Ignite Creation Date:
2024-05-06 @ 3:33 AM
Last Modification Date:
2024-10-26 @ 11:35 AM
Study NCT ID:
NCT02315833
Status:
COMPLETED
Last Update Posted:
2021-02-17
First Post:
2014-12-04
Brief Title:
The Efficacy of L-cysteine in Prevention of Headache Attacks in Migraine Patients
Sponsor:
Biohit Oyj
Organization:
Biohit Oyj
Study Overview
Official Title:
The Efficacy of L-cysteine in Prevention of Headache Attacks in Migraine Patients Randomized Intervention Trial With a Medical Device AcetiumCapsules
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 headache attacks in migraine patients
Detailed Description:
Background Globally 15 of the population is affected by migraines at some point in their life-time Pprophylactic treatment of migraines is an important part of the total management of migraine patients having twofold goals i to reduce the frequency painfulness andor duration of migraines 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 migraine attacks 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 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 migraine attacks Their headache attacks disappeared almost immediately after onset of L-cysteine administration all of them remaining in complete remission for several months up to several years by now
These spontaneous testimonials prompted us to formulate a novel study hypothesis that could possibly explain these dramatic effects of L-cysteine in migraine prevention to be tested in this RCT This novel hypothesis is starting from the fact that swelling and dilatation of cerebral blood vessels is necessary to provoke the attack in this vascular-type of headache
It is known that Nitric Oxide NO is the final trigger of migraine 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 migraine attack
Objective To validate the novel hypothesis that daily use of L-cysteine is an effective means to decrease the frequency of or completely abort the headache attacks in migraine patients
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 migraine attacks during a 3-month trial period A cohort of 200 voluntary subjects women and men with aural or non-aural migraine are invited through the Finnish Migraine Association FMA to participate in the study To be eligible the subjects should i have the attack frequency of 2-8 times per month ii have had migraine for at least 1 year iii have the onset of their migraine before 50 years of age iv be between 18 and 65 years of age and v have a minimum of co-morbidity Eligible patients are allowed if they want to continue their current migraine prophylactic medication prior to study entry Before enrolment in the cohort all subjects are requested to sign a written consent The study protocol will be subjected for approval by the Regional Committee on Medical Research Ethics HUS
Methods A 3-month retrospective history and 1-month prospective baseline run-in period is used to assess the baseline attack frequency The study setting is actually 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 blocks size of 4 and creating unique randomization codes for each subject The stratified randomization is based on the attack frequency is used as the stratification variable using 4 attacks per month as the cut-off for low-and high frequency
The treatment period in both study arms will be 3 months The participants should use and accurately report their usual symptomatic or acute treatment because not anticipated to interfere with the study medication During the 3-month treatment period participants will be evaluated at monthly intervals by the study coordinator As determined by the final study compliance data analyses might be necessary separately for i Per Protocol PePr and ii Intention-to-treat ITT groups
In addition to the baseline assessment of attack frequency each subject will be requested to fill in a structured Questionnaire recoding their detailed migraine history and other pertinent data on potential triggers to be used as covariates in multivariate analysis 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 These diaries are submitted to the study monitor on each FU visit to confirm the compliance
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 migraine RCTs a competing risks regression to model the natural outcomes of migraine during the intervention This study n100 per study arm is adequately powered Type II error 080 type I error 005 to detect a true difference in attack frequency between 4 attacksmonth in the placebo and 24 attacksmonth in the Acetium arm ie the difference in effect size of 16 attacks Given that the study subjects are selected among patients with 2-8 monthly attacks there figures seem reasonable estimates for the basis of these power calculations
Specific aims The null hypothesis of the study implicates that l-cysteine is no better than placebo in migraine prophylaxis during the intervention period of 3 months Rejection or not of the null hypothesis is based on comparison of the two arms for two primary study endpoints and to lesser extent for a series of secondary endpoints The two primary study endpoints efficacy measures are a Number of migraine attacks NMA per evaluation interval 1 month and ii Number of migraine days NMD per evaluation period Potentially useful secondary endpoints include i Intensity of headache 4-tier nominal scale ii Attack duration in hours potentially biased by treatment iii Drug consumption for symptomatic or acute treatment NMDs treated with abortive agents and the number of drug administrations for acute therapy iv Patients preferences and satisfaction v Responder rate proportion of study subjects with 50 improvement in NMA or NMD as compared to baseline values
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 Because each study subject shall complete only a 3-month trial period preceded by 1-month run-in time we expect that the study will be completed during the second half of 2014
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 migraine prophylaxis for years without concern about the side effects that are inherent to many of the current treatment modalities If the efficacy is proved in this formal RCT the concept of using Acetium capsules in prophylactic treatment of migraines would represent a major step forward in a better clinical control of these frequently intractable syndromes
Recently spontaneous case testimonials were received by Biohit Oyj from migraine patients 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 migraine attacks Their headache attacks disappeared almost immediately after onset of L-cysteine administration all of them remaining in complete remission for several months up to several years by now
These spontaneous testimonials prompted us to formulate a novel study hypothesis that could possibly explain these dramatic effects of L-cysteine in migraine prevention to be tested in this RCT This novel hypothesis is starting from the fact that swelling and dilatation of cerebral blood vessels is necessary to provoke the attack in this vascular-type of headache
It is known that Nitric Oxide NO is the final trigger of migraine 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 migraine attack
Objective To validate the novel hypothesis that daily use of L-cysteine is an effective means to decrease the frequency of or completely abort the headache attacks in migraine patients
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 migraine attacks during a 3-month trial period A cohort of 200 voluntary subjects women and men with aural or non-aural migraine are invited through the Finnish Migraine Association FMA to participate in the study To be eligible the subjects should i have the attack frequency of 2-8 times per month ii have had migraine for at least 1 year iii have the onset of their migraine before 50 years of age iv be between 18 and 65 years of age and v have a minimum of co-morbidity Eligible patients are allowed if they want to continue their current migraine prophylactic medication prior to study entry Before enrolment in the cohort all subjects are requested to sign a written consent The study protocol will be subjected for approval by the Regional Committee on Medical Research Ethics HUS
Methods A 3-month retrospective history and 1-month prospective baseline run-in period is used to assess the baseline attack frequency The study setting is actually 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 blocks size of 4 and creating unique randomization codes for each subject The stratified randomization is based on the attack frequency is used as the stratification variable using 4 attacks per month as the cut-off for low-and high frequency
The treatment period in both study arms will be 3 months The participants should use and accurately report their usual symptomatic or acute treatment because not anticipated to interfere with the study medication During the 3-month treatment period participants will be evaluated at monthly intervals by the study coordinator As determined by the final study compliance data analyses might be necessary separately for i Per Protocol PePr and ii Intention-to-treat ITT groups
In addition to the baseline assessment of attack frequency each subject will be requested to fill in a structured Questionnaire recoding their detailed migraine history and other pertinent data on potential triggers to be used as covariates in multivariate analysis 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 These diaries are submitted to the study monitor on each FU visit to confirm the compliance
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 migraine RCTs a competing risks regression to model the natural outcomes of migraine during the intervention This study n100 per study arm is adequately powered Type II error 080 type I error 005 to detect a true difference in attack frequency between 4 attacksmonth in the placebo and 24 attacksmonth in the Acetium arm ie the difference in effect size of 16 attacks Given that the study subjects are selected among patients with 2-8 monthly attacks there figures seem reasonable estimates for the basis of these power calculations
Specific aims The null hypothesis of the study implicates that l-cysteine is no better than placebo in migraine prophylaxis during the intervention period of 3 months Rejection or not of the null hypothesis is based on comparison of the two arms for two primary study endpoints and to lesser extent for a series of secondary endpoints The two primary study endpoints efficacy measures are a Number of migraine attacks NMA per evaluation interval 1 month and ii Number of migraine days NMD per evaluation period Potentially useful secondary endpoints include i Intensity of headache 4-tier nominal scale ii Attack duration in hours potentially biased by treatment iii Drug consumption for symptomatic or acute treatment NMDs treated with abortive agents and the number of drug administrations for acute therapy iv Patients preferences and satisfaction v Responder rate proportion of study subjects with 50 improvement in NMA or NMD as compared to baseline values
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 Because each study subject shall complete only a 3-month trial period preceded by 1-month run-in time we expect that the study will be completed during the second half of 2014
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 migraine prophylaxis for years without concern about the side effects that are inherent to many of the current treatment modalities If the efficacy is proved in this formal RCT the concept of using Acetium capsules in prophylactic treatment of migraines would represent a major step forward in a better clinical control of these frequently intractable syndromes
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