BrainCool-Migraine Intranasal Cooling Trial
Condition: Migraine
MeSH terms: Migraine Disorders
Study type: Interventional

Summary: 
      This study will be a randomised placebo controlled trial examining the effectiveness of using
      an intranasal evaporative cooling device (the RhinoChill intransal device) in providing
      relief of pain and symptoms of acute migraine.The treatment works by introducing cooling into
      the passageways of the nose through two small cannulas thereby cooling the local nasal tissue
      and the blood vessels which supply blood to the brain. This cooling effect will cause the
      blood vessels to constrict as well as stimulating special cold receptors that are thought to
      be involved in the relief of migraine, thereby providing both pain and associated symptomatic
      relief. In total, 90 patients randomised in a 1:1 fashio n will be recruited from three
      different NHS Trusts. The patients will have a 30-day period of data collection for their
      current migraine frequency, treatment and response to medication (with a minimum of 2
      migraine attacks recorded) before starting the treatment phase with the RhinoChill Device.
      Treatment will be for 3 migraine attacks. Only a single treatment is allowed for the first
      attack, but on the second attack the patient may deliver 2 treatments with a gap of at least
      2 hours between treatments, if indicated.
    

Detailed description: 
      Mechanical techniques to alleviate migraine symptoms have been used for many years, cooling
      and compression being the most frequently applied. Cryotherapy is the most common
      non-pharmacological self-administered pain-relieving method currently used by migraine
      sufferers. The first manuscript documenting the application of ice mixtures was published by
      James Arnott in 1849. Simple techniques based on cryotherapy, using various methods of cold
      and ice application have been reported over the last three decades. Friedman described a
      device using hollow metal tubes cooled by circulating cold water, applied to the periapical
      area of the maxillary molars. Sprouse-Blum reported benefit from applying frozen icepacks
      targeting carotid arteries at the front of the neck in migraine treatment.

      Several pathophysiological mechanisms of action have been proposed. These mechanisms include:

        1. Neurovascular mechanism: Application of cold induces vasoconstriction with subsequent
           decreased downstream blood flow. This leads to inhibition of the release of inflammatory
           mediators which results in decreased vascular permeability and local oedema.

        2. Pain gating by differential effect on nerve conduction: Cryotherapy induces analgesia by
           slowing nerve conduction velocity, with small myelinated fibers being affected first,
           followed by large myelinated fibers and the unmyelinated fibers being affected last. Via
           mechanism of the gate control of pain, affecting the small myelinated nociceptive pain
           afferents first, cryotherapy induces analgesia.

        3. Metabolic mechanism: Cryotherapy decreases metabolic and enzymatic activity, due to
           reduced demand for adenosine triphosphate (ATP) and oxygen.

        4. Transient Receptor Potential (TRP) channels: Recent studies suggest that TRP channels
           may have a role in headache and pain genesis due to their response to environmental
           stimuli such as temperature changes.

      The nasal cavity provides a large diffuse surface area that is highly vascular. Cooling via
      the nasal cavity therefore offers the ability to cool across the thin cribriform plate via
      both direct conductive mechanisms that do not rely on spontaneous circulation as well as
      indirect haematogenous mechanisms. Numerous subarachnoid and pial arterial branches exposed
      to the cerebrospinal fluid (CSF) have diameters in the range of the vessels of the retia
      mirabilia of animals in which selective brain cooling has been clearly established
      experimentally. Vascular anatomy allows transfer of venous blood from the skin of the head as
      well as nasal and paranasal mucous membranes to the dura mater thereby providing an excellent
      basis for the convective process of intranasal evaporative cooling. The dura mater, with its
      high vascularization, may transmit temperature changes to the CSF compartment, which may
      influence the temperature of brain parenchyma directly or indirectly, via brain arteries.

      We suppose that another effect of intranasal cooling may be local vasoconstriction and
      subsequent associated vasoconstriction of cerebral arteries due to the presence of the
      nebulized coolant in the nasal cavity.

      Many sufferers use mechanical techniques to relieve the headache. Simple techniques that have
      been recommended and tried include cryotherapy. Applying an icepack to the painful area has
      been the most frequently mentioned method. Many studies demonstrating the effectiveness of a
      variety of non-pharmacological modalities have been reviewed over the years. Although
      definite proof of effectiveness through traditional scientific method has been lacking in
      most instances. There is a trial reported by Friedman, where intraoral cooling was applied.
      Significant migraine relief has been obtained from chilling confined to the area. Thirty-five
      symptomatic episodic migraine patients were enrolled in this study, comparing 40 minutes of
      bilateral intraoral chilling, 50 mg of oral sumatriptan, and 40 minutes of sham (tongue)
      chilling. Hollow metal tubes chilled by circulating ice water were held in the maxillary
      molar periapical areas by the patient. Pain and nausea were recorded at baseline and 1, 2, 4,
      and 24 hours after start of treatment, using a numeric symptom-relief scale. Significant mean
      headache relief was obtained by maxillary chilling and sumatriptan at all four time
      intervals, with poor relief obtained by placebo. Maxillary chilling was more effective than
      sumatriptan at all four time intervals. Significant nausea relief was obtained by maxillary
      chilling and sumatriptan at post treatment and 2 and 4 hours later. At 24 hours, some
      headache and nausea recurrence was noted with sumatriptan. The repeated-measures analysis of
      variance indicated that both treatments, drug (P = 0.024) and maxillary chilling (P = 0.001),
      reduced the headache, as compared with the control group. Tenderness in the premolar area
      suggests local inflammation associated with vasodilatation and oedema. Because chilling can
      resolve local oedema, authors raised the possibility that an intraoral inflammation may be a
      factor in migraine aetiology. Although it is a possibility the cooling effect might have
      caused indirect vasoconstriction of the dilated meningeal blood vessels.

      In the COOLHEAD 1 trial, investigators found that the use of RhinoChill® intranasal cooling
      within a clinic environment for 15 patients provided a statistically significant reduction of
      pain and associated symptoms of migraine at 5 minutes and 10 minutes (during treatment), and
      at 1 hour and 2 hours following treatment (all p values <0.001) along with a significant
      effect on pain and symptoms at 24 hours (p <0.001). In total, 87% of patients enrolled into
      the trial received a treatment benefit following from a short term (<20minutes) period of
      intranasal cooling.

      Enrollment into the trial was challenging as participants were required to present at the
      hospital clinic for treatment between the hours of 9am to 7pm Monday to Friday, which for
      some, was too difficult while undergoing a migraine headache, and for others, the centre was
      not open for treatment at the time of their migraines. For those that did come in for
      treatment, it was found to be burdensome to travel while a migraine was present.

      The results of this trial demonstrate that the RhinoChill® intranasal cooling device is both
      safe and effective to treat migraine patients within the setting of a hospital clinic
      environment. In this planned BrainCool-Migraine trial, the treatment will be
      self-administered by the patient. To allow for a swifter enrollment of patients into the
      study, to evaluate this treatment methodology in an as close to real world environment as
      possible, and to minimize any burden or discomfort to the patient by traveling to the
      hospital clinic with an active migraine headache on the one hand and to achieve best possible
      control of the study on the other hand, the self-administration by the patient in this study
      will be allowed and required to be done at home, as opposed to the clinic or any other
      location. The proven treatment methods and procedures as examined and described in the
      COOLHEAD 1 in-clinic trial will be implemented throughout the BrainCool-Migraine trial
      treatment procedures so as to ensure the high quality and standards associated with the
      previous trial.

      It is recognised that migraine treatments are prone to placebo effects, which is further
      enhanced by the use of a medical device in an in-hospital setting, therefore in this
      BrainCool-Migraine trial, the design will be that of a double blinded, randomised, two arm,
      placebo control multicentre clinical trial.

      The hypothesis we propose is that the application of RhinoChill® nasal cavity cooling will
      provide effective relief of pain and symptoms associated with episodic migraine (with or
      without aura). The null hypothesis is that no significant difference in pain scores, headache
      response or symptom severity scores will be found between the active treatment and placebo
      groups.
    

Intervention name(s): Active RhinoChill; Control Rhinochill
Intervention type(s): Device; Device
Intervention description(s): Participants will be provided with a RhinoChill® device (Active) and an Intranasal Migraine catheter. Once they have the RhinoChill® device, they are asked to treat the next two of your migraines with the device. This requires a maximum of 10 minute intra-nasal treatment as soon as possible after the start of your migraine.
The participation in the trial will last until 3 migraine headaches have been treated with the RhinoChill® device.; Participants will be provided with a RhinoChill® device (Sham) and an Intranasal Migraine catheter. Once they have the RhinoChill® device, they are asked to treat the next two of your migraines with the device. This requires a maximum of 10 minute intra-nasal treatment as soon as possible after the start of your migraine.
The participation in the trial will last until 3 migraine headaches have been treated with the RhinoChill® device.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Post-market clinical study of one or more CE marked devices within intended purposes, involving a change to standard care or randomisation between groups
Masking: Single (Participant)
Primary purpose: Treatment