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NCT Number: NCT06544018

Circadian Rhythm Deregulation in Patients With 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.

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Key information

Conditions

Cryopyrin Associated Periodic Syndrome CINCA Syndrome Chronic Disease Chronic Inducible Urticaria Chronic Urticaria Cold Urticaria Congenital, Hereditary, and Neonatal Diseases and Abnormalities Cryopyrin-Associated Periodic Syndromes Disease Attributes Familial Cold Urticaria Genetic Diseases, Inborn Hereditary Autoinflammatory Diseases Hypersensitivity Hypersensitivity, Immediate Immune System Diseases Muckle-Wells Syndrome Pathologic Processes Pathological Conditions, Signs and Symptoms Skin Diseases Skin Diseases, Genetic Skin Diseases, Vascular Skin and Connective Tissue Diseases Urticaria

Age range

6 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Hôpital Femme-Mère-Enfant (HCL), Bron, France

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Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

---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)

Treatment and study plan

Genetic analysis of NLRP3

Genetic

Blood test for genetic analysis of NLRP3

Circadian rhythm measurement

Device

Wear a Withings Pulse HR (heart rate) actigraphic watch 24 hours a day for 1 month to define circadian rhythm

Saliva sampling

Biological

Saliva sampling for salivary melatonin determination

Questionnaire

Other

Questionnaire to determine chronotype

AIDAI score

Other

Disease activity score using AIDAI score (only for patients in the CAPS group) AIDAI : AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX

Blood sampling

Biological
  • Inflammatory cytokines measurement : IL1-beta (Interleukin-1) and IL-18.
  • Molecular characterization of circadian clock signaling pathways

Primary outcomes

  1. Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,

    Time frame: 6 months after inclusion

    Concentration of the peak secretion of melatonin in both arms

  2. Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,

    Time frame: 12 months after inclusion

    Concentration of the peak secretion of melatonin in both arms

  3. Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,

    Time frame: 6 months after inclusion

    time of the peak secretion of melatonin in both arms

  4. Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,

    Time frame: 12 months after inclusion

    time of the peak secretion of melatonin in both arms

Secondary outcomes

  1. Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.

    Time frame: 6 th month

    Determination of circadian rhythms : amplitude in both arms

  2. Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.

    Time frame: 6 th month

    Determination of circadian rhythms : period in both arms

  3. Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.

    Time frame: 6 th month

    Determination of circadian rhythms : phase in both arms

  4. Chronotype determination

    Time frame: 6 th month

    Number of patients in each chronotype for the 2 arms based on the specific questionnaire in both arm

  5. sleep duration

    Time frame: 6 th month

    sleep duration in both arms

  6. number of steps

    Time frame: 6 th month

    Daily activity in both arms

  7. Comparison of inflammatory state

    Time frame: 6 months after inclusion

    basal levels of IL1β in patient monocytes in both arms

  8. Comparison of inflammatory state

    Time frame: 12 months after inclusion

    basal levels of IL1β in patient monocytes in both arms

  9. Comparison of inflammatory state

    Time frame: 6 months after inclusion

    basal levels of IL18 in patient monocytes in both arms

  10. Comparison of inflammatory state

    Time frame: 12 months after inclusion

    basal levels of IL18 in patient monocytes in both arms

  11. Disease activity measurement

    Time frame: 6 months after inclusion

    Number of patient with active disease ie AIDAI (AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX) score >9 in CAPS patient arm

  12. Disease activity measurement

    Time frame: 12 months after inclusion

    Number of patient with active disease ie AIDAI (AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX) score >9 in CAPS patient arm

  13. presence or absence of an abnormality in the NLRP3 signalling pathway in CAPS arm compared control arm

    Time frame: 6 months after inclusion

    Biochemical characterization of the NLRP3 inflammasome protein regulatory pathway in both arms

  14. presence or absence of an abnormality in the NLRP3 signalling pathway in CAPS arm compared to control arm

    Time frame: 12 months after inclusion

    Biochemical characterization of the NLRP3 inflammasome protein regulatory pathway in both arms

  15. presence or absence of ASC inflammasome protein regulatory pathway in CAPs arm compared to control arm

    Time frame: 6 months after inclusion

    Biochemical characterization of the ASC inflammasome protein regulatory pathway in both arms

  16. presence or absence of ASC inflammasome protein regulatory pathway in CAPS arm compared to control arm

    Time frame: 12 months after inclusion

    Biochemical characterization of the ASC inflammasome protein regulatory pathway in both arms

  17. presence or absence of the CASPASE-1 inflammasome protein regulatory pathway in CAPS arm compared to control arm

    Time frame: 6 months after inclusion

    Biochemical characterization of the CASPASE-1 inflammasome protein regulatory pathway in both arms

  18. presence or absence of the CASPASE-1 inflammasome protein regulatory pathway in CAPS arm compared to control arm

    Time frame: 12 months after inclusion

    Biochemical characterization of the CASPASE-1 inflammasome protein regulatory pathway in both arms

  19. presence or absence of REV-ERBα inflammasome protein regulatory pathway in CAPS arm compared to control arm

    Time frame: 6 months after inclusion

    Biochemical characterization of the REV-ERBα inflammasome protein regulatory pathway in both arms

  20. presence or absence of REV-ERBα inflammasome protein regulatory pathway in CAPS arm compared to control arm

    Time frame: 12 months after inclusion

    Biochemical characterization of the REV-ERBα inflammasome protein regulatory pathway in both arms

Study contacts

Contact information is provided by the study sponsor or research team.

Alexandre Alexandre, PR

CONTACT

[email protected]

04 27 85 61 26 ext. 33

Samira Plassart

CONTACT

[email protected]

04 27 85 54 42 ext. 33

Sponsors and collaborators

Lead sponsor

Hospices Civils de Lyon

Other

Registry information

Official study title

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

Acronym: ICARUS

Important dates

Study start
2026
Primary completion
2029
Study completion
2029
First posted
Aug 9, 2024
Registry last updated
Feb 27, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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