Psychosocial outcomes of repeated treatment of seizure clusters with midazolam nasal spray: Results of a phase 3, open-label extension trial.

OBJECTIVE: To evaluate treatment satisfaction, level of anxiety, confidence about traveling with midazolam nasal spray (MDZ-NS), and health-related quality of life in patients with seizure clusters and their caregivers after repeated, intermittent use of MDZ-NS in the outpatient setting. METHODS: We analyzed the psychosocial outcome data from a phase 3, open-label extension trial (ARTEMIS-2; P261-402; NCT01529034) in patients 12 years of age and older with seizure clusters on a stable regimen of antiseizure medications. Caregivers administered MDZ-NS 5 mg when patients experienced a seizure cluster. A second dose could be given if seizures did not terminate within 10 min or recurred from 10 min to 6 h. Treatment Satisfaction Questionnaire for Medication (TSQM), the Intranasal Therapy Impact Questionnaire (ITIQ), and the Short Form-12 Health Survey version 2 (SF-12v2) were self-administered by patients and/or caregivers at prespecified visits. RESULTS: Of the one hundred and seventy-five patients enrolled in ARTEMIS-2, 161 (92.0%) received ≥ 1 dose of MDZ-NS and had a post-treatment seizure-related assessment and were included in the Efficacy Evaluable Set in this analysis, with a total of 1,998 treated seizure clusters over a median duration of 16.8 months. All TSQM scales showed improvement from the baseline of the double-blind ARTEMIS-1 trial (NCT01390220) to the last visit in ARTEMIS-2, indicating greater satisfaction with MDZ-NS across all domains, with a mean change from baseline of 8.8, 6.1, 4.3, and 6.2 for effectiveness (n = 135), side effects (n = 139), convenience (n = 139), and global satisfaction (n = 138), respectively. Change from baseline in TSQM scores generally increased with repeated MDZ-NS use. In both patients and caregivers, anxiety generally lessened with repeated MDZ-NS use, with a mean improvement in ITIQ scores in patients' anxiety since receiving MDZ-NS from 2.5 (n = 138) to 3.5 (n = 145) from visit 1 to the last visit (and from 2.6 [n = 156] to 3.6 [n = 160] for caregivers), respectively. From visit 1 (screening and enrollment in ARTEMIS-2) to visit 10 (after 16 seizure cluster episodes treated with MDZ-NS), the proportions of patients and caregivers who answered "strongly agree" or "agree" for confidence about traveling with an intranasal spray remained ≥ 79% and generally increased over repeated MDZ-NS use. Small positive mean changes in SF-12v2 scores from baseline to the last visit were observed in both patients and caregivers, respectively, for the domains of physical functioning (0.9, 1.1), role-physical (2.4, 0.3), bodily pain (1.7, 0.3), general health (0.6, 1.2), and role-emotional (2.1, 0.3), and in the physical health component (1.6, 1.0). CONCLUSION: Patients and caregivers perceived MDZ-NS favorably, with improvement from baseline on perceived effectiveness, side effects, convenience, and global satisfaction in the TSQM. This is supported by progressively lower anxiety and higher confidence levels about traveling with MDZ-NS over repeated intermittent use in the ITIQ. The positive mean changes observed in SF-12v2 scores from baseline to the last visit were small in magnitude. Limitations of this exploratory analysis include the open-label trial design and that these questionnaires have not been directly validated in epilepsy to identify clinically important changes; however, this does not mean these findings are not clinically meaningful. Overall, MDZ-NS is a socially acceptable drug device for outpatient treatment of seizure clusters that has the potential to improve quality of life and overall independence.

Safety and efficacy of midazolam nasal spray for the treatment of intermittent bouts of increased seizure activity in the epilepsy monitoring unit: A double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Midazolam nasal spray (MDZ-NS) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern, in patients 12 years of age and older with epilepsy. This trial evaluated safety and efficacy of MDZ-NS in patients with epilepsy who were admitted to the epilepsy monitoring unit for seizure characterization/presurgical evaluation. METHODS: In this randomized, double-blind, placebo-controlled phase 3 trial (P261-301; NCT01999777), eligible patients with ≥2 seizures in the 6-hour window preceding trial medication administration for whom treatment was appropriate based on investigator's judgment were randomized (1:1) to MDZ-NS 5 mg or placebo. Efficacy outcomes were proportion of patients seizure-free for 6 hours after treatment and time to first seizure within 6 hours. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Sixty-two patients were randomized (MDZ-NS n = 31; placebo n = 31), received trial medication, and completed the trial. A higher proportion of patients on MDZ-NS than placebo were seizure-free for 6 hours following treatment (54.8% vs 38.7%); however, the 16.1% difference was not statistically significant (P = .1972). The Kaplan-Meier curve of time to first seizure showed separation of both groups in favor of MDZ-NS from ~1.5 hours post-dose and throughout the 6-hour Treatment phase. Median time to first seizure was not estimable for MDZ-NS (>50% of patients had no seizure) and 3.9 hours for placebo (P = .1388). TEAEs with MDZ-NS were generally comparable to those with placebo. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. SIGNIFICANCE: Although the observed treatment difference may be clinically meaningful, statistical significance was not demonstrated. Results suggest that MDZ-NS 5 mg may provide improvement over placebo, with efficacy maintained for ≥6 hours post-dose. MDZ-NS was well tolerated in this population.

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: An open-label extension trial.

OBJECTIVE: To evaluate safety- and seizure-related outcomes with repeated intermittent use of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). METHODS: In this open-label extension trial (ClinicalTrials.gov NCT01529034), patients aged ≥12 years and on a stable regimen of antiepileptic drugs who completed the original phase III, randomized controlled trial were enrolled. Caregivers administered MDZ-NS 5 mg when patients experienced SCs; a second dose could be given if seizures did not terminate within 10 minutes or recurred within 10 minutes-6 hours. Patients were monitored for treatment-emergent adverse events (TEAEs) throughout, and the main seizure-related outcome was treatment success, defined as seizure termination within 10 minutes and no recurrence 10 minutes-6 hours after drug administration. RESULTS: Of 175 patients enrolled, 161 (92.0%) received ≥1 MDZ-NS dose, for a total of 1998 SC episodes. Median time spent by patients in the trial was 16.8 months (range = 1-55.7 months). TEAEs were experienced by 40.4% of patients within 2 days of drug administration and 57.1% overall. TEAEs reported by most patients (within 2 days and overall) were nasal discomfort (12.4%) and somnolence (9.3%). One patient each discontinued due to treatment-related nasal discomfort and somnolence. There were no patients with treatment-related respiratory depression, and none with TEAEs indicative of drug abuse or dependence. Treatment success criteria were met in 55% (1108/1998) of SC episodes after administration of a single 5-mg dose and in 80.2% (617/769) with the second dose. Treatment success was consistent over treated episode number. SIGNIFICANCE: Repeated, intermittent, acute treatment of patients experiencing SCs with MDZ-NS in the outpatient setting was well tolerated over an extended period, with maintenance of efficacy suggesting lack of development of tolerance.

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters-a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). METHODS: This was a phase III, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov NCT01390220) with patients age ≥12 years on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours, and time-to-next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout. RESULTS: Of 292 patients administered a test dose, 262 patients were randomized, and 201 received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ-NS- than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = 0.0109). Significantly, fewer MDZ-NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = 0.0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = 0.0124). Sixteen patients (5.5%) discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and placebo groups, respectively, experienced ≥1 TEAE. SIGNIFICANCE: MDZ-NS was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing an SC in the outpatient setting and was associated with a favorable safety profile.

Ecallantide for the treatment of acute attacks in hereditary angioedema.

BACKGROUND: Hereditary angioedema is a rare genetic disorder characterized by acute, intermittent, and potentially life-threatening attacks of edema of the skin and mucosa. We evaluated ecallantide, a newly developed recombinant plasma kallikrein inhibitor, for the treatment of acute attacks of angioedema. METHODS: In this double-blind, placebo-controlled trial, patients with hereditary angioedema presenting with an acute attack were randomly assigned, in a 1:1 ratio, to receive subcutaneous ecallantide, at a dose of 30 mg, or placebo. Two measures of patient-reported outcomes were used to assess the response: treatment outcome scores, which range from +100 (designated in the protocol as significant improvement in symptoms) to -100 (significant worsening of symptoms), and the change from baseline in the mean symptom complex severity score, which range from +2 (representing a change from mild symptoms at baseline to severe symptoms after) to -3 (representing a change from severe symptoms at baseline to no symptoms after). The primary end point was the treatment outcome score 4 hours after study-drug administration. Secondary end points included the change from baseline in the mean symptom complex severity score at 4 hours and the time to significant improvement. RESULTS: A total of 71 of the 72 patients completed the trial. The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (interquartile range [IQR], 0.0 to 100.0 in both groups; P=0.004). The median change in the mean symptom complex severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (P=0.01). The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (P=0.14). There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events. CONCLUSIONS: Four hours after administration of ecallantide or placebo for acute attacks of angioedema in patients with hereditary angioedema, patient-reported treatment outcome scores and mean symptom complex severity scores were significantly better with ecallantide than with placebo. (Funded by Dyax; ClinicalTrials.gov number, NCT00262080.)

Outcomes after ecallantide treatment of laryngeal hereditary angioedema attacks.

BACKGROUND: Hereditary angioedema (HAE) is a rare disorder associated with episodic attacks of well-demarcated angioedema. Attacks that affect the larynx can result in life-threatening airway obstruction. OBJECTIVES: To examine efficacy and safety of ecallantide treatment for laryngeal HAE attacks. METHODS: Data were combined from 4 clinical studies (EDEMA2, EDEMA3, EDEMA4, and DX-88/19) evaluating 30 mg of subcutaneous ecallantide for treatment of acute HAE attacks. Efficacy was assessed using 2 validated, HAE-specific, patient-reported outcome measures. The change in Mean Symptom Complex Severity (MSCS) score indicates change in symptom severity; a negative score indicates improvement. The calculated minimally important difference (MID) for change in severity is -0.30. The Treatment Outcome Score (TOS) measures treatment response. A positive score indicates improvement; the calculated MID is 30. RESULTS: Overall, 98 patients received ecallantide for 220 laryngeal attacks. The mean ± SD change in MSCS score was -1.1 ± 0.73 and -1.6 ± 0.68 at 4 and 24 hours, respectively. The mean ± SD TOS was 73.5 ± 35.8 and 85.5 ± 27.8 at 4 and 24 hours, respectively. Median time to significant improvement was 185 minutes (95% confidence interval, 167-226). One attack required intubation. Four treatment-emergent serious adverse events were reported, including 2 HAE attacks that resulted in hospitalization and 2 anaphylactic reactions. One of these reactions required treatment with epinephrine, but both patients recovered fully. There were no deaths. CONCLUSION: In this large attack series, ecallantide was effective for treatment of laryngeal HAE attacks. There is a risk of hypersensitivity, including anaphylaxis, consistent with product labeling. As such, ecallantide should be administered under the supervision of a health care professional. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: not applicable for EDEMA2 (trial was conducted before implementation of registration requirements); NCT00262080 for EDEMA3, NCT00457015 for EDEMA4, and NCT00456508 for DX-88/19.

Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study.

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of potentially life-threatening edema. The plasma kallikrein inhibitor ecallantide is approved for treatment of acute HAE attacks. This study evaluates the efficacy and safety of ecallantide for treatment of multiple HAE episodes in the DX-88/19 (continuation) study. Patients received 30 mg of subcutaneous ecallantide for acute HAE attack symptoms, with no limit on number of episodes treated. Primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Additional end points included change in MSCS score at 24 hours, treatment outcome score (TOS) at 4 and 24 hours, and time to response. Safety parameters included adverse events. Statistical analyses were conducted on qualifying treatment episodes (those with ≥12 patients). One hundred forty-seven patients received treatment for 625 episodes; analyses were conducted through 13 treatment episodes. Across 13 episodes at 4 hours, mean change in MSCS score ranged from -1.04 to -1.36, and mean TOSs ranged from 56.2 to 79.8. Median time to onset of sustained improvement ranged from 59 to 113 minutes. There was no indication of reduced efficacy with repeated ecallantide use. No new safety signals were detected. Eight patients (5.4%) reported potential hypersensitivity reactions, six of whom met the definition of anaphylaxis based on National Institute of Allergy and Infectious Diseases criteria. Ecallantide is effective for acute recurrent HAE attacks and maintains its efficacy and safety during multiple treatment episodes in patients with HAE. Potential hypersensitivity reactions were consistent with prior reports.

Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics.

Hereditary angioedema (HAE) is characterized by episodic attacks of edema. HAE is caused by low levels of the protein C1 esterase inhibitor, which inhibits plasma kallikrein, the enzyme responsible for converting high-molecular-weight kininogen to bradykinin. Unregulated production of bradykinin leads to the characteristic clinical symptoms of swelling and pain. Ecallantide is a novel plasma kallikrein inhibitor effective for treatment of acute HAE attacks. This study was designed to analyze the efficacy of ecallantide for treating HAE attacks by attack location, attack severity, patient gender, and body mass index (BMI). An analysis of integrated data from two double-blind, placebo-controlled trials of ecallantide for treatment of acute HAE attacks was undertaken. For the purpose of analysis, symptoms were classified by anatomic location and, for each location, by the patient-assessed severity of the attack. Efficacy versus placebo was examined using two validated patient-reported outcomes: treatment outcome score and mean symptom complex severity score. One hundred forty-three attacks were analyzed (73 ecallantide and 70 placebo). Ecallantide was equally effective in both male and female subjects. Ecallantide had decreased efficacy for patients with BMI > 30 kg/m(2). Ecallantide showed efficacy for treatment of severe and moderate attacks, and was effective for abdominal, internal head and neck, external head and neck, and cutaneous locations. In summary, ecallantide is effective for treatment of acute HAE attacks of different symptom locations and severity; outcomes were similar for men and women. However, the standard dose was less effective for obese patients.

Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies.

BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by recurrent angioedema attacks. Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks. OBJECTIVE: We sought to further characterize the safety and efficacy of ecallantide for HAE attacks by performing an integrated analysis of pooled data from 2 phase 3 studies. METHODS: An integrated analysis was conducted with data from 2 randomized, double-blind, placebo-controlled studies in which patients with HAE (age ≥10 years) received 30 mg of subcutaneous ecallantide or placebo within 8 hours of onset of a moderate-to-severe attack at any anatomic site. Efficacy was evaluated by using validated patient-reported outcome measures: the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). RESULTS: Compared with placebo, ecallantide resulted in significantly greater reduction in MSCS scores from baseline to 4 hours after dosing (ecallantide [mean ± SD], -0.97 ± 0.78; placebo, -0.47 ± 0.71; P < .001) and a significantly greater increase in TOSs at 4 hours (ecallantide, 55.5 ± 46.5; placebo, 20.0 ± 58.9; P < .001). Significantly greater symptomatic improvement over placebo occurred through 24 hours after dosing (MSCS score, P = .028; TOS, P = .039). Ecallantide demonstrated efficacy at all attack sites. The incidence of treatment-emergent adverse events was similar between groups. CONCLUSIONS: This integrated analysis supports and expands on the results of the phase 3 studies. Ecallantide appears to be effective and well tolerated for the treatment of HAE attacks.

Response time for ecallantide treatment of acute hereditary angioedema attacks.

BACKGROUND: Hereditary angioedema (HAE) is a rare, debilitating, and potentially fatal disease characterized by acute attacks of swelling that can affect the abdomen/gastrointestinal tract, larynx, face, genitals, and extremities. Ecallantide is a novel plasma kallikrein inhibitor developed for the treatment of acute HAE attacks. OBJECTIVE: To examine the speed of effect of ecallantide vs placebo. METHODS: Data were integrated from 2 randomized, double-blind, placebo-controlled phase 3 trials of ecallantide in patients with HAE. Eligible patients presented within 8 hours of onset of a moderate to severe HAE attack for 1:1 randomization to receive a single dose of 30 mg of subcutaneous ecallantide or placebo. End points included time to beginning of improvement, time to sustained overall improvement, and time to significant overall improvement. RESULTS: A total of 143 participants (70 receiving ecallantide and 73 receiving placebo) were included. The distribution curves for time to beginning of improvement demonstrated a trend in favor of ecallantide vs placebo within 4 hours (P(log rank) = .09). For time to onset of sustained improvement, the difference in the distribution of the curves between the 2 groups reached significance by 2 hours after dosing (P(log rank) = .04). For time to significant overall improvement, the difference in the distribution of the curves reached significance in favor of ecallantide by 90 minutes (P(log rank) = .04). The beneficial effect of ecallantide was demonstrated earliest for abdominal attacks, followed by laryngeal and peripheral attacks. CONCLUSIONS: Ecallantide provides relief of acute HAE attack symptoms, with rapidity of response commensurate with therapeutic needs for HAE attack locations.

EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a genetic disorder resulting from low levels of C1-inhibitor activity that manifests as acute attacks of variable and sometimes life-threatening edema. Ecallantide is a novel potent inhibitor of human plasma kallikrein, a key mediator of the excessive formation of bradykinin associated with the signs and symptoms of an HAE attack. OBJECTIVE: To evaluate the efficacy and safety of ecallantide in the treatment of acute HAE attacks. METHODS: In this double-blind, placebo-controlled study, patients with a moderate to severe HAE attack were randomized 1:1 to receive 30 mg of subcutaneous ecallantide or placebo. The primary efficacy end point was change from baseline in mean symptom complex severity score 4 hours after dosing. Additional end points included treatment outcome score 4 hours after dosing and maintenance of significant overall improvement through 24 hours. RESULTS: Ninety-six patients were enrolled. Mean (SD) change from baseline in mean symptom complex severity score 4 hours after dosing was significantly greater with ecallantide use (-0.8 [0.6]) compared with placebo use (-0.4 [0.8]) (P = .01 comparing distributions). Ecallantide therapy was also associated with a significantly larger mean (SD) treatment outcome score 4 hours after dosing vs placebo use (ecallantide: 53.4 [49.7]; placebo: 8.1 [63.2]; P = .003 comparing distributions). The benefit of ecallantide was apparent within 2 hours after dosing and was maintained through 24 hours after dosing. The safety profile was similar between the treatment groups. CONCLUSION: Ecallantide appears to be an effective and safe treatment for acute attacks of HAE.

Economic costs associated with acute attacks and long-term management of hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent acute attacks of swelling of the larynx, abdomen, and periphery. OBJECTIVE: To assess the economic burden associated with acute attacks and long-term management of HAE. METHODS: Burden was assessed via a Web-based survey of HAE patients (> or = 18 years old) that solicited information on attack characterization, short-term treatment, long-term disease management, impact on work, and patient costs. A standardized instrument, the Work Productivity and Activity Impairment questionnaire, was included to assess impact on work productivity. Standard medical costs and US average wage costs were assigned to survey items to assess direct medical and indirect costs, respectively. RESULTS: Total annual per-patient costs are estimated at $42,000 for the average HAE patient, with costs totaling $14,000 for patients with mild attacks, $27,000 for patients with moderate attacks, and $96,000 for patients with severe attacks. Hospital costs account for 67% of direct medical costs. Respondents reported high rates of missed work, lost productivity, and lost income, contributing to indirect costs totaling $16,000 annually for the average patient. Almost all costs increase with disease severity, although the distribution varies with severity: indirect costs account for 75% of costs for patients with mild attacks, whereas emergency department and hospital costs account for 68% of costs for patients with severe attacks. CONCLUSIONS: HAE results in considerable economic burden to patients, payers, and society in terms of direct medical and indirect costs and compounds the substantial humanistic burdens, which will be reported separately.