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Phase 3 Clinical Trial of AF-0901 - Open-label study in patients aged 15 years old or more with convulsive status epilepticus -

Phase 3 Clinical Trial of AF-0901 in patients with convulsive status epilepticus

21

There were 9 males (42.9%) and 12 females (57.1%), slightly more females, and the mean (SD) age was 62.90 (19.49) years and the mean (SD) body weight was 51.99 (17.42) kg. The age distribution was less than 20 years (1 patient, 4.8%), 20 years to less than 35 years (1 patient, 4.8%), 35 years to less than 50 years (4 patients, 19.0%), 50 years to less than 65 years (4 patients, 19.0%), 65 years to less than 80 years (5 patients, 23.8%), and 80 years or more (6 patients, 28.6%). Status epilepticus was predominantly caused by epilepsy in 19 patients (90.5%) and acute symptomatic seizures in 2 patients (9.5%).

Twenty one patients received the dose of AF-0901 by bolus intravenous injection (bolus iv), and 3 of them subjected to continuous intravenous infusion (Civ) period. Two patients were discontinued in the Civ period. A total of 19 patients were subjected to the post-treatment observation (18 patients only in the bolus iv period and 1 patient from the Civ period). Nine patients were discontinued in the post-treatment observation period (only in the bolus iv period: 8 patients, and from the Civ period: 1 patient). Ten patients (only in the bolus iv period: 10 patients, and from Civ period: 0 patients) completed the study, and 11 patients (Civ period: 2 patients, post-treatment observation period: 9 patients) were withdrawn from this study. Including patients who withdrew from the study, all subjects were subjected to the follow-up period, and no patients were discontinued in the follow-up period. All 21 patients treated with the AF-0901 were included in the efficacy or safety analysis sets.

Twenty six adverse events occurred in 12 (57.1%) of all patients (21 patients) who received the AF-0901. These adverse events were moderate in 8 patients (38.1%) and mild in 4 patients (19.0%) . No severe adverse events were observed. The most common adverse event was decreased blood pressure in 4 patients (19.0%), followed by constipation, respiratory depression, rash, increased blood creatine phosphokinase, and increased C-reactive protein each in 2 patients (9.5%). The incidence of adverse drug reactions was 28.6% (6/21 patients), with blood pressure decreased in 4 patients (19.0%), the most common, and constipation and respiratory depression each in 2 patients (9.5%). There were no deaths, serious adverse evensts, and adverse events led to the withdrawal.

The convulsive seizure cessation rate at the final assessment in the bolus iv period was 100.0% (21 of 21 patients) and the 95% CI was 83.9%-100.0%. This result was found to be significant (p < .001) by the one-sample proportion test (binomial distribution) based on a null hypothesis that the seizure cessation rate is 40.0%.

The convulsive seizure cessation rate was 90.5% (19 of 21 patients) and the 95% CI was 69.6%-98.8% in the final treatment assessment (Bolus iv period only: Final assessment of bolus iv period, and Civ period: Final assessment of Civ period). In the final assessment of the bolus iv period, the cumulative rate of convulsive seizure cessation by cumulative dose was 81.0% (17 of 21 patients) for doses 0.15 mg/kg or less and 95.2% (20 of 21 patients) for doses 0.3 mg/kg or less. One patient had achieved convulsive seizures cessation with a upper cumulative dose of 0.6 mg/kg. Of the 3 patients who achieved convulsive seizure cessation after bolus iv and entered the Civ period, 2 patients had recurrent convulsive seizures observed 24 hours after Civ. The other patient maintained convulsive seizure cessation. In the final assessment in the bolus iv or Civ period, the recurrence rate of convulsive seizures was 31.6% (6 of 19 patients) in the final assessment in the post-treatment observation period in 19 patients who achieved convulsive seizure cessation and entered the post-treatment observation period, and 33.3% (6 of 18 patients) and 0.0% (0 of 1 patient) in the patients who entered the bolus iv and Civ periods, respectively.

In this clinical study in patients aged 15 years old or more, all 21 patients with convulsive status epilepticus (18.0 to 89.0 years old) achieved convulsive seizure cessation when treated with 0.15 mg/kg of AF-0901 (0.1 mg/kg if more caution is required) and 0.1 to 0.3 mg/kg of additional bolus dose until convulsive seizures cessation was achieved or until cumulative 0.6 mg/kg was reached. The incidence of adverse drug reactions was 28.6% (6 of 21 patients).

No

Alfresa Pharma Corporation

iyaku-chiken@alfresa-pharma.co.jp

Alfresa Pharma Corporation

iyaku-chiken@alfresa-pharma.co.jp

completed

Jan. 15, 2019

Interventional

Uncontrolled, open-label, multi-center study

treatment purpose

3

Patients with a convulsive seizures episode lasting for 5 min or longer at the beginning of first intravenous bolus injection

Patients with current or previous history of psychogenic non-epileptic seizure, those with acute narrow angle glaucoma or myasthenia gravis, those receiving combination therapy with an HIV protease inhibitor, formulation contaning efavirenz or cobicistat, and those with a hypersensitivity to midazolam or benzodiazepine.

Both

Convulsive status epilepticus

investigational material(s)
Generic name etc : midazolam
INN of investigational material : midazolam
Therapeutic category code : 113 Antiepileptics
Dosage and Administration for Investigational material : intravenous

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

efficacy
Achievement of convulsive seizure cessation in the final assessment of bolus intravenous injection

efficacy
Achievement of convulsive seizure cessation in the final treatment assessment (Bolus intravenous injection period only: Final assessment of bolus intravenous injection period, and Continuous intravenous infusion period: Final assessment of continuous intravenous infusion period)
efficacy
Recurrence of convulsive seizures in 24-hour observation during continuous intravenous infusion
efficacy
Achievement of cumulative convulsive seizure cessation by cumulative dose in the final assessment of bolus intravenous injection period
efficacy
Recurrence of convulsive seizures in the final assessment during the post-treatment observation period (24 hours after the end of the last dose during bolus intravenous injeciton period or continuous intravenous infusion period)

Dec. 11, 2018