Levels of osteoarthritis clinical trials

Preclinical studies examine the potential mechanism of action and therapeutic range (effective - toxic dose) of a drug.

Results of a preclinical study may shorten the duration of a clinical trial of a potential drug that modifies cartilage structure.

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Phase I clinical trials for osteoarthritis

The pharmacokinetics and safety of the drug are studied, and sometimes the drug dose is also studied. Depending on the objectives, the subjects of the study are usually healthy volunteers or patients with osteoarthritis without concomitant pathology. A double-blind, placebo-controlled study with one or more doses of the drug is optimal for studying the safety of the test drug in phase I. Evaluation of the effectiveness of treatment may be a secondary task.

Phase II clinical trials for osteoarthritis

The objective of phase II is to determine the ideal therapeutic range and dosing regimens of the drug under study. The duration of the study and the number of patients depend on the mechanism of action of the drug, its duration of action, the efficacy criteria that will be used in the study protocol, the variability of the parameters under study, and the patient population. In this and subsequent studies, it is necessary to determine the minimum effective and maximum tolerated doses of the drug, as well as the effect profile of these doses in patients with osteoarthritis.

A phase II symptomatic drug trial should be placebo-controlled, randomized, and double-blind. Efficacy can be demonstrated within a few days of testing. A longer trial (over several weeks) may be needed to demonstrate the slow onset of action of the drug or the duration of the effect obtained. An even longer trial may be needed to study the safety of the drug. Long-term trials of symptomatic drugs may require the administration of analgesics. For this purpose, short-acting analgesics should be administered after an appropriate washout period.

Phase III clinical trials for osteoarthritis

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

The duration of phase III clinical trials of the efficacy of fast-acting symptomatic drugs should not exceed 4 weeks (sometimes significantly less). An adequate washout period is necessary to objectify the study. For a more in-depth study of the safety of a fast-acting symptomatic agent, a short double-blind study can be followed by a longer double-blind or open trial. To demonstrate the efficacy of slow-acting symptomatic agents, a longer period and additional pain relief will be needed.

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

Phase IV clinical trials for osteoarthritis

Phase IV clinical trials are conducted after the relevant authorities have approved the clinical use of the drug. Phase IV studies are conducted to study clinical observations in more depth, which expands the list of indications. In addition, the study examines rare side effects, as well as the effectiveness of long-term treatment with the drug being tested. Some phase IV studies may be open-label.

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 us to evaluate their dynamics. Thus, the following are mandatory criteria for inclusion of patients in the study of the effectiveness of symptomatic drugs:

• the severity of pain syndrome according to VAS is not less than 2.5 cm or according to the 5-point Likert scale - not less than 1 point;
• the presence of certain radiographic criteria for osteoarthritis, such as stage II (or higher) according to Kellgren and Lawrence for the knee joint (i.e. the presence of certain OFs) or stage II (or higher) according to the modified Croft scale for the hip joints.

Among the criteria for inclusion in the study of 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 stage 0 or stage I osteoarthrosis on radiographs according to Kellgren and Lawrence (i.e. the absence of certain osteophytes); to study the ability to slow down the pathological process of stage II or III or prevent its progression according to Kellgren and Lawrence, in which the degree of narrowing of the joint space allows us to assess the progression of the disease;
• The presence of pain in the joints under study at the time of inclusion or in the anamnesis is not required; the dynamics of pain syndrome can be studied as a secondary (additional) criterion of effectiveness.

In studies of drugs that modify cartilage structure, it is important to select a subpopulation of patients with a high risk of rapid progression of osteoarthritis. To identify such a subpopulation, some biological markers can be used that can predict the progression of changes in radiographs of affected joints.

In addition, the inclusion criteria must include the age and gender of the patients being studied, what diagnostic criteria will be used, and which joints affected by osteoarthritis will be studied (e.g. knees or hips).

Exclusion criteria should also be clearly defined and include the following:

• the severity of symptoms of osteoarthritis;
• degree of radiographic changes;
• concomitant diseases;
• history of peptic ulcer (if toxicity of the drug to the gastrointestinal mucosa is suspected);
• concomitant therapy;
• pregnancy/contraception;
• intra-articular injections of depot corticosteroids or hyaluronic acid;
• tidal lavage;
• presence of secondary osteoarthritis.

The time interval since the last intra-articular injection of a depot corticosteroid or hyaluronic acid is an important exclusion criterion. It is necessary to optimally minimize the possible impact of intra-articular injections on the symptoms of osteoarthritis. The recommended interval is at least 3 months. The investigator may increase this interval when using hyaluronic acid, since reliable data on the duration of its symptomatic effect are absent. When conducting long-term (more than 1 year) studies, stratification of patients who received intra-articular injections before the start of the trial is necessary.

Additional exclusion criteria are:

• serious trauma to the affected joint within 6 months prior to the start of the study;
• arthroscopy within 1 year prior to the start of the study;
• damage to the spine or joints of the lower extremities, accompanied by severe pain syndrome, which can complicate the assessment of the joint being examined;
• the patient's use of assistive devices for mobility (except for a cane or crutch);
• concomitant rheumatic diseases (eg, fibromyalgia);
• severe general condition of the patient.

Women of childbearing age should be examined for pregnancy and excluded from the study if pregnancy is detected. The clinical characteristics of patients should include:

• localization of osteoarthritis;
• number of symptomatic joints with clinical symptoms;
• the presence of hand joints affected by osteoarthritis (Heberden's nodes, Bouchard's nodes, erosive osteoarthritis);
• duration of symptoms of osteoarthritis;
• the period from the moment of diagnosis of osteoarthritis;
• previous treatment (medications, doses, duration of therapy);
• history of surgical treatment of the joint under examination (including arthroscopy) with mandatory indication of dates;
• use of assistive devices (canes, crutches, knee pads);
• history of intra-articular injections (drug, dose, frequency of injections, duration of treatment, number of courses) indicating the dates of the last injections.

Additionally, the clinical characteristics of patients may include:

• smoking (how many cigarettes a day, how long has he/she smoked; if he/she does not currently smoke, how many years he/she smoked and how long ago he/she quit smoking);
• hormonal status (postmenopausal period);
• concomitant chronic diseases;
• concomitant therapy (eg, estrogens, anti-inflammatory drugs).

The study protocol is limited to the assessment of one group of joints (e.g., knee or hip). In case of bilateral lesions, the joint with the most pronounced symptoms of the lesion is assessed. Changes in the contralateral joint can be considered as secondary criteria. When studying the effectiveness of potential drugs that modify the structure of cartilage, changes in the contralateral joint, which was intact or with minimal changes at the beginning of the study, may be clinically and statistically significant. This fact must be taken into account when drawing up the study protocol and analyzing the results.

During physical examination of the joints under study, attention should be paid to the presence of inflammation (e.g., joint effusion), decreased range of motion, deformities, and joint contractures. The presence of severe valgus/varus deformity of large joints is an exclusion criterion.

When assessing the degree of functional impairment in the joint under study, it is necessary to use the WOMAC or AFI Lekena system before starting the study.

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

An important condition for the inclusion of a patient in the study is the signing of an informed consent to participate in the study, drawn up in accordance with the Declaration of Helsinki, last revised, and approved by the relevant structure of the research institution.

Procedure for conducting a clinical trial

Studies of the efficacy of drugs used in osteoarthritis should be controlled, randomized, double-blind, and parallel-group studies. At the beginning of the study, screening and baseline (randomization) visits are used, during which anamnesis is collected, blood tests and other analyses are performed, whether the patient meets the inclusion criteria, etc. are checked; then patients are randomized according to a pre-developed 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 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 entire examination.

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

Washout period requirements

All painkillers and anti-inflammatory drugs, including topical agents, must be discontinued for a certain period before the start of treatment with the test symptomatic drug. The duration of this period is determined by the time required for the clinical effect to cease (e.g., 5 half-lives of the drug). During the washout period, patients may take paracetamol up to 4 mg/day (in the USA) and up to 3 mg/day (in European countries). The latter is also discontinued, taking into account that by the start of taking the test drug, its effect has ceased. Worsening of osteoarthrosis symptoms during the washout period must be noted in the protocol.

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

Purpose of the study drug

Control drugs may include a placebo or an active agent, such as an analgesic or NSAID. The advantage of the latter is the ability to demonstrate the superiority of the agent under study over drugs that are widely used at present. In the case of using a reference drug as a control, a larger number of patients is required. Intra-articular injections often result in a placebo effect, so studies of the efficacy of drugs administered intra-articularly should be placebo-controlled.

Topical preparations should be given to patients in the same containers as the comparison preparations (drug or placebo). The placebo should completely imitate the preparation under study in appearance, smell and local effect on the skin. Clear instructions on the use of the preparation should be given to the patient by the doctor personally, in writing, and also included in the informed consent. The accuracy of the use of the preparation is checked by weighing the tube with ointment, gel or other form returned by the patient or by measuring the volume of liquid in the bottle.

The type of preparations for oral and parenteral use (including intra-articular), as well as their packaging, should be identical to those of the comparison agents or placebo. Oral preparations are best given in blisters with adhesive labels indicating the exact date and time of issue. Monitoring of drug intake by patients is carried out by counting unused tablets (pills, capsules).

Concomitant medications (e.g. analgesics or NSAIDs in studies of cartilage-modifying drugs) may be given in vials. Tablets used are counted at each visit. Concomitant analgesics or anti-inflammatory medications should not be taken the evening before or on the day of the visit, as this may affect the pain assessment.

If it is not possible to ensure that the test drug administered parenterally is identical to the comparator, the actual administration should be performed by a third party (e.g. another physician or nurse) without informing the patient and the investigator which drug was administered.

Before intra-articular injections, effusion is removed from the joint cavity, and its volume is noted in the protocol.

Pharmacoeconomic analysis should be included in all clinical trials of osteoarthritis.

Concomitant drug treatment of osteoarthritis

It is illogical to expect patients to participate in a long-term study without additional use of symptomatic drugs. Therefore, the use of analgesics should be allowed, but limited. The list of drugs, maximum doses, and time of administration are limited (painkillers should not be taken the day before the visit and on the day of the visit). The protocol must necessarily include a section noting the use of analgesics and NSAIDs, and the performance of intra-articular injections. If intra-articular administration of depot corticosteroids is not part of the study protocol, their use is prohibited.

Concomitant therapy may interfere with adequate assessment of the efficacy of DMO AD. However, in long-term studies, it is neither practical nor ethical to exclude all concomitant medications. Only those that may affect joint structure should be excluded. Concomitant therapy should be standardized, monitored, and recorded in the protocol at each visit. As already noted, paracetamol is preferred. No concomitant medication should be taken on the day of the visit or the evening before the visit.

Concomitant non-drug therapy (physiotherapy, occupational therapy, exercise therapy) should also be standardized and brought into compliance with the protocol so that it does not affect the outcome of the study. The protocol should include a section that records information on changes in body weight (decrease/increase), the use of assistive devices (canes, crutches, etc.), as well as the appointment or change of procedures, etc.

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Lab tests

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

Routine synovial fluid analysis should include examination of cells and crystals.

Side effects are recorded in the protocol at each visit and between visits. The date of occurrence, severity, relation to the study drug (associated/not associated), prescribed treatment and its duration, resolution of the side effect are indicated.

Protocol violation

Repeated violation of the protocol by the patient is grounds for his/her exclusion from the study. The reasons for termination of participation in the study due to protocol violation must be specified. These may include taking drugs not permitted for this study, using auxiliary devices for pain relief, etc.

Criteria for the effectiveness of osteoarthritis treatment

In clinical studies of osteoarthritis, it is necessary to use published criteria that have been used by other authors in their studies, which allows comparison of the results of studies of different agents. The main list of criteria includes indicators:

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

Additional performance criteria that are also recommended to be included in the protocol include the following indicators:

• quality of life (mandatory) and
• General assessment by the doctor.

Selection criteria for osteoarthritis studies include indicators of:

• inflammation;
• biological markers;
• stiffness;
• requiring the performance of a certain amount of work (time to cover a certain distance, climb a certain number of steps, wrist strength, etc.);
• number of exacerbations;
• taking analgesics;
• range of motion;
• distance between ankles;
• distance between the medial condyles of the femurs;
• joint circumference, etc.

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

The severity of pain in the affected joint should be assessed using a 5-point Likert scale (0 - no pain, 1 - mild pain, 2 - moderate pain, 3 - severe pain, 4 - very severe pain) or a 10 cm VAS. In addition, it is necessary to specify what triggers the pain (e.g., carrying heavy objects, exercise, climbing stairs) and/or when the pain occurs (e.g., at night, at rest). Some health assessment systems (WOMAC, HAQ, AIMS) can be used to further characterize the pain.

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

The patient's general condition should be assessed by the patient himself and the physician using the Likert scale or VAS.

Determining the quality of life of patients with osteoarthritis during the study is mandatory, although it does not relate to the primary criteria. The final choice of the quality of life assessment system (e.g. SF-36, EuroQol) is up to the researcher.

The informativeness of the above selection criteria has not been finally determined, therefore their inclusion in the research protocol is not mandatory.

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Methods of diagnosing osteoarthritis

In studies of cartilage-modifying drugs, the primary criterion for efficacy is the assessment of the morphology of the affected joint, which is performed using indirect (radiography, ultrasound, MRI) and direct (arthroscopy) imaging methods. Clinical observation of patients receiving these drugs is performed at intervals of 3 months or less.

X-ray

Radiographs of one joint ( knee, hip ) or affected joints of the examined hand are evaluated. Despite the fact that it is necessary to evaluate the dynamics of not only the cartilage morphology but also the bone, the primary radiographic criterion for studies of the progression of gonarthrosis or coxarthrosis should be the measurement in millimeters of the height of the joint space, since this indicator is more sensitive than the methods of assessment by the point system or by degrees. Osteophytosis and other changes in the underlying bone should be studied as secondary criteria either measuring in millimeters or by degrees using published atlases. When studying the factors preventing the development of osteoarthritis, the primary criterion is osteophytosis, since this sign is associated with pain in the knee joint, is included in the ACR classification criteria for gonarthrosis and is a criterion for the radiographic classification of gonarthrosis according to Kellgren and Lawrence. Criteria for osteoarthritis of the hands should be based on those published in special atlases.

Performing radiographic examination of the joints under study at each visit is an important condition for adequate assessment of osteoarthritis progression. Radiography should be performed in strict compliance with the conditions of a standardized protocol, which is developed on the basis of published recommendations, since the variability of joint space height measurement depends on the patient's position (upright or weight-bearing, horizontal), the radiography procedure itself, and other factors.

MRI

MRI allows visualization of all joint structures simultaneously, which makes it possible to evaluate the joint as an organ. In addition, MRI allows quantitative evaluation of a number of morphological parameters of osteoarthritis. The developed non-invasive methods for quantitative evaluation of articular cartilage volume, its thickness, water content, especially in the early stages of the disease, will probably be widely used in therapeutic studies in the future.

Ultrasound and scintigraphy

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

Arthroscopy

Arthroscopy can directly visualize articular cartilage and other intra-articular structures, including menisci, synovium, ligaments, and chondrophytes. Attempts to quantify this information have led to the development of two types of semi-quantitative scoring systems. One codes information about each cartilage lesion (primarily the depth and area of damage) into scores that are then summed up; the other uses the physician's global assessment of cartilage degeneration in various compartments, which is recorded on a VAS.

The informativeness of molecular markers as criteria for the effectiveness of pathogenetic therapy for osteoarthrosis has not been proven. However, biological markers can be used to assess the effect of drugs on certain pathogenetic mechanisms, as well as to study pharmacodynamics in phase I clinical trials.

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