Brief Summary

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.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

participants targeted

Target at below P25 for not_applicable

Timeline

35mo left

Started Feb 2026

Typical duration for not_applicable

Geographic Reach

1 country

6 active sites

Status

recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

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Study Timeline

Key milestones and dates

3 years study duration

Study Progress7%

Feb 2026Feb 2029

First Submitted

Initial submission to the registry

May 7, 2024

Completed

3 months until next milestone

First Posted

Study publicly available on registry

August 9, 2024

Completed

1.5 years until next milestone

Study Start

First participant enrolled

February 25, 2026

Completed

3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

February 25, 2029

Expected

Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

February 25, 2029

Last Updated

February 27, 2026

Status Verified

February 1, 2026

Enrollment Period

3 years

First QC Date

May 7, 2024

Last Update Submit

February 25, 2026

Conditions

Cryopyrin Associated Periodic Syndrome Familial Cold Urticaria Muckle-Wells Syndrome CINCA Syndrome

Keywords

Circadian clockcryopyrin-associated periodic syndromefamilial cold urticariamuckle-wells syndromemelatonin

Outcome Measures

Primary Outcomes (4)

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 Outcomes (20)

Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.
6 th month
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.
6 th month
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.
6 th month
Chronotype determination
6 th month
sleep duration
6 th month
+15 more secondary outcomes

Study Arms (2)

Patients with cryopyrin-associated periodic syndrome (CAPS)

ACTIVE COMPARATOR

Confirmed by genetic analysis of NLRP3

Genetic: Genetic analysis of NLRP3Device: Circadian rhythm measurementBiological: Saliva samplingOther: QuestionnaireOther: AIDAI scoreBiological: Blood sampling

Control group

PLACEBO COMPARATOR

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 NLRP3Device: Circadian rhythm measurementBiological: Saliva samplingOther: QuestionnaireBiological: Blood sampling