An Open-Label, Safety and Tolerability Study of Chronic Intermittent Use of Diazepam Nasal Spray.

• Sponsor: Acorda Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02316847
• Collaborator: (none)
• Enrollment: 126
• Locations: 33
• Arms: 2
• Duration (Months): 21
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will assess long-term safety and tolerability of repeat dose diazepam nasal spray in adolescents and adults with cluster seizures, with a focus on potential local effects (changes in nasal mucosa, olfaction, and taste).

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: diazepam nasal spray	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 126 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multi-center, Open-label, Study of Safety and Tolerability of Chronic Intermittent Usage of Diazepam Nasal Spray in Adolescents and Adult Patients With Cluster Seizures, Including Assessment of Olfaction and Reported Changes in Taste.
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: diazepam nasal spray (Adults) One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.	Drug: diazepam nasal spray
Experimental: Diazepam Nasal Spray (Adolescents) One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.	Drug: diazepam nasal spray

Outcome Measures

Primary Outcome Measures

1. Olfactory Changes as Measured by the Smell Identification Test (SIT) [Screening, weeks 12, 24, 36, 48 and 51]

   The SIT is a 50-item multiple-choice standardized test of olfactory function. Scoring of the test in the ability to smell ranges from normal (Normosmia: score 35 - 40 Women; 34 - 40 Men); to inability to smell (Anosmia score 6 - 18); or Malingering (not engaged in the test) ranges 0 - 5.

2. Change From Baseline (Screening) in Nasal Mucosa. [Screening, Weeks 12, 24, 36, 48 and 51]

   Change from baseline treatment visits using a focused nasal exam was based on a scale of nasal irritation "none" to Grade 4 "septal perforation."

3. Change in Taste as Measured by a Taste Change Questionnaire [Weeks 12, 24]

   Change in taste questionnaire was administered to subjects at every study visit only if the subject complained of a change in taste or as needed to report a related AE. The taste change profile included sweet, salty, sour, bitter, oily, sharp, chalky, metallic. The subject rated the change on a 10-point scale ranging from a weak change (1) to very strong (10).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of drug-resistant epilepsy

• Patients who experience multiple episodes of acute repetitive seizures requiring at least one concomitant antiepileptic drug (AED)

• Occurrence of at least 3 seizure clusters within the past 12 months, including at least one cluster in the 4 months prior to the Screening Visit

• A caregiver must consent to participate together with the subject for purposes of observation and data collection

• The caregiver must be present when the investigational product is administered

• Screening body weight between 26 to 111 kg, inclusive

Exclusion Criteria:

• Female subject who is pregnant, breastfeeding, or planning to become pregnant

• Presence or history of any abnormality or illness that may affect the absorption, distribution, metabolism or elimination of diazepam

• Known allergy or hypersensitivity to diazepam, related drugs, or any of the formulation components

• Positive screening test for ethanol or other drugs of abuse

• Unable to receive medications intranasally

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Acorda Site #227	Phoenix	Arizona	United States	85054
2	Acorda Site #204	Little Rock	Arkansas	United States	72205
3	Acorda Site #213	Los Angeles	California	United States	90095
4	Acorda Site #220	Orange	California	United States	92868
5	Acorda Site #206	Orlando	Florida	United States	32819
6	Acorda Site #241	Port Charlotte	Florida	United States	33592
7	Acorda Site #231	Tallahassee	Florida	United States	32308
8	Acorda Site #201	Tampa	Florida	United States	33606
9	Acorda Site #234	Tampa	Florida	United States	33609
10	Acorda Site #217	Augusta	Georgia	United States	30912
11	Acorda Site #232	Honolulu	Hawaii	United States	96817
12	Acorda Site #225	Fort Wayne	Indiana	United States	46804
13	Acorda Site #226	Ames	Iowa	United States	50010
14	Acorda Site #202	Bethesda	Maryland	United States	20817
15	Acorda Site #212	Boston	Massachusetts	United States	02115
16	Acorda Site #214	Boston	Massachusetts	United States	02115
17	Acorda Site #208	Boston	Massachusetts	United States	02215
18	Acorda Site #216	Kansas City	Missouri	United States	64111
19	Acorda Site #205	Saint Louis	Missouri	United States	63131
20	Acorda Site #222	Hackensack	New Jersey	United States	07601
21	Acorda Site #223	New York	New York	United States	10016
22	Acorda Site #233	Rochester	New York	United States	14642
23	Acorda Site #230	Portland	Oregon	United States	97239
24	Acorda Site #219	Philadelphia	Pennsylvania	United States	19104
25	Acorda Site #237	Philadelphia	Pennsylvania	United States	19107
26	Acorda Site #203	Charleston	South Carolina	United States	29425
27	Acorda Site #235	Memphis	Tennessee	United States	38103
28	Acorda Site #218	Nashville	Tennessee	United States	37232
29	Acorda Site #221	Dallas	Texas	United States	75251
30	Acorda Site #229	Houston	Texas	United States	77030
31	Acorda Site #215	Richmond	Virginia	United States	23298
32	Acorda Site #224	Renton	Washington	United States	98057
33	Acorda Site #210	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• Acorda Therapeutics

Investigators

• Study Director: MinJae Lee, SK Biopharmaceuticals Co, Ltd

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acorda Therapeutics
• ClinicalTrials.gov Identifier: NCT02316847
• Other Study ID Numbers: DZNS-EP-1025
• First Posted: Dec 15, 2014
• Last Update Posted: Jul 30, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Acorda Therapeutics: Cluster Seizures; Seizures; Clusters; Acute repetitive seizures
• Additional relevant MeSH terms: Epilepsy; Diazepam

Study Results

Participant Flow

Recruitment Details	Adolescents or adults who have refractory epilepsy (drug resistant epilepsy per Kwan 2010) with a history of cluster seizures, also known as multiple episodes of acute repetitive seizures, for which acute treatment with a benzodiazepine was indicated as part of the standard of care or an individualized rescue treatment plan.

Arm/Group Title	DZNS - Adolescents (Ages 12 - 15)	DZNS - Adults (Ages 16 - 65)
Arm/Group Description	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.
Period Title: Overall Study
STARTED	9	99
COMPLETED	0	13
NOT COMPLETED	9	86

Baseline Characteristics

Arm/Group Title	Diazapam Nasal Spray (DZNS) Adults	Diazapam Nasal Spray (DZNS) Adolescents	Total
Arm/Group Description	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.	Total of all reporting groups
Overall Participants	99	9	108
Age (Count of Participants)
<=18 years	7 7.1%	9 100%	16 14.8%
Between 18 and 65 years	91 91.9%	0 0%	91 84.3%
>=65 years	1 1%	0 0%	1 0.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.6 (12.58)	13.4 (1.13)	32.9 (13.40)
Sex: Female, Male (Count of Participants)
Female	48 48.5%	3 33.3%	51 47.2%
Male	51 51.5%	6 66.7%	57 52.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 6.1%	2 22.2%	8 7.4%
Not Hispanic or Latino	93 93.9%	7 77.8%	100 92.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1%	0 0%	1 0.9%
Native Hawaiian or Other Pacific Islander	5 5.1%	0 0%	5 4.6%
Black or African American	9 9.1%	1 11.1%	10 9.3%
White	75 75.8%	8 88.9%	83 76.9%
More than one race	2 2%	0 0%	2 1.9%
Unknown or Not Reported	7 7.1%	0 0%	7 6.5%
Region of Enrollment (Count of Participants)
United States	99 100%	9 100%	108 100%

Outcome Measures

1. Primary Outcome

Title	Olfactory Changes as Measured by the Smell Identification Test (SIT)
Description	The SIT is a 50-item multiple-choice standardized test of olfactory function. Scoring of the test in the ability to smell ranges from normal (Normosmia: score 35 - 40 Women; 34 - 40 Men); to inability to smell (Anosmia score 6 - 18); or Malingering (not engaged in the test) ranges 0 - 5.
Time Frame	Screening, weeks 12, 24, 36, 48 and 51

Outcome Measure Data

Analysis Population Description

Of 91 subjects in the Safety Population, data was available for 62 subjects at screening.

Arm/Group Title	Diazepam Nasal Spray (Adults)	Diazepam Nasal Spray (Adolescents)
Arm/Group Description	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.
Measure Participants	57	5
Normosmia	18 18.2%	0 0%
Mild Microsmia	15 15.2%	1 11.1%
Moderate Microsmia	8 8.1%	3 33.3%
Severe Micromisia	7 7.1%	1 11.1%
Anosmia	9 9.1%	0 0%
Probable Malingering	0 0%	0 0%
Normosmia	6 6.1%	0 0%
Mild Microsmia	16 16.2%	0 0%
Moderate Microsmia	9 9.1%	1 11.1%
Severe Micromisia	1 1%	2 22.2%
Anosmia	2 2%	0 0%
Probable Malingering	0 0%	0 0%
Normosmia	5 5.1%	0 0%
Mild Microsmia	9 9.1%	0 0%
Moderate Microsmia	2 2%	0 0%
Severe Micromisia	5 5.1%	0 0%
Anosmia	0 0%	0 0%
Probable Malingering	0 0%	0 0%
Normosmia	2 2%	0 0%
Mild Microsmia	6 6.1%	0 0%
Moderate Microsmia	4 4%	0 0%
Severe Micromisia	1 1%	0 0%
Anosmia	1 1%	0 0%
Probable Malingering	0 0%	0 0%
Normosmia	0 0%	0 0%
Mild Microsmia	5 5.1%	0 0%
Moderate Microsmia	1 1%	0 0%
Severe Micromisia	3 3%	0 0%
Anosmia	1 1%	0 0%
Probable Malingering	0 0%	0 0%
Normosmia	1 1%	0 0%
Mild Microsmia	3 3%	0 0%
Moderate Microsmia	1 1%	0 0%
Severe Micromisia	4 4%	0 0%
Anosmia	1 1%	0 0%
Probable Malingering	0 0%	0 0%

2. Primary Outcome

Title	Change From Baseline (Screening) in Nasal Mucosa.
Description	Change from baseline treatment visits using a focused nasal exam was based on a scale of nasal irritation "none" to Grade 4 "septal perforation."
Time Frame	Screening, Weeks 12, 24, 36, 48 and 51

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Adults	Adolescents
Arm/Group Description	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.
Measure Participants	84	7
Screening : Nasal Irritation None	67 67.7%	6 66.7%
Screening : Nasal Irritation Grade 1a	10 10.1%	1 11.1%
Screening : Nasal Irritation Grade 1b	3 3%	0 0%
Screening : Nasal Irritation Grade 2	0 0%	0 0%
Screening : Mucosal Edema None	71 71.7%	6 66.7%
Screening : Mucosal Edema Mild	9 9.1%	1 11.1%
Screening : Nasal Discharge None	66 66.7%	6 66.7%
Screening : Nasal Discharge Mild	14 14.1%	1 11.1%
Screening : Mucosal Erythema None	65 65.7%	5 55.6%
Screening : Mucosal Erythema Mild	13 13.1%	2 22.2%
Screening : Mucosal Erythema Moderate	2 2%	0 0%
Screening : Mucosal Bleeding/Epistaxis None	79 79.8%	6 66.7%
Screening : Mucosal Bleeding/Epistaxis Mild	1 1%	1 11.1%
Screening : Crusting of Mucosa None	77 77.8%	7 77.8%
Screening : Crusting of Mucosa Mild	3 3%	0 0%
Week 12 : Nasal Irritation None	50 50.5%	4 44.4%
Week 12 : Nasal Irritation Grade 1a	5 5.1%	0 0%
Week 12 : Nasal Irritation Grade 1b	3 3%	0 0%
Week 12 : Nasal Irritation Grade 2	1 1%	0 0%
Week 12 : Mucosal Edema None	55 55.6%	3 33.3%
Week 12 : Mucosal Edema Mild	4 4%	1 11.1%
Week 12 : Nasal Discharge None	49 49.5%	4 44.4%
Week 12 : Nasal Discharge Mild	10 10.1%	0 0%
Week 12 : Mucosal Erythema None	39 39.4%	4 44.4%
Week 12 : Mucosal Erythema Mild	20 20.2%	0 0%
Week 12 : Mucosal Erythema Moderate	0 0%	0 0%
Week 12 : Mucosal Bleeding/Epistaxis None	58 58.6%	4 44.4%
Week 12 : Mucosal Bleeding/Epistaxis Mild	1 1%	0 0%
Week 12 : Crusting of Mucosa None	58 58.6%	4 44.4%
Week 12 : Crusting of Mucosa Mild	1 1%	0 0%
Week 24: Nasal Irritation None	37 37.4%	1 11.1%
Week 24: Nasal Irritation Grade 1a	1 1%	0 0%
Week 24: Nasal Irritation Grade 1b	1 1%	0 0%
Week 24: Mucosal Edema None	35 35.4%	0 0%
Week 24: Mucosal Edema Mild	4 4%	1 11.1%
Week 24: Nasal Discharge None	31 31.3%	1 11.1%
Week 24: Nasal Discharge Mild	8 8.1%	0 0%
Week 24: Mucosal Erythema None	33 33.3%	1 11.1%
Week 24: Mucosal Erythema Mild	6 6.1%	0 0%
Week 24: Mucosal Bleeding/Epistaxis None	39 39.4%	1 11.1%
Week 24: Crusting of Mucosa None	37 37.4%	1 11.1%
Week 24: Crusting of Mucosa Mild	2 2%	0 0%
Week 36: Nasal Irritation None	21 21.2%	1 11.1%
Week 36: Nasal Irritation Grade 1a	1 1%	0 0%
Week 36: Mucosal Edema None	21 21.2%	0 0%
Week 36: Mucosal Edema Mild	1 1%	1 11.1%
Week 36: Nasal Discharge None	20 20.2%	1 11.1%
Week 36: Nasal Discharge Mild	1 1%	0 0%
Week 36: Mucosal Erythema None	20 20.2%	1 11.1%
Week 36: Mucosal Erythema Mild	2 2%	0 0%
Week 36: Mucosal Bleeding/Epistaxis None	22 22.2%	1 11.1%
Week 36: Crusting of Mucosa None	21 21.2%	1 11.1%
Week 36: Crusting of Mucosa Mild	1 1%	0 0%
Week 48: Nasal Irritation None	12 12.1%	0 0%
Week 48: Nasal Irritation Grade 1a	1 1%	0 0%
Week 48: Mucosal Edema None	13 13.1%	0 0%
Week 48: Nasal Discharge None	13 13.1%	0 0%
Week 48: Mucosal Erythema None	13 13.1%	0 0%
Week 48: Mucosal Bleeding/Epistaxis None	13 13.1%	0 0%
Week 48: Crusting of Mucosa None	13 13.1%	0 0%
Week 51: Nasal Irritation None	13 13.1%	0 0%
Week 51: Mucosal Edema None	13 13.1%	0 0%
Week 51: Nasal Discharge None	12 12.1%	0 0%
Week 51: Nasal Discharge Mild	1 1%	0 0%
Week 51: Mucosal Erythema None	13 13.1%	0 0%
Week 51: Mucosal Bleeding/Epistaxis None	13 13.1%	0 0%
Week 51: Crusting of Mucosa None	13 13.1%	0 0%

3. Primary Outcome

Title	Change in Taste as Measured by a Taste Change Questionnaire
Description	Change in taste questionnaire was administered to subjects at every study visit only if the subject complained of a change in taste or as needed to report a related AE. The taste change profile included sweet, salty, sour, bitter, oily, sharp, chalky, metallic. The subject rated the change on a 10-point scale ranging from a weak change (1) to very strong (10).
Time Frame	Weeks 12, 24

Outcome Measure Data

Analysis Population Description

Safety Population - Number of subjects with at least one change in taste after dose administration. 6 Adults at 12 Weeks and 4 Adults at 24 weeks. No Adolescents participated.

Arm/Group Title	Diazepam Nasal Spray (Adults)
Arm/Group Description	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.
Measure Participants	84
Week 12	7.7 (2.73)
Week 24	8.3 (0.50)

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Adverse events were reported on the safety population which included only those who received at least one dose of DZNS. Adults = 84 Adolescents = 7
Arm/Group Title	Adults		Adolescents
Arm/Group Description	One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.		One dose of diazepam nasal spray is two intranasal sprays; one in each nostril using a nasal spray device. The dose is administered while the subject is sitting up or lying down.
All Cause Mortality
	Adults		Adolescents
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/84 (0%)		0/7 (0%)
Serious Adverse Events
	Adults		Adolescents
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/84 (13.1%)		1/7 (14.3%)
Blood and lymphatic system disorders
Leukopenia	1/84 (1.2%)		0/7 (0%)
Gastrointestinal disorders
Oesophagitis Ulcerative	1/84 (1.2%)		0/7 (0%)
Vomiting	1/84 (1.2%)		0/7 (0%)
Infections and infestations
Otitis Media	1/84 (1.2%)		0/7 (0%)
Septic Shock	1/84 (1.2%)		0/7 (0%)
Metabolism and nutrition disorders
Dehydration	1/84 (1.2%)		0/7 (0%)
Diebetes Mellitus	1/84 (1.2%)		0/7 (0%)
Diabetic Ketoacidosis	1/84 (1.2%)		0/7 (0%)
Hypocalcaemia	1/84 (1.2%)		0/7 (0%)
Musculoskeletal and connective tissue disorders
Muscular Weakness	1/84 (1.2%)		0/7 (0%)
Nervous system disorders
Convulsion	1/84 (1.2%)		0/7 (0%)
Depressed Level of Consciousness	1/84 (1.2%)		0/7 (0%)
Migraine	2/84 (2.4%)		0/7 (0%)
Status Epilepticus	3/84 (3.6%)		1/7 (14.3%)
Status Migrainosus	1/84 (1.2%)		0/7 (0%)
Psychiatric disorders
Psychogenic Seizure	1/84 (1.2%)		0/7 (0%)
Renal and urinary disorders
Nephrolithiasis	1/84 (1.2%)		0/7 (0%)
Renal Failure Acute	1/84 (1.2%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia Aspiration	1/84 (1.2%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Adults		Adolescents
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/84 (76.2%)		5/7 (71.4%)
Eye disorders
Lacrimation increased	7/84 (8.3%)		1/7 (14.3%)
Injury, poisoning and procedural complications
Overdose	6/84 (7.1%)		0/7 (0%)
Nervous system disorders
Somnolence	6/84 (7.1%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal Discomfort	25/84 (29.8%)		2/7 (28.6%)
Dysgeusia	15/84 (17.9%)		0/7 (0%)
Nasal Mucosal Disorder	6/84 (7.1%)		1/7 (14.3%)
Rhinorrhoea	8/84 (9.5%)		1/7 (14.3%)
Throat Irritation	7/84 (8.3%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding the study results for a period up to 30 days from the date the communication is submitted to the sponsor. The sponsor shall have the right to defer proposed publication an additional 60 days from the end of the review period. The sponsor cannot require changes to the communication and cannot unilaterally extend the embargo.