Study of the Safety and Effectiveness of NXN-188 for the Acute Treatment of Migraine Attacks With Aura

Migraine With Aura Clinical Trial

Official title:

A Phase 2a Study of the Safety and Effectiveness of NXN-188 for the Acute Treatment of Migraine Attacks With Aura

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00877838
• Other study ID #: NXN-188-202
• Status: Recruiting
• Phase: Phase 2
• First received: April 7, 2009
• Last updated: July 27, 2009
• Start date: May 2009
• Est. completion date: December 2010

Study information

• Verified date: July 2009
• Source: Danish Headache Center
• Contact: Peer Tfelt-Hansen, MD, Dr Med Sci
• Phone: +4543 23 27 14
• Email: andhou05[@]glo.regionh.dk
• Is FDA regulated: No
• Health authority: Denmark: Danish Medicines Agency
• Study type: Interventional

Clinical Trial Summary

The following study is being conducted to explore the safety and effectiveness of a new chemical entity called NXN-188 in subjects with a history of migraine with aura. In this study subjects will treat two attacks of migraine with aura during the aura phase - once with placebo and once with NXN-188.

Description:

The purpose of this study is to examine a new chemical entity with 5HT agonist activity and an inhibition of the nitric oxide synthase enzyme (NOS) in patients suffering from migraine with aura. Nitric oxide has diverse roles both in normal and pathological processes including the regulation of blood pressure, neurotransmission, and macrophage defense systems. NO is synthesized by three isoforms of the NOS enzyme: neuronal (n), inducible (i) and endothelial (e). Neuronal NOS (nNOS) is found mainly in neuronal tissue and regulates changes in response sensitivity and cellular plasticity; iNOS is found in macrophages and other tissue, produces NO in response to stress and injury and is one source of inflammation; eNOS is found in endothelial cells, responsible for vascular homeostasis and the presumed mechanism for the effects of nitroglycerine therapy in angina; nitroglycerine is an NO donor. NXN-188 is selectively inhibits nNOS.

There is ample scientific and clinical evidence that NO is involved in the pathogenesis of migraine pain, as well as other pain states characterized by central sensitization (e.g., neuropathic pain). NO donors such as trinitroglycerine induce headache followed by migraine in migraineurs with or without aura ; moreover, platelet nitrates (a signal for increased NO) increase before and during a migraine attack. In addition, increasing NO levels can enhance pain responses in animals, including allodynia in rats; NO is a component of several pathways where pain systems converge in the PNS and CNS and regulates the activity of numerous transmitter systems ; NO is involved in central sensitization particularly those involving NMDA and calcium channels and thought to be a major component of the formation of neuropathic pain states Non-specific NOS inhibitors have been reported to relieve migraine and chronic tension type headaches in human studies. In animals, NOS inhibitors reduce pain-related behaviors in multiple neuropathic pain models and spinal cord ischemia as well as reducing pain related behaviors in chemically-induced pain models, particularly in secondary pain states.

The development of central sensitization in the course of a migraine attack suggests a role for the neuronal isoform of the NOS enzyme.

NXN-188 can bind to both 5-HT1D and 5-HT1B receptors with potency similar to sumatriptan; it also selectively binds to nNOS with a level of nNOS inhibition similar to L-NMMA. NXN-188 is devoid of any relevant eNOS inhibition in in vitro cloned human enzyme assays or ex vivo in human coronary arteries and is expected to be effective in treating migraine by inhibition of the nNOS enzyme without vasoconstrictive effects associated with non-selective compounds such as L-NMMA.

The following study is being conducted to further explore NXN-188 response in subjects with a migraine history of aura. In this study subjects will treat two attacks of migraine with aura during the aura phase - once with placebo and once with NXN-188.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 2010
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Male or female migraineurs with aura between 18 and 65 years old, inclusive

2. Meets the following criteria for migraine headache with aura:

• Diagnosed with a history of migraine with aura

• Aura consisting of at least one of the following, but no muscle weakness or paralysis:

• Fully reversible visual symptoms (e.g. flickering lights, spots, lines, loss of vision)

• Fully reversible sensory symptoms (e.g. pins and needles, numbness)

• Fully reversible dysphasia (speech disturbance)

• Aura has at least two of the following characteristics:

• Visual symptoms affecting just one side of the field of vision and/or sensory symptoms affecting just one side of the body

• At least one aura symptom develops gradually over more than 5 minutes and/or different aura symptoms occur one after the other over more than 5 minutes

• Each symptom lasts from 5-60 minutes

3. At least one migraine headache with aura every 8-weeks and resulting in moderate to severe pain (on a 4-point categorical scale) within 2 hours of the onset of aura.

4. Migraine pain following aura in at least 75% of occurrences

5. The subject has a body mass index (BMI) within the range of 18 to 32

6. The subject is in general good health as determined by the medical history, physical exam, clinical laboratory tests, vital signs [heart rate (HR) and blood pressure (BP; after a 3-minute sitting period)] and ECG

• ALT cannot be above 1.5x upper limit of normal; creatinine and urea must be within normal limits

7. The subject must be able to speak, read, and understand Danish sufficiently to understand the nature of the study, to provide written informed consent, and complete all study assessments

8. The subject is willing and able to comply with all testing requirements defined in the protocol

9. All females will avoid pregnancy at least 10 days before Visit 1, during the study and up until 3 months after Visit 2

10. Women of childbearing potential must be using a reliable form of contraception. A reliable form of contraception is defined as follows:

• sterilisation (via hysterectomy or bilateral tubal ligation)

• sterilisation of partner

• IUD,

• birth control pills on stable dose for at least three months before Visit 1, and one month after visit 2.

• Medroxyprogesterone acetate (Depo-Provera) or etonogestrel (implanon) active for at least three months prior to the study and with continued administration at intervals sufficient to maintain contraceptive efficacy throughout the study period and at least one month after visit 2. Males must use condoms as contraception.

Exclusion Criteria:

1. Presence of any clinically significant condition that would preclude study participation, as evaluated by the investigator

2. Are pregnant or lactating

3. History of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, rheumatologic, autoimmune, or metabolic disease

4. Receiving any medication that, in the opinion of the Investigator or designee, may pose a risk of compromising tolerance or compliance

5. Are known to or suspected to be currently abusing alcohol or drugs, or have a history (within the past 12 months) of active alcohol or drug abuse

6. Participation in another drug or biologic study within 30 days preceding randomization into this study or during participation in this study

7. Subjects who are unable or unwilling, in the opinion of the Investigator, to comply with all study procedures and cooperate fully with study center staff

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Migraine Disorders
• Migraine with Aura

Intervention

Drug:
• NXN-188
NXN-188 600 mg (3 gelatin capsules each containing 200 mg) when experiencing migraine aura.
• Placebo
Gelatin capsules resembling the ones containing the active substance

Locations

Country	Name	City	State
Denmark	Danish Headache Center	Glostrup

Sponsors (2)

Lead Sponsor	Collaborator
Danish Headache Center	NeurAxon Inc.

Country where clinical trial is conducted

Denmark, 

References & Publications (19)

Afridi S, Kaube H, Goadsby PJ. Occipital activation in glyceryl trinitrate induced migraine with visual aura. J Neurol Neurosurg Psychiatry. 2005 Aug;76(8):1158-60. — View Citation

Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001 Aug 1;357(Pt 3):593-615. Review. — View Citation

Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol. 2004 Jan;55(1):19-26. — View Citation

Costa A, Smeraldi A, Tassorelli C, Greco R, Nappi G. Effects of acute and chronic restraint stress on nitroglycerin-induced hyperalgesia in rats. Neurosci Lett. 2005 Jul 22-29;383(1-2):7-11. Epub 2005 Apr 18. — View Citation

Handy RL, Moore PK. Effects of selective inhibitors of neuronal nitric oxide synthase on carrageenan-induced mechanical and thermal hyperalgesia. Neuropharmacology. 1998;37(1):37-43. — View Citation

Heinzen EL, Pollack GM. Pharmacodynamics of morphine-induced neuronal nitric oxide production and antinociceptive tolerance development. Brain Res. 2004 Oct 15;1023(2):175-84. — View Citation

Inoue T, Mashimo T, Shibata M, Shibuta S, Yoshiya I. Rapid development of nitric oxide-induced hyperalgesia depends on an alternate to the cGMP-mediated pathway in the rat neuropathic pain model. Brain Res. 1998 May 11;792(2):263-70. — View Citation

Lassen LH, Christiansen I, Iversen HK, Jansen-Olesen I, Olesen J. The effect of nitric oxide synthase inhibition on histamine induced headache and arterial dilatation in migraineurs. Cephalalgia. 2003 Nov;23(9):877-86. — View Citation

Levy D, Zochodne DW. NO pain: potential roles of nitric oxide in neuropathic pain. Pain Pract. 2004 Mar;4(1):11-8. — View Citation

Martelletti P, D'Alò S, Stirparo G, Rinaldi C, Cifone MG, Giacovazzo M. Modulation of nitric oxide synthase by nitric oxide donor compounds in migraine. Int J Clin Lab Res. 1998;28(2):135-9. — View Citation

Mungrue IN, Bredt DS, Stewart DJ, Husain M. From molecules to mammals: what's NOS got to do with it? Acta Physiol Scand. 2003 Oct;179(2):123-35. Review. — View Citation

Naik AK, Tandan SK, Kumar D, Dudhgaonkar SP. Nitric oxide and its modulators in chronic constriction injury-induced neuropathic pain in rats. Eur J Pharmacol. 2006 Jan 13;530(1-2):59-69. Epub 2005 Dec 20. — View Citation

Osborne MG, Coderre TJ. Effects of intrathecal administration of nitric oxide synthase inhibitors on carrageenan-induced thermal hyperalgesia. Br J Pharmacol. 1999 Apr;126(8):1840-6. — View Citation

Shimomura T, Murakami F, Kotani K, Ikawa S, Kono S. Platelet nitric oxide metabolites in migraine. Cephalalgia. 1999 May;19(4):218-22. — View Citation

Taffi R, Vignini A, Lanciotti C, Luconi R, Nanetti L, Mazzanti L, Provinciali L, Silvestrini M, Bartolini M. Platelet membrane fluidity and peroxynitrite levels in migraine patients during headache-free periods. Cephalalgia. 2005 May;25(5):353-8. — View Citation

Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs. 2000 Dec;60(6):1259-87. Review. — View Citation

Thomsen LL, Olesen J. Nitric oxide theory of migraine. Clin Neurosci. 1998;5(1):28-33. Review. — View Citation

van der Kuy PH, Lohman JJ. The role of nitric oxide in vascular headache. Pharm World Sci. 2003 Aug;25(4):146-51. Review. — View Citation

Yoon YW, Sung B, Chung JM. Nitric oxide mediates behavioral signs of neuropathic pain in an experimental rat model. Neuroreport. 1998 Feb 16;9(3):367-72. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The severity of headache measured with a 4 point scale (The Headache Severity Score (HSS))		2 hours after dosing	No
Primary	Absence of headache		2 hours after dosing	No
Secondary	The occurence of any type(s) of adverse events(s)		0-48 hours after dosing	Yes
Secondary	The severity of headache measured with a 4 point scale (The Headache Severity Score (HSS))		0, 1, 2, 4, 8 and 24 hours after dosing	No
Secondary	Clinical Disability measured on a 4 point scale		0, 1, 2, 4, 8 and 24 hours after dosing	No
Secondary	Overall evaluation of the study medication		24 hours after dosing	No