Study of the Safety and Effectiveness of NXN-188 for the Acute Treatment of Migraine Attacks With Aura
Recruitment status was: Recruiting
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Official Title:||A Phase 2a Study of the Safety and Effectiveness of NXN-188 for the Acute Treatment of Migraine Attacks With Aura|
- The severity of headache measured with a 4 point scale (The Headache Severity Score (HSS)) [ Time Frame: 2 hours after dosing ] [ Designated as safety issue: No ]
- Absence of headache [ Time Frame: 2 hours after dosing ] [ Designated as safety issue: No ]
- The occurence of any type(s) of adverse events(s) [ Time Frame: 0-48 hours after dosing ] [ Designated as safety issue: Yes ]
- The severity of headache measured with a 4 point scale (The Headache Severity Score (HSS)) [ Time Frame: 0, 1, 2, 4, 8 and 24 hours after dosing ] [ Designated as safety issue: No ]
- Clinical Disability measured on a 4 point scale [ Time Frame: 0, 1, 2, 4, 8 and 24 hours after dosing ] [ Designated as safety issue: No ]
- Overall evaluation of the study medication [ Time Frame: 24 hours after dosing ] [ Designated as safety issue: No ]
|Study Start Date:||May 2009|
|Estimated Study Completion Date:||December 2010|
|Estimated Primary Completion Date:||March 2010 (Final data collection date for primary outcome measure)|
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00877838
|Danish Headache Center|
|Glostrup, Denmark, 2600|
|Principal Investigator:||Peer Tfelt-Hansen, MD, Dr Med Sci||Department of Neurology, Glostrup Hospital, Denmark|