Clinical trial NCT05698680: Prednisolone Versus Colchicine for Acute Gout in Primary Care
Official title: Pragmatic, Randomized, Multicenter, Double-blind, Controlled, Clinical Trial of Prednisolone Versus Colchicine for Acute Gout in Primary Care
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Acute Gout
Keywords: Primary care
Prednisolone
Colchicine
Pragmatic
Lead sponsor: University Medicine Greifswald
Sponsor class: OTHER
Collaborators: name: University of Göttingen
name: Wuerzburg University Hospital
First posted: 2023-01-26
Enrollment: 314
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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 (Greifswald or Göttingen; 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.

Eligibility criteria: 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)
* The onset of pain was no more than 2 days ago (e.g., presentation on Monday afternoon, onset of pain on Saturday morning)
* 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

Primary outcomes:
measure: Most severe pain in the last 24 hours
timeFrame: Day 3
Secondary outcomes:
measure: Average response to treatment
timeFrame: Day 1, 2, 3, 4, 5, 6
measure: Swelling and tenderness of the joint
timeFrame: Day 3
measure: Physical function
timeFrame: Day 1 and 6
measure: Patients' global assessment of treatment success
timeFrame: Day 6
measure: Most severe pain in the last 24 hours depending on disease duration
timeFrame: Day 1 and 6
measure: Frequency of use of additional pain medication by treatment group
timeFrame: Day 1 - 6
measure: Frequency of use of non-pharmacological pain therapies
timeFrame: Day 1 - 6
Other outcomes:
measure: Dual Energy Computed Tomography Investigation: Presence of monosodium urate crystals
timeFrame: one assessment during days 7 - 13
measure: Dual Energy Computed Tomography Investigation: Patient characteristics
timeFrame: one assessment during days 7 - 13
measure: Dual Energy Computed Tomography Investigation: Use of uricostats and uricosurics
timeFrame: one assessment during days 7 - 13
measure: Dual Energy Computed Tomography Investigation: Pain intensity
timeFrame: one assessment during days 7 - 13
Locations:
city: Ittlingen
country: Germany
facility: Arztpraxis Burgtorstr. 2
state: Baden-Württemberg
city: Neckargemünd
country: Germany
facility: Hausarztpraxis Neckarsteinacher Str. 22
state: Baden-Württemberg
city: Bad Bocklet
country: Germany
facility: Hausarztpraxis Kleinfeldlein 3
state: Bayern
city: Bad Kissingen
country: Germany
facility: Hausarztpraxis Kapellenstraße 3
state: Bayern
city: Bad Kissingen
country: Germany
facility: Hausarztpraxis Ludwigstraße 18
state: Bayern
city: Bad Neustadt An Der Saale
country: Germany
facility: Hausarztpraxis Goethestraße 15 G
state: Bayern
city: Bischofsheim
country: Germany
facility: Hausarztpraxis Ahornstraße 1
state: Bayern
city: Erlenbach am Main
country: Germany
facility: Hausarztpraxis Mechenharder Straße 174
state: Bayern
city: Gössenheim
country: Germany
facility: Hausarztpraxis Hauptstraße 12
state: Bayern
city: Hammelburg
country: Germany
facility: Hausarztpraxis Bahnhofstraße 24
state: Bayern
city: Haßfurt
country: Germany
facility: Hausarztpraxis Torgraben 3
state: Bayern
city: Kitzingen
country: Germany
facility: Hausarztpraxis Kaiserstraße 43
state: Bayern
city: Leinach
country: Germany
facility: Hausarztpraxis Rathausstraße 31
state: Bayern
city: Rimpar
country: Germany
facility: Hausarztpraxis Herrngasse 11 A
state: Bayern
city: Schweinfurt
country: Germany
facility: Hausarztpraxis Spitalstr. 9
state: Bayern
city: Stadtlauringen
country: Germany
facility: Hausarztpraxis Sulzdorfer Straße 6a
state: Bayern
city: Würzburg
country: Germany
facility: Hausarztpraxis Dorfgraben 2a
state: Bayern
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
state: Bayern
city: Würzburg
country: Germany
facility: Hausarztpraxis Moltkestraße 5
state: Bayern
city: Zellingen
country: Germany
facility: Hausarztpraxis Point 3
state: Bayern
city: Anklam
country: Germany
facility: Hausarztpraxis Bluthsluster Straße 2
state: Mecklenburg-Vorpommern
city: Barth
country: Germany
facility: Hausarztpraxis Am Westhafen 1
state: Mecklenburg-Vorpommern
city: Dargun
country: Germany
facility: Hausarztpraxis Schlossstraße 43
state: Mecklenburg-Vorpommern
city: Greifswald
country: Germany
facility: Krankenhaus Universitätsmedizin Greifswald
state: Mecklenburg-Vorpommern
city: Greifswald
country: Germany
facility: Hausarztpraxis Am Mühlentor 5
state: Mecklenburg-Vorpommern
city: Greifswald
country: Germany
facility: Hausarztpraxis Anklamer Straße 66
state: Mecklenburg-Vorpommern
city: Greifswald
country: Germany
facility: Hausarztpraxis Lange Straße 53
state: Mecklenburg-Vorpommern
city: Greifswald
country: Germany
facility: Hausarztpraxis Markt 1
state: Mecklenburg-Vorpommern
city: Greifswald
country: Germany
facility: Hausarztpraxis Ernst-Thälmann-Ring 66
state: Mecklenburg-Vorpommern
city: Groß Kiesow
country: Germany
facility: Hausarztpraxis Schulstraße 1a
state: Mecklenburg-Vorpommern
city: Gützkow
country: Germany
facility: Hausarztpraxis Pommersche Straße 18
state: Mecklenburg-Vorpommern
city: Klausdorf
country: Germany
facility: Hausarztpraxis Prohner Straße 43
state: Mecklenburg-Vorpommern
city: Loitz
country: Germany
facility: Hausarztpraxis August-Levin-Straße 22c
state: Mecklenburg-Vorpommern
city: Lübstorf
country: Germany
facility: Hausarztpraxis Bahnhofstraße 16
state: Mecklenburg-Vorpommern
city: Lühmannsdorf
country: Germany
facility: Hausarztpraxis Oberreihe 41
state: Mecklenburg-Vorpommern
city: Neubrandenburg
country: Germany
facility: Hausarztpraxis Juri-Gagarin-Ring 24
state: Mecklenburg-Vorpommern
city: Plate
country: Germany
facility: Hausarztpraxis Störstraße 2
state: Mecklenburg-Vorpommern
city: Reuterstadt Stavenhagen
country: Germany
facility: Hausarztpraxis Werdohler Straße 3
state: Mecklenburg-Vorpommern
city: Stralsund
country: Germany
facility: Hausarztpraxis Marienstraße 2-4
state: Mecklenburg-Vorpommern
city: Trent
country: Germany
facility: Hausarztpraxis Dorfstraße 57
state: Mecklenburg-Vorpommern
city: Trinwillershagen
country: Germany
facility: Hausarztpraxis Birkenweg 5
state: Mecklenburg-Vorpommern
city: Trollenhagen
country: Germany
facility: Hausarztpraxis Otto-Lilienthal-Straße 3
state: Mecklenburg-Vorpommern
city: Ueckermünde
country: Germany
facility: Hausarztpraxis Ueckerstraße 48
state: Mecklenburg-Vorpommern
city: Waren
country: Germany
facility: Hausarztpraxis Lange Straße 55
state: Mecklenburg-Vorpommern
city: Wolgast
country: Germany
facility: Hausarztpraxis Wilhelmstraße 3
state: Mecklenburg-Vorpommern
city: Bad Lauterberg Im Harz
country: Germany
facility: Hausarztpraxis Wissmannstraße 14
state: Niedersachsen
city: Bilshausen
country: Germany
facility: Hausarztpraxis Hoher Weg 17
state: Niedersachsen
city: Gleichen
country: Germany
facility: Hausarztpraxis Bohlendamm 2
state: Niedersachsen
city: Goslar
country: Germany
facility: Hausarztpraxis Liererstr. 28
state: Niedersachsen
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
state: Niedersachsen
city: Göttingen
country: Germany
facility: Hausarztpraxis Ewaldstr. 40a
state: Niedersachsen
city: Göttingen
country: Germany
facility: Hausarztpraxis Hennebergstr. 14a
state: Niedersachsen
city: Göttingen
country: Germany
facility: Hausarztpraxis Backhausstraße 21
state: Niedersachsen
city: Göttingen
country: Germany
facility: Hausarztpraxis Godehardtstraße 26
state: Niedersachsen
city: Hann. Münden
country: Germany
facility: Hausarztpraxis Professor-Eberlein-Str. 6
state: Niedersachsen
city: Hann. Münden
country: Germany
facility: Hausarztpraxis Steinstraße 19
state: Niedersachsen
city: Hardegsen
country: Germany
facility: Hausarztpraxis Vor dem Tore 2
state: Niedersachsen
city: Herzberg am Harz
country: Germany
facility: Hausarztpraxis Eckert Osteroder Str. 9
state: Niedersachsen
city: Herzberg Am Harz
country: Germany
facility: Hausarztpraxis Poppe Osteroder Str. 9
state: Niedersachsen
city: Krebeck
country: Germany
facility: Hausarztpraxis Hauptstraße 34
state: Niedersachsen
city: Moringen
country: Germany
facility: Hausarztpraxis Neue Straße 22
state: Niedersachsen
city: Scheden
country: Germany
facility: Hausarztpraxis Bahnhofstraße 6
state: Niedersachsen
city: Seesen
country: Germany
facility: Hausarztpraxis Kampstr. 32
state: Niedersachsen
city: Höxter
country: Germany
facility: Hausarztpraxis Lambertweg 6
state: Nordrhein-Westfalen
city: Uder
country: Germany
facility: Hausarztpraxis Straße der Einheit 56
state: Thüringen
Study officials:
affiliation: University Medicine Greifswald
name: Sylvia Stracke
role: PRINCIPAL_INVESTIGATOR
References:
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