ARTEMIS1: Study to Evaluate the Safety and Efficacy of USL261 (Intranasal Midazolam) in Patients With Seizure Clusters

• Sponsor: UCB Biopharma S.P.R.L. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01390220
• Collaborator: (none)
• Enrollment: 292
• Locations: 90
• Arms: 2
• Actual Duration (Months): 69
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the safety and effectiveness of USL261 for the outpatient treatment of seizure clusters.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: USL261; Drug: Placebo	Phase 3

Detailed Description

Qualifying participants underwent an in-clinic administration (Test Dose Phase [TDP]) of two doses of USL261 (intranasal midazolam 5 mg), separated by 10 minutes, in the absence of seizures. Eligible participants were then randomized to USL261 versus Placebo in an outpatient Comparative Phase (CP). When the participant had a qualifying seizure cluster episode, as described in an individualized patient management plan, the participant's caregiver administered the double-blind dose. An open-label USL261 dose could be administered after 10 minutes and up to 6 hours after the double-blind dose, if the participant had persistent or recurrent seizures. Initial participants could not proceed to CP until an independent data safety monitoring board (DSMB) reviewed safety data from at least the first 25 participants in TDP; the DSMB performed additional safety reviews at pre-set intervals based on enrollment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 292 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Intranasal Midazolam (USL261) in the Outpatient Treatment of Subjects With Seizure Clusters. ARTEMIS-1: Acute Rescue Therapy in Epilepsy With Midazolam Intranasal Spray-1
• Actual Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Mar 1, 2017
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: USL261 intranasal midazolam 5mg	Drug: USL261; Other Names: Midazolam nasal spray (MDZ NS)
Experimental: Placebo Intranasal placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Participants Who Met the Criteria for Treatment Success After Administration of the Double-blind Dose in the Comparative Phase (CP) [6 hours]

   Treatment Success is defined as achieving both of the following: 1) termination of seizure(s) within 10 minutes after double-blind study drug administration, and 2) no recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours after study drug administration. Participants who received the open-label second dose within 6 hours of administration of the double-blind dose were analyzed as having had a seizure.

Secondary Outcome Measures

1. Participants With Seizure(s) >10 Minutes to 4 Hours After Administration of the Double-blind Dose [4 hours]

   Participants with recurrence of seizure(s) >10 minutes and up to 4 hours after administration of the double-blind dose in the CP. Participants who received the open-label second dose within 4 hours of administration of the double-blind dose were analyzed as having had a seizure.

2. Occurrence of Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose [24 hours]

   Occurrence of next seizure with a start time >10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration.

3. Time to Next Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose [24 hours]

   Time to next seizure with a start time >10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has a competent, adult caregiver who can recognize and observe the subject's seizure cluster episodes

• Has an established diagnosis of partial or generalized epilepsy that includes the following:

• A documented history of seizure clusters lasting a minimum of 10 minutes

• Seizure cluster pattern is observable, stereotyped, and recognizably different from the subject's other non-cluster seizure activity (if any)

• A second seizure in the seizure cluster typically occurring within 6 hours from the time of cluster recognition

• A seizure cluster pattern composed of multiple (≥ 2) partial or generalized seizures

• A seizure cluster pattern established > 3 months before Visit 1

• A frequency of ≥ 3 seizure clusters during the year before Visit 1

• At least 1 seizure cluster occurring ≤ 4 months before Visit 1

• Seizure cluster pattern is confirmed by a central reviewer

• Currently on a stable regimen of anti-epileptic drugs (AEDs) with no changes in type of AEDs since Visit 1 and for ≥ 7 days before Visit 2, with or without intermittent use of benzodiazepines at a constant dose

• Weight is 40 kg to 125 kg, inclusive

Exclusion Criteria:

• Has a neurological disorder that is likely to progress in the next year

• Has severe chronic cardio-respiratory disease

• Has had psychogenic, non-epileptic seizure(s) within the 5 years before Visit 1

• Has a history of their stereotypical seizure cluster progressing to status epilepticus within the 2 years before Visit 1

• Has a history of acute narrow-angle glaucoma.

• Has had active suicidal plan/intent or active suicidal thoughts in the 6 months before Visit 1 or a suicide attempt in the past 5 years

• Currently using a vagal nerve stimulator (VNS) unless the device has been implanted for at least 6 months and the setting stable for 4 weeks before Visit 1

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	United States, Arizona	Phoenix	Arizona	United States
2	United States, Arizona	Tucson	Arizona	United States
3	United States, Arkansas	Little Rock	Arkansas	United States
4	United States, California	Fresno	California	United States
5	United States, California	Irvine	California	United States
6	United States, California	Loma Linda	California	United States
7	United States, California	Sacramento	California	United States
8	United States, California	Ventura	California	United States
9	United States, Colorado	Aurora	Colorado	United States
10	United States, Connecticut	New Haven	Connecticut	United States
11	United States, Florida	Gainesville	Florida	United States
12	United States, Florida	Gulf Breeze	Florida	United States
13	United States, Florida	Port Charlotte	Florida	United States
14	United States, Florida	Tampa	Florida	United States
15	United States, Florida	Wellington	Florida	United States
16	United States, Idaho	Boise	Idaho	United States
17	United States, Illinois	Chicago	Illinois	United States
18	United States, Kansas	Manhattan	Kansas	United States
19	United States, Kentucky	Lexington	Kentucky	United States
20	United States, Maryland	Baltimore	Maryland	United States
21	United States, Michigan	Detroit	Michigan	United States
22	United States, Minnesota	Saint Paul	Minnesota	United States
23	United States, Missouri	Chesterfield	Missouri	United States
24	United States, Missouri	Saint Louis	Missouri	United States
25	United States, Nevada	Reno	Nevada	United States
26	United States, New Hampshire	Lebanon	New Hampshire	United States
27	United States, New Jersey	Flemington	New Jersey	United States
28	United States, New Jersey	Hackensack	New Jersey	United States
29	United States, New York	Bronx	New York	United States
30	United States, New York	New York	New York	United States
31	United States, New York	Stony Brook	New York	United States
32	United States, North Carolina	Durham	North Carolina	United States
33	United States, North Carolina	Winston-Salem	North Carolina	United States
34	United States, Ohio	Columbus	Ohio	United States
35	United States, Oklahoma	Oklahoma City	Oklahoma	United States
36	United States, Oregon	Portland	Oregon	United States
37	United States, Pennsylvania	Philadelphia	Pennsylvania	United States
38	United States, Tennessee	Memphis	Tennessee	United States
39	United States, Tennessee	Nashville	Tennessee	United States
40	United States, Texas	Dallas	Texas	United States
41	United States, Texas	Fort Worth	Texas	United States
42	United States, Texas	Greenville	Texas	United States
43	United States, Texas	San Antonio	Texas	United States
44	United States, Texas	Temple	Texas	United States
45	United States, Virginia	Norfolk	Virginia	United States
46	United States, Wisconsin	Madison	Wisconsin	United States
47	Australia, New South Wales	Chatswood	New South Wales	Australia
48	Australia, New South Wales	Randwick	New South Wales	Australia
49	Australia, Queensland	Herston	Queensland	Australia
50	Australia, Vctoria	Heidelberg West	Victoria	Australia
51	Australia, Victoria	Parkville	Victoria	Australia
52	Canada, Ontario	Toronto	Ontario	Canada
53	Canada, Quebec	Montreal	Quebec	Canada
54	Germany, Baden-Wurttemberg	Freiburg	Baden-Wurttemberg	Germany
55	Germany, Bayern	Munich	Bayern	Germany
56	Germany, Hessen	Marburg	Hessen	Germany
57	Germany, Nordrhein-Westfalen	Bonn	Nordrhein-Westfalen	Germany
58	Germany, Westfalen-Lippe	Bielefeld	Wetsfalen-Lippe	Germany
59	Hungary	Budapest		Hungary
60	Hungary	Kazincbarcika		Hungary
61	Israel	Haifa		Israel
62	Israel	Holon		Israel
63	Israel	Jerusalem		Israel
64	Israel	Petach Tikva		Israel
65	Israel	Ramat Gan		Israel
66	Israel	Tel Aviv		Israel
67	Italy	Firenze		Italy
68	Italy	Genova		Italy
69	Italy	Milano		Italy
70	Italy	Napoli		Italy
71	Italy	Pavia		Italy
72	Italy	San Fermo della Battaglia		Italy
73	New Zealand, Auklund	Grafton	Auklund	New Zealand
74	New Zealand, Canterbury	Christchurch	Canterbury	New Zealand
75	Poland	Gdansk		Poland
76	Poland	Katowice		Poland
77	Poland	Krakow		Poland
78	Poland	Olsztyn		Poland
79	Spain, Andalucia	Sevilla	Andalucia	Spain
80	Spain, Catalonia	Barcelona	Catalonia	Spain
81	Spain, Catalonia	Girona	Catalonia	Spain
82	Spain, Madrid	Fuencarral-El Pardo	Madrid	Spain
83	Spain, Madrid	Moncloa-Aravaca	Madrid	Spain
84	Spain, Madrid	Pozuelo De Alarcón	Madrid	Spain
85	Ukraine, Ivano-Frankivsk	Ivano-Frankivsk		Ukraine
86	Ukraine	Kharkiv		Ukraine
87	Ukraine	Odessa		Ukraine
88	Ukraine	Poltava		Ukraine
89	Ukraine	Ternopil		Ukraine
90	Ukraine	Vinnytsya		Ukraine

Sponsors and Collaborators

• UCB Biopharma S.P.R.L.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 20, 2015
• Statistical Analysis Plan - Apr 14, 2017

More Information

Publications

None provided.

• Responsible Party: UCB Biopharma S.P.R.L.
• ClinicalTrials.gov Identifier: NCT01390220
• Other Study ID Numbers: P261-401; 2011-001318-32
• First Posted: Jul 8, 2011
• Last Update Posted: Oct 10, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by UCB Biopharma S.P.R.L.: Epilepsy; seizure clusters; acute repetitive seizures; rescue treatment; ARTEMIS
• Additional relevant MeSH terms: Epilepsy; Seizures; Midazolam

Study Results

Participant Flow

Pre-assignment Detail	Participants underwent in-clinic administration of open-label USL261 5 mg followed by USL261 5 mg 10 minutes in absence of a seizure (Test Dose Phase [TDP]). Participants were then randomized to double-blind USL261 5 mg or Placebo to be administered by caregiver to treat a seizure cluster in Comparative Phase (CP) in the outpatient setting.

Arm/Group Title	USL261 TDP	USL261 CP	Placebo CP
Arm/Group Description	Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP)	Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)	Participants completing TDP who received placebo as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)
Period Title: Test Dose Phase
STARTED	292	0	0
COMPLETED	201	0	0
NOT COMPLETED	91	0	0
Period Title: Test Dose Phase
STARTED	0	134	67
COMPLETED	0	133	67
NOT COMPLETED	0	1	0

Baseline Characteristics

Arm/Group Title	USL261 Test Dose
Arm/Group Description	Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP)
Overall Participants	292
Age (Count of Participants)
<=18 years	18 6.2%
Between 18 and 65 years	272 93.2%
>=65 years	2 0.7%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	31.5
Sex: Female, Male (Count of Participants)
Female	146 50%
Male	146 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	22 7.5%
Not Hispanic or Latino	270 92.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.7%
Asian	2 0.7%
Native Hawaiian or Other Pacific Islander	1 0.3%
Black or African American	7 2.4%
White	275 94.2%
More than one race	0 0%
Unknown or Not Reported	5 1.7%
Region of Enrollment (participants) [Number]
New Zealand	1 0.3%
Canada	4 1.4%
Hungary	18 6.2%
United States	118 40.4%
Ukraine	70 24%
Poland	14 4.8%
Italy	5 1.7%
Israel	18 6.2%
Australia	19 6.5%
Germany	13 4.5%
Spain	12 4.1%
Body mass index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	24.69
Seizure cluster episodes in year before Visit 1 of study (seizure cluster episodes) [Median (Full Range) ]
Median (Full Range) [seizure cluster episodes]	15
Years had seizure cluster episodes prior to study (years) [Median (Full Range) ]
Median (Full Range) [years]	6.0
Typical number of seizures in seizure cluster episode (seizures) [Median (Full Range) ]
Median (Full Range) [seizures]	6.0
Typical duration of seizure cluster episode (minutes) [Median (Full Range) ]
Median (Full Range) [minutes]	67.5

Outcome Measures

1. Primary Outcome

Title	Participants Who Met the Criteria for Treatment Success After Administration of the Double-blind Dose in the Comparative Phase (CP)
Description	Treatment Success is defined as achieving both of the following: 1) termination of seizure(s) within 10 minutes after double-blind study drug administration, and 2) no recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours after study drug administration. Participants who received the open-label second dose within 6 hours of administration of the double-blind dose were analyzed as having had a seizure.
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

Randomized participants who received the double-blind dose in the CP.

Arm/Group Title	USL261 CP	Placebo CP
Arm/Group Description	5 mg intranasal midazolam USL261	Intranasal placebo Placebo
Measure Participants	134	67
Count of Participants [Participants]	72 24.7%	23 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	USL261 CP, Placebo CP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0109
	Comments
	Method	Fisher Exact
	Comments	2-sided

2. Secondary Outcome

Title	Participants With Seizure(s) >10 Minutes to 4 Hours After Administration of the Double-blind Dose
Description	Participants with recurrence of seizure(s) >10 minutes and up to 4 hours after administration of the double-blind dose in the CP. Participants who received the open-label second dose within 4 hours of administration of the double-blind dose were analyzed as having had a seizure.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

Randomized participants who received the double-blind dose in the CP.

Arm/Group Title	USL261 CP	Placebo CP
Arm/Group Description	5 mg intranasal midazolam USL261	Intranasal placebo Placebo
Measure Participants	134	67
Count of Participants [Participants]	51 17.5%	40 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	USL261 CP, Placebo CP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0043
	Comments
	Method	Fisher Exact
	Comments	2-sided

3. Secondary Outcome

Title	Occurrence of Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose
Description	Occurrence of next seizure with a start time >10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Randomized participants who received the double-blind dose in the CP.

Arm/Group Title	USL261 CP	Placebo CP
Arm/Group Description	5 mg intranasal midazolam USL261	Intranasal placebo Placebo
Measure Participants	134	67
Count of Participants [Participants]	50 17.1%	31 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	USL261 CP, Placebo CP
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0124
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Time to Next Seizure With a Start Time >10 Minutes After Administration of the Double-blind Dose
Description	Time to next seizure with a start time >10 minutes and up to 24 hours after administration of the double-blind dose in the CP. Participants who did not have another seizure before the end of the 24-hour observation period were censored at the end of the observation period. Participants administered the open-label second dose who did not have a seizure were censored at the time of the administration.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Randomized participants who received the double-blind dose in the CP

Arm/Group Title	USL261 CP	Placebo CP
Arm/Group Description	5 mg intranasal midazolam USL261	Intranasal placebo Placebo
Measure Participants	134	67
Median (95% Confidence Interval) [Hours]	NA	12.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	USL261 CP, Placebo CP
	Comments	Kaplan-Meier estimates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0124
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	Treatment emergent adverse events (TEAEs) collected from administration of first open-label dose of USL261 5 mg in Test Dose Phase (TDP) until completion of the final study visit or 7 days after the last administration of study drug, whichever was later. The duration of individual participant participation was variable as administration of the double-blind dose in the Comparative Phase (CP) was dependent on occurrence of a seizure cluster episode meeting trial criteria after randomization.
Adverse Event Reporting Description	Adverse events collected at each visit from participant and/or caregiver. TEAEs presented for TDP and CP separately. Due to the short systemic half-life of active (midazolam), TEAEs within 2 days after administration of first open-label USL261 5 mg dose presented for TDP, and within 2 days after administration of double-blind dose for CP.
Arm/Group Title	USL261 TDP		USL261 CP, USL261 5 mg Only		USL261 CP, USL261 5 mg + 5 mg		Placebo CP, Placebo Only		Placebo CP, Placebo + USL261 5 mg
Arm/Group Description	Participants who received at least 1 open-label USL261 5 mg dose in Test Dose Phase (TDP)		Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)		Participants completing TDP who received USL261 5 mg as randomized dose to treat a seizure cluster episode and received an open-label USL261 5 mg dose in the Comparative Phase (CP)		Participants completing TDP who received Placebo as randomized dose to treat a seizure cluster episode in the Comparative Phase (CP)		Participants completing TDP who received Placebo as randomized dose to treat a seizure cluster episode and received an open-label USL261 5 mg dose in the Comparative Phase (CP)
All Cause Mortality
	USL261 TDP		USL261 CP, USL261 5 mg Only		USL261 CP, USL261 5 mg + 5 mg		Placebo CP, Placebo Only		Placebo CP, Placebo + USL261 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/292 (0%)		0/91 (0%)		0/43 (0%)		0/26 (0%)		0/41 (0%)
Serious Adverse Events
	USL261 TDP		USL261 CP, USL261 5 mg Only		USL261 CP, USL261 5 mg + 5 mg		Placebo CP, Placebo Only		Placebo CP, Placebo + USL261 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/292 (0.7%)		0/91 (0%)		0/43 (0%)		0/26 (0%)		1/41 (2.4%)
Nervous system disorders
Sedation	1/292 (0.3%)	1	0/91 (0%)	0	0/43 (0%)	0	0/26 (0%)	0	0/41 (0%)	0
Somnolence	1/292 (0.3%)	1	0/91 (0%)	0	0/43 (0%)	0	0/26 (0%)	0	0/41 (0%)	0
Seizure cluster	0/292 (0%)	0	0/91 (0%)	0	0/43 (0%)	0	0/26 (0%)	0	1/41 (2.4%)	1
Other (Not Including Serious) Adverse Events
	USL261 TDP		USL261 CP, USL261 5 mg Only		USL261 CP, USL261 5 mg + 5 mg		Placebo CP, Placebo Only		Placebo CP, Placebo + USL261 5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	78/292 (26.7%)		17/91 (18.7%)		10/43 (23.3%)		3/26 (11.5%)		7/41 (17.1%)
Eye disorders
Lacrimation increased	20/292 (6.8%)	26	1/91 (1.1%)	1	1/43 (2.3%)	1	0/26 (0%)	0	1/41 (2.4%)	1
General disorders
Product taste abnormal	17/292 (5.8%)	19	4/91 (4.4%)	4	0/43 (0%)	0	0/26 (0%)	0	0/41 (0%)	0
Nervous system disorders
Somnolence	28/292 (9.6%)	30	9/91 (9.9%)	9	4/43 (9.3%)	4	1/26 (3.8%)	1	4/41 (9.8%)	4
Headache	1/292 (0.3%)	1	6/91 (6.6%)	6	1/43 (2.3%)	1	0/26 (0%)	0	0/41 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal discomfort	47/292 (16.1%)	61	5/91 (5.5%)	5	7/43 (16.3%)	8	2/26 (7.7%)	2	3/41 (7.3%)	3
Throat irritation	15/292 (5.1%)	15	2/91 (2.2%)	2	3/43 (7%)	3	0/26 (0%)	0	1/41 (2.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A manuscript or abstract should not be submitted by investigator(s) for publication or presentation until a New Drug Application is approved by the US FDA or permission is granted in writing by sponsor.