Ignite Creation Date:
2024-10-26 @ 3:35 PM
Last Modification Date:
2024-10-26 @ 3:35 PM
Study NCT ID:
NCT06503328
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-07-09
Brief Title:
Role of Specific microRNAs in Cluster Headache
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Role of Specific microRNAs in Cluster Headache Implications for Disease Phenotype and Neuropeptide Expression
Status:
RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
51000
Brief Summary:
Cluster headache CH is a primary headache included in the trigeminal autonomic cephalalgias TACs according to the International Calssification of Headache Disorder Third Edition CH is characterized by a multifaceted and incompletely understood pathophysiology Recent experimental evidence has increasingly emphasized the role of specific microRNAs miRNAs in the pathophysiology of primary headaches including migraine
In a recent study we observed an upregulation in the gene expression of two miRNAs miR-382-5p and miR-34a-5p in peripheral blood mononuclear cells PBMCs of subjects with chronic migraine CM These miRNAs are involved in inflammation modulation and the release of γ-aminobutyric acid GABA Notably this upregulation correlated with the migraine phenotype and its severity
Several neuropeptides have been established to play an active role in CH Studies by the Danish group have demonstrated that intravenous administration of CGRP PACAP or VIP can induce CH attacks in at least 50 of participants in the active phase of the disease
However no data currently exists regarding the potential involvement of miRNAs in CH Given this context the primary aim of this study is to investigate the gene expression of specific miRNAs miR-382-5p miR-34a-5p and miR-155 in PBMCs and plasma levels of neuropeptides CGRP PACAP VIP in subjects with episodic CH in the active phase eCH-act episodic CH in the remission phase eCH-rem chronic CH cCH and healthy control subjects HCs
In a recent study we observed an upregulation in the gene expression of two miRNAs miR-382-5p and miR-34a-5p in peripheral blood mononuclear cells PBMCs of subjects with chronic migraine CM These miRNAs are involved in inflammation modulation and the release of γ-aminobutyric acid GABA Notably this upregulation correlated with the migraine phenotype and its severity
Several neuropeptides have been established to play an active role in CH Studies by the Danish group have demonstrated that intravenous administration of CGRP PACAP or VIP can induce CH attacks in at least 50 of participants in the active phase of the disease
However no data currently exists regarding the potential involvement of miRNAs in CH Given this context the primary aim of this study is to investigate the gene expression of specific miRNAs miR-382-5p miR-34a-5p and miR-155 in PBMCs and plasma levels of neuropeptides CGRP PACAP VIP in subjects with episodic CH in the active phase eCH-act episodic CH in the remission phase eCH-rem chronic CH cCH and healthy control subjects HCs
Detailed Description:
Background Cluster headache CH is a primary headache included in the trigeminal autonomic cephalalgias TACs according to the International Calssification of Headache Disorder Third Edition CH is characterized by a multifaceted and incompletely understood pathophysiology The hypothalamus the trigeminal-vascular complex and the trigeminal-autonomic reflex are believed to play a significant role
Increasing experimental evidence has highlighted the involvement of specific microRNAs miRNAs in the chronic pain and primary headaches including migraine miRNAs are small endogenous noncoding RNAs that are around 22 nucleotides in length miRNAs operate as post-transcriptional regulator of gene expression by promoting messenger RNA mRNA degradation or repressing mRNA translation The regulation process performed by miRNAs is complex and articulated since an individual miRNA might target hundreds of different mRNAs and conversely each mRNA may be regulated by multiple miRNAs It has been estimated that more than 60 of all protein-coding genes are regulated by miRNAs which consequentially determine the pleiotropic modulation of a wide variety of cellular processes involving differentiation development and signaling miRNAs are involved in the generation and maintenance of pain and several evidence suggest that specific miRNAs could play a role in migraine
In a recent study we observed an upregulation of gene expression in two miRNAs miR-382-5p and miR-34a-5p in peripheral blood mononuclear cells PBMCs in subjects with chronic migraine CM These miRNAs are involved in inflammation modulation and the release of γ-aminobutyric acid GABA compared to individuals with episodic migraine and healthy subjects HCs These findings underscore a correlation between the gene expression of these miRNAs and the migraine phenotype as well as its severity
Recent studies suggest an active role for certain neuropeptides in CH The Danish group has indeed demonstrated that the intravenous administration of CGRP PACAP or VIP can induce acute CH attacks in at least 50 of participants when studied in the active phase of the disease
As of now there is no data regarding the potential involvement of miRNAs in CH This study aims to provide a detailed exploration of the role of miRNAs in cluster headache contributing to our understanding of the pathophysiology of this primary headache disorder Furthermore the results obtained may pave the way for the development of a new generation of molecules that could be used in the field of CH such as miRNA agonists Agomir and antagonists Antagomir
Aims The primary objective of our current project is to investigate the peripheral expression of miRNAs implicated in pain modulation miR-382-5p miR-34a-5p and miR-155 in subjects with episodic CH in the active phase eCH-act episodic CH in the remission phase eCH-rem chronic CH cCH and healthy control subjects HC
Methods
All subjects will perform a single evaluation over time during which they will undergo
explanation of study procedures and informed consent signing
screening visit
clinical and demographic data collection based on revision of a headache diary
fasting venous blood sampling
administration of questionnaires
All subjects will be evaluated in the morning after night fasting For subjects affected by cCH or eCH-act sampling is expected to be carried out in the inter-critical phase as defined by the absence of CH attacks for at least 3 hours in patients with eCH and for at least 8 hours in patients with cCH After blood sampling patients will stay at Center to complete a set of questionnaires This will allow the investigator to monitor the patients for at least 2 hours to exclude that a blood sampling is performed immediately before a CH attack
For patients with eCH the active and remission phases will be defined as follows
Active phase the phase during which CH attacks have been present for at least 7 days
Remission phase characterized by an absence of cluster headache attacks for at least 15 consecutive days without pharmacological therapy
miR-382-5p miR-34a-5p and miRNA-155 gene expression will be evaluated in PBMCs by real-time reverse transcription RT-PCR This assessment will be normalized with U6 a type of small nuclear RNA used as housekeeping gene and expressed as Relative Quantification RQ Plasma levels of CGRP alpha PACAP and VIP will be measured using validated commercial ELISA kits A detailed description of the methods planned for the biochemical analyses could be found here httpsdoiorg101186s10194-020-01189-0
The set of clinical questionnaires will include Migraine Disability Assessment MIDAS Headache Impact Test HIT-6 Cluster headache Impact Questionnarie CHIQ
Sample size calculation and pre-planned statistical analysis The following parameters were considered for the calculation Effect Size 05 alpha error 005 beta error 005 power 95 number of groups 4
Sample size calculation was conducted using the freeware platform GPower ver 3197 for an ANOVA test with Bonferroni correction applied to the 4 groups The minimum suggested sample size is 76 subjects 19 subjects per group To account for potential variability we plan to enroll a total of 100 subjects with 25 subjects per group
Parametric or non-parametric correlations will be used to measure the relationship between biochemical variables and clinical variables Multivariate analyses will be performed according to the results of the univariate analysis Statistical significance will be set at the 5 level p005
Increasing experimental evidence has highlighted the involvement of specific microRNAs miRNAs in the chronic pain and primary headaches including migraine miRNAs are small endogenous noncoding RNAs that are around 22 nucleotides in length miRNAs operate as post-transcriptional regulator of gene expression by promoting messenger RNA mRNA degradation or repressing mRNA translation The regulation process performed by miRNAs is complex and articulated since an individual miRNA might target hundreds of different mRNAs and conversely each mRNA may be regulated by multiple miRNAs It has been estimated that more than 60 of all protein-coding genes are regulated by miRNAs which consequentially determine the pleiotropic modulation of a wide variety of cellular processes involving differentiation development and signaling miRNAs are involved in the generation and maintenance of pain and several evidence suggest that specific miRNAs could play a role in migraine
In a recent study we observed an upregulation of gene expression in two miRNAs miR-382-5p and miR-34a-5p in peripheral blood mononuclear cells PBMCs in subjects with chronic migraine CM These miRNAs are involved in inflammation modulation and the release of γ-aminobutyric acid GABA compared to individuals with episodic migraine and healthy subjects HCs These findings underscore a correlation between the gene expression of these miRNAs and the migraine phenotype as well as its severity
Recent studies suggest an active role for certain neuropeptides in CH The Danish group has indeed demonstrated that the intravenous administration of CGRP PACAP or VIP can induce acute CH attacks in at least 50 of participants when studied in the active phase of the disease
As of now there is no data regarding the potential involvement of miRNAs in CH This study aims to provide a detailed exploration of the role of miRNAs in cluster headache contributing to our understanding of the pathophysiology of this primary headache disorder Furthermore the results obtained may pave the way for the development of a new generation of molecules that could be used in the field of CH such as miRNA agonists Agomir and antagonists Antagomir
Aims The primary objective of our current project is to investigate the peripheral expression of miRNAs implicated in pain modulation miR-382-5p miR-34a-5p and miR-155 in subjects with episodic CH in the active phase eCH-act episodic CH in the remission phase eCH-rem chronic CH cCH and healthy control subjects HC
Methods
All subjects will perform a single evaluation over time during which they will undergo
explanation of study procedures and informed consent signing
screening visit
clinical and demographic data collection based on revision of a headache diary
fasting venous blood sampling
administration of questionnaires
All subjects will be evaluated in the morning after night fasting For subjects affected by cCH or eCH-act sampling is expected to be carried out in the inter-critical phase as defined by the absence of CH attacks for at least 3 hours in patients with eCH and for at least 8 hours in patients with cCH After blood sampling patients will stay at Center to complete a set of questionnaires This will allow the investigator to monitor the patients for at least 2 hours to exclude that a blood sampling is performed immediately before a CH attack
For patients with eCH the active and remission phases will be defined as follows
Active phase the phase during which CH attacks have been present for at least 7 days
Remission phase characterized by an absence of cluster headache attacks for at least 15 consecutive days without pharmacological therapy
miR-382-5p miR-34a-5p and miRNA-155 gene expression will be evaluated in PBMCs by real-time reverse transcription RT-PCR This assessment will be normalized with U6 a type of small nuclear RNA used as housekeeping gene and expressed as Relative Quantification RQ Plasma levels of CGRP alpha PACAP and VIP will be measured using validated commercial ELISA kits A detailed description of the methods planned for the biochemical analyses could be found here httpsdoiorg101186s10194-020-01189-0
The set of clinical questionnaires will include Migraine Disability Assessment MIDAS Headache Impact Test HIT-6 Cluster headache Impact Questionnarie CHIQ
Sample size calculation and pre-planned statistical analysis The following parameters were considered for the calculation Effect Size 05 alpha error 005 beta error 005 power 95 number of groups 4
Sample size calculation was conducted using the freeware platform GPower ver 3197 for an ANOVA test with Bonferroni correction applied to the 4 groups The minimum suggested sample size is 76 subjects 19 subjects per group To account for potential variability we plan to enroll a total of 100 subjects with 25 subjects per group
Parametric or non-parametric correlations will be used to measure the relationship between biochemical variables and clinical variables Multivariate analyses will be performed according to the results of the univariate analysis Statistical significance will be set at the 5 level p005
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None