Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02315833 |
| Other study ID # |
AC-MIGPREV-1 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
December 17, 2013 |
| Est. completion date |
September 7, 2020 |
Study information
| Verified date |
February 2021 |
| Source |
Biohit Oyj |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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, and/or
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 e.g. 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 (e.g. 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 (n=100 per study arm) is adequately powered (Type II error 0.80,
type I error 0.05) to detect a true difference in attack frequency between 4 attacks/month in
the placebo and 2.4 attacks/month in the Acetium arm, i.e., the difference in effect size of
1.6 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.
