Circadian Rhythm Deregulation in Patients With CAPS (ICARUS)

Identification of Circadian Rhythm Deregulation in Patients With Cryopyrin-associated Periodic Syndrome (CAPS)

Circadian rhythms are characterized by the physiology's adaptation to the alternation of day and night, enabling to adapt to the environment. These rhythms are generated by a molecular clock within each cell. At the molecular level, the circadian clock is based on a complex system of cell-autonomous transcription loops. These exert positive and negative feedback on themselves, generating cyclic transcriptional activity.

• In the main loop, the BMAL1 transcription factor links with CLOCK or NPAS2 ( (Neuronal PAS Domain Protein 2) to activate transcription of per1,2 and 3 and cryptochrome (cry1 and cry2), which in turn repress BMAL1/CLOCK1 transcriptional activity.. The BMAL1/CLOCK complex also activates transcription of numerous target genes (per and cry, Rev-erb, etc.)..
• other secondary loops refine the function of the first.

Recent studies suggest that many aspects of innate immunity are controlled by circadian rhythm through inhibition of NLRP3 inflammasome activation. Nevertheless, the regulation of the NLRP3 inflammasome by the circadian clock has yet to be elucidated. Inflammasomes are molecular platforms that control caspase-1 activation and consequently the maturation of precursors of (interleukine) IL-1β, pro-IL-18, a pro-inflammatory cytokine. Since its discovery, its functions have been widely characterized as part of the innate immune response as a sensor of pathogens and danger signals (extracellular ATP (Adenosine triphosphate), atmospheric pollutants). NLRP3 (nucleotide-binding domain LRR (leucin-rich repeat ) and pyrin-containing receptor 3) has been described for its genetic association with dominant monogenic hereditary syndromes characterized by recurrent systemic inflammatory episodes in the absence of any infection or autoimmune disease, known as CAPS (cryopyrin-associated periodic syndrome) or cryopyrinopathies which is a continuum of diseases ranging from a moderate to the most severe form of the syndrome: familial cold urticaria syndrome, Muckle-Wells syndrome (MWS), and CINCA/NOMID syndrome.

Interestingly, patients with Muckle-Wells syndrome show a circadian pattern of symptoms, with a recurrent, predominantly vesperal fever peak lasting a few hours, and extreme fatigue on a daily basis. However, a molecular link between the circadian clock and CAPS pathology remains to be determined.

The aim of this protocol is to identify circadian rhythm dysregulation in patients with CAPS confirmed by genetic analysis of NLRP3, to demonstrate a link between circadian clock and CAPS syndrome, and to identify circadian clock regulatory pathways.

Study Overview

• Status: Recruiting
• Conditions: Muckle-Wells Syndrome; Familial Cold Urticaria; Cryopyrin Associated Periodic Syndrome; CINCA Syndrome
• Intervention / Treatment: Genetic: Genetic analysis of NLRP3; Device: Circadian rhythm measurement; Biological: Saliva sampling; Other: Questionnaire; Other: AIDAI score; Biological: Blood sampling

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alexandre Alexandre, PR; Phone Number: 33 04 27 85 61 26; Email: Alexandre.belot@chu-lyon.fr
• Study Contact Backup: Name: Samira Plassart; Phone Number: 33 04 27 85 54 42; Email: Samira.plassart@chu-lyon.fr

Study Locations

• France
  • Bron, France, 69677
    • Recruiting
    • Hôpital Femme-Mère-Enfant (HCL)
    • Contact: Alexandre Belot, MD;PhD; Phone Number: 33 04 27 85 61 26; Email: Alexandre.belot@chu-lyon.fr
    • Principal Investigator: Alexandre Belot, MD;PhD
  • Lille, France, 59037
    • Not yet recruiting
    • Hôpital Claude Huriez (CHU de Lille)
    • Contact: Éric HACHULLA, MD;PhD; Email: eric.hachulla@chru-lille.fr
    • Principal Investigator: Éric HACHULLA, MD;PhD
  • Lyon, France, 69004
    • Not yet recruiting
    • Hôpital de la Croix-Rousse (HCL)
    • Contact: Yvan Jamilloux, MD;PhD; Email: yvan.jamilloux@chu-lyon.fr
    • Principal Investigator: Yvan Jamilloux, MD;PhD
  • Lyon, France, 69437
    • Not yet recruiting
    • Hôpital Edouard Herriot (HCL)
    • Principal Investigator: Thomas Barba, MD
    • Contact: Thomas Barba, MD; Email: thomas.barba@chu-lyon.fr
  • Paris, France, 94270
    • Not yet recruiting
    • Hôpital Kremlin-Bicêtre (AP-HP)
    • Contact: Isabelle Koné-Paut, MD;PhD; Phone Number: 01 45 21 32 46; Email: isabelle.kone-paut@aphp.fr
    • Principal Investigator: Isabelle Koné-Paut, MD;PhD
  • Paris, France, 75020
    • Not yet recruiting
    • Hôpital Tenon (AP-HP)
    • Contact: Sophie Georgin-Lavialle, MD;PhD; Phone Number: 33 01 56 01 60 77; Email: sophie.georgin-lavialle@aphp.fr
    • Principal Investigator: Sophie Georgin-Lavialle, MD;PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

---Inclusion Criteria:

Patient with CAPS group :

• Patients aged 6 and over
• Participant with CAPS confirmed by NLRP3 genetic analysis
• Weight greater than or equal to 25 Kg
• Parents/guardians who have been informed of the study and have signed a consent form.
• Patient affiliated to a social security scheme

Control group (healthy participant):

• Participant aged 6 and over
• Weight greater than or equal to 25 Kg
• Participant living in the same household as a subject with CAPS genetically confirmed by NLRP3 analysis and included in the protocol
• Participant with no CAPS (a priori) who consents to NLRP3 genetic analysis
• Parents/guardians who have been informed of the study and have signed a consent form.
• Participant who has been informed of the study and has agreed to take part

• Participant affiliated to a social security scheme

  • Exclusion Criteria :

Patient with CAPS group :

• Patients with chronic sleep disorders (narcolepsy, hypersomnia) requiring medication (sleeping pills, melatonin).
• Patients with sleep apnea syndrome
• Patients working regular night shifts or alternating day and night shifts
• Pregnant or breast-feeding women
• Parents with an infant under 6 months of age
• Patient participating in another interventional drug study
• Deprivation of civil rights (curators, guardianship, safeguard of justice)

Control group (healthy participant):

• Participants with a chronic illness (ALD beneficiaries)
• Participants with chronic sleep disorders (narcolepsy, hypersomnia) requiring medication (sleeping pills, melatonin)
• Participants working regular night shifts or alternating day and night shifts
• Pregnant or breast-feeding women
• Parents with an infant under 6 months of age
• Participant participating in another interventional drug study
• Deprivation of civil rights (curators, guardianship, safeguard of justice)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Patients with cryopyrin-associated periodic syndrome (CAPS); Confirmed by genetic analysis of NLRP3	Genetic: Genetic analysis of NLRP3; Blood test for genetic analysis of NLRP3; Device: Circadian rhythm measurement; Wear a Withings Pulse HR (heart rate) actigraphic watch 24 hours a day for 1 month to define circadian rhythm; Biological: Saliva sampling; Saliva sampling for salivary melatonin determination; Other: Questionnaire; Questionnaire to determine chronotype; Other: AIDAI score; Disease activity score using AIDAI score (only for patients in the CAPS group) AIDAI : AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX; Biological: Blood sampling; Inflammatory cytokines measurement : IL1-beta (Interleukin-1) and IL-18.; Molecular characterization of circadian clock signaling pathways
Placebo Comparator: Control group; Healthy participant (absence of CAPS, verified by NLRP3 gene analysis) living in the same household as a CAPS participant included in the protocol	Genetic: Genetic analysis of NLRP3; Blood test for genetic analysis of NLRP3; Device: Circadian rhythm measurement; Wear a Withings Pulse HR (heart rate) actigraphic watch 24 hours a day for 1 month to define circadian rhythm; Biological: Saliva sampling; Saliva sampling for salivary melatonin determination; Other: Questionnaire; Questionnaire to determine chronotype; Biological: Blood sampling; Inflammatory cytokines measurement : IL1-beta (Interleukin-1) and IL-18.; Molecular characterization of circadian clock signaling pathways

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,	Concentration of the peak secretion of melatonin in both arms	6 months after inclusion
Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,	Concentration of the peak secretion of melatonin in both arms	12 months after inclusion
Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,	time of the peak secretion of melatonin in both arms	6 months after inclusion
Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,	time of the peak secretion of melatonin in both arms	12 months after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.	Determination of circadian rhythms : amplitude in both arms	6 th month
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.	Determination of circadian rhythms : period in both arms	6 th month
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.	Determination of circadian rhythms : phase in both arms	6 th month
Chronotype determination	Number of patients in each chronotype for the 2 arms based on the specific questionnaire in both arm	6 th month
sleep duration	sleep duration in both arms	6 th month
number of steps	Daily activity in both arms	6 th month
Comparison of inflammatory state	basal levels of IL1β in patient monocytes in both arms	6 months after inclusion
Comparison of inflammatory state	basal levels of IL1β in patient monocytes in both arms	12 months after inclusion
Comparison of inflammatory state	basal levels of IL18 in patient monocytes in both arms	6 months after inclusion
Comparison of inflammatory state	basal levels of IL18 in patient monocytes in both arms	12 months after inclusion
Disease activity measurement	Number of patient with active disease ie AIDAI (AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX) score >9 in CAPS patient arm	6 months after inclusion
Disease activity measurement	Number of patient with active disease ie AIDAI (AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX) score >9 in CAPS patient arm	12 months after inclusion
presence or absence of an abnormality in the NLRP3 signalling pathway in CAPS arm compared control arm	Biochemical characterization of the NLRP3 inflammasome protein regulatory pathway in both arms	6 months after inclusion
presence or absence of an abnormality in the NLRP3 signalling pathway in CAPS arm compared to control arm	Biochemical characterization of the NLRP3 inflammasome protein regulatory pathway in both arms	12 months after inclusion
presence or absence of ASC inflammasome protein regulatory pathway in CAPs arm compared to control arm	Biochemical characterization of the ASC inflammasome protein regulatory pathway in both arms	6 months after inclusion
presence or absence of ASC inflammasome protein regulatory pathway in CAPS arm compared to control arm	Biochemical characterization of the ASC inflammasome protein regulatory pathway in both arms	12 months after inclusion
presence or absence of the CASPASE-1 inflammasome protein regulatory pathway in CAPS arm compared to control arm	Biochemical characterization of the CASPASE-1 inflammasome protein regulatory pathway in both arms	6 months after inclusion
presence or absence of the CASPASE-1 inflammasome protein regulatory pathway in CAPS arm compared to control arm	Biochemical characterization of the CASPASE-1 inflammasome protein regulatory pathway in both arms	12 months after inclusion
presence or absence of REV-ERBα inflammasome protein regulatory pathway in CAPS arm compared to control arm	Biochemical characterization of the REV-ERBα inflammasome protein regulatory pathway in both arms	6 months after inclusion
presence or absence of REV-ERBα inflammasome protein regulatory pathway in CAPS arm compared to control arm	Biochemical characterization of the REV-ERBα inflammasome protein regulatory pathway in both arms	12 months after inclusion

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2026
• Primary Completion (Estimated): February 25, 2029
• Study Completion (Estimated): February 25, 2029

Study Registration Dates

• First Submitted: May 7, 2024
• First Submitted That Met QC Criteria: August 6, 2024
• First Posted (Actual): August 9, 2024

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: melatonin; Circadian clock; cryopyrin-associated periodic syndrome; familial cold urticaria; muckle-wells syndrome
• Additional Relevant MeSH Terms: Chronic Inducible Urticaria; Chronic Urticaria; Cold Urticaria; Pathologic Processes; Chronic Disease; Disease Attributes; Genetic Diseases, Inborn; Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Skin Diseases; Urticaria; Skin Diseases, Vascular; Skin Diseases, Genetic; Hereditary Autoinflammatory Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Cryopyrin-Associated Periodic Syndromes; Health Care Quality, Access, and Evaluation; Investigative Techniques; Epidemiologic Methods; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Data Collection; Health Care Evaluation Mechanisms; Quality of Health Care; Public Health; Environment and Public Health; Surveys and Questionnaires; Blood Specimen Collection
• Other Study ID Numbers: 69HCL23_0417; 2023-A01088-37 (Other Identifier: ID-RCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No