Anakinra versus treatment as usual in the treatment of acute gout

Acute Gout is a common form of inflammatory arthropathy characterized by severe
pain and reduced physical functioning. The predominant risk factor for gout is
hyperuricemia. When left untreated, elevated uric acid levels in the blood can
lead to formation and precipitation of monosodium urate crystals in and around
the joints, stimulating and initiating a local inflammatory response. The
current standard treatments, colchicine, corticosteroids or NSAIDs, are
therefore designed to rapidly relieve the pain and inflammation in the affected
joints. Although gout is one of the most well understood rheumatic diseases,
currently available treatment options are frequently contra-indicated or poorly
tolerated by gout patients, which frequently presents in the presence of
significant multi-morbidity (hypertension, diabetes mellitus, renal disease).
For this complex group of gout patients, the finding of interleukin-1* (IL-1*)
in the pathophysiology of gout was promising. In 2013, a new agent, the IL-1*
inhibitor canakinumab, was registered in the Netherlands for the treatment of
acute gout. However, this agent is limited by the high cost per treatment (> ¤
10,000 ). It is reimbursable for patients in whom conventional treatments are
not suitable and who are faced with more than two gout attacks each year.

Anakinra (Kineret), a DNA recombinant IL-1 receptor antagonist, is a medicinal
product currently registered for the treatment of rheumatoid arthritis. It acts
by competitively inhibiting the binding of IL-1* and IL-1* to IL-1 type I
receptors, causing the biological activity of these interleukins to be
neutralized. The clinical efficacy and safety of anakinra in acute gout have
been investigated and reported in a handful of case series or small open-label
studies. These studies provide a proof of concept of the plausibility and
clinical importance of a large scale clinical trial. The goal of this project
is to determine whether anakinra could be a safe, more applicable and possibly
more effective agent to treat gouty arthritis.

The primary aim of this research is to demonstrate the noninferiority of
anakinra compared with the standard of care in the treatment of acute gout
flares.
Secondary objectives are to compare the cost per quality-adjusted life day
between anakinra and standard of care and to evaluate the safety of ankinra use
in gout. Also to compare the 3 and 12 months clinical outcome of patients
initially treated with anakinra versus Standard of care and starting Urate
lowering therapy.

The total study duration is 12 months. The initial 3 month study is a
multi-center randomized, double (dummy)-blinded, placebo controlled NI trial,
followed by a 9 month open label extension study.

200 patients diagnosed with crystal proven acute gout, will be randomly
allocated in the ratio 1:1 to either:

1. 5 consecutive days of 100 mg daily anakinra injection and standard of care
pill placebo
2. one of the standard of care treatment options (colchicine, naproxen,
corticosteroids) and 5 consecutive days of 100 mg anakinra injection
placebo.The dose and duration of the standard treatment options will be as
follows:
- colchicine (active or placebo): 3 daily dosages of 0.5 mg for 90 days
- naproxen (active or placebo): 2 times daily 500 mg for 90 days
- prednisolon (active of placebo): 35 mg / day for 5 days.

Colchicine and naproxen have a treatment duration of 90 days because they are
used/extended prophylactically when initiating urate lowering therapy at
baseline. Both groups will also be given urate lowering therapy (standard care)
at baseline. This will be allopurinol and if not applicable then febuxostat or
benzbromaron will be given, also according to the dose/duration recommendations
by the gout guidelines from the NVR.

During the 12 month study period, patients will need to at 6 different time
points fill in questionnaires. In total, patients will need to give blood 3
times. 5 days longs patients will receive a treatment whereby they will need to
inject themselves with a anakinra placebo or verum and need to orally take a
standard of care pill or standard of care pill placebo. During the gout flare,
patients will need to 7 days long fill in daily a short questionnaire regarding
the gout flare. For diagnostic purposes and to determine if a patient is
eligible for study participation, aspiration of the main joint will be done (if
needed).

The potential risks associated with anakinra for the treatment of acute gouty
arthritis are:
* Physical discomfort of SC treatment injection
* Local (skin) injection site reaction associated with pain, inflammation,
erythema, or ecchymoses, rash
* Serious infections including respiratory infections and skin infections,
Influenza infections
* Allergic reaction and anaphylaxis (angioedema, urticarial and pruritus) to
anakinra or other constituents, including latex
* Decreased neutrophil count, potentially leading to neutropenia
* possible drug interaction between Urate lowering therapy and anakinra
* Elevated levels of liver enzymes
* Increased total blood cholesterol levels
* Thrombocytopenia (low level of blood platelets)
* Gastrointestinal disturbances related to liver disorders (yellow skin and
eyes, nausea, loss of appetite, dark-colored urine, light-colored stools)
* Headaches
* NSAIDs and colchicine are intended as prophylactics for gout flares when
initiating ULT. Patients receiving anakinra treatment or prednisolone treatment
(when allocated into the SoC group) will not receive colchicine or NSAID
prophylactics when initiating ULT. Relapse of a gout flare might occur sooner
in this population compared to the other study arm that will receive
prophylactics.

To ensure the risks associated with the intake of anakinra remain limited, the
inclusion and exclusion criteria of this study are strict. Eligible patients
will be excluded from the study if contraindicated to anakinra or any of its
constituents. Additionally, patients with pre-existing neutropenia or with
untreated infections will not be included in the study to ensure the chance for
worsening of or getting neutropenia are decreased in the study population.
Also, a DSMB will be established to ensure the safety of the participants.
Also, active safety monitoring will take place by the different
centres/rheumatologists of reported side effects/complications/AE/SAE and these
will be evaluated for seriousness and relatedness to anakinra or treatment as
usual. At last, the long use of this product in RA patients has resulted in a
good description of its safety profile and the possible side effects. Such
information has contributed to clearly defining the potential risks associated
with using anakinra in the present study. The group not receiving prophylactic
agents will receive the same optimal care as patients receiving prophylactics.
In some cases it might be needed to break the randomization (treatment) code to
be able to provide the patient the best care. The strain for patients
participating in this study will remain limited as questionnaires can be filled
in digitally from home (or if needed by paper and pencil). Therefore patients
will not have to make an additional visit to the center.