Efficacy, Tolerability, and Safety of DFN-15

• DFN-15 Active (Drug), also known as Celecoxib Oral Solution
• DFN-15 Placebo (Other)

Primary outcomes

• Percentage of Subjects Who Are Pain-free at 2 Hours Postdose (First Treated Double-blind Treatment Period) [2 hours postdose]: The primary efficacy end point (for first treated DB1 attack only) were the percentage of subjects who were pain-free 2 hours postdose compared between DFN-15 and placebo (defined as a reduction from predose moderate \[Grade 2\] or severe \[Grade 3\] pain to none \[Grade 0\]
• Percentage of Subjects Who Are Free From Their MBS at 2 Hours Postdose [2 hours postdose]: Percentage of subjects who are free from their Most Bothersome Symptom (MBS) among nausea, photophobia, and phonophobia (first double-blind treatment period)

Secondary outcomes

• The Number of Subjects With TEAEs After Study Drug Compared Between DFN-15 and Placebo [Per protocol, the maximum dosing timeframe for DB2 was 10 weeks; therefore, the maximum AE collection window was 11 weeks total.]: For DB1: TEAE that started or worsening of a pre-existing condition on or after the first dose of study drug (DFN-15 or placebo) in to taking DB2 study drug, whichever occurs first. For DB2: TEAE that started or worsened on or after the first dose of study drug in DB2 up to 5 days after the date of the last dose of study drug in DB2.
• Freedom From Nausea, Photophobia, and Phonophobia Postdose (DB1 and DB2) [15 minutes to 24 hours postdose]: The percentage of subjects who were free from nausea, photophobia, and phonophobia at 15, 30, and 45 minutes and 1, 1.5, 2, 4, and 24 hours postdose compared between DFN-15 and placebo
• Time to Headache Pain Relief Postdose (DB1 and DB2) [2 hours postdose]: The time to headache pain relief was defined as the time in minutes from when a subject took study drug until the time pain relief was indicated by the subject in the eDiary within 2 hours postdose.
• Time to Headache Pain Freedom Postdose (DB1 and DB2) [2 hours postdose]: The time to headache pain freedom was defined as the time in minutes from when a subject took study drug until the time pain freedom was indicated by the subject in the eDiary within 2 hours postdose.
• Headache Pain Relief Postdose (DB1 and DB2) [15 minutes to 24 hours postdose]: Headache pain relief was defined for DB1 as a reduction from moderate or severe pain before dosing to mild or none postdose, and for DB2 as moderate or severe pain before dosing reduced to mild or none postdose, or mild pain before dosing reduced to none postdose. Data are reported by percentage reporting headache pain relief over time postdose.
• Headache Pain Freedom Postdose (DB1 and DB2) [15 minutes to 24 hours postdose]: The percentage of subjects who were pain-free at 15, 30, and 45 minutes and 1, 1.5, 2 (DB2 period), 4, and 24 hours postdose compared between DFN-15 and placebo
• Absence of Screening MBS at Time Points Postdose (DB1 and DB2) [15 minutes to 24 hours postdose]: The percentage of subjects with their Screening MBS (Most Bothersome Symptom) absent at 15, 30, and 45 minutes and 1, 1.5, 2 (DB2 period), 4, and 24 hours postdose compared between DFN-15 and placebo.
• Change in Functional Disability Score Postdose (DB1 and DB2) [2 to 24 hours postdose]: Change in functional disability score at 2, 4, and 24 hours postdose compared between DFN-15 and placebo. The values of the functional disability scale were: 0=no disability, able to function normally; 1=performance of daily activities mildly impaired, can still do everything but with difficulty; 2=performance of daily activities moderately impaired, unable to do some things; 3=performance of daily activities severely impaired, cannot do all or most things, bed rest may be necessary. A decrease in values indicates improvement from baseline.
• Headache Pain Freedom Among Subjects With Cutaneous Allodynia (DB1 and DB2) [2 and 4 hours postdose]: The percentage of subjects who were pain-free at 2 and 4 hours postdose compared between DFN-15 and placebo, among those reporting cutaneous allodynia predose
• Headache Pain Freedom Among BMI Category (DB1 and DB2) [2 and 4 hours postdose]: The percentage of subjects who were pain-free at 2 and 4 hours postdose whose BMI was < 30 kg/m2 vs. subjects whose BMI was ≥ 30 kg/m2, and whose BMI was < 25 kg/m2 vs. subjects whose BMI was ≥ 25 kg/m2
• Headache Pain Recurrence Postdose (DB1 and DB2) [2 to 24 hours postdose]: The percentage of subjects who had pain recurrence between 2 to 24 hours (i.e., pain-free at 2 hours postdose, with pain \[mild, moderate, or severe\] reported at 24 hours postdose) compared between DFN-15 and placebo
• Sustained Headache Pain Relief Postdose (DB1 and DB2) [2 to 24 hours postdose]: The percentage of the population of subjects who reported headache pain relief between 2 and 24 hours postdose.
• Sustained Headache Pain Freedom Postdose (DB1 and DB2) [2 to 24 hours postdose]: The percentage of subjects who had sustained pain freedom at 2 to 24 hours postdose compared between DFN-15 and placebo in each DB period. Sustained pain freedom at 2 to 24 hours postdose is defined as pain-free at 2 hours postdose, with no use of rescue medication, and no recurrence of headache pain within 2 to 24 hours postdose
• Use of Rescue Medication Postdose (DB1 and DB2) [2 to 24 hours postdose]: The percentage of subjects who used rescue medication after 2 hours (2 to 24 hours) postdose compared between DFN-15 and placebo in each DB period
• Subject-Rated Treatment Satisfaction Postdose (DB1 and DB2) [2 and 4 hours postdose]: Subject-rated treatment overall satisfaction was based on a 7-point scale at 2 and 4 hours postdose during each DB treatment period. The difference between the subject-rated study drug treatment satisfaction score at 2 and 4 hours postdose and the baseline PPMQ-R (Patient Perception of Migraine Questionnaire) response for the same question were summarized by treatment group (global satisfaction item at baseline asked about the subject's usual migraine treatment). The possible values of the subject treatment satisfaction scale were: 1=very satisfied, 2=satisfied, 3=somewhat satisfied, 4=neither satisfied nor dissatisfied, 5=somewhat dissatisfied, 6=dissatisfied, 7=very dissatisfied. A decrease in values indicates improvement from baseline.
• Subject-Rated Treatment Satisfaction at 24 Hours Postdose - PPMQ-R (DB1 and DB2) [24 hours postdose]: Patient Perception of Migraine Questionnaire-Revised had 30 questions assessing subject's satisfaction with migraine medication, including 3 global items \& 4 subscales (i.e., efficacy, function, ease of use, tolerability). A 5-point scale (1-Not At All to 5-Extremely) was used for tolerability subscale questions; a 7-point scale (1-Very Satisfied to 7-Very Dissatisfied) was used for all other subscales and global items. Total score was average of efficacy/function/ease of use subscale scores. Each subscale \& total scores were transformed to range from 0-100, with higher scores indicating better satisfaction or tolerability. Total raw score/global items were not transformed. The total raw score could range from 17 (min) to 119 (max), with lower scores indicating better satisfaction. Change from baseline scores at 24-hour-postdose for each subscale score, global item score, total score, \& total raw score were summarized by treatment group below.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

1. A history of episodic migraine, who experience 2 to 8 migraine attacks per month for at least the past 12 months, with no more than 14 headache days per month, and with 48 hours of headache-free time between migraine attacks.
2. Patients who have migraine with or without aura with onset before age 50 years
3. Report usual migraine pain of 2 (moderate) or 3 (severe) on headache pain severity scale without treatment.
4. Subjects who are willing and able to:

   1. Evaluate and record pain, migraine symptoms, and study drug effectiveness information in real-time using a subject eDiary for the duration of the study;
   2. Record each instance of the use of study drug and rescue medication in real-time using a subject eDiary for the duration of the study;
   3. Comply with all other study procedures and scheduling requirements.

Exclusion Criteria:

1. Minors, even if they are in the specified study age range
2. Medication overuse:

   1. Opioids greater than or equal to 10 days during the 90 days prior to screening
   2. Combination medications (e.g., Fiorinal®) greater than or equal to 10 days during the 90 days prior to screening (applies only if includes opioid and/or barbiturate)
   3. Nonsteroidal Anti-inflammatory Drugs or other simple medications greater than 14 days a month during the 90 days prior to screening
   4. Triptans or ergots greater than or equal to 10 days a month during the 90 days prior to screening
3. Treated with onabotulinumtoxin A (Botox®) for migraine within 4 months prior to screening. (If treated for cosmetic reasons, subjects may be included).
4. Current treatment with antipsychotics or use of antipsychotics within 30 days prior to randomization.
5. Patients who have received treatment with an investigational drug or device within 30 days of randomization, or participated in a central nervous system clinical trial within 2 months prior to randomization
6. Patients with positive screening test for human immunodeficiency virus \[HIV\], positive hepatitis B surface antigen (HBsAg), or positive hepatitis C virus \[HCV\] antibody
7. Subjects who are employees or immediate relatives of the employees of the Sponsor, any of its affiliates or partners, or of the clinical research study site.

Participant flow

Outcome results

• Percentage of Subjects Who Are Pain-free at 2 Hours Postdose (First Treated Double-blind Treatment Period) (Primary), Number, percentage of subjects: DFN-15 Placebo (LOCF) 25.8 (20.7 to 31.5); DFN-15 Active (LOCF) 32.9 (27.4 to 38.7); DFN-15 Placebo (OC) 24.6 (19.5 to 30.4); DFN-15 Active (OC) 32.4 (26.9 to 38.2) (p 0.075)
• Percentage of Subjects Who Are Free From Their MBS at 2 Hours Postdose (Primary), Number, percentage of subjects: DFN-15 Placebo (LOCF) 45.0 (38.5 to 51.7); DFN-15 Active (LOCF) 58.9 (52.4 to 65.2); DFN-15 Placebo (OC) 44.4 (37.8 to 51.2); DFN-15 Active (OC) 58.5 (51.9 to 64.8) (p 0.003)
• The Number of Subjects With TEAEs After Study Drug Compared Between DFN-15 and Placebo (Secondary), Count of participants, Participants: Placebo DB1 28; DFN-15 DB1 31; Placebo DB2 26; DFN-15 DB2 21
• Freedom From Nausea, Photophobia, and Phonophobia Postdose (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 Nausea 20.3 (13.7 to 28.3); DFN-15 DB1 Nausea 14.3 (8.8 to 21.4); Placebo DB1 Photophobia 6.2 (3.3 to 10.3); DFN-15 DB1 Photophobia 9.0 (5.5 to 13.6); Placebo DB1 Phonophobia 11.1 (6.9 to 16.6); DFN-15 DB1 Phonophobia 15.5 (10.5 to 21.8); Placebo DB2 Nausea 10.4 (5.1 to 18.3); DFN-15 DB2 Nausea 16.2 (9.7 to 24.7); Placebo DB2 Photophobia 3.3 (1.2 to 7.1); DFN-15 DB2 Photophobia 10.4 (6.4 to 15.8); Placebo DB2 Phonophobia 8.7 (4.7 to 14.4); DFN-15 DB2 Phonophobia 13.2 (8.1 to 19.8)
• Time to Headache Pain Relief Postdose (DB1 and DB2) (Secondary), Mean, time (hours): Placebo DB1 NA (NA to NA); DFN-15 DB1 NA (NA to NA); Placebo DB2 NA (NA to NA); DFN-15 DB2 NA (NA to NA)
• Time to Headache Pain Freedom Postdose (DB1 and DB2) (Secondary), Median, time (minutes): Placebo DB1 NA (NA to NA); DFN-15 DB1 NA (NA to NA); Placebo DB2 NA (NA to NA); DFN-15 DB2 NA (NA to NA)
• Headache Pain Relief Postdose (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 12.6 (8.6 to 17.4); DFN-15 DB1 12.6 (8.7 to 17.3); Placebo DB2 7.9 (4.7 to 12.3); DFN-15 DB2 15.0 (10.5 to 20.4)
• Headache Pain Freedom Postdose (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 2.9 (1.2 to 5.9); DFN-15 DB1 1.2 (0.3 to 3.5); Placebo DB2 0.5 (0.0 to 2.6); DFN-15 DB2 2.8 (1.0 to 6.0)
• Absence of Screening MBS at Time Points Postdose (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 8.3 (4.9 to 12.9); DFN-15 DB1 10.4 (6.6 to 15.3); Placebo DB2 5.8 (2.8 to 10.5); DFN-15 DB2 9.6 (5.7 to 14.9)
• Change in Functional Disability Score Postdose (DB1 and DB2) (Secondary), Mean, units on a scale: Placebo DB1 -0.7 +/- 0.95; DFN-15 DB1 -0.9 +/- 0.89; Placebo DB2 -0.6 +/- 0.94; DFN-15 DB2 -0.9 +/- 0.91
• Headache Pain Freedom Among Subjects With Cutaneous Allodynia (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 26.2 (16.0 to 38.5); DFN-15 DB1 26.2 (15.8 to 39.1); Placebo DB2 25.5 (14.3 to 39.6); DFN-15 DB2 39.5 (25.0 to 55.6)
• Headache Pain Freedom Among BMI Category (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 22.9 (16.3 to 30.7); DFN-15 DB1 25.6 (19.0 to 33.2); Placebo DB2 22.1 (15.1 to 30.5); DFN-15 DB2 34.3 (26.5 to 42.8)
• Headache Pain Recurrence Postdose (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 10.1 (4.2 to 19.8); DFN-15 DB1 7.6 (3.1 to 15.1); Placebo DB2 6.9 (1.9 to 16.7); DFN-15 DB2 4.5 (1.3 to 11.1)
• Sustained Headache Pain Relief Postdose (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 39.8 (33.0 to 46.9); DFN-15 DB1 55.1 (48.4 to 61.7); Placebo DB2 44.3 (37.0 to 51.8); DFN-15 DB2 56.6 (49.1 to 63.9)
• Sustained Headache Pain Freedom Postdose (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 18.9 (13.7 to 25.0); DFN-15 DB1 27.6 (21.8 to 33.9); Placebo DB2 20.0 (14.5 to 26.5); DFN-15 DB2 29.1 (22.6 to 36.3)
• Use of Rescue Medication Postdose (DB1 and DB2) (Secondary), Number, percentage of subjects: Placebo DB1 28.5 (23.2 to 34.2); DFN-15 DB1 18.8 (14.4 to 23.9); Placebo DB2 22.9 (17.8 to 28.6); DFN-15 DB2 18.4 (13.7 to 23.8)
• Subject-Rated Treatment Satisfaction Postdose (DB1 and DB2) (Secondary), Mean, units on a scale: Placebo DB1 0.7 +/- 2.49; DFN-15 DB1 -0.1 +/- 2.35; Placebo DB2 0.3 +/- 2.45; DFN-15 DB2 -0.1 +/- 2.26
• Subject-Rated Treatment Satisfaction at 24 Hours Postdose - PPMQ-R (DB1 and DB2) (Secondary), Mean, units on a scale: Placebo DB1 -4.866 +/- 32.6258; DFN-15 DB1 5.112 +/- 30.638; Placebo DB2 0.491 +/- 32.5487; DFN-15 DB2 6.691 +/- 28.1563

Adverse events

Time frame: Per protocol, the maximum dosing timeframe for DB2 was 10 weeks; therefore, the maximum AE collection window was 11 weeks total.

Serious adverse events by term

Other adverse events by term

• Results publication: Lipton RB, Munjal S, Tepper SJ, Iaconangelo C, Serrano D. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Tolerability, and Safety of Celecoxib Oral Solution (ELYXYB) in Acute Treatment of Episodic Migraine with or without Aura. J Pain Res. 2021 Aug 19;14:2529-2542. doi: 10.2147/JPR.S322292. eCollection 2021. PMID 34447267

• Study Protocol (PDF, 2017-05-09)
• Statistical Analysis Plan (PDF, 2017-11-08)