SGEM#279: Do You Really Want to Hurt Me and Use a Placebo Control for a Migraine Trial?

Date: January 10th, 2020 Reference: Dodick DW et al. Ubrogepant for the Treatment of Migraine. NEJM 2019 Guest Skeptic: Dr. Anand Swaminathan is an Assistant Professor of Emergency Medicine at St. Joseph’s Hospital in Paterson, NJ. He is also the managing editor of EM:RAP and associate editor at REBEL EM. Case: A 23-year-old man with a history of migraines presents with two days of headache, nausea and photo-photophobia typical of his prior migraines. He’s tried a number of medications at home including ibuprofen, acetaminophen, aspirin and sumatriptan without any considerable improvement in symptoms. You start to offer him your standard medications like metoclopramide and haloperidol when he asks about a new drug he heard about called ubrogepant. Background: Migraine headaches are a chronic neurologic disease characterized by throbbing, often unilateral headaches that are often associated with nausea, vomiting, photophobia and phonophobia. It is a common disease and can be severe enough to impede on people’s lives. Headaches themselves are not only a common emergency department presentation but one that is filled with potential dangers. There are a number of causes of headache that are life and limb threatening – subarachnoid hemorrhage (SGEM#201), meningitis, encephalitis, cerebral venous thrombosis, vertebral artery dissection among other things but, most headaches are benign in nature. There is an international classification system of headaches (IHS 2018). The current system classifies them into primary and secondary headaches. An important part of our job as emergency physicians is to differentiate the lethal headache from the benign headache. Though we rarely make a de novo diagnose of migraines in the emergency department, many patients with migraines present to us for symptom management. The pathophysiology of migraines is both complicated and poorly understood but there are a number of potential treatments including NSAIDs, acetaminophen, aspirin, neuroleptics, triptans and even propofol. More recently, calcitonin gene-related peptide antagonists (CGRPs) have emerged as a new potential treatment. The first big study that came out on these drugs was published in the NEJM in 2019 and was entitled Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist for Migraine (Lipton et al). Now, we have a second study published in the NEJM on a related drug, ubrogepant. Clinical Question: Does ubrogepant increase the percentage of patients who were free from pain and absent of the most bothersome migraine-associated symptom at two hours from initial dose in comparison to placebo? Reference: Dodick DW et al. Ubrogepant for the Treatment of Migraine. NEJM 2019 Population: Adult patients (18-75 years of age) with at least a one-year history of migraine with or without aura that met criteria from the International classification of headache disorders and had migraine onset before the age of 50. Patients had to have a history of migraines between 4-72 hours and a history of migraine attacks separated by at least 48 hours of freedom from headache. Additionally, they had to have suffered from two to eight migraines per month over the last three months. Exclusions: Patients with 15 or more headaches/month on average in the previous six months. Hard to distinguish the type of headache. Use of acute migraine treatment on ten or more days in the previous three months. Participated in a trial involving CGRP. Had clinically significant cardiovascular or cerebrovascular disease. History of hepatitis in the last six months or laboratory findings of liver disease (elevated AST, AST, Bilirubin or low serum albumin). Additional Exclusions from ClinicalTrials.gov Has a history of migraine aura with diplopia or impairment of level of consciousness, hemiplegic migraine, or retinal migraine Has a current diagnosis of new persistent daily headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy Required hospital treatment of a migraine attack 3 or more times in the previous 6 months Has a chronic non-headache pain condition requiring daily pain medication Has a history of malignancy in the prior 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer Has a history of any prior gastrointestinal conditions (eg, diarrhea syndromes, inflammatory bowel disease) that may affect the absorption or metabolism of investigational product; participants with prior gastric bariatric interventions which have been reversed are not excluded Intervention: Ubrogepant 50 mg or 100 mg Comparison: Placebo Outcomes: Co-Primary Outcome: Freedom from pain at two hours from initial dose of medication. Absence of the most bothersome symptom associated with migraine two hours from initial dose of medication. Secondary Outcomes: Change in severity of headache at two hours, sustained pain relief, sustained freedom from pain, absence of photophobia, absence of photophobia and absence of nausea at two hours from initial dose. Adverse events were also collected. Authors’ Conclusions:“A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. No The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. No The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Unsure All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). No All patient-important outcomes were considered. No The treatment effect was large enough and precise enough to be clinically significant. Unsure Key Results: They enrolled 1,672 patients with roughly equal numbers allocated to each of the three groups. The mean age was around 40 years and almost 90% were female. The modified ITT analysis excluded 345 (21%) of participants. Ubrogepant was superior to placebo in treating migraine headaches. Primary Outcomes: (100mg/50mg/placebo) Freedom from pain at two hours: 21%/19%/12% (both doses statistically better than placebo but, not better than the other). That gives an absolute difference of about 8% and Number Needed to Treat for Benefit (NNTB) of 13 Absence of most bothersome symptom at two hours: 38%/39%/28%. This is an absolute difference of 10% with a NNTB of 10. Secondary Outcomes:  Pain relief at two hours (61%/61%/49%) and sustained pain relief (38%/36%/21%) was better with ubrogepant compared to placebo. Serious Adverse Events:There were five SAE with all of them being in the intervention group (two appendicitis, pericardial effusion, spontaneous abortion and seizure). Only the seizure was considered related to the trial drug. Six patients had ALT levels three times the upper limit of normal (one in the placebo group and five in the treatment group). Only one of the treatment group was considered possibly related to the trial regimen. Details are in the supplemental appendix. 1. Patients: We had a few issues with the patients included in this study. First, these were not emergency department patients but rather those recruited from outpatient clinic. Whether or not these are the same patients that present to the emergency department is unknown.  We are also unsure if the patients were recruited consecutively. This is an important aspect to avoid potential selection bias. Remember that when we use the term “bias” we are not talking about random noise in the data but something that systematically moves us away from the “truth”. The third question we had about the included patients was whether or not both groups were similar with respect to prognostic factors. Baseline demographics are reported in Table 1. However, things like number of headaches/month, refractory headaches in the past, and other things are not reported. This could impact the results and therefore the conclusions. 2. Comparison to Placebo: Randomized control trials (RCTs) are considered an ideal study design to establish causality and effect of a medication. Drug intervention RCT design requires that the intervention be compared to something (active drug, standard treatment, no treatment or placebo). It is widely agreed upon that comparison to placebo is acceptable when no proven intervention exists (Millum and Grady 2013). In contrast, placebo comparison is not considered acceptable in life-threatening conditions if there is an available treatment that is known to prolong life. The use of placebo for comparison in non-life-threatening conditions has been hotly debated for decades, particularly when an accepted treatment exists. The argument against the use of placebos in these circumstances is guided by the Declaration of Helsinki. This documents state:  “In any medical study, every patient — including those of a control group, if any — should be assured of the best proven diagnostic and therapeutic methods.”  Thus, if an effective treatment exists, it should be prescribed to patients (Simon 2000).