the digestive tract);
• concomitant therapy;
• pregnancy / contraception;
• intra-articular injection of depot corticosteroids or hyaluronic acids;
• tidal lavage;
• presence of secondary osteoarthritis.

The time interval elapsed after the last intra-articular injection of a depot corticosteroid drug or hyaluronic acid is an important exclusion criterion. It is necessary for optimal minimization of the possible influence of intraarticular injections on the symptoms of osteoarthritis. The recommended interval is at least 3 months. The researcher can increase this interval when using hyaluronic acid, since there is no reliable data on the duration of its symptomatic effect. When conducting long (more than 1 year) studies, stratification of patients receiving intraarticular injections prior to testing is necessary.

Additional exclusion criteria are:

• serious injury of the affected joint within 6 months before the start of the study;
• arthroscopy for 1 year before the start of the study;
• damage to the spine or joints of the lower extremities, accompanied by severe pain syndrome, which can make it difficult to evaluate the joint being examined;
• use of auxiliary devices for movement (except for the cane, crutch);
• concomitant rheumatic diseases (eg, fibromyalgia);
• severe general condition of the patient.

Women of childbearing age should be examined for pregnancy and, when detected, excluded from the study. Clinical characteristics of patients should include:

• localization of osteoarthritis;
• the number of symptomatic joints with clinical symptoms;
• presence of joints of brushes affected by osteoarthritis (nodes of Geberden, Bushara, erosive osteoarthrosis);
• duration of symptoms of osteoarthritis;
• the period from the date of diagnosis of osteoarthritis;
• previous treatment (drugs, doses, duration of therapy);
• surgical treatment of the examined joint in the anamnesis (including arthroscopy) with obligatory indication of dates;
• the use of auxiliary devices (walking sticks, crutches, knee pads);
• intra-articular injections in the anamnesis (drug, dose, multiplicity of injections, duration of treatment, number of courses), indicating the dates of the last injections.

In addition, the clinical characteristics of patients can specify:

• Smoking (how many cigarettes a day, how long has it been smoked, if it does not smoke at present, how many years have they smoked and how long ago they refused to smoke);
• hormonal status (the period of postmenopause);
• associated chronic diseases;
• concomitant therapy (eg, estrogens, anti-inflammatory drugs).

The study protocol is limited to the evaluation of one group of joints (eg, knee or hip). With a bilateral lesion, the joint is evaluated with the most severe symptoms of the lesion. Changes in the contralateral joint may be considered secondary criteria. When studying the effectiveness of potential drugs modifying the structure of cartilage, changes in the contralateral joint, which at the beginning of the study was intact or with minimal changes, can be clinically and statistically significant. This fact must be taken into account when drawing up a research protocol and analyzing the results obtained.

In the physical examination of the joints studied, attention should be paid to the presence of inflammation (eg, joint effusion), a reduction in the volume of movements, deformities and contractures of the joint. The presence of severe valgus / varus deformity of large joints is a criterion for exclusion.

When assessing the degree of functional disorders in the joint being examined, the WOMAC or the LEUKEN system should be used before starting the study.

A general physical examination should be performed at the beginning and at the end of the study.

An important condition for the inclusion of a patient in the study is the signing of informed consent for participation in a study compiled in accordance with the Helsinki Declaration of the last revision and approved by the relevant structure of the research institution.

Procedure for conducting a clinical trial

Studies of the effectiveness of drugs used in osteoarthritis should be controlled by randomized double-blinds involving parallel groups. At the beginning of the study, screening and basic (randomized) visits are used, during which an anamnesis is collected, blood tests and other tests are performed, it is checked whether the patient meets inclusion criteria, etc .; then randomized patients according to a pre-designed scheme.

During each visit, in addition to examining the affected joint, it is also necessary to measure blood pressure, pulse, determine the patient's body weight, and also ask him about the side effects of treatment. To objectify the information received, the patient should be examined by the same doctor, preferably at the same time of day and day of the week throughout the study.

When compiling a study protocol, it is necessary to single out a primary (preferably one) criterion of effectiveness. The choice of these / these criteria depends on the research objectives and the class of the test drug. To strengthen the study design, the protocol should be supplemented with one or more secondary criteria.

The requirements of the "washout" period

For a certain period before the start of treatment with the symptomatic drug tested, all painkillers and anti-inflammatory drugs, including topical agents, should be discarded. The duration of this period is determined by the time necessary to stop the clinical effect (for example, 5 half-lives of the drug). During the washout period, patients can take paracetamol up to 4 mg / day (in the US) and up to 3 mg / day (in European countries). The latter is also canceled taking into account that at the beginning of taking the test drug, its effect was terminated. Deterioration of symptom osteoarthritis in the washout period should be noted in the protocol.

When carrying out studies of drugs that modify the structure of the cartilage, a washout period is not required. If there is a need to study the symptomatic effect of the test agent, the washout period is included in the protocol.

Purpose of the study drug

Control preparations may include a placebo or an active agent, for example an analgesic or an NSAID. The second advantage is the ability to demonstrate the predominance of the efficacy of the test agent over drugs that are widely used at present. In the case of using the reference preparation, a larger number of patients are required as a control. When treating intraarticular injections, there is often a placebo effect, so studies of the effectiveness of drugs administered intraarticularly should be placebo-controlled.

Topical preparations should be given to patients in the same containers as the reference drugs (drug or placebo). Placebo should completely mimic the test drug in appearance, smell and local effects on the skin. Clear instructions on the use of the drug should be stated to the patient physician in person, in writing, and also given in informed consent. Accuracy of the drug is checked by weighing the patient's returned tube with an ointment, gel or other form, or by measuring the volume of the liquid in the vial.

Type of preparations for oral and parenteral use (including intraarticular), as well as their packaging should be identical to those of the comparison agents or placebo. Oral preparations should preferably be given in blisters provided with glued labels, which indicate the exact date and time of delivery. Monitoring of the drug intake by patients is carried out by counting unused tablets (dragees, capsules).

Preparations for concomitant therapy (for example, analgesics or NSAIDs in studies of drugs that modify the structure of the cartilage) can be given in vials. During each visit, the counted tablets are counted. In the evening on the eve of the visit, as well as on the day of the visit, one should not take a concomitant anesthetic or anti-inflammatory drug, as this may affect the evaluation of the pain syndrome.

If it is not possible to ensure the identity of the test drug taken parenterally, to the comparison agent, a third person (for example, another doctor or nurse) should directly administer it, without telling the patient and the researcher which medication was administered.

Before intraarticular injections, the effusion is extracted from the joint cavity, its volume is noted in the protocol.

In carrying out all clinical studies of osteoarthritis, it is necessary to carry out a pharmacoeconomic analysis.

Concomitant drug treatment of osteoarthritis

It is illogical to expect that patients will participate in a long-term study without additional use of symptomatic drugs. Therefore, taking analgesics should be allowed, but limited. Limit the list of drugs, the maximum dose, as well as the time of admission (the day before the visit and the day of the visit should not take anesthetic). The protocol should necessarily include a section that notes the use of analgesics and NSAIDs, the implementation of intraarticular injections. If intra-articular injection of depot corticosteroids is not part of the study protocol, their use is prohibited.

Concomitant therapy may interfere with an adequate evaluation of the effectiveness of DMO AD. However, in the conduct of long-term studies it is impractical and unethical to exclude all concomitant medications. Exclusion is only those that can affect the structure of the joints. Concomitant therapy should be standardized, monitored and recorded in the protocol at each visit. As already noted, paracetamol is preferred. On the day of visit, as well as the evening before the visit, the drug concomitant therapy is not accepted.

Concomitant non-pharmacological therapy (physiotherapy, occupational therapy, exercise therapy) should also be standardized and brought into line with the protocol in such a way that it does not affect the outcome of the study. In the protocol it is necessary to allocate a section in which information on changes in body weight (decrease / increase), on the use of auxiliary devices (canes, crutches, etc.), and the appointment or modification of procedures, etc., will be recorded.

[13], [14], [15], [16], [17], [18], [19]

Laboratory Tests

For most multicenter studies routine laboratory tests ( complete blood count, urinalysis, blood chemistry) should be performed in central laboratories.

Routine analysis of synovial fluid should include the study of cells and crystals.

Side effects are recorded in the protocol at each visit and between visits. Indicate the date of occurrence, the degree of severity, the relationship to the study drug (associated / unrelated), the intended treatment and its duration, resolution of the adverse reaction.

Protocol violation

A repeated violation of the protocol by the patient is the basis for excluding him from the study. The reasons for termination of participation in the study in connection with the violation of the protocol should be specified. These may include taking unauthorized drugs for this study, using ancillary devices to relieve pain, etc.

Criteria for the effectiveness of treatment of osteoarthritis

In clinical trials of osteoarthritis, published criteria should be used, which other authors used in their works, which allows comparing the results of studies of various agents. The main list of criteria includes indicators:

• pain;
• physical function;
• general assessment of the patient's condition;
• X-ray or other imaging techniques (for 1 year studies).

Additional performance criteria, which are also recommended for inclusion in the protocol, are:

• quality of life (compulsory) and
• general assessment of the doctor.

The selection criteria for osteoarthritis studies include:

• inflammation;
• biological markers;
• stiffness;
• requiring the performance of a certain work (time of passage of a certain distance, overcoming a certain number of steps, carpentry, etc.);
• number of exacerbations;
• taking analgesics;
• volume of movements;
• distance between the ankles;
• distance between medial condyles of the femur;
• circumference of the joint, etc.

The primary criterion for the effectiveness of symptomatic drugs is pain. Her research should be conducted at regular intervals, the duration of which depends on the joint being studied and the research tasks (at least 1 month).

Assessment of pain in the affected joint should be made using a 5-point Likert scale (0 - no pain, 1 - mild pain, 2 - moderate pain, 3 - severe pain, 4 - very severe pain) or 10 cm of VASH. In addition, it is necessary to clarify what causes (for example, weight lifting, physical exercises, climbing the stairs) and / or when there is pain (for example, at night, at rest). For additional pain characteristics, some health assessment systems (WOMAC, HAQ, AIMS) can be used.

To assess the function of the affected knee and / or hip joints in patients with osteoarthritis, it is recommended to use WOMAC or API Leken, to a lesser extent HAQ and AIMS.

Assessment of the general condition of the patient by himself and the doctor should be carried out using the Likert scale or VASH.

Determining the quality of life of patients with osteoarthritis during the study is mandatory, although it does not apply to the primary criteria. The final choice of the system for assessing the quality of life (for example, SF-36, EuroQol) - for the researcher.

The information content of the above-mentioned selection criteria is not definitively defined, therefore, their inclusion in the study protocol is not mandatory.

[20], [21], [22], [23]

Methods of diagnosing osteoarthritis

In studies of drugs modifying the structure of the cartilage, the primary efficacy criterion is the evaluation of the morphology of the affected joint, which is performed with the help of indirect methods (X-ray, ultrasound, MRI) and direct (arthroscopy) imaging techniques. Clinical observation of patients receiving these drugs is performed at intervals of 3 months or less.

Radiography

Assess the radiographs of one joint ( knee, hip ) or affected joints of the test brush. Although the dynamics of not only the cartilage morphology but also the bone dynamics should be evaluated, the primary radiographic criterion for studies of the progression of gonarthrosis or coxarthrosis should be a measurement in millimeters of the height of the joint gap, since this indicator is more sensitive than the scoring methods by point system or degrees . Osteophytosis and other changes in the underlying bone should be studied as secondary criteria either by measuring in millimeters or by degrees using published atlases. When studying the factors preventing the development of osteoarthritis, the primary criterion is osteophyto, because this particular symptom is associated with pain in the knee joint, it enters the classification criteria for ACR for gonarthrosis and is the criterion of roentgenologic classification of gonarthrosis according to Kellgren and Lawrence. Criteria for osteoarthrosis of brushes should be based on those published in special atlases.

Performing an x-ray study of the joints under study at each visit is an important condition for an adequate evaluation of the progression of osteoarthritis. Radiography should be performed with strict adherence to the standardized protocol, which is developed on the basis of published recommendations, since the variability in measuring the height of the joint gap depends on the position of the patient (vertical or weight-bearing, horizontal), the procedure of radiography and other factors.

MRI

MRI allows you to visualize all the joint structures at the same time, which makes it possible to evaluate the joint as an organ. In addition, MRI allows you to quantify a number of morphological parameters of osteoarthritis. Developed non-invasive methods for quantifying the articular cartilage volume, its thickness, water content, especially in the early stages of the disease, are likely to be widely used in therapeutic studies in the future.

Ultrasound and scintigraphy

The informativity of computed tomography, ultrasound and scintigraphy has not been sufficiently studied, therefore, these methods are not recommended for use in long-term studies.

Arthroscopy

Arthroscopy is able to directly visualize articular cartilage and other intraarticular structures, including meniscus, synovial membrane, ligaments, chondrophytes. Attempts to quantify this information led to the development of two types of semi-quantitative systems. One of them encodes information on each cartilage damage (mainly - the depth and area of damage) in points, which are then added up, the second uses the global assessment of the doctor for degeneration of the cartilage in various departments, which is fixed on YOURS.

The informative value of molecular markers as criteria for the effectiveness of pathogenetic therapy of osteoarthritis has not been proven. However, biological markers can be used to evaluate the effect of drugs on certain pathogenetic mechanisms, as well as to study pharmacodynamics in Phase I of clinical trials.

[24], [25], [26], [27], [28], [29],