Randomized Controlled Trial in Patients on Long-term Colchicine With Colchicine-resistant Familial Mediterranean Fever (FMF) to Evaluate the Efficacy of On-demand Anakinra Treatment for Painful Attacks in Patients Who Refuse Continuous Daily Therapy (KIN-ATTACK-FMF)

To evaluate the efficacy on clinical symptoms in case of FMF attack among FMF patients resistant to Colchicine of

• on demand anakinra treatment (100 mg/d from the prodromal phase of the attack until 24 hours of remission (during 7 days maximum) associated with daily colchicine.
• compared to analgesic associated with daily colchicine in patients refusing continuous anti-IL-1 treatment.

Study Overview

• Status: Recruiting
• Conditions: FMF
• Intervention / Treatment: Drug: ANAKINRA

Detailed Description

KIN-ATTACK-FMF will be the first randomized prospective study comparing the efficacy of on-demand anakinra versus standard of care treatment in patients with colchicine resistant symptoms of FMF who refuse continuous daily therapy.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (100,000 people worldwide and 7500 in France). It causes monthly recurrent febrile abdominal pain with a biological inflammatory syndrome.

To prevent FMF attacks and development of inflammatory amyloidosis (IA) daily oral colchicine is the first line recommended treatment. 10 to 15% of patients are resistant to colchicine: persistence of 1attack/month over a period of 3 months (in spite of taking the maximum tolerated dose of colchicine daily). Subcutaneous anti-interleukin 1 biotherapies were recently allowed in France combined to daily oral colchicine for colchicine resistant FMF: anakinra (short-acting anti-IL1 drug, daily) or canakinumab (long acting monoclonal anti IL1 antibody, every 2 months). These treatments cost respectively 30 and 12,000 euros/injection.

If abdominal attacks are controlled by colchicine, patients still suffer from lower limb pains, particularly erysipelas like erythema and exertional myalgias, which are very disabling and require use of analgesics or anti-inflammatory. However, in the referral center, 20% of colchicine resistant FMF patients don't receive chronic anti IL1 treatment, despite an indication. Main reasons are: 1-they do not want to inject themselves every day (for anakinra); 2-women of childbearing age are afraid about the impact of biotherapies on their fetus; 3-some do not want to ask for 100% coverage because of the biotherapy cost; 4- the authorization for anti IL1 in FMF is very recent and they want more certainty about its effectiveness.

The hypothesis of the study is that on-demand use of Anakinra from onset of attack until 24 hours of remission (during 7 days maximum) associated with chronic daily colchicine as background treatment in case of attack could stop it, thus reducing its length and pain compared to standard of care treatment which includes only classical antalgics with colchicine in patients refusing chronic daily anti IL1 treatment.

In the experimental arm, patients receive on demand anakinra treatment (100 mg/d from the prodromal phase of the attack until 24 hours of remission (during 7 days maximum) associated with daily colchicine. In the control arm, patients receive analgesics associated with daily colchicine.

50 participants should be included in the study during a period of 24 months with a 6 months participation period (treatment + follow up)

It's a Multicenter national study including 11 centers.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Léa SAVEY; Phone Number: 0033 1 56 01 67 91; Email: lea.savey@aphp.fr
• Study Contact Backup: Name: Sophie Georgin-Lavialle, MD,PHD; Phone Number: 00 33 1 56 01 74 31; Email: sophie.georgin-lavialle@aphp.fr

Study Locations

• France
  • Paris, France, 75020
    • Recruiting
    • Service de Médecine interne Hopital Tenon
    • Contact: Léa SAVEY; Phone Number: 00 33 1 56 01 60 77; Email: lea.savey@aphp.fr
    • Contact: Sophie Georgin-Lavialle, MD,PHD; Phone Number: 0 33 1 56 01 74 31; Email: sophie.georgin-lavialle@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >= 6 years old with no upper limit
• Proven FMF according to Livneh international criteria and 2 non ambiguous MEFV mutations.
• Colchicine resistance defined as persistent FMF attack despite the maximum daily posology of colchicine (average one or more attacks per month over a 3-months period)

FMF Attack is defined by:

• Arthritis or
• Chest pain or
• Abdominal pain or
• Myalgia or
• Erysipelas-like skin lesion Duration of episodes 1-4 days.
• Patient refusing daily anakinra injections-
• Patients covered at 100% by the health insurance (ALD)
• Patient who do not have biological inflammation between attacks
• Written informed consent of the patients and or his legal representatives

Exclusion Criteria:

• Evidence of active tuberculosis
• Infection requiring treatment with intravenous antibiotics within 2 weeks prior to inclusion
• History of recurrent infection (Need more than 4 courses of antibiotic treatment per year (in children) or more >2 times per year (in adults), experience pneumonia twice over any time or >3 bacterial sinusitis in 1 year)
• Contraindication to anakinra (Hypersensitivity to the active substance or to any of the excipients (Citric acid, anhydrous Sodium chloride, Disodium edetate dehydrate, Polysorbate 80, Sodium hydroxide, Water for injections ) or to E. coli derived proteins
• Patients with neutropenia (ANC <1.5 x 10^9/l)
• Inability to provide informed consent
• Ongoing chronic treatment with anti IL1 biotherapy since at least 3 months
• Pregnant women
• Women in labor and nursing mothers
• Patients in emergency situations and people hospitalized without consent
• No health care insurance
• Contraindication to colchicine
• Patient participating in another interventional clinical trial
• Patient deprived of liberty
• Patient under guardianship or curatorship
• Patient under court protection

Randomization criteria :

• Absence of active or latent tuberculosis (no tuberculosis sign on chest X-ray and a negative quantiferon)
• Negative pregnancy test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ANAKINRA on Demand; On demand Anakinra 100 mg/j from the prodromal phase of the attack until 24 hours of remission (during 7 days maximum) + colchicine + on demand analgesics	Drug: ANAKINRA; On demand Anakinra 100 mg/j from the prodromal phase of the attack until 24 hours of remission (during 7 days maximum) + colchicine + on demand analgesics
No Intervention: Standard of Care; Usual analgesics + colchicine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean number of FMF-attacks per month at 6 months of treatment.	FMF attacks is defined by a painful (consensual definition) manifestation during 12 to 72 hours, in either :abdomen (with features consistent with a diagnosis of peritonitis),chest (with features consistent with a diagnosis of pleuritis),joints (with features consistent with a diagnosis of lower extremity large joint monoarthritis),skin (with features consistent with a diagnosis of erysipeloid rash); The painful manifestation can be (or not) accompanied by fever of ≥ 38°C Patients will be asked to note the number of days of pain of each inflammatory attack on a diary.	At Months 0 (baseline), Month 1, Month 3 and Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AIDAI (Auto-inflammatory Diseases activity index) score	Patients will complete the AIDAI (Auto-inflammatory Diseases activity index) score monthly.	At Months 0 (baseline), Month 1, Month 3 and Month 6
Number of painful days and severity of FMF attacks occurring between randomization and M6	Number of painful days will be measured by VAS (Visual Analogue Scale) and collected via a notebook).	At Months 0 (baseline), Month 1, Month 3 and Month 6
Quality of life score measured by EuroQOL questionnaire (EQ-5D5L)	The EQ5D5L will be completed at each visit	At Months 0 (baseline), Month 1, Month 3 and Month 6
Number of local cutaneous reactions at 6 months (erythema and oedema involving the injection sites) in the anakinra arm	Number of local cutaneous reaction will be collected via a notebook	At Months 0 (baseline), Month 1, Month 3 and Month 6
Proportion of Adverse events	Adverse events will be collected via a notebook	At Months 0 (baseline), Month 1, Month 3 and Month 6
Cumulative days of FMF attack treatment from randomization to 6 months	The number of days of injections (for anakinra arm) or number of days of consumption of analgesics (for control group) will be collected via a notebook . Safety	At Months 0 (baseline), Month 1, Month 3 and Month 6

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Léa Léa Léa SAVEY, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2024
• Primary Completion (Estimated): December 4, 2026
• Study Completion (Estimated): December 4, 2026

Study Registration Dates

• First Submitted: March 15, 2024
• First Submitted That Met QC Criteria: March 26, 2024
• First Posted (Actual): March 29, 2024

Study Record Updates

• Last Update Posted (Estimated): June 25, 2025
• Last Update Submitted That Met QC Criteria: June 20, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Familial Mediterranean fever; Anakinra; Colchicine resistance; Randomized prospective study
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Infections; Skin Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Skin Diseases, Genetic; Brucellosis; Familial Mediterranean Fever; Hereditary Autoinflammatory Diseases; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: APHP220828

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Individual participant data that underlie the results reported in this article, after deidentification (text, tables,figures, and appendices) could be shared.

Data would be available Beginning 9 months and ending 36 months following article publication with Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose for individual participant data meta-analysis.

Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No