Treatment of Refractory Hemochromatosis Rheumatism by Anakinra: a Preliminary Phase II Study (THERA)

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

Study Overview

• Status: Terminated
• Conditions: Refractory Hemochromatosis Rheumatism
• Intervention / Treatment: Drug: Anakinra

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lille, France
    • CHRU de Lille
  • Paris, France
    • Groupe Hospitalier Lariboisière
  • Rennes, France, 35033
    • Rennes University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Anakinra; One daily subcutaneous injection of a fixed dose of 100 mg will be administered at a fixed time by a nurse during a five day period	Drug: Anakinra; One daily subcutaneous injection of a fixed dose of 100 mg will be administered at a fixed time during a five day period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of patients with improvement of joint pain	Improvement is defined as the minimal clinically important improvement of joint pain and is assessed on a 0-100 mm visual analogue scale (VAS)	Day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the disease activity	Assessment of the disease activity by Visual analog scale (VAS)	Day 0, day 15, day 30, day 60, day 90
Assessment of the number of painful joints	Assessment of the number of painful joints by a clinical exam	Day 0, day 15, day 30, day 60, day 90
Assessment of the number of swollen joints	Assessment of the number of swollen joints by a clinical exam	Day 0, day 15, day 30, day 60, day 90
Assessment of analgesics consumption		Day 0, day 15, day 30, day 60, day 90
Assessment of non-steroidal anti-inflammatory drugs (NSAID) consumption		Day 0, day 15, day 30, day 60, day 90
Assessment of colchicine consumption		Day 0, day 15, day 30, day 60, day 90
Assessment of steroids injections consumption		Day 0, day 15, day 30, day 60, day 90
Assessment of the quality of life	Assessment of the quality of life by the SF36 questionnaire	Day 0, day 15, day 30, day 90
Assessment of the quality of life	Assessment of the quality of life by the HAQ questionnaire	Day 0, day 15, day 30, day 90
Functional evaluation	Functional evaluation by WOMAC index for hip and knee	Day 0, day 15, day 30, day 90
Functional evaluation	Functional evaluation by Dreiser index for hands	Day 0, day 15, day 30, day 90
Assessment of joint damage	Assessment of joint damage by X-rays and Doppler ultrasound	Day 0, day 90
Synovial fluid analysis	Puncture if acute joint effusion : cells count	3 months
Synovial fluid analysis	Puncture if acute joint effusion : search for crystals presence	3 months
Synovial fluid analysis	Puncture if acute joint effusion : iron parameters markers	3 months
Biological effects on inflammation and iron metabolism	Biological/Vaccine : iron and inflammatory markers	Day 0, day 15, day 30, day 60, day 90
Time at which Cmax of anakinra was observed (Tmax)	Pharmacokinetics study	Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
Maximum observed concentration (Cmax) of anakinra	Pharmacokinetics study	Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
Half-life (T1/2) of anakinra	Pharmacokinetics study	Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
Area under the concentration-time curve of time 0 to the last detectable concentration (AUC0-last) of anakinra	Pharmacokinetics study	Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
Area under the concentration-time curve of time 0 to infinity (AUC0-∞) of anakinra	Pharmacokinetics study	Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose
Plasma clearance after administration (CL/F) of anakinra	Pharmacokinetics study	Predose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24 hours post-dose

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Principal Investigator: Pascal Richette, Groupe Hospitalier Lariboisière - Paris; Principal Investigator: Pascal Guggenbuhl, Rennes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2015
• Primary Completion (Actual): September 4, 2018
• Study Completion (Actual): September 4, 2018

Study Registration Dates

• First Submitted: September 23, 2014
• First Submitted That Met QC Criteria: October 8, 2014
• First Posted (Estimate): October 13, 2014

Study Record Updates

• Last Update Posted (Actual): March 12, 2019
• Last Update Submitted That Met QC Criteria: March 8, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: anakinra; rheumatism; hereditary haemochromatosis
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Iron Metabolism Disorders; Metabolism, Inborn Errors; Metal Metabolism, Inborn Errors; Iron Overload; Rheumatic Diseases; Collagen Diseases; Hemochromatosis; Hemosiderosis; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: 2014-000609-10; 35RC13_8811_THERA (Other Identifier: Rennes University Hospital)