Migraines
Conditions
Brief summary
The investigators propose to test the efficacy of ketorolac nasal spray versus sumatriptan nasal spray versus placebo for acute abortive therapy of migraine head pain as well as for migraine associated symptoms including nausea and allodynia.
Detailed description
Participants are randomized to Ketorolac NS 31.5 mg, Sumatriptan NS 20 mg or placebo to treat three moderate to severe migraine attacks and switched treatments with each attack so that they received each treatment only once. For each treated attack (moderate to severe migraine attack), participants utilized two study treatments (A and B). Study treatment A administered as one spray in each nostril, and study treatment B administered as one spray in one nostril. Randomized to Ketorolac, A=Ketorolac, B=Placebo Randomized to Sumatriptan, A=Placebo, B=Sumatriptan Randomized to Placebo, A=Placebo, B=Placebo
Interventions
DRUGKetorolac
Single dose of Ketorolac (Sprix) nasal spray 31.5 mg, one spray in each nostril for an acute migraine attack.
DRUGSumatriptan
Sumatriptan (Imitrex) 20 mg one single dose of nasal spray for an acute migraine attack.
DRUGPlacebo
Placebo one spray in each nostril and placebo one nasal spray.
Sponsors
American Regent, Inc.
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Inclusion/
Exclusion criteria
At the Screening Visit, a subject must meet the following criteria to participate in this study: 1.18-65 years of age 2.Fulfills International Classification of Headache Disorders (ICHD)-II Criteria of migraine as noted below in Table 1 3.History of migraines for at least one year 4.Migraine onset prior to the age of 50 years of age 5.Headache frequency (of any headaches, migraine or non-migraine) \< 9 days per month 6.At visit 2, participants must report two or more headache days during the 28-day run-in period on the headache diary. 7.At least 48 hours of freedom from headache between treated migraine attacks. 8.If currently using headache preventive medications, must be on a stable dose for at least 3 months prior to enrollment and throughout the study period and be on no more than one prophylactic agent. 9.Able to complete all study procedures, including the questionnaire (assessing demographics, headache characteristics, headache comorbidities and medical history at the initial visit and headache characteristics) and the required headache calendars, and all study visits; 10.Able to understand, read and sign an informed consent (English).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2- Hour Pain Relief | 2 hours | The primary outcome was 2-hour headache relief; headache relief was defined as headache pain from moderate or severe pain to none or mild pain. Pain was assessed using a 4-point scale (none, mild, moderate, and severe) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absence of Photophobia | 2-hours | 2\) Defined as reduction of photophobia to none. Symptom was assessed using a 4-point scale (none, mild, moderate, and severe) |
| Absence of Phonophobia | 2-hours | 3\) Defined as reduction of phonophobia to none. Symptom was assessed using a 4-point scale (none, mild, moderate, and severe) |
| Absence of Nausea | 2-hours | 4\) Defined as reduction of nausea to none. Symptom was assessed using a 4-point scale (none, mild, moderate, and severe) |
| Absence of Allodynia | 2-hours | 5\) Absence of allodynia The presence of allodynia was assessed based on a series of 8 questions inquiring as to the presence of allodynia. Participants answering 2 or more questions positively were considered to have allodynia. |
| Pain Freedom | 2-hours | 1\) Pain Freedom: Pain Freedom at 2 hours is defined as being free of pain. Pain was assessed using a 4-point scale (none, mild, moderate, and severe). |
| Sustained Pain Relief (SPR) | 24 and 48 hours | 7\) 24 and 48 hours sustained pain relief (SPR) Defined as the reduction of pain to none or mild from moderate or severe, on a 4-point scale (none, mild, moderate, and severe). |
| Sustained Pain Freedom (SPF) | 24 and 48 hours | 8\) 24 and 48 hours sustained pain freedom (SPF); Defined as the reduction of pain to none. Pain was assessed using a 4-point scale (none, mild, moderate, and severe). |
| Time to Pain Relief | following each treated migraine attack | 9\) The time, in minutes, will be measured from the time study drug is taken to the time when significant pain relief is first observed and maintained through 2 hours with no rescue medication use at or prior to this point. |
| Self-assessment of Disability: Percentage of Participants With Moderate or Severe Disability | 2-hours | Participants' self-assessment of disability was assessed using 4-point scales (none, mild, moderate, and severe). A binary outcome variable was created grouping none and mild vs moderate to severe. . |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketorolac Then Sumatriptan Then Placebo Participants were randomized for three attacks. For each treated attack, participants utilized two study treatments (A and B). Study treatment A administered as one spray in each nostril, and study treatment B administered as one spray in one nostril.
Randomized to Ketorolac, A=Ketorolac, B=Placebo Randomized to Sumatriptan, A=Placebo, B=Sumatriptan Randomized to Placebo, A=Placebo, B=Placebo
Attack 1: Ketorolac: Single dose of Ketorolac spray 31.5 kg, one spray in each nostril for acute migraine attack (Treatment A), placebo spray (Treatment B) in one nostril.
Attack 2: Sumatriptan: Placebo spray (treatment A) in one nostril, 20 mg single dose of Sumatriptan spray (Treatment B) into one nostril.
Attack 3: Placebo: Placebo spray (Treatment A) in each nostril, Placebo Spray (Treatment B) in each nostril. | 12 |
| Ketorolac Then Placebo Then Sumatriptan Participants were randomized for three attacks. For each treated attack, participants utilized two study treatments (A and B). Study treatment A administered as one spray in each nostril, and study treatment B administered as one spray in one nostril.
Randomized to Ketorolac, A=Ketorolac, B=Placebo Randomized to Sumatriptan, A=Placebo, B=Sumatriptan Randomized to Placebo, A=Placebo, B=Placebo
Attack 1: Ketorolac: Single dose of Ketorolac spray 31.5 kg, one spray in each nostril for acute migraine attack (Treatment A), placebo spray (Treatment B) in one nostril.
Attack 2: Placebo: Placebo spray (Treatment A) in each nostril, Placebo Spray (Treatment B) in each nostril.
Attack 3: Sumatriptan: Placebo spray (treatment A) in one nostril, 20 mg single dose of Sumatriptan spray (Treatment B) into one nostril. | 12 |
| Sumatriptan Then Ketorolac Then Placebo Participants were randomized for three attacks. For each treated attack, participants utilized two study treatments (A and B). Study treatment A administered as one spray in each nostril, and study treatment B administered as one spray in one nostril.
Randomized to Ketorolac, A=Ketorolac, B=Placebo Randomized to Sumatriptan, A=Placebo, B=Sumatriptan Randomized to Placebo, A=Placebo, B=Placebo
Attack 1: Sumatriptan: Placebo spray (treatment A) in one nostril, 20 mg single dose of Sumatriptan spray (Treatment B) into one nostril.
Attack 2: Ketorolac: Single dose of Ketorolac spray 31.5 kg, one spray in each nostril for acute migraine attack (Treatment A), placebo spray (Treatment B) in one nostril.
Attack 3: Placebo: Placebo spray (Treatment A) in each nostril, Placebo Spray (Treatment B) in each nostril. | 12 |
| Sumatriptan Then Placebo Then Ketorolac Participants were randomized for three attacks. For each treated attack, participants utilized two study treatments (A and B). Study treatment A administered as one spray in each nostril, and study treatment B administered as one spray in one nostril.
Randomized to Ketorolac, A=Ketorolac, B=Placebo Randomized to Sumatriptan, A=Placebo, B=Sumatriptan Randomized to Placebo, A=Placebo, B=Placebo
Attack 1: Sumatriptan: Placebo spray (treatment A) in one nostril, 20 mg single dose of Sumatriptan spray (Treatment B) into one nostril.
Attack 2: Placebo: Placebo spray (Treatment A) in each nostril, Placebo Spray (Treatment B) in each nostril.
Attack 3: Ketorolac: Single dose of Ketorolac spray 31.5 kg, one spray in each nostril for acute migraine attack (Treatment A), placebo spray (Treatment B) in one nostril. | 12 |
| Placebo Then Ketorolac Then Sumatriptan Participants were randomized for three attacks. For each treated attack, participants utilized two study treatments (A and B). Study treatment A administered as one spray in each nostril, and study treatment B administered as one spray in one nostril.
Randomized to Ketorolac, A=Ketorolac, B=Placebo Randomized to Sumatriptan, A=Placebo, B=Sumatriptan Randomized to Placebo, A=Placebo, B=Placebo
Attack 1: Placebo: Placebo spray (Treatment A) in each nostril, Placebo Spray (Treatment B) in each nostril.
Attack 2: Ketorolac: Single dose of Ketorolac spray 31.5 kg, one spray in each nostril for acute migraine attack (Treatment A), placebo spray (Treatment B) in one nostril.
Attack 3: Sumatriptan: Placebo spray (treatment A) in one nostril, 20 mg single dose of Sumatriptan spray (Treatment B) into one nostril. | 12 |
| Placebo Then Sumatriptan Then Ketorolac Participants were randomized for three attacks. For each treated attack, participants utilized two study treatments (A and B). Study treatment A administered as one spray in each nostril, and study treatment B administered as one spray in one nostril.
Randomized to Ketorolac, A=Ketorolac, B=Placebo Randomized to Sumatriptan, A=Placebo, B=Sumatriptan Randomized to Placebo, A=Placebo, B=Placebo
Attack 1: Placebo: Placebo spray (Treatment A) in each nostril, Placebo Spray (Treatment B) in each nostril.
Attack 2: Sumatriptan: Placebo spray (treatment A) in one nostril, 20 mg single dose of Sumatriptan spray (Treatment B) into one nostril.
Attack 3: Ketorolac: Single dose of Ketorolac spray 31.5 kg, one spray in each nostril for acute migraine attack (Treatment A), placebo spray (Treatment B) in one nostril. | 12 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 2 | 5 | 1 | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 1 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | Ketorolac Then Placebo Then Sumatriptan | Sumatriptan Then Ketorolac Then Placebo | Sumatriptan Then Placebo Then Ketorolac | Ketorolac Then Sumatriptan Then Placebo | Placebo Then Ketorolac Then Sumatriptan | Placebo Then Sumatriptan Then Ketorolac | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 12 Participants | 12 Participants | 12 Participants | 12 Participants | 72 Participants |
| Age, Continuous | 36.3 years STANDARD_DEVIATION 9.8 | 36.3 years STANDARD_DEVIATION 9.8 | 36.3 years STANDARD_DEVIATION 9.8 | 36.3 years STANDARD_DEVIATION 9.8 | 36.3 years STANDARD_DEVIATION 9.8 | 36.3 years STANDARD_DEVIATION 9.8 | 36.3 years STANDARD_DEVIATION 9.8 |
| Region of Enrollment United States | 12 participants | 12 participants | 12 participants | 12 participants | 12 participants | 12 participants | 72 participants |
| Sex: Female, Male Female | 12 Participants | 12 Participants | 12 Participants | 11 Participants | 12 Participants | 11 Participants | 70 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 43 / 52 | 39 / 50 | 11 / 50 |
| serious Total, serious adverse events | 0 / 52 | 0 / 50 | 0 / 50 |
Outcome results
Primary
2- Hour Pain Relief
The primary outcome was 2-hour headache relief; headache relief was defined as headache pain from moderate or severe pain to none or mild pain. Pain was assessed using a 4-point scale (none, mild, moderate, and severe)
Time frame: 2 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketorolac/ Placebo | 2- Hour Pain Relief | 72.5 percentage of participants |
| Sumatriptan/ Placebo | 2- Hour Pain Relief | 69.4 percentage of participants |
| Ketorolac Placebo/ Sumatriptan Placebo | 2- Hour Pain Relief | 38.8 percentage of participants |
Secondary
Absence of Allodynia
5\) Absence of allodynia The presence of allodynia was assessed based on a series of 8 questions inquiring as to the presence of allodynia. Participants answering 2 or more questions positively were considered to have allodynia.
Time frame: 2-hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketorolac/ Placebo | Absence of Allodynia | 70.5 percentage of patients |
| Sumatriptan/ Placebo | Absence of Allodynia | 75.5 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Absence of Allodynia | 69.0 percentage of patients |
Secondary
Absence of Nausea
4\) Defined as reduction of nausea to none. Symptom was assessed using a 4-point scale (none, mild, moderate, and severe)
Time frame: 2-hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketorolac/ Placebo | Absence of Nausea | 82.7 percentage of patients |
| Sumatriptan/ Placebo | Absence of Nausea | 74.0 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Absence of Nausea | 66.0 percentage of patients |
Secondary
Absence of Phonophobia
3\) Defined as reduction of phonophobia to none. Symptom was assessed using a 4-point scale (none, mild, moderate, and severe)
Time frame: 2-hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketorolac/ Placebo | Absence of Phonophobia | 75.0 percentage of patients |
| Sumatriptan/ Placebo | Absence of Phonophobia | 66.0 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Absence of Phonophobia | 56.0 percentage of patients |
Secondary
Absence of Photophobia
2\) Defined as reduction of photophobia to none. Symptom was assessed using a 4-point scale (none, mild, moderate, and severe)
Time frame: 2-hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketorolac/ Placebo | Absence of Photophobia | 65.4 percentage of patients |
| Sumatriptan/ Placebo | Absence of Photophobia | 64.0 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Absence of Photophobia | 46.0 percentage of patients |
Secondary
Pain Freedom
1\) Pain Freedom: Pain Freedom at 2 hours is defined as being free of pain. Pain was assessed using a 4-point scale (none, mild, moderate, and severe).
Time frame: 2-hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketorolac/ Placebo | Pain Freedom | 43.1 percentage of patients |
| Sumatriptan/ Placebo | Pain Freedom | 36.7 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Pain Freedom | 18.4 percentage of patients |
Secondary
Self-assessment of Disability: Percentage of Participants With Moderate or Severe Disability
Participants' self-assessment of disability was assessed using 4-point scales (none, mild, moderate, and severe). A binary outcome variable was created grouping none and mild vs moderate to severe. .
Time frame: 2-hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketorolac/ Placebo | Self-assessment of Disability: Percentage of Participants With Moderate or Severe Disability | 1.9 percentage of patients |
| Sumatriptan/ Placebo | Self-assessment of Disability: Percentage of Participants With Moderate or Severe Disability | 8.1 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Self-assessment of Disability: Percentage of Participants With Moderate or Severe Disability | 10.2 percentage of patients |
Secondary
Sustained Pain Freedom (SPF)
8\) 24 and 48 hours sustained pain freedom (SPF); Defined as the reduction of pain to none. Pain was assessed using a 4-point scale (none, mild, moderate, and severe).
Time frame: 24 and 48 hours
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ketorolac/ Placebo | Sustained Pain Freedom (SPF) | 24 hour sustained pain freedom | 35.3 percentage of patients |
| Ketorolac/ Placebo | Sustained Pain Freedom (SPF) | 48 hour sustained pain freedom | 33.3 percentage of patients |
| Sumatriptan/ Placebo | Sustained Pain Freedom (SPF) | 24 hour sustained pain freedom | 22.4 percentage of patients |
| Sumatriptan/ Placebo | Sustained Pain Freedom (SPF) | 48 hour sustained pain freedom | 18.4 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Sustained Pain Freedom (SPF) | 48 hour sustained pain freedom | 12.2 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Sustained Pain Freedom (SPF) | 24 hour sustained pain freedom | 12.2 percentage of patients |
Secondary
Sustained Pain Relief (SPR)
7\) 24 and 48 hours sustained pain relief (SPR) Defined as the reduction of pain to none or mild from moderate or severe, on a 4-point scale (none, mild, moderate, and severe).
Time frame: 24 and 48 hours
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ketorolac/ Placebo | Sustained Pain Relief (SPR) | 24 hour sustained pain relief | 49.0 percentage of patients |
| Ketorolac/ Placebo | Sustained Pain Relief (SPR) | 48 hour sustained pain relief | 49.0 percentage of patients |
| Sumatriptan/ Placebo | Sustained Pain Relief (SPR) | 24 hour sustained pain relief | 40.8 percentage of patients |
| Sumatriptan/ Placebo | Sustained Pain Relief (SPR) | 48 hour sustained pain relief | 30.6 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Sustained Pain Relief (SPR) | 24 hour sustained pain relief | 20.4 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Sustained Pain Relief (SPR) | 48 hour sustained pain relief | 20.4 percentage of patients |
Secondary
Time to Pain Relief
9\) The time, in minutes, will be measured from the time study drug is taken to the time when significant pain relief is first observed and maintained through 2 hours with no rescue medication use at or prior to this point.
Time frame: following each treated migraine attack
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ketorolac/ Placebo | Time to Pain Relief | 30 minutes | 54.9 percentage of patients |
| Ketorolac/ Placebo | Time to Pain Relief | 20 minutes | 43.1 percentage of patients |
| Ketorolac/ Placebo | Time to Pain Relief | 1 hour | 58.8 percentage of patients |
| Ketorolac/ Placebo | Time to Pain Relief | 10 minutes | 15.7 percentage of patients |
| Ketorolac/ Placebo | Time to Pain Relief | 15 minutes | 35.3 percentage of patients |
| Sumatriptan/ Placebo | Time to Pain Relief | 15 minutes | 36.0 percentage of patients |
| Sumatriptan/ Placebo | Time to Pain Relief | 20 minutes | 44.9 percentage of patients |
| Sumatriptan/ Placebo | Time to Pain Relief | 30 minutes | 53.1 percentage of patients |
| Sumatriptan/ Placebo | Time to Pain Relief | 1 hour | 57.1 percentage of patients |
| Sumatriptan/ Placebo | Time to Pain Relief | 10 minutes | 14.3 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Time to Pain Relief | 1 hour | 32.6 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Time to Pain Relief | 15 minutes | 14.3 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Time to Pain Relief | 10 minutes | 12.2 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Time to Pain Relief | 30 minutes | 26.5 percentage of patients |
| Ketorolac Placebo/ Sumatriptan Placebo | Time to Pain Relief | 20 minutes | 22.4 percentage of patients |