The Efficacy of L-cysteine in Prevention of Cluster Headache
Condition: Cluster Headache
MeSH terms: Cluster Headache; Headache
Study type: Interventional

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 125/100,000, or approximately 0.1%, with
      clear male dominance (4:1). Prophylactic treatment is an important part of the total
      management of cluster headache patients, having twofold goals: i) to reduce the frequency,
      painfulness, and/or 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 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 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 (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 cluster
      headache RCTs, a competing risks regression to model the natural outcomes of the headache
      during the intervention. This study (n=60; the most modest scenario) is adequately powered
      (Type II error 0.80, type I error 0.05) to detect a true difference in attack frequency
      between 15 attacks/week in the placebo and 13.1 attacks/week in the Acetium arm. Given that
      the study subjects are enrolled among patients with typically 1-3 attacks/day, i.e., 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 n=60) 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.
    

Intervention name(s): Acetium; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Capsule for oral administration contains L-cysteine 100mg; A placebo capsule matching Acetium for oral administration.
Other intervention name(s): Acetium capsule; Acetium capsule placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Cluster headache; Migrainous neuralgia; Horton's headache; Histaminic cephalalgia