Prednisolone Versus Colchicine for Acute Gout in Primary Care (COPAGO)

Pragmatic, Randomized, Multicenter, Double-blind, Controlled, Clinical Trial of Prednisolone Versus Colchicine for Acute Gout in Primary Care

Gout is the most common form of rheumatic disease in which monosodium urate crystals are deposited in the joints followed by acute inflammatory reactions. There are various approved drugs that can be prescribed for pain relief during an acute gout attack. However to date, no direct comparison of efficacy of colchicine and prednisolone for the treatment of acute gout attacks has been investigated. Furthermore, majority of previous research studies were not only conducted in tertiary centres but also excluded patients with common comorbidities due to contraindications with naproxen. This pragmatic, prospective, double-blind, parallel-group, randomized, non-inferiority trial will investigate whether prednisolone (treatment drug) is comparable or only acceptably worse than treatment with colchicine (comparison drug) in patients presenting with acute gout. Patients presenting with acute gout to their general practitioners in 60 practices across 3 university sites (Greifswald, Göttingen, and Würzburg) will be invited to participate. Patients often excluded by previous studies due to contraindications with naproxen will also be able to participate. The investigators will compare the absolute levels of the most severe pain on day 3 (in the last 24 hours) measured with an 11-item numerical rating scale as the primary endpoint. Day 0 is the day patients take their study medication for the first time. They are then asked to fill out a study diary at the same time each day to quantify their pain. Pain scores will then be used as comparison between the two medications.

SCIENTIFIC BACKGROUND: Gout is one of the most common rheumatic diseases, affecting 3-6% of men and 1-2% of women in western countries. Due to the severe pain and impaired quality of life, the individual burden of disease during an acute gout attack is very high. Currently, there are several approved medications available for the treatment of acute gout attacks. The EULAR (European League Against Rheumatism) guideline recommends colchicine as the drug of first choice for acute gout attacks. But according to it, non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids can also be used. In contrast, DEGAM (German Society for General Medicine and Family Medicine) recommends using prednisolone. Most commonly, gout attacks are treated in general practices. However, studies on the treatment of acute gout attacks have so far been conducted mainly in specialised centres, and thus in a selective patient group. The gold standard for the diagnosis of gout in rheumatology centres is the detection of monosodium urate crystals in aspirated joint fluid. In primary care, however, the diagnosis of gout is made on the basis of clinical symptoms alone. Because of the risk of injury and infection, joint puncture is not usually performed on patients in a general practice setting. Prednisolone and low-dose colchicine were selected for the study due to a high prevalence of patients with contraindications to NSAIDs, including, cardiovascular disease, oral anticoagulation, chronic kidney disease or a history of gastrointestinal disease. Approximately 20-30% of patients with gout are poorly suited for NSAID administration and in previous studies, those patients were excluded. RESEARCH QUESTION: This non-inferiority trial is going to investigate whether prednisolone (treatment drug) is comparable or only acceptably worse than treatment with colchicine (comparator drug). Both treatments will be compared on the basis of the absolute pain scores achieved on day 3 of follow-up. Unlike most studies conducted in tertiary care centres, this study is going to be set in primary care. The dosage of the study's medications will be according to the recommendations of the EULAR and DEGAM guidelines. Both drugs are in tablet form. Since a preference of the treating physicians regarding the use of prednisolone or colchicine is suspected, the study will be conducted in a double-blinded manner. Due to the different intake regimen, placebos will be used in addition to the effective medications (double-dummy method). DUAL ENERGY COMPUTED TOMOGRAPHY: The dual energy computed tomography (DECT) is able to detect monosodium urate crystals. The amount of monosodium urate crystals in the joint (volume) is an indicator of disease burden and can also be used to make treatment decisions regarding uric acid-lowering therapy (ULT) to avoid the occurrence of potential future gout attacks. Although imaging techniques, such as DECT, show promise in classifying symptomatic gout, studies to date are small and mainly involve people with long-standing, established disease from a hospital setting. In those with the first acute gout attack, diagnostic sensitivity ranges from 35.7 % to 61.5 %. Due to the unclear diagnostic sensitivity in first attacks, the DECT examination will not be mandatory in the present study. It will be offered to all participants as optional. About 10% of the participants are expected to have a gout attack in the hand. Since the joints of the feet are the main site of manifestation of acute gout attacks, crystal deposits in the feet are also expected in these study participants. In order to ensure comparability of the volume measurement, the dual energy CT examination is therefore limited to the feet. The aim of the dual energy CT examination is to describe the frequency and volume of monosodium urate crystals in patients with gout in primary care. In a sensitivity analysis, the primary endpoint in patients with positive DECT findings will be analysed. Furthermore, the association between the duration of gout diagnosis and crystal volume as a marker for disease burden will be investigated. The investigation of the frequency and volume of monosodium urate crystals provides the basis for the design of further studies on the usefulness of DECT for the indication and monitoring of uric acid-lowering therapies in primary care. STUDY PROCEDURE: During the study, the participants will attend their General Practitioner's practice twice (baseline and one-off on day 6-8), as well as, an optional visit for a DECT at the university medical centre in the local region (day 7-13) and a one-off telephone interview on day 27-34. The study period for the individual participant will be 4 weeks. On day 0 (day of first presentation at the general practice), patients with an acute gout attack in the hand or foot present to their general practitioner. If the diagnosis of gout is confirmed and patients are eligible for participation in the study, they will be consented and randomly assigned to one of two treatment groups. While patient group 1 is treated with prednisolone for 5 days, patient group 2 receives colchicine for 5 days. So that neither the patient nor the general practitioner knows the allocation, both treatment groups also receive a placebo (dummy medication). A laboratory test will also be performed to determine serum uric acid levels, as well as, inflammatory markers and renal function. The aim of blood collection and determination of laboratory parameters is to descriptively describe the patient population and to perform subgroup analyses with regard to the primary endpoint. During days 1 to 6, patients are requested to complete a patient diary. The primary and secondary endpoints (pain, joint swelling, joint tenderness) and, if further analgesia is needed, the use of additional pain medication will be recorded in the diary. Participants who have a blood pressure monitor will be asked to measure and record their blood pressure daily. On day 6, the patients are also asked to assess potential functional limitations caused by the gout attack and to give a global assessment of the treatment success. After one week, patients return for their follow-up visit (visit 2) to their general practitioners. They are examined again and are asked to return their study diary and any remaining medication packets. After 4 weeks, the patients will be contacted by telephone by our study nurses and asked about the clinical course of their gout attack (recurrence of an acute gout attack, further treatment, duration of incapacity to work, adverse events). The telephone call lasts about 15 minutes. In addition, study participants will receive the optional offer to have a one-time dual-energy CT examination of their feet on days 7-13 to check for the presence of uric acid crystals. Imaging of both feet using a Siemens Dual Source SOMATOM Definition Flash or SOMATOM Force will be performed.

This clinical trial is a two-arm multicentre, pragmatic, prospective, randomised, double-blind, controlled clinical trial of prednisolone and colchicine for non-inferiority with a parallel group design (phase IV). According to the guidelines of the German Society of General Medicine (DEGAM), the decision to start gout treatment is made clinically. As this is a pragmatic study, eligibility will be determined during a routine clinical examination. The clinical diagnosis is made without new laboratory tests, joint puncture with synovial analysis or imaging. 314 patients with an acute gout attack are going to be recruited in 60 General Practitioner's practices across 3 university sites (Greifswald, Göttingen, and Würzburg). All study participants receive active treatments, but are randomised into either the prednisolone group (treatment group) or the colchicine group (comparison group). The study lasts 4 weeks for each participant.

There are 2 active and effective treatments (colchicine vs. prednisolone). The allocation to the treatment arms is 1:1, and study participants are randomised to either group. Randomisation is intended to reduce selection and allocation bias. As both drugs have different dosing regimens, the investigators provide identical blisters for both drugs including the active substance and corresponding placebos. This way, all study participants receive the same number of tablets and the possibility of drug prediction is more difficult. This is achieved by using tablets that are identical in taste and appearance (double-dummy design). Participants randomised to the colchicine arm will receive colchicine plus prednisolone placebo. Participants randomised to the prednisolone arm will receive prednisolone plus a colchicine placebo. The prednisolone placebos contain a bittering agent due to the bitter taste of prednisolone to ensure a similar taste.

As both drugs have different dosing regimens, the investigators provide identical blisters for both drugs including the active substance and corresponding placebos. This way, all study participants receive the same number of tablets and the possibility of drug prediction is more difficult. This is achieved by using tablets that are identical in taste and appearance (double-dummy design). Participants randomised to the prednisolone arm will receive prednisolone plus a colchicine placebo. The prednisolone placebos contain a bittering agent due to the bitter taste of prednisolone to ensure a similar taste. The dosage is according to EULAR guideline and also within the recommended range of the DEGAM guideline. The cumulative total dose taken per participant within the clinical trial is 150 mg for prednisolone.

As both drugs have different dosing regimens, the investigators provide identical blisters for both drugs including the active substance and corresponding placebos. This way, all study participants receive the same number of tablets and the possibility of drug prediction is more difficult. This is achieved by using tablets that are identical in taste and appearance (double-dummy design). Participants randomised to the colchicine arm will receive colchicine plus prednisolone placebo. The dosage is according to EULAR guideline and also within the recommended range of the DEGAM guideline. The cumulative total dose taken per participant within the clinical trial is 5.5mg for colchicine.

To investigate whether the efficacy of prednisolone in General Practitioner's care is equally good or only marginally weaker than treatment with low-dose colchicine, the most severe pain in the last 24 hours on day 3 after baseline on an 11-point numerical rating scale is used and compared across groups. The study participants take their study medication for the first time on day 0 and are then asked to fill out their diary daily at the same time to quantify their pain. 0 stands for no pain and 10 for the strongest pain imaginable.

For this purpose, the most severe pain described on an 11-point numerical rating scale across treatment days (from day 1 - 6 of follow-up) is used and compared across groups. The study participants take their study medication for the first time on day 0 and are then asked to fill out their diary daily at the same time to quantify their pain. 0 stands for no pain and 10 for the strongest pain imaginable.

Reduction in joint swelling and tenderness measured using 4-point Likert scale on day 3 after baseline per treatment arm, e.g.: Swelling quantified as no joint swelling, palpable, visible, and bulging beyond the joint margins. Sensitivity to touch of the joint is quantified as no pain, pain, pain and winces, and pain, winces and withdraws, and subsequent comparison.

Physical function on day 6 compared to baseline will be assessed with the following questions: How much are you now restricted in your normal daily activities by the gout attack? How much trouble do you have putting on a shoe today? How much pain do you have when you walk today? How much trouble do you have grasping and holding something with your affected hand (for example, when unscrewing a bottle)? All questions will be described on an 11-point numerical rating scale, 0 indicating "not at all/no problem" and 10 indicating "worst pain ever".

This is going to be measured measured with 5-point Likert scale (excellent, very good, good, fair, poor) on day 6 after baseline and treatment arms will be compared.

For this outcome the same model specification as for the primary outcome is applied and the adjustment for age will be substituted with adjustment for disease duration.

The frequency and volume of monosodium urate crystals (milliliter) in feet joints in patients with gout in primary care will be investigated.

The investigators will investigate the association between the volume of monosodium urate crystals (milliliter) in feet joints and patient characteristics (e.g. age, sex, previous gout attacks).

The investigators will investigate the association between frequency and volume of monosodium urate crystals (milliliter) in feet joints in patients with gout in primary care and (previous) use of uricostats and uricosurics.

The investigators will investigate the association between the volume of monosodium urate crystals (milliliter) in feet joints in patients with gout in primary care and pain intensity at baseline (on an 11-point numerical rating scale).

Inclusion Criteria: Adult patients ≥ 18 years of age Clinical diagnosis of acute attack of gout (symptoms: pain, swelling, tenderness, redness or local hyperthermia). Acute pain in hand or foot (podagra, chiragra) (existing since the previous day at the most) Willingness to participate in the study and ability to give written informed consent. Exclusion Criteria: Known intolerance or contraindication to either medication Known intolerance to the placebo (e.g. lactose intolerance). Existing (or less than 2 weeks ago) oral treatment with corticosteroids or colchicine. Known chronic kidney disease (CKD stage 4 or greater) or an available value of estimated glomerular filtration rate (eGFR) < 30ml/min/1.73 m². Known haematopoietic disorder or available values of platelets < 30,000 µl or leucocytes < 4000 µl, or Hb <5 mmol/l/ or 8 g/dl Uncontrolled high blood pressure (systolic blood pressure permanently above 160 mmHg). Known liver cirrhosis or severe liver disease or available liver enzymes results (ie. Serum Glutamate Oxalate Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase(SGPT)) being elevated by more than twice the respective reference range Known current gastric or duodenal ulcer (diagnosed in the last 4 weeks) Current chemotherapy or chemotherapy completed less than 3 months ago Known HIV infection Solid organ transplant with immune suppression Desire to have children within the next 6 months in both men and women Existing pregnancy or breastfeeding Participation in other studies according to the German Medicines Act in the last 3 months Participation in the COPAGO study with past gout attack

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