Ignite Creation Date:
2024-05-06 @ 3:32 AM
Last Modification Date:
2024-10-26 @ 11:35 AM
Study NCT ID:
NCT02310828
Status:
COMPLETED
Last Update Posted:
2021-02-17
First Post:
2014-12-04
Brief Title:
The Efficacy of L-cysteine in Prevention of Cluster Headache
Sponsor:
Biohit Oyj
Organization:
Biohit Oyj
Study Overview
Official Title:
The Efficacy of L-cysteine in Prevention of Cluster Headache Randomized Intervention Trial With a Medical Device Acetium Capsules
Status:
COMPLETED
Status Verified Date:
2021-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to validate the novel hypothesis that daily use of L-cysteine Acetium capsules is an effective means to decrease the frequency of or completely abort the attacks of cluster headache
Detailed Description:
Background Cluster headache belongs to a group of idiopathic headache entities the trigeminal autonomic cephalalgias TACs all of which involve short-lasting unilateral severe headache attacks and typical accompanying autonomic symptoms The life-time prevalence of cluster headache for adults of all ages is around 125100000 or approximately 01 with clear male dominance 41 Prophylactic treatment is an important part of the total management of cluster headache patients having twofold goals i to reduce the frequency painfulness andor duration of headache attacks and ii to increase the effectiveness of abortive therapy During the past several decades a large number of optional modalities have been tested as preventive measures of cluster headache Not unexpectedly the effects of any such preventive therapies are highly variable and in many patients the attack frequency is not under satisfactory control Many of these drugs also have untoward side effects that offset their potential benefits
Recently spontaneous case testimonials were received by Biohit Oyj from migraine patients and one with cluster headache reporting that our new medical device Acetium capsule containing 100mg l-cysteine developed for inactivation of acetaldehyde in the stomach contents after alcohol intake proved to be highly effective against their headache attacks Their attacks disappeared almost immediately after onset of L-cysteine administration all of them remaining in complete remission for several months up to several years
These spontaneous testimonials prompted us to formulate a novel study hypothesis that could possibly explain this dramatic effect of L-cysteine in prevention of headache attacks to be tested in this RCT This novel hypothesis is starting from the fact that in cluster headache a vascular-type of headache swelling and dilatation of the blood vessels is necessary to provoke the attack
It is known that Nitric Oxide NO is the final trigger of vascular headache attack operating through phosphorylated protein kinase G PKG and Ca2 channels slowing the influx of calcium into the cell which leads to smooth muscle relaxation and vasodilation Histamine is a potent inducer of NO Synthase making NO available locally on the vasculature acting through endothelial H1-receptors Histamine is synthesized from histidine in tissue mast cells which are ubiquitous cells and their activation eg in the meninges has long been suspected to be involved in generating migraine headaches Finally one of the potent liberators of histamine from the mast cells is acetaldehyde which in turn is effectively inactivated by L-cysteine Acetium capsule This led us to rational that by eliminating acetaldehyde in the stomach L-cysteine could block or reduce below the threshold levels histamine liberation from the tissue mast cells and ECL cells in the stomach thus arresting its multitude of functions of which vasodilatation is critically involved in the cluster headache attack
Objective To validate the novel hypothesis that daily use of L-cysteine Acetium capsules 100mg twice a day is an effective means to decrease the frequency of or completely abort the headache attacks in patients suffering from cluster headache
Study design A double-blind randomized placebo-controlled multi-centre trial comparing Acetium capsules 100mg L-cysteine twice a day and placebo in prevention of headache attacks during a 1-month trial period In brief a cohort of 60 up to100 voluntary subjects women and men with periodic or chronic cluster headache are invited through the Finnish Migraine Association FMA To be eligible for the study the subjects should i have the frequency of typical attacks up to 5 per day ii age between 18 and 65 years and iii have a minimum of co-morbidity There are no restrictions on duration since the diagnosis or the age at the onset of cluster headache They should discontinue other prophylactic medication prior to study entry Before enrolment all subjects are requested to sign a written consent The study protocol will be subjected for approval by the Committee on Medical Research Ethics HUS
Methods The study setting is triple-blinded participant-blind investigator-blind sponsor-blind Placebo preparation with design and package identical to the test preparation will be used Parallel group design instead of cross-over design is used Randomization will be performed using a random number generator with block size of 4 and stratified by gender
The treatment period in both study arms will be 1 month The participants should use but accurately report their usual symptomatic or acute treatment because not anticipated to interfere with the study medication During the 1-month treatment period participants will be evaluated at weekly intervals by the study coordinator
In addition to the baseline assessment of attack frequency each subject will be requested to fill in a structured Questionnaire recoding their detailed headache history and other pertinent data on potential triggers The headache diary is the main research tool used to monitor the efficacy of the test preparations recording all predefined assessment measures efficacy tolerability and safety and submitted to the study monitor on each FU visit
In statistical analysis both conventional techniques eg non-parametric paired-samples and non-paired samples t-test and more sophisticated methods will be used The latter include i life-table methods like Kaplan-Meier and Cox proportional hazards regression as well as ii generalized linear models GEE and panel Poisson and as a new technique in cluster headache RCTs a competing risks regression to model the natural outcomes of the headache during the intervention This study n60 the most modest scenario is adequately powered Type II error 080 type I error 005 to detect a true difference in attack frequency between 15 attacksweek in the placebo and 131 attacksweek in the Acetium arm Given that the study subjects are enrolled among patients with typically 1-3 attacksday ie 7-21 up to 35 attacks per week and assuming a 10 reduction by placebo there figures seem reasonable estimates for these power calculations
Specific aims The null hypothesis of the study implicates that l-cysteine is no better than placebo in prophylaxis of cluster headache during the 1-month intervention period Rejection or not of the null hypothesis is based on comparison of the two arms for the primary study endpoint and to lesser extent for a series of secondary endpoints The primary study endpoint efficacy measure is the number of attacks per week Potentially useful secondary endpoints include i intensity of headache 4-tier nominal scale ii drug consumption for symptomatic or acute treatment and iii patients preferences and satisfaction
Study execution and time table Meanwhile the final protocol is under evaluation for ethical approval by HUS preparatory measures have been taken by informing the FMA about the planned study and asking their co-operation in encouraging the interested migraine patients to contact the study coordinator Given the preliminary interest shown by the FMA we are optimistic that the required cohort of volunteers can be enrolled within a short time most likely by the end of 2013 However because the subjects with episodic cluster headache must be enrolled during their on-going cluster episodes that typically follow a seasonal pattern the enrolment of the total cohort even n60 inevitably needs to be completed over several months up to one year
Impact of the study Given that L-cysteine is a natural semi-essential amino acid converted to inert substance MTCA in the alimentary tract it would comprise an ideal means to conduct prophylaxis of cluster headaches for years without concern about the side effects that are inherent to many of the current treatment modalities If the efficacy is proven in this formal RCT the concept of using Acetium capsules in prophylactic treatment of cluster headache would represent a major step forward in a better clinical control of these frequently excruciating headaches
Recently spontaneous case testimonials were received by Biohit Oyj from migraine patients and one with cluster headache reporting that our new medical device Acetium capsule containing 100mg l-cysteine developed for inactivation of acetaldehyde in the stomach contents after alcohol intake proved to be highly effective against their headache attacks Their attacks disappeared almost immediately after onset of L-cysteine administration all of them remaining in complete remission for several months up to several years
These spontaneous testimonials prompted us to formulate a novel study hypothesis that could possibly explain this dramatic effect of L-cysteine in prevention of headache attacks to be tested in this RCT This novel hypothesis is starting from the fact that in cluster headache a vascular-type of headache swelling and dilatation of the blood vessels is necessary to provoke the attack
It is known that Nitric Oxide NO is the final trigger of vascular headache attack operating through phosphorylated protein kinase G PKG and Ca2 channels slowing the influx of calcium into the cell which leads to smooth muscle relaxation and vasodilation Histamine is a potent inducer of NO Synthase making NO available locally on the vasculature acting through endothelial H1-receptors Histamine is synthesized from histidine in tissue mast cells which are ubiquitous cells and their activation eg in the meninges has long been suspected to be involved in generating migraine headaches Finally one of the potent liberators of histamine from the mast cells is acetaldehyde which in turn is effectively inactivated by L-cysteine Acetium capsule This led us to rational that by eliminating acetaldehyde in the stomach L-cysteine could block or reduce below the threshold levels histamine liberation from the tissue mast cells and ECL cells in the stomach thus arresting its multitude of functions of which vasodilatation is critically involved in the cluster headache attack
Objective To validate the novel hypothesis that daily use of L-cysteine Acetium capsules 100mg twice a day is an effective means to decrease the frequency of or completely abort the headache attacks in patients suffering from cluster headache
Study design A double-blind randomized placebo-controlled multi-centre trial comparing Acetium capsules 100mg L-cysteine twice a day and placebo in prevention of headache attacks during a 1-month trial period In brief a cohort of 60 up to100 voluntary subjects women and men with periodic or chronic cluster headache are invited through the Finnish Migraine Association FMA To be eligible for the study the subjects should i have the frequency of typical attacks up to 5 per day ii age between 18 and 65 years and iii have a minimum of co-morbidity There are no restrictions on duration since the diagnosis or the age at the onset of cluster headache They should discontinue other prophylactic medication prior to study entry Before enrolment all subjects are requested to sign a written consent The study protocol will be subjected for approval by the Committee on Medical Research Ethics HUS
Methods The study setting is triple-blinded participant-blind investigator-blind sponsor-blind Placebo preparation with design and package identical to the test preparation will be used Parallel group design instead of cross-over design is used Randomization will be performed using a random number generator with block size of 4 and stratified by gender
The treatment period in both study arms will be 1 month The participants should use but accurately report their usual symptomatic or acute treatment because not anticipated to interfere with the study medication During the 1-month treatment period participants will be evaluated at weekly intervals by the study coordinator
In addition to the baseline assessment of attack frequency each subject will be requested to fill in a structured Questionnaire recoding their detailed headache history and other pertinent data on potential triggers The headache diary is the main research tool used to monitor the efficacy of the test preparations recording all predefined assessment measures efficacy tolerability and safety and submitted to the study monitor on each FU visit
In statistical analysis both conventional techniques eg non-parametric paired-samples and non-paired samples t-test and more sophisticated methods will be used The latter include i life-table methods like Kaplan-Meier and Cox proportional hazards regression as well as ii generalized linear models GEE and panel Poisson and as a new technique in cluster headache RCTs a competing risks regression to model the natural outcomes of the headache during the intervention This study n60 the most modest scenario is adequately powered Type II error 080 type I error 005 to detect a true difference in attack frequency between 15 attacksweek in the placebo and 131 attacksweek in the Acetium arm Given that the study subjects are enrolled among patients with typically 1-3 attacksday ie 7-21 up to 35 attacks per week and assuming a 10 reduction by placebo there figures seem reasonable estimates for these power calculations
Specific aims The null hypothesis of the study implicates that l-cysteine is no better than placebo in prophylaxis of cluster headache during the 1-month intervention period Rejection or not of the null hypothesis is based on comparison of the two arms for the primary study endpoint and to lesser extent for a series of secondary endpoints The primary study endpoint efficacy measure is the number of attacks per week Potentially useful secondary endpoints include i intensity of headache 4-tier nominal scale ii drug consumption for symptomatic or acute treatment and iii patients preferences and satisfaction
Study execution and time table Meanwhile the final protocol is under evaluation for ethical approval by HUS preparatory measures have been taken by informing the FMA about the planned study and asking their co-operation in encouraging the interested migraine patients to contact the study coordinator Given the preliminary interest shown by the FMA we are optimistic that the required cohort of volunteers can be enrolled within a short time most likely by the end of 2013 However because the subjects with episodic cluster headache must be enrolled during their on-going cluster episodes that typically follow a seasonal pattern the enrolment of the total cohort even n60 inevitably needs to be completed over several months up to one year
Impact of the study Given that L-cysteine is a natural semi-essential amino acid converted to inert substance MTCA in the alimentary tract it would comprise an ideal means to conduct prophylaxis of cluster headaches for years without concern about the side effects that are inherent to many of the current treatment modalities If the efficacy is proven in this formal RCT the concept of using Acetium capsules in prophylactic treatment of cluster headache would represent a major step forward in a better clinical control of these frequently excruciating headaches
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