Clinical trial NCT02263638: Treatment of Refractory Hemochromatosis Rheumatism by Anakinra: a Preliminary Phase II Study
Official title: Treatment of Refractory Hemochromatosis Rheumatism by Anakinra: a Preliminary Phase II Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Refractory Hemochromatosis Rheumatism
Keywords: hereditary haemochromatosis
rheumatism
anakinra
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2014-10-13
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Treatment of refractory hemochromatosis rheumatism by Anakinra. Prospective, multicenter, non-randomised, single-arm, open-label, phase II trial.

Detailed description: Hereditary hemochromatosis (HH) is a genetic disease characterized by tissue iron overload. The most common genotype is homozygosity for the p.Cys282Tyr mutation of the HFE gene (MIM 235200). It is a serious disease which can lead to life threatening complications such as cirrhosis, liver carcinoma, heart failure or diabetes mellitus. Currently, these complications can be prevented by phlebotomies. Two-thirds of patients complain of joint symptoms which represent a major cause of impaired quality of life. Phlebotomies are ineffective on HH rheumatism and patients' quality of life is very often altered while life threatening complications are prevented. Furthermore, there is a significant higher risk for joint replacement surgery in these patients compared to controls (X 9). There is currently no approved treatment for hemochromatosis rheumatism. As it looks like severe osteoarthritis, calcium pyrophosphate deposition disease (CPDD) or chondrocalcinosis, symptomatic treatments are employed such as analgesics (type I or II), non-steroidal anti-inflammatory drugs or colchicine in case of acute joint flare, corticosteroids intra-articular injections or occasionally oral glucocorticoids. However in some cases these treatments remain ineffective leading to a true disability.

Frequently, there are local inflammatory symptoms. Interleukin 1ß (IL1ß) plays a key role in the pathogenesis of crystal arthropathies (CPDD or gout).

Anakinra (IL-1Ra), a drug approved in France for rheumatoid arthritis, has been tested in short series or case controls in refractory gout, CPDD and only in two patients with HH rheumatism. The aim of this phase II study is to test the efficacy of anakinra in patients with hemochromatosis and refractory joint pain. It is also to evaluate the opportunity to perform a phase III trial. In the absence of available data on the evolution of this rheumatism treated by anakinra in this population of patients resistant to standard therapy, the investigators consider that a phase III trial would not be justifiable if the rate of success is insufficient.

Eligibility criteria: Inclusion Criteria:

* Patients with age equal to or over 18 years old,
* Patients with proved hereditary hemochromatosis with homozygosity for the C282Y mutation of the HFE gene,
* Patients with rheumatism related to hemochromatosis, considered by the rheumatologist refractory to usual treatment defined by a persistent painful symptomatology despite a treatment of at least one month with level 2 analgesics (weak opioids) at maximal dose, NSAID, colchicine, steroid injection or a combination of these treatments,
* Patients with pain \> 40/100mm measured by VAS (pain of the last 48 hours),
* Effective contraception to be used during treatment and until 48h after the last administration for women of reproductive age,
* Patients who have given written informed consent.

Exclusion Criteria:

* Other cause of inflammatory rheumatisms such as Rheumatoid Arthritis, Spondyloarthropathies, psoriatic arthritis, or systemic diseases,
* Ongoing treatment with Methotrexate, Hydroxychloroquine, biologic or immunosuppressive drugs
* Malignant pathology, monoclonal gammopathy,
* Intolerance to anakinra,
* Contraindications to the use of anakinra: pregnancy or breastfeeding, hypersensitivity to any of the excipients or to proteins from E. coli, severe renal impairment (creatinine clearance \<30 ml / minute), neutropenia (neutrophil count \<1.5 x 109 / l), ongoing infection
* Patients that cannot follow the protocol,
* Persons subject to major legal protection (safeguarding justice, guardianship, trusteeship), persons deprived of liberty.

Primary outcomes:
measure: Rate of patients with improvement of joint pain
timeFrame: Day 15
Secondary outcomes:
measure: Assessment of the disease activity
timeFrame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of the number of painful joints
timeFrame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of the number of swollen joints
timeFrame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of analgesics consumption
timeFrame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of non-steroidal anti-inflammatory drugs (NSAID) consumption
timeFrame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of colchicine consumption
timeFrame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of steroids injections consumption
timeFrame: Day 0, day 15, day 30, day 60, day 90
measure: Assessment of the quality of life
timeFrame: Day 0, day 15, day 30, day 90
measure: Assessment of the quality of life
timeFrame: Day 0, day 15, day 30, day 90
measure: Functional evaluation
timeFrame: Day 0, day 15, day 30, day 90
measure: Functional evaluation
timeFrame: Day 0, day 15, day 30, day 90
measure: Assessment of joint damage
timeFrame: Day 0, day 90
measure: Synovial fluid analysis
timeFrame: 3 months
measure: Synovial fluid analysis
timeFrame: 3 months
measure: Synovial fluid analysis
timeFrame: 3 months
measure: Biological effects on inflammation and iron metabolism
timeFrame: Day 0, day 15, day 30, day 60, day 90
measure: Time at which Cmax of anakinra was observed (Tmax)
timeFrame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
measure: Maximum observed concentration (Cmax) of anakinra
timeFrame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
measure: Half-life (T1/2) of anakinra
timeFrame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
measure: Area under the concentration-time curve of time 0 to the last detectable concentration (AUC0-last) of anakinra
timeFrame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
measure: Area under the concentration-time curve of time 0 to infinity (AUC0-∞) of anakinra
timeFrame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
measure: Plasma clearance after administration (CL/F) of anakinra
timeFrame: Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
Other outcomes:
Locations:
city: Lille
country: France
facility: CHRU de Lille
city: Paris
country: France
facility: Groupe Hospitalier Lariboisière
city: Rennes
country: France
facility: Rennes University Hospital
Study officials:
affiliation: Groupe Hospitalier Lariboisière - Paris
name: Pascal Richette
role: PRINCIPAL_INVESTIGATOR
affiliation: Rennes University Hospital
name: Pascal Guggenbuhl
role: PRINCIPAL_INVESTIGATOR
References: