Randomized Controlled Trial of the Efficacy and Safety of Deferiprone: Subgroup Analysis of Pediatric Patients in Iron-Overloaded Patients with Sickle Cell Disease and Other Anemias

Children with sickle cell disease (SCD) who have their disease managed with frequent blood transfusions often require iron chelation therapy to prevent iron overload. Deferoxamine (DFO) is an iron chelator approved for pediatric use that is often administered via infusion; however, postmarketing research revealed that adherence to treatment in pediatric populations is a key challenge experienced by patients and caregivers due to the burdensome nature of the administration route. Deferiprone (DFP), an oral iron chelator, has recently been approved as a first-line treatment for transfusional iron overload in pediatric and adult patients with SCD and other anemias. We previously reported that DFP is noninferior to DFO in patients with SCD and iron overload (as assessed by liver iron concentration [LIC]) and has an acceptable safety profile. Here, we report a subgroup analysis of the FIRST (NCT02041299) study to assess whether the efficacy and safety of DFP are comparable to DFO in children with SCD. In this phase 4, multicenter, 2-arm, randomized, open-label study, eligible patients were randomized in a 2:1 ratio to receive DFP or DFO for 12 months. The subgroup analysis included children (2-16 years of age) with SCD or another rare anemia who were treated for transfusional iron overload. Children received either DFP orally tid or DFO by subcutaneous infusion 5-7 days a week. Iron load was monitored during the trial and dosage adjustments were allowed when necessary. The primary efficacy endpoint was the change in LIC from baseline to month 12, and data were analyzed for all patients who had a baseline and a follow-up LIC assessment (efficacy population). Absolute neutrophil counts were assessed weekly for the first 6 months, and then every 2 weeks until the end of the study. Additional safety assessments were done monthly with analysis including all patients who received at least 1 dose of the study drug (safety population). Statistical significance between DFP- and DFO-treated groups was calculated via t-test for continuous variables and Fisher's exact test for discrete variables. Of the 228 patients in the safety population, 128 (n=86 in DFP; n=42 in DFO) were children. Five children withdrew from the study due to adverse events (AEs) and 19 withdrew for other reasons. Most children in each treatment group (DFP, 75.6 %; DFO, 80.9%) had a primary diagnosis of SCD (HbS); the remainder had another form of anemia that required chronic transfusions. At the time of first exposure, mean ages (SD) in the DFP- and DFO-treated groups were 9.9 (3.7) years and 10.9 (3.0) (P=0.09), respectively. There were no significant differences between the DFP- and DFO-treatment groups in sex (males 59.3% vs 57.1%; P=0.85), ethnicity (P=0.68), or race (P=0.34). Children treated with DFP or DFO showed no significant differences in overall incidence of AEs (P=0.77) (including neutropenias (P=0.30)), severe AEs (P=0.10), serious AEs (P=0.16), or withdrawals due to an AE (P=0.17). However, a difference in the overall incidence of nonserious AEs considered at least possibly related to DFP treatment (59.3% vs 33.3%; P=0.01) was found. Table 1 shows the most common (≥5%) AEs in children by treatment group. The only individual AE for which the rate was significantly higher in the DFP group vs the DFO group was elevated liver enzymes (P=0.03), a known transient reaction to DFP that typically resolves with continued DFP therapy. In DFP-treated children, there were no AEs observed that had not been previously reported in other patient populations; 1 child developed agranulocytosis; and children <6 years of age treated with DFP demonstrated a comparable safety profile to that of older children (6-16 years of age) treated with DFP. In the efficacy population, after 12 months of treatment, there was no significant difference in the mean (SD) LIC change from baseline in children treated with DFP (n=78) compared to DFO (n=40) (-3.39 ± 4.24 mg/g vs -2.99 ± 3.16 mg/g, respectively; P=0.57). This subgroup analysis of children receiving chronic transfusion therapy for SCD or other anemias corroborates previous findings that treatment with DFP is comparable to DFO in reducing LIC. No new safety concerns were observed in children that have not been previously noted in other populations. Thus, the present findings may benefit children and their healthcare providers when considering effective iron chelation therapy that may also address treatment-adherence concerns. Figure 1 Figure 1. Disclosures Hamdy: Amgen: Honoraria; Bayer: Honoraria; Novartis: Honoraria; ApoPharma: Honoraria; NovoNordisk: Honoraria; Roche: Honoraria; Takeda: Honoraria. Kwiatkowski: Terumo BCT: Research Funding; Sangamo: Research Funding; Bluebird Bio: Research Funding; Novartis: Research Funding; ApoPharma: Research Funding; Agios: Honoraria; Silence Therapeutics: Honoraria; Celgene: Honoraria; Imara: Other: Consultancy Fees; Bluebird Bio: Other: Consultancy Fees. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Lee: Chiesi Canada Corp: Current Employment. Temin: Chiesi Canada Corp: Current Employment. Fradette: Chiesi Canada Corp: Current Employment. Tricta: Chiesi Canada Corp: Current Employment.

P.030 Long-term Safety and Tolerability of Atogepant 60 mg Following Once-Daily Dosing Over 1 Year for the Preventive Treatment of Migraine

Background: The goal of the study was to assess the safety and tolerability of atogepant, an oral, calcitonin gene-related peptide receptor antagonist in development for migraine preventive treatment, once daily over 1 year. Methods: Multicenter, open-label trial (NCT03700320). Adults with migraine were randomized 5:2 to atogepant or oral standard-of-care (SOC) migraine prevention. Results: 744 randomized participants (n=546 atogepant), 739 safety population participants (n=543 atogepant). Adverse events (AEs) were reported by 67.0% of atogepant participants; 18.0% had AEs considered related to atogepant. AEs reported by ≥5% of atogepant-treated participants were upper respiratory tract infection (10.3%), constipation (7.2%), nausea (6.3%), and urinary tract infection (5.2%). 4.4% of atogepant participants reported serious AEs that included various, common medical conditions; no event occurred in ≥1 participant and none were atogepant-related. Two deaths were reported in atogepant-treated participants (homicide victim; toxic shock syndrome); both were considered not treatment-related. 5.7% of atogepant participants discontinued due to AEs. Alanine aminotransferase/aspartate aminotransferase levels ≥3X upper limit of normal were reported for 2.4% of atogepant participants (n=13/531) and 3.2% of SOC participants (n=6/190). No cases of potential Hy’s Law were reported. Conclusions: Once-daily use of atogepant for preventive treatment of migraine over 1 year was safe and well-tolerated with no safety concerns identified.

Effects of Body Weight on the Safety of High-Dose Donepezil in Alzheimer’s Disease: Post hoc Analysis of a Multicenter, Randomized, Open-Label, Parallel Design, Three-Arm Clinical Trial

<b><i>Background:</i></b> Donepezil 23 mg is considered for Alzheimer’s disease (AD) to optimize cognitive benefits; however, increased adverse events (AEs) can negatively influence drug adherence. We investigated whether body weight (BW) differs based on the presence of AEs, and which baseline factors were relevant to the safety of high-dose donepezil. <b><i>Methods:</i></b> This study was a post hoc analysis of a multicenter randomized trial between 2014 and 2016. We included patients with moderate to severe AD treated with 10 mg/day of donepezil, and the daily dose was escalated to 23 mg with/without dose titration. Dose titration indicates 15 mg/day of donepezil before escalation or 10 mg and 23 mg/day on alternate days before escalation during the first 4 weeks. The patients were divided into 2 groups based on occurrence of AEs of special interest (AESIs) to compare baseline characteristics. We also assessed relationships between BW and AESIs. <b><i>Results:</i></b> Among the 160 participants in the safety population, the baseline BWs differed between the AESI (+) (<i>n</i> = 67) and AESI (−) (<i>n</i> = 93) groups. Baseline BW was inversely correlated with the occurrence of AESIs (<i>p</i> = 0.020), and this relationship was prominent in the no-dose titration group (<i>p</i> = 0.009) but absent in the dose-titration groups (<i>p</i> &#x3e; 0.05). <b><i>Conclusions:</i></b> BW is the most important factor that correlated with cholinergic AEs. Hence, stepwise dose titration should be considered, particularly in patients with low BW, to minimize the inverse relationship between BW and the occurrence of AEs (“Clinicaltrials.gov” No. NCT02550665 registered on September 15, 2015).

Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis.

5002 Background: The randomized phase III EORTC-1333-GUCG (NCT02194842) trial compares enzalutamide vs. a combination of Radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) patients. The premature unblinding of ERA223 (NCT02043678) in Nov 2017 due to a significant increase in the rate of fractures in the combination of abiraterone and Ra223 arm led to the implementation of the mandatory use of bone protecting agents (BPA) in the EORTC-1333-GUCG trial. Skeletal fractures, pathological or not, are a frequent and underestimated adverse event of systemic treatment of advanced prostate cancer. Whether this mandated use of BPA (zoledronic acid or denosumab) would mitigate the risk of fractures in this patient population was unclear. An early safety analysis (Tombal, ASCO, 2019) suggested that the risk of fractures was well controlled in both arms when patients receive BPA. We present here an updated analysis of fracture incidence with longer follow-up. Methods: As of 28/01/2021, a total of 253 patients (134 after making BPA mandatory) were randomized between enzalutamide/Ra223 and enzalutamide. The fracture rate was estimated with the cumulative incidence method in the safety population of 237 (122 after making BPA mandatory) treated patients. Death in absence of fracture was analyzed as competing risk and censoring was applied at last follow-up. Results: Overall, 69.5% of enzalutamide/Ra223 patients (95.2% after making BPA mandatory) and 73.1% of enzalutamide patients (95% after making BPA mandatory) received BPA on treatment: 13.6% in the enzalutamide/Ra223 arm and 21.8% in the enzalutamide arm did not use BPA at registration, but started during protocol treatment and 55.9% and 51.3% respectively, received BPA since entry. At 36.7 months median follow-up in patients without BPA and 23.1 months median follow-up in patients receiving BPA, a total of 39 patients reported a fracture. Among them, 30 patients (20 in enzalutamide/Ra223 arm) did not receive BPA and 9 (4 in the enzalutamide/Ra223 arm) received BPA (see table). Conclusions: The updated safety analysis confirms the early fracture rate results. In the absence of BPA, the risk of fracture is increased when RA223 is added to enzalutamide. Strikingly, in both arms, the risk remains almost abolished by a preventive continuous administration of BPA, thus stressing the importance of complying to international recommendations in terms of giving BPA to mCRPC patients. This study is sponsored by EORTC and supported by Bayer and Astellas. Clinical trial information: NCT02194842. [Table: see text]

Updated overall efficacy and safety of selpercatinib in patients (pts) with RET fusion+ non-small cell lung cancer (NSCLC).

9065 Background: Selpercatinib, a first-in-class highly selective and potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients (safety population: N = 345 vs N = 329). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, ongoing LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites) were included in this analysis. Pts with the opportunity to be followed ≥6 months from their first dose were included in the efficacy-evaluable population for these analyses. Integrated analysis set (IAS) included 218 NSCLC pts with prior platinum-chemotherapy. Primary analysis set (PAS) was a subset of the IAS and included the first 105 consecutively enrolled pts. The treatment-naïve population included 48 efficacy-evaluable pts. Primary endpoint was objective response rate (ORR, RECIST v1.1) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. Safety population (N = 345) included all pts with NSCLC who received ≥1 selpercatinib dose by data cutoff (30 Mar 2020). Results: In pts with prior treatment (N = 218) and treatment-naïve (N = 48) pts, 56% and 60% were female, with a median pt age of 61 and 64 years, respectively. The ORR with selpercatinib was 57% in the IAS, 64% in the PAS, and 85% in the treatment-naïve population (Table). In both the IAS and PAS, the median DoR was 17.5 months, median PFS was 19.3 months at median follow-up of 12.0 and 15.7 months, respectively (Table). The most common treatment-emergent adverse events (TEAEs) reported in ≥25% of pts were dry mouth, diarrhea, hypertension, increased ALT/AST, edema peripheral, and fatigue. Twenty-five pts (7%) permanently discontinued due to TEAEs, with 10 pts (3%) discontinuing selpercatinib due to treatment-related AEs as per investigator. Conclusions: In this updated data set, selpercatinib continued to demonstrate durable antitumor activity in pts with RET-fusion+ NSCLC. Selpercatinib was well-tolerated with a safety profile consistent with previous reports. A global, randomized, phase 3 trial (LIBRETTO-431) evaluating selpercatinib compared with standard frontline therapy is ongoing. Clinical trial information: NCT03157128. [Table: see text]

Safety of trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive locally advanced or metastatic breast cancer (mBC): Final results from KAMILLA Cohorts 1 (global) and 2 (Asia).

1039 Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC (NCT01702571). The treated (safety) population of KAMILLA comprises 2 cohorts: a larger global Cohort 1 (n=2002) and a smaller Asia Cohort 2 (n=181 [China, n=154; Thailand, n=15; Indonesia, n=12]). Here we report results from Cohort 2 in the context of those previously reported for Cohort 1. Methods: Pts had HER2-positive, locally advanced or mBC with progression after chemotherapy and anti-HER2 therapy or ≤6 months (mo) of completing adjuvant therapy. T-DM1 3.6 mg/kg was given intravenously every 3 weeks until disease progression, consent withdrawal, or unacceptable toxicity. Primary endpoints were grade ≥3 (G≥3) adverse events of primary interest (AEPIs), specifically hepatic events, allergic reactions, thrombocytopenia (TCP), and hemorrhage events; all other G≥3 treatment-related AEs (TRAEs); and all-grade pneumonitis. Results: As of 31 July 2019,KAMILLA enrolled 2185 pts (Cohort 1, n=2003; Cohort 2, n=182), of which 2002 and 181 in each cohort, respectively, received ≥1 study dose and were included in the safety population. Baseline characteristics were generally similar between cohorts. Median (range) T-DM1 exposure was 5.6 mo (0–46) for Cohort 1 and 5.0 mo (0–31) for Cohort 2. The overall G≥3 AEPI rate was higher in Cohort 2 vs Cohort 1 (Table), mostly driven by a higher G≥3 TCP rate in Cohort 2. In Cohort 2, G≥3 TCP (the most frequently reported G≥3 AEPI) did not appear to be associated with G≥3 hemorrhagic events — the majority of G≥3 TCP events (128/138) fully resolved, with a duration of ≤15 days for 98/138 of these events. G≥3 TRAE rates were 18.4% in Cohort 1 and 48.6% in Cohort 2, the latter mainly due to TCP and platelet count decreased; any-grade pneumonitis rates were 1.0% and 2.2%, respectively. No other safety signals were identified. Median progression-free survival and overall survival were similar for both cohorts (Table). Conclusions: These data confirm prior observations in an Asian subgroup of the phase 3 EMILIA trial of T-DM1 in pts with previously treated mBC. Although the G≥3 TCP rate was higher in the Asia cohort, the majority of these events resolved fully. OS and PFS were similar in both cohorts. These data reinforce the favorable T-DM1 benefit-risk profile in mBC. Clinical trial information: NCT01702571 .[Table: see text]

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage

Background and Purpose: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH). Methods: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days. Results: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population). Conclusions: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02329327.

486 Timing and Duration of Adverse Events in a Clinical Trial of Lower-Sodium Oxybate in Participants With Narcolepsy With Cataplexy

Introduction This analysis evaluated treatment-emergent adverse events (TEAEs) during a double-blind, placebo-controlled, randomized withdrawal trial (NCT03030599) of lower-sodium oxybate (LXB; Xywav™), an FDA-approved treatment for excessive daytime sleepiness or cataplexy in narcolepsy. Methods At study entry, participants were taking sodium oxybate (SXB) alone, SXB with other anticataplectics, other anticataplectics alone, or were anticataplectic treatment-naive. Participants taking SXB transitioned to the same LXB dose (gram-for-gram); oxybate-naive participants initiated LXB (4.5 g/night). TEAEs were analyzed in the safety population (N=201, received ≥1 study drug dose) during a 12-week open-label optimized treatment/titration period (while other anticataplectics were tapered/discontinued) and subsequent 2-week stable-dose period (SDP). TEAE duration was defined as time from TEAE start to end date (or end of SDP, if TEAE end date was unrecorded). Results LXB-emergent TEAEs varied by treatment at entry. Anticataplectic treatment-naive participants reported TEAEs including headache (n=36/90, 40%; median duration [range]=1 [1–76] day), nausea (n=19/90, 21%; duration=9 [1–37] days), and dizziness (n=15/90, 17%; duration=10 [1–117] days); peak incidence was week 2 (n=8/89, 9%) for headache, week 3 (n=3/88, 3%) for dizziness, and week 1 (n=6/90, 7%) for nausea. Anticataplectic treatment-naive participants (n=13/90, 14%) also reported decreased appetite, with relatively long duration (58 [2–358] days). Participants taking SXB alone reported TEAEs including headache (n=17/52, 33%; duration=1 [1–122] day) and diarrhea (n=4/52, 8%; duration=41 [2–101] days); peak headache incidence was week 4 (n=4/52, 8%); diarrhea had no peak. Participants taking other anticataplectics alone reported TEAEs including headache (n=14/36, 39%; duration=1 [1–94] day), nausea (n=9/36, 25%; duration=3 [1–16] days), and dizziness (n=9/36, 25%; duration=4 [1–29] days); peak incidence was week 1 (n=3/36, 8%) for headache, week 6 (n=2/32, 6%) for nausea, and week 4 (n=3/33, 9%) for dizziness. One participant taking SXB with other anticataplectics (n=1/23, 4%) reported headache in weeks 1–2 and 4; one reported nausea (4%) persisting from week 1 to 8. Overall, study discontinuations attributed to TEAEs were 20/57 (35%). Conclusion Most TEAEs with LXB treatment occurred early, were consistent with the known SXB safety profile, and were relatively short-lived (except decreased appetite). Participants previously taking SXB reported fewer TEAEs than oxybate-naive participants. Support (if any) Jazz Pharmaceuticals, Inc.

487 Effect of Lower-Sodium Oxybate on Sleep Inertia in Idiopathic Hypersomnia in a Double-Blind, Randomized Withdrawal Study

Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness. A common feature is sleep inertia, which is prolonged difficulty waking up accompanied by confusion, disorientation, poor motor coordination, and repeated returns to sleep. Sleep inertia is burdensome to patients, resulting in missed work or school, and patients may be dependent on others to wake them. No treatment is currently approved for IH. The efficacy and safety of lower-sodium oxybate (LXB; Xywav™), a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®), was evaluated in a phase 3 study (NCT03533114) in adults with IH. We focus here on the drug effect on sleep inertia. Methods Eligible participants aged 18–75 years with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP). Participants were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale score. The visual analog scale for sleep inertia (VAS-SI) was included as an exploratory endpoint. The VAS-SI, administered daily during the last 2 weeks of screening before baseline, SDP, and DBRWP, is a self-reported retrospective measure of difficulty awakening each morning using a 100-mm line with anchors 0 (very easy) and 100 (very difficult). Results The safety population included 154 participants (mean±SD age, 40±14 years; 68% female); modified intent-to-treat population, n=115. VAS-SI scores gradually decreased from week 2 of screening (mean±SD, 56.6±25.1) to week 2 of SDP (29.0±20.8). During week 2 of DBRWP, VAS-SI scores worsened in participants randomized to placebo (n=59) compared with maintenance of improvement in participants continuing LXB treatment (n=56); LS mean difference (95% CI) in change from SDP, −22.2 (−29.7, −14.8); P&lt;0.0001 (nominal). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion Sleep inertia improved with LXB treatment and significant differences were seen between placebo and LXB after DBRWP. The overall safety profile in participants with IH is consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals, Inc

Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II

Objective To examine the safety and efficacy of ubrogepant for acute treatment of migraine across cardiovascular (CV) disease risk categories. Methods ACHIEVE I and II were multicenter, double-blind, single-attack, phase 3 trials in adults with migraine, with or without aura. Participants were randomized 1:1:1 to placebo or ubrogepant (50 or 100 mg in ACHIEVE I; 25 or 50 mg in ACHIEVE II), to treat one migraine attack of moderate or severe headache pain intensity. This post-hoc analysis pooled data from ubrogepant 50 mg and placebo groups from the ACHIEVE trials to examine the safety and efficacy of ubrogepant by baseline cardiovascular disease risk factors. Using a cardiovascular risk assessment algorithm, participants were categorized as having no cardiovascular risk, low cardiovascular risk or moderate-high cardiovascular risk at baseline. Treatment-emergent adverse events were documented 48 h and 30 days after taking the trial medication. Co-primary efficacy outcomes were 2-h pain freedom and 2-h absence of most bothersome migraine-associated symptom. Results Overall, 3358 participants were randomized in the ACHIEVE trials (n = 2901 safety population; n = 2682 modified intent-to-treat population). In the safety population, 11% of participants were categorized as moderate-high (n = 311), 32% low (n = 920), and 58% no cardiovascular risk factors (n = 1670). The proportion of ubrogepant participants reporting a treatment-emergent adverse event was comparable across risk categories and similar to placebo. The treatment effects of ubrogepant versus placebo were consistent across cardiovascular risk categories for all efficacy outcomes. Conclusion The safety and efficacy of ubrogepant for the acute treatment of a single migraine attack did not differ by the presence of major cardiovascular risk factors. No evidence of increased treatment-emergent adverse events or cardiac system organ class adverse events with ≥2 major cardiovascular risk factors and no safety concerns were identified. Trial Registration: ACHIEVE I ClinicalTrials.gov number, NCT02828020; ACHIEVE II ClinicalTrials.gov number, NCT02867709