Most Bothersome Symptom Research Articles

Headache/migraine-related stigma, quality of life, disability, and most bothersome symptom in adults with current versus previous high-frequency headache/migraine and medication overuse: results of the Migraine Report Card survey

BackgroundHigh-frequency headache/migraine (HFM) and overuse of acute medication (medication overuse [MO]) are associated with increased disability and impact. Experiencing both HFM and MO can potentially compound impacts, including stigma; however, evidence of this is limited. The objective of this report was to evaluate self-reported stigma, health-related quality of life (HRQoL), disability, and migraine symptomology in US adults with HFM + MO from the Harris Poll Migraine Report Card survey.MethodsUS adults (≥ 18 yrs., no upper age limit) who screened positive for migraine per the ID Migraine™ screener completed an online survey. Participants were classified into “current HFM + MO” (≥ 8 days/month with headache/migraine and ≥ 10 days/month of acute medication use over last few months) or “previous HFM + MO” (previously experienced HFM + MO, headaches now occur ≤ 7 days/month with ≤ 9 days/month of acute medication use). Stigma, HRQoL, disability, and most bothersome symptom (MBS) were captured. The validated 8-item Stigma Scale for Chronic Illnesses (SSCI-8) assessed internal and external stigma (scores ≥ 60 are clinically significant). Raw data were weighted to the US adult population. Statistically significant differences were determined by a standard t-test of column proportions and means at the 90% (p < 0.1) and 95% (p < 0.05) confidence levels.ResultsParticipants (N = 550) were categorized as having current (n = 440; mean age 41.1 years; 54% female; 57% White, not Hispanic; 24% Hispanic; 11% Black, not Hispanic) or previous (n = 110; mean age 47.2 years; 49% female; 75% White, not Hispanic; 13% Hispanic; 4% Black, not Hispanic) HFM + MO. Compared to those with previous HFM + MO (21%), adults with current HFM + MO were more likely to experience clinically significant levels of stigma (47%). Men with current HFM + MO (52% compared to men with previous HFM + MO [25%] and women with current [41%] or previous [18%] HFM + MO), non-Hispanic Black (51% compared to White, not Hispanic [45%] and Hispanic [48%] current HFM + MO groups and White, not Hispanic previous HFM + MO [12%]), current HFM + MO aged 18–49 years (50% compared to those with current HFM + MO aged ≥ 50 years [33%] and those with previous HFM + MO aged 18–49 [34%] and ≥ 50 years [4%]), and employed respondents (53% current and 29% previous compared to those not employed [32% current and 12% previous]) reported higher rates of clinically significant stigma. Those with current HFM + MO were more likely to have worse HRQoL and disability due to headache/migraine. Respondents aged ≥ 50 years with current HFM + MO were more likely than respondents aged 18–49 years with current HFM + MO to indicate that their overall quality of life (66% vs. 52%) and their ability to participate in hobbies/activities they enjoy were negatively impacted by headache/migraine (61% vs. 49%). Pain-related symptoms were identified as the MBS.ConclusionsTogether these data suggest that current and previous HFM + MO can be associated with undesirable outcomes, including stigma and reduced HRQoL, which were greatest among people with current HFM + MO, but still considerable for people with previous HFM + MO.Graphical abstract

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial

Background Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China.Methods Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests.ResultsOverall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p < 0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group.ConclusionsA single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo.Trial registration Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.Graphical

P.016 Impact of eptinezumab on patient-reported outcomes in patients with prior preventive treatment failures

Background: In DELIVER, eptinezumab reduced migraine frequency and was well tolerated in patients with migraine and prior preventive treatment failures. This analysis evaluated changes in patient-reported outcomes (PROs). Methods: DELIVER (NCT04418765; phase 3b double-blind study) randomized adults with migraine and 2-4 prior preventive treatment failures to eptinezumab or placebo every 12 weeks. The assessed PROs included EuroQol 5-Dimensions 5-Levels visual analogue scale (EQ-5D-5L VAS); 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), most bothersome symptom (MBS), and Migraine-Specific Quality of Life Questionnaire (MSQ, v2.1). Results: Patients received eptinezumab 100mg (n=299), 300mg (n=294), or placebo (n=298). Mean changes from baseline to Wk12 in EQ-5D-5L VAS scores were 2.0 (100mg, P=0.0007) and 4.4 (300mg, P&lt;0.0001) versus -3.1 (placebo), and were maintained or further improved to Wk24 (2.0, 5.2, -2.8, respectively). Mean baseline HIT-6 total scores were ~66.4, with mean changes of -6.9 (100mg, P&lt;0.0001) and -8.5 (300mg, P&lt;0.0001) versus -3.1 (placebo) at Wk12 that were further improved through Wk24 (-8.9 and -9.9 vs -3.9). PGIC, MBS, and MSQ domain scores showed greater improvement for eptinezumab than placebo. Conclusions: In adults with migraine and prior preventive treatment failures, eptinezumab robustly improved health-related quality of life and migraine-related burden over 24 weeks versus placebo.

Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine in Black and African American Adults: Results From 3 Randomized, Placebo-Controlled Clinical Trials (P9-12.009)

Efficacy and Safety of Rimegepant for the Acute Treatment of Migraine in Black and African American Adults: Results From 3 Randomized, Placebo-Controlled Clinical Trials (P9-12.009)

Efficacy and Safety of Zavegepant Nasal Spray for the Acute Treatment of Migraine: Results of a Phase 3 Double-Blind, Randomized, Placebo Controlled Trial (PL5.002)

Efficacy and Safety of Zavegepant Nasal Spray for the Acute Treatment of Migraine: Results of a Phase 3 Double-Blind, Randomized, Placebo Controlled Trial (PL5.002)

Rimegepant for the Acute and Preventive Treatment of Migraine in Women: Results From 4 Randomized, Placebo-Controlled Clinical Trials (P9-12.007)

Rimegepant for the Acute and Preventive Treatment of Migraine in Women: Results From 4 Randomized, Placebo-Controlled Clinical Trials (P9-12.007)

Safety and Efficacy of Concomitant Erenumab and INP104 Use From the Phase 3 STOP 301 Study in Migraine Patients (P13-12.002)

<h3>Objective:</h3> To report safety and efficacy in migraine patients who concomitantly used erenumab and INP104 over 24 weeks. <h3>Background:</h3> Breakthrough migraine attacks can occur while a patient is on preventive therapy; therefore, effective acute medications that can be used concomitantly without an increased risk of adverse events (AEs) are needed. INP104 is a combination of dihydroergotamine mesylate (DHE) and Precision Olfactory Delivery approved for the acute treatment of migraine. <h3>Design/Methods:</h3> This was a post hoc analysis of the Phase 3, open-label study (STOP 301) that assessed the safety, tolerability, and exploratory efficacy of INP104 in migraine. Patients used their best usual care during a 28-day screening period. Eligible patients were provided INP104 to nasally self-administer (1.45 mg) with self-recognized attacks over 24 weeks. Concomitant preventive migraine medications were permitted if stable and not contraindicated with DHE. Erenumab was the only approved calcitonin gene-related peptide monoclonal antibody at study initiation. <h3>Results:</h3> Over 24 weeks, 8 patients concomitantly used erenumab and INP104; 5 reported no AEs. Most AEs were mild or moderate in severity. One patient reported severe AEs, which included bronchitis and serious AEs of pulmonary embolism and visual disturbance; none was treatment related. One mild case of abnormal olfactory test in another patient was possibly treatment related. At baseline, 2-hour pain and most bothersome symptom (MBS) freedom was self-reported by 22.0% and 51.5% of patients on their best usual care, respectively. At months 1, 2, 3, 4, 5, and 6, 32.3% and 54.3%, 37.1% and 70.8%, 33.3% and 50.0%, 40.3% and 68.1%, 28.0% and 42.7%, and 26.7% and 33.3% self-reported 2-hour pain and MBS freedom post-INP104, respectively. <h3>Conclusions:</h3> Results suggest that INP104 may be an effective and well-tolerated acute therapy for migraine patients who concomitantly use erenumab as a preventive therapy, with sustained benefits over 6 months. <b>Disclosure:</b> Dr. Ahmed has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Abbvie. Dr. Ahmed has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biohaven. Dr. Vann has received personal compensation for serving as an employee of Impel Neuropharma. Dr. Vann has received personal compensation for serving as an employee of Biogen. Dr. Fitzpatrick has received personal compensation for serving as an employee of Impel Pharmaceuticals. Dr. Ray has received personal compensation for serving as an employee of Impel Pharmaceuticals. Dr. Ray has stock in Impel Pharmaceuticals. Dr. Shrewsbury has received personal compensation for serving as an employee of Impel NeuroPharma. Dr. Shrewsbury has received stock or an ownership interest from Impel NeuroPharma. Dr. Aurora has received personal compensation for serving as an employee of Impel Neuropharma. Dr. Aurora has stock in Impel Neurpharma.

Zavegepant 10 mg Nasal Spray is Effective for the Acute Treatment of Migraine Regardless of Attack Frequency: Pooled Results From 2 Randomized, Placebo-Controlled Clinical Trials (S47.003)

Zavegepant 10 mg Nasal Spray is Effective for the Acute Treatment of Migraine Regardless of Attack Frequency: Pooled Results From 2 Randomized, Placebo-Controlled Clinical Trials (S47.003)

Efficacy of Celecoxib Oral Solution in Adults With and Without Baseline Nausea: Post Hoc Analysis of Results From Two Randomized, Double-Blind Placebo-Controlled Trials in the Acute Treatment of Migraine (P14-12.009)

Efficacy of Celecoxib Oral Solution in Adults With and Without Baseline Nausea: Post Hoc Analysis of Results From Two Randomized, Double-Blind Placebo-Controlled Trials in the Acute Treatment of Migraine (P14-12.009)

Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease

ObjectivesEvaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)–approved labeling claims that used these approaches. MethodsA targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. ResultsA total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. ConclusionsMulticomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.

Laser versus sham for genitourinary syndrome of menopause: A randomised controlled trial.

To assess whether CO2 laser treatment is more effective than sham application in relieving the most bothersome symptom (MBS) in women with genitourinary syndrome of menopause (GSM). Single-centre, sham-controlled, double-blind, randomised trial. A tertiary centre in Belgium. Sixty women with moderate to severe GSM symptoms. All participants eventually received three consecutive laser and three consecutive sham applications, either first laser followed by sham, or conversely. The primary outcome was the participant-reported change in severity of the MBS at 12 weeks. Secondary outcomes included subjective (patient satisfaction, sexual function, urinary function) and objective (pH, Vaginal Health Index Score, in vivo microscopy) measurements assessing the short-term effect and the longevity of treatment effects at 18 months after start of the therapy. Adverse events were reported at every visit. The MBS severity score decreased from 2.86 ± 0.35 to 2.17 ± 0.93 (-23.60%; 95% CI -36.10% to -11.10%) in women treated with laser compared with 2.90 ± 0.31 to 2.52 ± 0.78 (-13.20%; 95% CI -22.70% to -3.73%) in those receiving sham applications (p=0.13). There were no serious adverse events reported up to 18 months. In women with GSM, the treatment response 12 weeks after laser application was comparable to that of sham applications. There were no obvious differences for secondary outcomes and no serious adverse events were reported.

Ubrogepant Is Safe and Efficacious in Participants Taking Concomitant Preventive Medication for Migraine: A Pooled Analysis of Phase3 Trials.

IntroductionUbrogepant is a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine that can be used to treat breakthrough attacks in individuals taking preventive treatment for migraine. We evaluated the impact of preventive medication use on the efficacy and safety of ubrogepant for the acute treatment of migraine.MethodsThis was an analysis of pooled efficacy data from the ACHIEVE I and ACHIEVE II phase 3 trials, in which efficacy of ubrogepant was assessed at 2 h after taking study medication for pain freedom, absence of most bothersome symptom (MBS), and pain relief. In addition, a long-term safety (LTS) extension trial was completed where safety was assessed on the basis of incidence and severity of treatment-emergent adverse events (TEAEs). Outcomes were compared between participants with or without prior (within 6 months) preventive medication use (anticonvulsants, beta blockers, antidepressants, or onabotulinumtoxinA). For efficacy analyses, data were pooled across ACHIEVE trials for the 50 mg and placebo groups; for safety analyses, data for all dose groups (50 mg and 100 mg) in the LTS trial were pooled.ResultsPreventive treatments were used by 417 of 2247 (18.6%) participants analyzed in the ACHIEVE trials and by 143 of 813 (17.5%) participants in the LTS trial. Responder rates for all outcomes were similar between participants with or without preventive treatment within each dose group (p > 0.05). No significant differences were noted across the different preventive medications. Rates and types of TEAEs were similar between participants with or without preventive treatment. No serious treatment-related adverse events were reported.ConclusionEfficacy and safety of ubrogepant for the acute treatment of migraine were similar between participants with or without prior or current use of concomitant preventive medication.Trial RegistrationClinicalTrials.gov identifiers: NCT02828020 (ACHIEVE I), NCT02867709 (ACHIEVE II), and NCT02873221 (long-term safety trial).Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01923-3.

P.027 Efficacy and Safety of Eptinezumab Initiated During a Migraine Attack: Results from the RELIEF Study

Background: Eptinezumab is approved for migraine prevention, with demonstrated rapid onset of preventive benefit. RELIEF evaluated the efficacy and safety of eptinezumab initiated during a migraine attack. Methods: RELIEF (NCT04152083; parallel-group, double-blind, placebo-controlled) randomized adults with migraine (4-15d/mo in 3mo prior to screening) to eptinezumab 100mg or placebo, administered IV within 1-6h of qualifying migraine onset. Co-primary efficacy endpoints were time to headache pain freedom and time to absence of most bothersome symptom (MBS). Results: Eptinezumab (n=238) compared with placebo (n=242) achieved significantly faster headache pain freedom (median 4h vs 9h; hazard ratio=1.54, P=0.0006) and absence of MBS (2h vs 3h; 1.75, P&lt;0.0001). At 2h, 23.5% and 12.0% (P=0.0009) of eptinezumab-treated and placebo patients, respectively, reported headache pain freedom, and 55.5% and 35.8% (P&lt;0.0001) reported absence of MBS. Significantly fewer eptinezumab-treated patients used rescue medication within 24h (31.5% vs 59.9%; P&lt;0.0001). Treatment-emergent adverse events occurred in 10.9% eptinezumab-treated and 10.3% placebo patients; no serious adverse events occurred. Conclusions: Infusion of the preventive migraine treatment, eptinezumab, during a migraine resulted in rapid and sustained freedom from headache pain and MBS vs placebo, starting 2h post-infusion, decreasing need for acute medication within 24h post-infusion. No notable safety findings were identified.

Progress in the Treatment of Migraine Attacks: From Traditional Approaches to Eptinezumab.

Migraine is the second cause of disability and of lost years of healthy life worldwide. Migraine is characterized by recurrent headache attacks and accompanying disabling symptoms lasting 4–48 h. In episodic migraine, attacks occur in less than 15 days per month and in chronic migraine, in more than 15 monthly days. Whilst successful translation of pharmacological discoveries into efficacious therapeutics has been achieved in the preventative therapy of chronic migraine, treatment of acute migraine suffers the lack of effective advancements. An effective treatment affords complete freedom from pain two hours after therapy and provides the absence of the most bothersome symptom (MBS) associated with migraine after 2 h. However, available anti-migraine abortive treatments for acute attacks do not represent an effective and safe treatment for all the populations treated. In particular, the most used specific treatment is represented by triptans that offer 2-h sustained freedom from pain achieved in 18–50% of patients but they are contraindicated in coronary artery disease, stroke and peripheral vascular disease due to the vasoconstriction at the basis of their pharmacologic action. The most novel therapies, i.e., gepants and ditans, are without sufficient post-marketing data for secure use. Here, an attempt is proposed to analyse the rational basis and evidence in favour of investigating the efficacy and safety in acute migraine attacks of eptinezumab, i.e., monoclonal antibody (mAb) directed towards calcitonin gene-related peptide (CGRP) unique for intravenous infusion administration.

A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN

BackgroundWhile pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing.MethodsPatient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom.ResultsPatients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time.ConclusionsThis study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint.Trial RegistrationSAMURAI (NCT02439320); SPARTAN (NCT02605174).

Lasmiditan efficacy in migraine attacks with mild vs. moderate or severe pain

Objective To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity. Methods Pooled data from two single-attack, placebo-controlled studies (SAMURAI [NCT02439320] and SPARTAN [NCT02605174]), and a prospective, randomized, open-label study (GLADIATOR [NCT02565186]) were assessed. Efficacy measures included the proportion of attacks with 2-h pain freedom (PF), 2-h most bothersome symptom (MBS) freedom, and 24-h sustained pain freedom (SPF). Fisher’s exact test was used to compare the proportion of PF, SPF, or MBS freedom outcomes among attacks treated at mild, moderate, or severe pain. Results In SAMURAI and SPARTAN, most treated attacks were of moderate (N = 2768) or severe (N = 1147) intensity, compared to mild (N = 65). Numerically greater 2-h PF and 24-h SPF response rates were observed in attacks treated at mild compared to moderate or severe pain. Analysis of GLADIATOR data included 273 (1.5%), 11,644 (65.1%), and 5948 (33.3%) attacks treated when pain was mild, moderate, and severe, respectively. In general, a significantly greater proportion of attacks treated at mild pain achieved 2-h PF and MBS freedom, as well as 24-h SPF. The incidence of treatment-emergent adverse events in LTN treatment groups were similar regardless of baseline head pain intensity. Conclusions Data from two placebo-controlled, single-attack trials, and an open-label study including treatment of multiple attacks, suggested a tendency to relatively better efficacy outcomes when LTN treatment was initiated at mild vs. moderate to severe pain. Further research is needed to better understand the relationship of lasmiditan outcomes to the time of administration in the course of a migraine attack.

Effect of a change in lasmiditan dose on efficacy and safety in patients with migraine

ABSTRACT Background: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg. Objective: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses. Methods: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study. Eight patient groups were created based on the initial dose received in SAMURAI or SPARTAN and the subsequent dose in GLADIATOR: placebo-100, placebo-200, 50–100, 50–200, 100–100, 100–200, 200–100, 200–200. Migraine pain freedom, migraine-related functional disability freedom, most bothersome symptom (MBS) freedom, and pain relief were evaluated at 2-h post-dose. The occurrence of most common treatment-emergent adverse events (MC-TEAE) was evaluated. Shift analyses were performed for pain freedom and ≥1 MC-TEAE. The incidence of patients with a specific outcome from the first and subsequent doses were compared within each dose change group using McNemar’s test. Results: Small, but consistent, increases in incidences of pain freedom, migraine-related functional disability freedom, MBS freedom, and pain relief occurred when the second lasmiditan dose was higher than the initial dose. For patients starting on 50 mg, increasing to 100 or 200 mg provided a positive efficacy-TEAE balance, despite an increase in incidence of ≥1 MC-TEAE. For patients starting on 100 mg, increasing to 200 mg provided a positive efficacy-TEAE balance. If the initial dose was 100 or 200 mg, the incidence of patients experiencing ≥1 MC-TEAE decreased or stayed the same with their subsequent dose, regardless of dose. Decreasing from 200 to 100 mg led to a decrease in patients with pain freedom and ≥1 MC-TEAE, resulting in a neutral efficacy-TEAE balance. Shift analyses supported these findings. Conclusion: A positive efficacy-TEAE balance exists for patients increasing their lasmiditan dose for treatment of a subsequent migraine attack. These results could be important for optimizing dosing for individual patients. Clinicaltrials.gov: SAMURAI (NCT02439320); SPARTAN (NCT02605174); GLADIATOR (NCT02565186).

Lasmiditan in patients with common migraine comorbidities: a post hoc efficacy and safety analysis of two phase 3 randomized clinical trials

Objective Determine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT1F receptor agonist approved in the United States for the acute treatment of migraine. Methods In SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 h after dose compared with placebo. Most common treatment-emergent adverse events (TEAEs) were dizziness, paraesthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Based upon literature review of common migraine comorbidities, Anxiety, Allergy, Bronchial, Cardiac, Depression, Fatigue, Gastrointestinal, Hormonal, Musculoskeletal/Pain, Neurological, Obesity, Sleep, and Vascular Comorbidity Groups were created. Using pooled results, efficacy and TEAEs were assessed to compare patients with or without a given common migraine comorbidity. To compare treatment groups, p-values were calculated for treatment-by-subgroup interaction, based on logistic regression with treatment-by-comorbidity condition status (Yes/No) as the interaction term; study, treatment group, and comorbidity condition status (Yes/No) were covariates. Differential treatment effect based upon comorbidity status was also examined. Trial registration at clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Results Across all the Comorbidity Groups, with the potential exception of fatigue, treatment-by-subgroup interaction analyses did not provide evidence of a lasmiditan-driven lasmiditan versus placebo differential treatment effect dependent on Yes versus No comorbidity subgroup for either efficacy or TEAE assessments. Conclusions The efficacy and safety of lasmiditan for treatment of individual migraine attacks appear to be independent of comorbid conditions.

Effect of estradiol vaginal gel on vaginal atrophy in postmenopausal women: A randomized double-blind controlled trial.

To evaluate the efficacy and safety of 25 μg of estradiol gel on postmenopausal vaginal tissue. This randomized double-blind controlled trial included postmenopausal women with vaginal atrophy who attended our menopause clinic during July 2017-January 2018. Women were randomly assigned to the estradiol gel group or control group (K-Y® Jelly). Treatment consisted of 2 mL of product applied intravaginally daily for 2 weeks, and two doses per week for the next 6 weeks. The most bothersome symptom (MBS), vaginal health index (VHI), vaginal pH, vaginal maturation index, vaginal maturation value (VMV), female sexual function index (FSFI), serum estradiol level and endometrial thickness were evaluated at baseline, 4 and 8 weeks. Seventy-five of 80 women completed the trial. After 8 weeks of treatment, VMV, VHI, vaginal pH and FSFI improved significantly in the estradiol group, with no observed change in the control group. The MBS was decreased in both groups with no significant difference between groups. Serum estradiol level and endometrial thickness were not significantly different between groups at baseline or at week 8. Estradiol vaginal gel demonstrated an ability to reverse vaginal atrophy with a high safety profile and low systemic absorption of estradiol.

PND102 CORRELATION ANALYSIS OF THE CHANGE IN THREE SF-36 DOMAINS WITH CHANGE IN PATIENT-IDENTIFIED MOST BOTHERSOME SYMPTOM AND MONTHLY MIGRAINE DAYS IN PATIENTS WITH CHRONIC MIGRAINE: RESULTS OF THE PROMISE-2 STUDY

A previous PROMISE-2 analysis demonstrated that Patient Global Impression of Change responses are more closely correlated with changes in patient-identified most bothersome symptom (MBS) (r=0.83) than changes in monthly migraine days (MMDs) (r=0.51). It is not known whether changes in health-related quality of life (HRQOL) are more closely associated with changes in MBS or MMDs in patients with migraine. This analysis evaluated the relationship between changes in 36-item Short-Form Heath Survey (SF-36) domains most impacted in patients with migraine and changes in patient-identified MBS and MMDs among patients with chronic migraine (CM). PROMISE-2 (NCT02974153) was a double-blind, randomized, placebo-controlled trial evaluating eptinezumab (100mg, 300mg) for the preventive treatment of CM (N=1072). Unlike MBS in acute trials, patients verbally identified any MBS associated with migraine attacks at screening and rated changes using a 7-point Likert scale ranging from “very much worse” to “very much improved.” The SF-36 measures overall HRQOL; this analysis focuses on HRQOL changes from baseline in bodily pain (BP), role-physical (RP), and social functioning (SF) domains. Associations between variables were evaluated with Spearman correlations in the total pooled population. At Weeks 4 and 12, improvements for both eptinezumab doses versus placebo were noted in change from baseline in MMDs, MBS, and SF-36 scores. All SF-36 scores were numerically more closely correlated with MBS than with MMDs at Week 4 (BP: MBS, r=0.40; MMDs, r=−0.32; RP: MBS, r=0.39; MMDs, r=−0.29; SF: MBS, r=0.30; MMDs, r=−0.23). At Week 12, the correlations were similar (BP: MBS, r=0.35; MMDs, r=−0.32; RP: MBS, r=0.33; MMDs, r=−0.29; SF: MBS, r=0.26; MMDs, r=−0.27). After initial administration of eptinezumab, changes in MBS and MMDs were similarly correlated with improvements in SF-36 domains most impacted in patients with migraine at the end of 12 weeks, supporting MBS as an important influence on HRQOL.