A Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy and Safety of Subcutaneous Histamine Dihydrochloride for Migraine Prophylaxis

• Sponsor: BioHealthonomics Inc.
• Information provided by (Responsible Party): BioHealthonomics Inc.

Study Description

Brief Summary:

This is a prospective multi-center, randomized, double-blind, two treatment period, placebo-controlled study in subjects with migraine headache requiring prophylactic treatment. The patients will be randomized to receive either histamine dihydrochloride sc or placebo (matching vehicle only) sc for 16 weeks. The safety and efficacy outcome measures will be assessed at selected dosing segments during the 16 week treatment phase and 4 weeks (week 20), 8 weeks (week 24) after the last Injection.

Condition or disease	Intervention/treatment	Phase
Migraine Prophylaxis	Drug: Histamine Dihydrochloride; Drug: Subcutaneous placebo (Evan's solution = phenol 0.4%, isotonic sodium chloride).	Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	130 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Phase II Study to Assess the Efficacy and Safety of Subcutaneous Histamine Dihydrochloride for Migraine Prophylaxis
Study Start Date :	September 2015
Estimated Primary Completion Date :	September 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Histamine Dihydrochloride; Placebo-controlled Trial to Assess the Efficacy and Safety of Subcutaneous Histamine Dihydrochloride for Migraine Prophylaxis.	Drug: Histamine Dihydrochloride
Placebo Comparator: Evan's solution = phenol 0.4%, isotonic sodium chloride; Placebo-controlled Trial to Assess the Efficacy and Safety of Subcutaneous Histamine Dihydrochloride for Migraine Prophylaxis.	Drug: Subcutaneous placebo (Evan's solution = phenol 0.4%, isotonic sodium chloride).; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Mean change from baseline in monthly migraine days [time frame: baseline and average over Weeks 3-22]. [ Time Frame: 4 week intervals over weeks 3-22 ]
   Mean change from baseline in monthly migraine days [time frame: baseline and average over Weeks 3-22].

Secondary Outcome Measures :

1. Mean change from baseline in monthly migraine days by 4 week intervals [Weeks 3-6, 7-10, 11-14, 15-18, 19-22]. [ Time Frame: 4 week time interval ]
   Mean change from baseline in monthly migraine days by 4 week intervals [Weeks 3-6, 7-10, 11-14, 15-18, 19-22].
2. Mean Change from Baseline in Monthly Migraine Index (MMI) [ Time Frame: Baseline and average over observation period (weeks 3-22) ]

   Mean Change from Baseline in Monthly Migraine Index (MMI) [ Time Frame: baseline and average over observation period (Weeks 3-22).

   Monthly Migraine Index (MMI):

   Migraine headaches are assigned a number based on the peak intensity of that migraine headache:

   • 1 for a mild migraine headache
   • 2 for a moderate migraine headache
   • 3 for a severe migraine headache.

   The MMI is calculated as follows:

   MMI= Sum of [(Migraine Peak Intensity Level (1-3)) x (Migraine Duration (hours))] / (Distinct Number of Migraine Headaches for that 4 week period)

   Sample Calculation:

   The patient experiences 3 migraine headaches (M1, M2, and M3) in 4 weeks . M1: Intensity Level 3, Duration is 7 hrs M2: Intensity Level 2, Duration 3 hrs M3: Intensity Level 3, Duration 15 hrs MMI= (3x7 + 2x3 + 3x15) / 3 = 24

3. Mean change from baseline in monthly number of migraines [ Time Frame: Baseline and over weeks 3-22 ]
   Mean change from baseline in monthly number of migraines [time frame: baseline and over Weeks 3-22].
4. Mean change from baseline in monthly number of migraines [ Time Frame: 4 week intervals [Weeks 3-6, 7-10, 11-14, 15-18, 19-22]. ]
   Mean change from baseline in monthly number of migraines by 4 week intervals [Weeks 3-6, 7-10, 11-14, 15-18, 19-22].

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Patients of any race, 18 to 65 years of age inclusive.
2. Patients with a history of migraine (with or without aura) according to the Headache Classification Committee of the IHS. Migraine attacks have to have had an onset before age 50 and have to have been present for at least 12 months.
3. Patients with 4-20 qualified migraine attacks per month over the past three months prior to Screening, as well as during the four weeks of the Baseline Phase will be eligible for entry into this study. The interval between two qualified migraine attacks should be at least 24 hours to be counted as distinct migraine attacks. A qualified migraine attack without aura is defined as a headache that lasts 4-72 hours (if untreated or unsuccessfully treated) or if successfully treated. This attack has at least two of the following characteristics: unilateral location, pulsating quality, moderate or severe intensity that inhibits or prohibits daily activities or aggravation by routine physical activities such as walking up stairs. In addition, at least one of the following symptoms must be present during the headache: nausea, vomiting, or photophobia and phonophobia. A qualified migraine attack with aura must fulfill the same criteria as the headache attack, plus have an associated aura as defined by the Migraine Criteria of the Headache Classification Committee of the International Headache Society. An aura alone that requires acute migraine treatment will also be considered a migraine attack.
4. Male and female patients will be eligible for enrollment. Females should be either of non-childbearing potential by reason of surgery, radiation, menopause (one year post onset), or of childbearing potential and practicing a medically acceptable method of contraception (eg, abstinence, a barrier method plus spermicide, or IUD) for at least one month before study randomization and for two months after the end of the study, and have a negative serum B-hCG at Screening. Pregnant and/or lactating females are excluded. Those women using hormonal contraceptives must also be using an additional approved method of contraception (eg, a barrier method plus spermicide, or IUD) starting with the Baseline Phase and continuing throughout the entire study period.
5. Patients who are willing to participate and have provided written informed consent prior to being exposed to any study-related procedures.

Exclusion Criteria:

1. Patients with chronic daily headaches as defined by more than 20 headache days per month on average during the three months prior to Screening,
2. Patients with cluster headaches and other trigeminal autonomic cephalalgias, and other primary headaches (except tension-type headache) and secondary headaches (defined according to the Headache Classification Committee of the IHS 2004),
3. Patients with a history of being non-responsive to more than two classes of adequately conducted, prophylactic migraine treatments (e.g., beta blockers, calcium channel blockers, tricyclics, MAOIs, valproate (divalproex), topiramate, gabapentin),

4. Patients who use the following medications as described:

   • Use of marketed triptans for 12 days or greater per month on average,
   • Use of ergot-containing medications for 12 days or greater per month on average,
   • Use of NSAIDs, acetaminophen, or isometheptene-containing agents for 15 days or greater per month on average,
   • Use of opioids for 12 days or greater per month on average,  - Use of any two or more of the above medications for 15 days or greater per month on average,
5. Patients with clinically significant neurological illness, other than migraine, that, in the opinion of the Investigators, may have the potential of altering pain perception or reporting,
6. Patients with a history of or currently having major psychiatric disorders including schizophrenia, major depressive disorder, or bipolar disorder,
7. Patients with elevations of liver enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) >= 1.5 times the upper limit of normal (ULN),
8. Patients with evidence of significant active hematological disease; White blood cell (WBC) count cannot be <= 2500/μL or an absolute neutrophil count <= 1000/μL.
9. Patients with clinically significant ECG abnormality, including prolonged QTc (Fridericia correction) defined as >= 450 msec for males and >= 470 msec for females,
10. Patients with clinically significant active hepatic disease, cardiovascular, metabolic, respiratory, renal, endocrinological, gastrointestinal diseases, and bacterial or viral infections within 30 days prior to Screening or during the Baseline Phase,
11. Pregnant or lactating females
12. History of transmeridian travel (across >3 time zones) or shift work (defined as permanent night shift or rotating day/night shift work) within the past 2 weeks or anticipates needing to travel (across >3 time zones) at any time during the study.

Contacts and Locations

No Contacts or Locations Provided

More Information

Publications of Results:

Millán-Guerrero RO, Isais-Millán R. [New therapeutic alternatives in migraine prophylaxis using histamine H3 receptor agonists]. Gac Med Mex. 2008 Jul-Aug;144(4):291-5. Spanish.

Millán-Guerrero RO, Isais-Millán S, Barreto-Vizcaíno S, Rivera-Castaño L, Rios-Madariaga C. Subcutaneous histamine versus botulinum toxin type A in migraine prophylaxis: a randomized, double-blind study. Eur J Neurol. 2009 Jan;16(1):88-94. doi: 10.1111/j.1468-1331.2008.02352.x.

Millán-Guerrero RO, Isais-Millán R, Barreto-Vizcaíno S, Gutiérrez I, Rivera-Castaño L, Trujillo-Hernández B, Baltazar LM. Subcutaneous histamine versus topiramate in migraine prophylaxis: a double-blind study. Eur Neurol. 2008;59(5):237-42. doi: 10.1159/000115637. Epub 2008 Feb 8.

Millán-Guerrero RO, Isais-Millán R, Barreto-Vizcaíno S, Rivera-Castaño L, Garcia-Solorzano A, López-Blanca C, Membrila-Maldonado M, Muñoz-Solis R. Subcutaneous histamine versus sodium valproate in migraine prophylaxis: a randomized, controlled, double-blind study. Eur J Neurol. 2007 Oct;14(10):1079-84.

Millán-Guerrero RO, Isais-Millán R, Benjamín TH, Tene CE. Nalpha-methyl histamine safety and efficacy in migraine prophylaxis: phase III study. Can J Neurol Sci. 2006 May;33(2):195-9.

Millán Guerrero R, Trujillo Hernández B, Tene CE. [Subcutaneous histamine in migraine prophylaxis. Initial effects and long-term outcome]. Neurologia. 2006 Mar;21(2):55-9. Spanish.

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Responsible Party:	BioHealthonomics Inc.
ClinicalTrials.gov Identifier:	NCT02021474 History of Changes
Other Study ID Numbers:	HSC-201
First Posted:	December 27, 2013
Last Update Posted:	January 27, 2015
Last Verified:	January 2015

Additional relevant MeSH terms:

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Migraine Disorders; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Histamine; Histamine phosphate; Phenol; Histamine Agonists	Histamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Disinfectants; Sclerosing Solutions; Pharmaceutical Solutions