Objective
The objective of this study is to assess whether metoclopramide 10 mg IV is non-inferior to sumatriptan 3 mg SQ as treatment for acute migraine attack in the ED setting.
Trial design
This is a single-center, prospective, open-label, cluster-randomized controlled, non-inferiority trial that conforms to the Consolidated Standards of Reporting Trials (CONSORT)11. The timing of interventions and data collection is presented in Figure 1. A flowchart of the study is shown in Figure. 2.
Study setting
This trial will be performed in the ED of the Center Hospital of the National Center for Global Health and Medicine in Japan. About 11,000 patients are emergently transported to the ED annually.
Participants
- Patients emergently transported to the ED for headache are eligible to participate if they fulfill the following criteria.
- Eligibility criteria
Inclusion
- Informed consent obtained from the patient
- Age 20–65 years
- Satisfies the criteria for migraine according to the International Classification of Headache Disorders of the International Headache Society, third edition, beta version12. Time duration can be excluded because of the emergency setting.
- More than moderate headache intensity, having a great deal of difficulty doing daily activities at presentation
Exclusion
- Judged as having a high likelihood of secondary headache
- Temperature ≥38.0℃
- A new objective finding of neurological abnormality
- History of myocardial infarction or suspected ischemic heart disease
- History of cerebrovascular disease or transient ischemic attack
- History of peripheral vascular disorder
- Uncontrolled hypertension or systolic blood pressure > 180 mmHg at presentation
- Severe liver dysfunction
- Suspected gastrointestinal bleeding, perforation, or obstruction
- Suspected pheochromocytoma
- Use of an ergotamine derivative, other kind of triptan, or monoamine oxidase (MAO) inhibitor
- Pregnancy or breastfeeding
- Allergy to any of the investigational medications
- Participation judged to be inappropriate by emergency physicians
- Rationale for exclusion criteria
- 1–3: The cause of headache might be disease other than migraine.
- 4–8: Contraindications to sumatriptan use
- 9–10: Contraindications to metoclopramide use
Interventions
The doctors in charge obtain informed consent from each participant before entry to the study. Informed consent cannot be obtained by proxy. After providing informed consent, participants are allocated to one of the two treatment according to the month (see Randomization and Concealment). Participants in the metoclopramide arm receive metoclopramide 10 mg IV. Participants in the sumatriptan arm receive sumatriptan 3 mg SQ.
- There are no criteria for discontinuing the intervention because participants receive the study drug only once. If improvement of symptoms is unsatisfactory after 30 min, a suppository of acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) may be given as rescue medication upon patient request and doctor approval. The peak serum concentration of sumatriptan 3mg SQ is 0.21 h, so patients can receive rescue medication at least 30 min after the study medication, and this will be reported in case report forms (CRFs).
Patients are not allowed to receive ergotamine derivatives, other kinds of triptans, or monoamine oxidase inhibitors during the study period.
Outcomes
- Primary outcome
- Change in headache pain intensity 1 h after baseline, measured with the Numerical Rating Scale for Pain (NRS)13.
- Secondary endpoints
- Change in NRS score 30 min after medication administration
- Headache relief 1 h after medication administration, defined as the patient’s description of headache from severe or moderate to either mild or none
- Concomitant symptoms 1 h after medication administration
- Time duration from study medication administration to leaving the ED
- Receipt of rescue medication during the ED visit
- Adverse events
Sample size
- A previous study indicated an expected NRS pain score reduction of 6 and 5 in the metoclopramide and sumatriptan groups, respectively.12 Even though the doses of the study medication are not the same, findings from other studies indicate that a high metoclopramide dose is no better than a lower dose for pain relief.13 Based on previous data, we set the standard deviation as 3 NRS points. The non-inferiority margin is set as –1.0 NRS points, because findings from a previous study indicated that a 1.3-NRS-point between-group difference is a valid and reproducible minimum clinically significant change in the ED.15 Thus, a sample size of 37 in each group is calculated to be sufficient with a one-sided α of 0.025 and a power of 0.8.16 Taking potential dropout rates into account, a sample size of 40 in each group is eventually determined.
Randomization and concealment
Metoclopramide and sumatriptan require different routes of administration, so for patient safety in the busy ED, randomization is performed on a monthly basis and neither physicians nor participants are blinded. The monthly allocation is done with computer-generated random numbers. The principal investigator (PI) generated the random numbers prior to the first enrollment and keeps the list. With cluster randomization by month, participants can receive the study medication soon after enrollment. The doctors in charge fill in the competency checklist to confirm eligibility and allocate the patient to the group for the current month.
Data collection and management
- The time of medication administration is considered Time 0. Pain intensity is assessed with the NRS at Time 0, 30, and 60 min. Patients are then asked to rate their pain on a scale between 0 and 10, with 0 representing no pain and 10 representing the worst pain imaginable. Pain intensity is also assessed with 4 rankings (none, mild, moderate, and severe) at Time 0 and 60 min. Vital signs are monitored after medication administration. The presence of nausea, vomiting, optic hyperesthesia, and auditory hyperesthesia is assessed at Time 0 and 60 min. If rescue medication is used, the timing and drug used are recorded. At the completion of the visit, patients are asked about adverse symptoms during their ED stay and instructed to call if they have any adverse symptoms. Vital signs are monitored and the duration of ED stay is also recorded after medication administration.
We will use paper CRFs to recode case information with only the study ID number. The PI will enter the data from CRFs into an Excel file, which will be password-protected.
Access to the collected data will be strictly limited to investigators. The collected data will be anonymized and stored in a locked cabinet or a password-protected computer.
Statistical analysis
- All randomized participants who fulfill the eligibility criteria and sign the informed consent form will be included in the intention-to-treat (ITT) set. All participants who take either study medication will be included in the safety analysis set. All analyses of efficacy will be based on the ITT set. Analysis of adverse events will be based on the safety analysis set.
- For the primary outcome, we will report the within-group improvement in NRS pain score between baseline and 1 h. Student’s t test will be used to compare mean differences in NRS score and lower one-sided 95% confidence interval (CI), along with a one-sided p < 0.025. The missing data will be treated as missing at random, and the multiple imputation procedure will be used for the primary outcome. The
- For secondary analyses, the chi-square test will be used to compare rates, and Student’s t tests will be used to compare mean differences.
- For the safety analysis, adverse events will be listed with the relationship to the study medications. The chi-square test will be used to compare the rates of participants who have at least one adverse event between groups in the safety analysis set.
- Statistical analyses will be performed using JMP statistical software, version 14.0.0 (SAS Institute Inc., Cary, NC). A two-sided p < 0.05 will be considered significant. No interim analysis will be performed in this study.
Data monitoring
To guarantee the quality of the trial, monitoring staff will audit the trial implementation process and data entry process every 4 months. This periodic audit will be performed to ensure that the protocol and Good Clinical Practice (GCP) guidelines are being followed. The monitoring staff may review source documents to confirm that the data recorded on CRFs are accurate.
Harms
In this study, adverse events may include, but are not limited to, chest symptoms and flushing with sumatriptan, and akathisia, drowsiness, and dystonic reactions with metoclopramide. Patients are closely monitored during the ED stay. If any participant experiences any untoward effects as a direct result of trial participation, compensation will be provided as covered by clinical study insurance.
- Participants are free to withdraw from the study at any time upon request. An investigator may withdraw a participant from the study for the following reasons:
- ・Voluntary withdrawal of consent
- ・Serious adverse events (e.g., shock, loss of consciousness, or ischemic heart diseases)
- ・Disadvantages of the study outweigh the advantages
If serious adverse events occur, the Efficacy and Safety Assessment Committee will meet to evaluate the study’s safety and efficacy. The committee will advise the PIr of any need for revision of the study protocol or termination of the study.