Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000126011
Ethics application status
Approved
Date submitted
26/01/2010
Date registered
8/02/2010
Date last updated
8/02/2010
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of N-Alpha Methyl Histamine versus Propranolol in prevention of miigraine.
Scientific title
Efficacy of N alpha Methyl histamine versus propranolol in migraine prophylaxis
Secondary ID [1] 1361 0
nil
Universal Trial Number (UTN)
U1111-1113-4606
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
migraine prophylaxis 256664 0
Condition category
Condition code
Neurological 256824 256824 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
a) Name of the treatment: N alpha methyl histamine in Evan’s solution (phenol 0.4%, isotonic sodium chloride) (10 ug/ml)
b) Dose administered 0.1 ml
c) Frequency and duration administered: twice a week for 12 weeks
d) Mode of administration: subcutaneous injection into back region of the upper arm.

The number of treatment/control arms in this trial.
Arm 1: N alpha methyl histamine + placebo propanolol
Arm 2: placebo N alpha methyl histamine + propanolol
Intervention code [1] 255899 0
Treatment: Drugs
Comparator / control treatment
Patients randomized to receive oral propanolol will be given 40 mg/day for one week; then the dose will be increased 40 mg/week until a total daily dose of 120 mg/day which will be sustained for a period of twelve weeks. These patients will also receive subcutaneous placebo (Evan’s solution in back region of the upper arm) twice a week for a period of twelve weeks, administered in the same escalated-dose as N alpha methyl histamine.
Control group
Placebo

Outcomes
Primary outcome [1] 257694 0
Significant decrease (with respect to basal values) in the magnitude of all parameters studied: assessed every month after randomisation (for 3 months).
1) Reduction in to rescue medication.
"Significant decrease" is a 20% reduction in the number of tablets ingested per month. This information will be recorded by the patient in the patient's diary.
Timepoint [1] 257694 0
Recorded weekly for twelve weeks after randomisation.
Primary outcome [2] 257695 0
Significant decrease (with respect to basal values) in the magnitude of
all parameters studied: assessed every month after randomisation (for 3 months)
2) Reduction in headache intensity (1-2-3). Recorded in the patient's diary.
Timepoint [2] 257695 0
Recorded weekly for twelve weeks after randomisation.
Primary outcome [3] 257781 0
Significant decrease (with respect to basal values) in the magnitude of
all parameters studied: assessed every month after randomisation (for 3 months)
3) Frequency of headache per month. Recorded by the patient in the patient's diary. Significant decrease is a 20% reduction in the number of attacks per month.
Timepoint [3] 257781 0
Recorded weekly for twelve weeks after randomisation.
Secondary outcome [1] 263182 0
Significant decrease (with respect to basal values) in the magnitude of all parameters studied: assessed every month after randomisation (for 3 months).
1) Duration of migraine attacks.
Recorded by the patient in the patient's diary. Significant decrease is a 20% reduction in the amount of hours each episode lasts. Measured in hours.
Timepoint [1] 263182 0
Recorded weekly for twelve weeks after randomisation.

Eligibility
Key inclusion criteria
Inclusion Criteria.—The study will include outpatient male and female patients of any race between the ages of 18 and 65 years who have been diagnosed with migraine not attributable to another cause; with or without aura occurring for at least 15 consecutive days in a month, for 3 months in the absence of medication overuse. Migraine must have at least 2 of the following characteristics: unilateral location, pulsating quality, moderate or severe pain intensity, and/or aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs). With the following occurring during the attack: nausea and/or vomiting or photophobia and/or phonophobia.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria.—The following criteria are grounds for exclusion: female patients who are pregnant (positive urine pregnancy test) or planning to become pregnant during the study period, are breast feeding, or are of childbearing potential and not practicing a reliable method of birth control; patients with evidence of underlying conditions judged to preclude treatment with either test medication; patients who have previously used study medications for any reason; patients unable to discontinue any prohibited medication(s) including carbonic anhydrase inhibitors (eg, acetazolamide, dichlorphenamide), digoxin, metformin, central nervous system depressants (including alcohol), nonstudy anticonvulsant or antiepileptic medications, agents that might interfere with neuromuscular function (eg, aminoglycoside antibiotics, curare-like agents), or hormonal contraceptives; patients with evidence of recent alcohol/drug abuse or acute medication overuse; patients with diabetes mellitus, liver or kidney disease, recent (within 3 months) sepsis or vascular surgery, history of clinically significant pulmonary disease (eg, chronic obstructive pulmonary disease, asthma) active within the previous 12 months, history of heart attack or stroke, cardiac disorder (eg, any clinically significant dysrhythmia), aortic aneurysm, as well as patients at intermediate or higher risk for cardiac disease defined as having 2 or more major risk factors (cigarette smoking, hypotension).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Selected patients will undergo a one-month period of prophylactic agent washout, during which headache frequency will be monitored.

The method of allocation concealment was the use of sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation by using a randomisation table from a statistic book
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/03/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment outside Australia
Country [1] 2435 0
Mexico
State/province [1] 2435 0
Colima

Funding & Sponsors
Funding source category [1] 256410 0
Self funded/Unfunded
Name [1] 256410 0
Country [1] 256410 0
Primary sponsor type
Hospital
Name
Hospital General deZona 1 Intituto Mexicano del Seguro Social
Address
Av. de los Maestros 149
Centro CP 28000
Colima, Colima
Country
Mexico
Secondary sponsor category [1] 251715 0
None
Name [1] 251715 0
Address [1] 251715 0
Country [1] 251715 0
Other collaborator category [1] 1083 0
Individual
Name [1] 1083 0
Saul Barreto Vizcaino
Address [1] 1083 0
Instituto Mexicano del Seguro Social
Hospital General deZona1
Av. de los Maestros 149
Centro CP 28000
Colima, Colima
Country [1] 1083 0
Mexico

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258455 0
Comite de Etica del Hospital General de Zona 1 IMSS
Ethics committee address [1] 258455 0
Hospital General de Zona 1 IMSS
No R-2007-601-9

Av. de los Maestros 149
Centro CP28000
Colima, Colima
Ethics committee country [1] 258455 0
Mexico
Date submitted for ethics approval [1] 258455 0
01/05/2009
Approval date [1] 258455 0
20/05/2009
Ethics approval number [1] 258455 0
No R-2007-601-9

Summary
Brief summary
N alpha methyl histamine, possesses a greater affinity for H3 receptors, and could constitute a new therapeutic drug in migraine prophylaxis.
OBJETIVE. To compare the superior efficacy of the subcutaneous administration of N alpha-methyl histamine versus oral propranolol in migraine prophylaxis, undertaking double-blind, placebo-controlled study.
Hypothesis
That subcutaneously injected N alpha methyl histamine (1-3ug) is more effective than propranolol (120mg/ day) in migraine prophylaxis.

Null Hypothesis
There is no difference between the subcutaneous administration of N- alpha methyl histamine in doses of 1-3 ng and oral propanolol as prophylactic agents against migraine

METHODS. A randomized, double–blind study in 60 patients with migraine, male or female adults between the ages of 18 and 65 years. Selected patients will undergo a one-month period of prophylactic agent washout, they will then be divided into two groups for treatment in randomized blocks of three, double-blind fashion: N-alpha metyl histamine study group (n=30) and the propranolol control group (n=30). The treatment will consist of subcutaneous (back region of the upper arm) administration of N alpha methyl histamine twice a week, plus an oral placebo for a period of twelve weeks. Therapy with propranolol will begin at 40 mg/day for one week; until a total daily dose of 120 mg/day for a period of twelve weeks; plus a subcutaneous placebo. The variables we will study are: headache frequency; intensity of pain; duration of pain; intake of rescue analgesics and MIDAS. Statistical Analysis: The intent-to-treat (ITT) population will include all randomized patients. Two-tailed Student’s t test. Mann-Whitney U rank sum test. In order to analyze the temporal course of each treatment, a Friedman repeated measures ANOVA on ranks test will be used to evaluate the statistical significance of differences between basal values and values found for the 4th, 8th, and 12th weeks of treatment. This study has been approved by the Ethical and Scientific Committee of our hospital.
Trial website
Trial related presentations / publications
1.Millan-Guerrero RO, Isais CM, Antonio OA, Pacheco-Carrasco MF. Histamine as a therapeutic alternative in migraine prophylaxis: A randomized, placebo-controlled, double-blind study. Headache 1999;39:576-580

2.Millan-Guerrero RO, Pineda-Lucatero AG. Trujillo-Hernandez B, Tene CE, Pacheco MF. Na-Methyl histamine safety and efficacy in migraine prophylaxis: Phase I and Phase II study. Headache 2003;43:389-94

3.Millan-Guerrero RO, Isais- Millan R, Trujillo Hernandez B, Tene PC. . Na-Methyl Histamine safety and efficacy in migraine prophylaxis: Phase III study. Can J Neurol Sci 2006;33:195-199

4.Millan-Guerrero RO, Trujillo Hernandez B, Tene PC. Histamina subcutanea en profilaxis de migrana. Efectos iniciales y seguimiento a largo plazo. Neurologia 2006; 21:55-59

5.Millan-Guerrero RO, Isais-Millan R, Barreto-Vizcaino S, Rivera-Castano L, Garcia-SA, Lopez BC, Membrila MM, Munoz SR. Subcutaneous histamine versus sodium valproate in migraine prophylaxis: A Randomized, Controlled, double-blind study. Eur J. Neurol.2007;14:1079-1084

6.Millan-Guerrero RO, Isais-Millan S, Barreto-Vizcaino S, Rivera-Castano L, Rios-Madariaga C. Subcutaneous histamine versus botulinum toxin type A in migraine prophylaxis: a randomized, double-blind study. Eur J. Neurol 2009, 16: 88–94
Public notes

Contacts
Principal investigator
Name 30761 0
Address 30761 0
Country 30761 0
Phone 30761 0
Fax 30761 0
Email 30761 0
Contact person for public queries
Name 14008 0
Dr. Rebeca Olivia Millan Guerrero
Address 14008 0
Hospital General de Zona 1 IMSS
Avenida de los Maestros 149
Colonia Centro
CP 28000
Colima, Colima
Country 14008 0
Mexico
Phone 14008 0
01 52 31 23 14 17 57
Fax 14008 0
01 52 31 23 14 17 57
Email 14008 0
rebeca.millan@imss.gob.mx
Contact person for scientific queries
Name 4936 0
Dr. Rebeca Olivia Millan Guerrero
Address 4936 0
Hospital General de Zona 1 IMSS
Avenida de los Maestros 149
Colonia Centro
CP 28000
Colima, Colima
Country 4936 0
Mexico
Phone 4936 0
0152 31 23 14 17 57
Fax 4936 0
01 52 31 23 14 17 57
Email 4936 0
rebeca.millan@imss.gob.mx

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