Ignite Creation Date:
2024-10-26 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06562400
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-08-08
Brief Title:
Searching for Novel Therapeutic Approaches in Migraine Patients Resistant to Treatments
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Unraveling the Spectrum of Migraine Resistant to Treatments Searching for Novel Biological PHEnotypes and theRApeutic Approaches SPHERA Project
Status:
RECRUITING
Status Verified Date:
2024-08
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:
SPHERA_WP2
Brief Summary:
Primary working hypothesis is that NON-responders to mAbs bear a dysfunction of the endocannabidiome system eCBome as suggested by pre-clinical and clinical data by our group
They will be identified as patients showing a reduction of monthly migraine days 50 after three months of treatment
The clinical biochemical and neurofunctional impact of novel therapeutic approaches expected to interfere with eCBome will be evaluated in NON-responder patients
They will be identified as patients showing a reduction of monthly migraine days 50 after three months of treatment
The clinical biochemical and neurofunctional impact of novel therapeutic approaches expected to interfere with eCBome will be evaluated in NON-responder patients
Detailed Description:
Monoclonal antibodies directed against the calcitonin gene related peptide pathway mAbs have recently become available as the first targeted-therapy for migraine prevention Despite their revolution in migraine therapy clinical evidence demonstrated that nearly one-third of patients do not respond to mAbs Even among Responders namely those with a reduction in monthly migraine days - MMDs of at least 50 almost half still suffers from 8 residual MMDs or more
There is therefore room for improvement and understanding the pathophysiological mechanisms involved in these processes is mandatory to develop novel therapies and optimize treatment outcome
Among several non-CGRP pathways the eCBome may play a major role in migraine as it interacts with multiple pathways to modulate inflammation and pain
Previous evidence showed that genes expression of eCBome system is altered in migraine patients
Interestingly it seems possible to normalize eCBome dysfunction in migraineurs as demonstrated by the decrease of FAAH levels in chronic migraineurs with medication overuse who underwent a successful detoxification
From a therapeutic point of view a potential role for PEA in the termination of experimentally-induced migraine attack in humans and in the acute treatment of spontaneous attacks were published
Polyunsaturated fatty acids PUFAs are other eCBome precursors involved in neuronal processes and anti-inflammatory properties Data supports an interconnection between dietary n-3 PUFAs intake also showing a protective action of high PUFAs intake in inflammation and neurodegenerative disease
Another therapeutic weapon is represented by the ketogenic diet KD a fat diet that induces an increase in PUFAs In migraine KD reduced the frequency of migraine attacks when compared to a standard mediterranean diet in episodic migraine
It may interfere with the eCBome at multiple levels gut and brain and via multiple mechanisms i increase in substrate availability ii improvement of cortical metabolism and hyperexcitability enhancing glutamate clearing from astrocytes ii modulation of neuro-inflammation
Preliminary evidence also support a role for KD in treatment-resistant migraine and in a small number of CM patients resistant to approved therapies with preliminary data suggest a positive response Its efficacy in patients who failed mAbs treatment is yet to be elucidated though
As intriguing data suggests the possibility to interfere with the eCBome via multiple modalities ranging from PEA administration to dietary adaptations it seems extremely interesting to identify an eCBome-dependent migraine phenotype and to test its performance in proof-of-concept therapeutic challenges
The investigators intend to act on the alteration of microbiota through the ketogenic diet KD and on the alteration in endocannabinoids related lipids with PEA or PUFA supplementation These therapeutic modalities are already available for clinical use and have a highly safe profile easily ready to be used for improving health in a group of highly disabled patients
The investigators will also try a concomitant therapy mAbs PEA PUFA in order to provide insights on the effect of a concomitant dual modulation CGRP and eCBome system in patients undergoing mAbs treatment
Furthermore a comprehensive biochemical set of potential biomarkers will be evaluated including neuropeptides microRNAs inflammatory cytokines kynurenine metabolites and brain cortical connectivity trough recording of HD- EEG and rs-fMRI The biochemical and functional phenotyping will allow the identification of a multibiomarkers panel signature of migraine patients resisting to specifically targeted preventive treatments potentially associated to the clinical response to treatments that targets different pathways
Study design
Patients will be enrolled among those receiving treatment with monoclonal antibodies against the calcitonin gene receptor peptide pathway mAbs at the clinic of IRCCS Mondino Institute Pavia and Neurology Department of the University of LAquila Avezzano
The following groups will be identified
NON-responder group patients who show a reduction 50 of MMDs after 3 to 6 months of mAbs treatment compared to baseline
Partial Responder patients who show a reduction 50 of MMDs after 3 to 6 months of treatment compared to baseline but still having at least 5 MMDs
NON-responders will stop mAbs treatment and will receive one of the following
PEA supplementation 600mg twice a day for three months
ketogenic diet KD for three months characterized by the following percentages of macronutrients 65 fat 27 protein and 8 carbohydrates
Partial responders will be assigned to add-on to mAbs
- PEA 600mg twice a day for three months
Clinical data will be collected and biochemical and neurofunctional profiling of migraine patients will be performed before starting novel treatment PEA or KD V0 and after three months of treatment V1 Clinical data will be collected up to 6 months from treatment starting V2
Methods
BIOCHEMICAL PROFILING
All patients will undergo a biochemical profiling that will include analysis of
eCBome system FAAH MAGL DAGL NAPE NAAA mRNA in PBMCs
plasma levels of AEA 2-AG PEA and OEA CGRP PACAP and VIP IL-1beta TNF-alpha IL-4 and IL-10 kynurenic and quinolinic acids
miR-382-5p miR-34a miR-30a and miR-155 in PBMCs
shotgun analysis of microbiota in patients faeces Biochemical sampling will be collected between 9 and 11 am to avoid circadian rhythm influence All evaluation will be performed in the interictal phase All samples will be pre-processed within 30 minutes from blood sampling and immediately stored at -80 C The final processing will be performed within 3 months
The following collection methods will be adopted
mRNA of eCBome enzymes and microRNA analysis in PBMCs Blood samples will be collected within ethylenediamine tetra-acetic acid tubes with isolation of PBMCs and total RNA Ubiquitin C and U6 will act as housekeeping genes for genes coding for the eCBome enzymes and miRNAs
Endocannabinoids and related lipids extraction kynurenic acid and quinolinic acid AEA PEA 2-AG and OEA will be determined according to the method published by Gao and collaborators with minor modificationsGao 2020 Measurement of kinurenine metabolite levels will be performed according to the method described by Fuertig et al with minor modifications Fuertig 2016
Plasma samples will be prepared by centrifugation of blood samples CGRP alpha PACAP-38 and VIP levels will be measured using a commercial enzyme linked immunosorbent assay while IL-1beta TNF-alpha IL-4 IL-10 cytokine will be measured by the Ella Automated Immunoassay System with a Simple Plex assay panel
Microbiome analysis patients will be instructed for the correct collection and preservation of stool specimens these will be delivered to the Translational Neurovascular Research Unit IRCCS Mondino Foundation for DNA extraction DNA samples will be stored at -80C until shotgun microbiome analysis
NEUROFUNCTIONAL PROFILING All patients will undergo high density-EEG and subset of 40 patients will also be studied in parallel with resting state- functional MRI at T0
- HD-EEG the investigators will randomly acquire 4 recordings 6 minutes each in resting-state condition 2 with opened eyes and 2 with closed eyes The following frequency bands will be considered delta 1-4 Hz theta 4-8 Hz alfa 8-13 Hz beta 13-30 Hz gamma 30-80 Hz
Acquisition parameters will be High-Pass 05 Hz Low-Pass 100 Hz Notch 50 Hz For analysis of HD-EEG data a previously developed and validated tailored analysis pipe-line will be used to reconstruct neural sources from corticalsubcortical gray matter EEG signals will be band-pass filtered 1-80 Hz and down-sampled at 250 Hz Biological artifacts will be rejected using Independent Component Analysis ICA EEG signals will be referenced with a customized version of the Reference Electrode Standardization Technique REST A matrix will estimate the relationship between the measured scalp potentials and the dipoles corresponding to brain sources Sources reconstruction will be performed with the exact low-resolution brain electromagnetic tomography eLORETA algorithm
Statistical analysis As a pilot study sample size is not calculated and our data will provide the fundament for further confirmatory randomized controlled studies
The investigators will separately evaluate the clinical effects of Ketogenic Diet and PEA supplementation in NON-responders and PEA supplementation in partial responders
As statistical test ANOVA for repeated measure test with a within-subject TIME factor T0 vs T3 vs T6 will be used The primary outcome will be the reduction in MMDs at T3 compared with baseline As secondary outcome the investigators will analyze modification of monthly headache days monthly days of acute drug intake monthly doses of acute drugs percentage of patients with a 30-50 reduction of MMDs migraine related disability MIDAS HIT-6 and quality of life MSQ
There is therefore room for improvement and understanding the pathophysiological mechanisms involved in these processes is mandatory to develop novel therapies and optimize treatment outcome
Among several non-CGRP pathways the eCBome may play a major role in migraine as it interacts with multiple pathways to modulate inflammation and pain
Previous evidence showed that genes expression of eCBome system is altered in migraine patients
Interestingly it seems possible to normalize eCBome dysfunction in migraineurs as demonstrated by the decrease of FAAH levels in chronic migraineurs with medication overuse who underwent a successful detoxification
From a therapeutic point of view a potential role for PEA in the termination of experimentally-induced migraine attack in humans and in the acute treatment of spontaneous attacks were published
Polyunsaturated fatty acids PUFAs are other eCBome precursors involved in neuronal processes and anti-inflammatory properties Data supports an interconnection between dietary n-3 PUFAs intake also showing a protective action of high PUFAs intake in inflammation and neurodegenerative disease
Another therapeutic weapon is represented by the ketogenic diet KD a fat diet that induces an increase in PUFAs In migraine KD reduced the frequency of migraine attacks when compared to a standard mediterranean diet in episodic migraine
It may interfere with the eCBome at multiple levels gut and brain and via multiple mechanisms i increase in substrate availability ii improvement of cortical metabolism and hyperexcitability enhancing glutamate clearing from astrocytes ii modulation of neuro-inflammation
Preliminary evidence also support a role for KD in treatment-resistant migraine and in a small number of CM patients resistant to approved therapies with preliminary data suggest a positive response Its efficacy in patients who failed mAbs treatment is yet to be elucidated though
As intriguing data suggests the possibility to interfere with the eCBome via multiple modalities ranging from PEA administration to dietary adaptations it seems extremely interesting to identify an eCBome-dependent migraine phenotype and to test its performance in proof-of-concept therapeutic challenges
The investigators intend to act on the alteration of microbiota through the ketogenic diet KD and on the alteration in endocannabinoids related lipids with PEA or PUFA supplementation These therapeutic modalities are already available for clinical use and have a highly safe profile easily ready to be used for improving health in a group of highly disabled patients
The investigators will also try a concomitant therapy mAbs PEA PUFA in order to provide insights on the effect of a concomitant dual modulation CGRP and eCBome system in patients undergoing mAbs treatment
Furthermore a comprehensive biochemical set of potential biomarkers will be evaluated including neuropeptides microRNAs inflammatory cytokines kynurenine metabolites and brain cortical connectivity trough recording of HD- EEG and rs-fMRI The biochemical and functional phenotyping will allow the identification of a multibiomarkers panel signature of migraine patients resisting to specifically targeted preventive treatments potentially associated to the clinical response to treatments that targets different pathways
Study design
Patients will be enrolled among those receiving treatment with monoclonal antibodies against the calcitonin gene receptor peptide pathway mAbs at the clinic of IRCCS Mondino Institute Pavia and Neurology Department of the University of LAquila Avezzano
The following groups will be identified
NON-responder group patients who show a reduction 50 of MMDs after 3 to 6 months of mAbs treatment compared to baseline
Partial Responder patients who show a reduction 50 of MMDs after 3 to 6 months of treatment compared to baseline but still having at least 5 MMDs
NON-responders will stop mAbs treatment and will receive one of the following
PEA supplementation 600mg twice a day for three months
ketogenic diet KD for three months characterized by the following percentages of macronutrients 65 fat 27 protein and 8 carbohydrates
Partial responders will be assigned to add-on to mAbs
- PEA 600mg twice a day for three months
Clinical data will be collected and biochemical and neurofunctional profiling of migraine patients will be performed before starting novel treatment PEA or KD V0 and after three months of treatment V1 Clinical data will be collected up to 6 months from treatment starting V2
Methods
BIOCHEMICAL PROFILING
All patients will undergo a biochemical profiling that will include analysis of
eCBome system FAAH MAGL DAGL NAPE NAAA mRNA in PBMCs
plasma levels of AEA 2-AG PEA and OEA CGRP PACAP and VIP IL-1beta TNF-alpha IL-4 and IL-10 kynurenic and quinolinic acids
miR-382-5p miR-34a miR-30a and miR-155 in PBMCs
shotgun analysis of microbiota in patients faeces Biochemical sampling will be collected between 9 and 11 am to avoid circadian rhythm influence All evaluation will be performed in the interictal phase All samples will be pre-processed within 30 minutes from blood sampling and immediately stored at -80 C The final processing will be performed within 3 months
The following collection methods will be adopted
mRNA of eCBome enzymes and microRNA analysis in PBMCs Blood samples will be collected within ethylenediamine tetra-acetic acid tubes with isolation of PBMCs and total RNA Ubiquitin C and U6 will act as housekeeping genes for genes coding for the eCBome enzymes and miRNAs
Endocannabinoids and related lipids extraction kynurenic acid and quinolinic acid AEA PEA 2-AG and OEA will be determined according to the method published by Gao and collaborators with minor modificationsGao 2020 Measurement of kinurenine metabolite levels will be performed according to the method described by Fuertig et al with minor modifications Fuertig 2016
Plasma samples will be prepared by centrifugation of blood samples CGRP alpha PACAP-38 and VIP levels will be measured using a commercial enzyme linked immunosorbent assay while IL-1beta TNF-alpha IL-4 IL-10 cytokine will be measured by the Ella Automated Immunoassay System with a Simple Plex assay panel
Microbiome analysis patients will be instructed for the correct collection and preservation of stool specimens these will be delivered to the Translational Neurovascular Research Unit IRCCS Mondino Foundation for DNA extraction DNA samples will be stored at -80C until shotgun microbiome analysis
NEUROFUNCTIONAL PROFILING All patients will undergo high density-EEG and subset of 40 patients will also be studied in parallel with resting state- functional MRI at T0
- HD-EEG the investigators will randomly acquire 4 recordings 6 minutes each in resting-state condition 2 with opened eyes and 2 with closed eyes The following frequency bands will be considered delta 1-4 Hz theta 4-8 Hz alfa 8-13 Hz beta 13-30 Hz gamma 30-80 Hz
Acquisition parameters will be High-Pass 05 Hz Low-Pass 100 Hz Notch 50 Hz For analysis of HD-EEG data a previously developed and validated tailored analysis pipe-line will be used to reconstruct neural sources from corticalsubcortical gray matter EEG signals will be band-pass filtered 1-80 Hz and down-sampled at 250 Hz Biological artifacts will be rejected using Independent Component Analysis ICA EEG signals will be referenced with a customized version of the Reference Electrode Standardization Technique REST A matrix will estimate the relationship between the measured scalp potentials and the dipoles corresponding to brain sources Sources reconstruction will be performed with the exact low-resolution brain electromagnetic tomography eLORETA algorithm
Statistical analysis As a pilot study sample size is not calculated and our data will provide the fundament for further confirmatory randomized controlled studies
The investigators will separately evaluate the clinical effects of Ketogenic Diet and PEA supplementation in NON-responders and PEA supplementation in partial responders
As statistical test ANOVA for repeated measure test with a within-subject TIME factor T0 vs T3 vs T6 will be used The primary outcome will be the reduction in MMDs at T3 compared with baseline As secondary outcome the investigators will analyze modification of monthly headache days monthly days of acute drug intake monthly doses of acute drugs percentage of patients with a 30-50 reduction of MMDs migraine related disability MIDAS HIT-6 and quality of life MSQ
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