A Pharmacokinetic Study of a Single-Dose of Diazepam Nasal Spray in Adult Epileptic Patients Experiencing a Seizure Episode

• Sponsor: Acorda Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01417078
• Collaborator: (none)
• Enrollment: 31
• Locations: 4
• Arm: 1
• Duration (Months): 18
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the pharmacokinetics of Diazepam Nasal Spray following a single dose in epileptic patients experiencing a seizure episode.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: Diazepam	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Study to Determine the Pharmacokinetics of a Single Dose of Diazepam Nasal Spray in Adult Epileptic Patients Experiencing a Seizure Episode for Which Acute Treatment With a Benzodiazepine is Clinically Indicated
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Diazepam Nasal Spray	Drug: Diazepam; single-dose; dosage in mg, based on patient body weight

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetic (PK) Parameter: Maximum Measure Plasma Concentration (Cmax), [Pre-dose, 10, 15, 30, and 45 mins, and 1, 1.5, 2, 4, 6, 9,and 12 hours]

   Summary of Dose-Adjusted Diazepam and Nordiazepam PK parameter Cmax. The mean Cmax value was adjusted to a 20 mg dose.

2. Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) [Pre-dose, 10, 15, 30, and 45 mins, and 1, 1.5, 2, 4, 6, 9,and 12 hours]

   Summary of Dose-Adjusted Diazepam and Nordiazepam PK parameter Tmax. The mean Tmax value was adjusted to a 20 mg dose.

3. Pharmacokinetic (PK) Parameter: Area Under The Concentration Curve From Time 0 to 12 Hours (AUC(0-12)) and AUC Time to Last Measurable Plasma Concentration [Pre-dose, 10, 15, 30, and 45 mins, and 1, 1.5, 2, 4, 6, 9,and 12 hours]

   Summary of Dose-Adjusted Diazepam and Nordiazepam PK parameter AUC(0-12) and AUC(last). The mean estimate of AUC(0-12) was adjusted to a 20 mg dose. AUC(last) was used for the calculation of AUC for nordiazepam. AUC(0-12) values could not be estimated for nordiazepam given that nordiazepam concentrations were rising between 6 and 12 hours.

Secondary Outcome Measures

1. Number of Patients With Treatment Emergent Adverse Events (TEAEs) [Pre-dose to 48 hours post-dose]

   TEAEs refer to adverse events with start dates occurring after dosing. Treatment-Related TEAEs refer to those 'possibly' or 'probably' related to study drug. Intensity definitions: Mild: Usually transient, required no special treatment, and did not interfere with the patient's daily activities. Moderate: Usually caused a low degree of inconvenience or concern to the patient, and may have interfered with daily activities, but was usually ameliorated by simple therapeutic measures. Severe: Interrupted a patient's usual daily activities, and generally required systemic drug therapy or other treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provide signed informed consent for study participation.

• General good health with no clinically significant unstable abnormalities.

• Diagnosis of epilepsy.

Exclusion Criteria:

• Individuals receiving warfarin (Coumadin®) or dabigatran (Pradaxa®).

• Use of any investigational drug within 30 days.

• Blood or plasma donation within 30 days.

• Not willing or unable to tolerate blood draws.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barrow Neurology Clinics at St Joseph's Hospital	Phoenix	Arizona	United States	85013
2	Johns Hopkins University	Baltimore	Maryland	United States	21287
3	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
4	Vanderbilt University	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Acorda Therapeutics

Investigators

• Study Director: David P Ward, MD, Neuronex, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acorda Therapeutics
• ClinicalTrials.gov Identifier: NCT01417078
• Other Study ID Numbers: DZNS-ARS-103
• First Posted: Aug 16, 2011
• Last Update Posted: Mar 29, 2017
• Last Verified: Feb 1, 2017

• Additional relevant MeSH terms: Seizures; Diazepam

Study Results

Participant Flow

Arm/Group Title	Diazepam Nasal Spray
Arm/Group Description	Diazepam: single-dose; dosage in mg, based on patient body weight
Period Title: Overall Study
STARTED	31
COMPLETED	30
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Diazepam Nasal Spray
Arm/Group Description	Diazepam: single-dose; dosage in mg, based on patient body weight
Overall Participants	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.2 (12.80)
Sex: Female, Male (Count of Participants)
Female	18 58.1%
Male	13 41.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 9.7%
Not Hispanic or Latino	23 74.2%
Unknown or Not Reported	5 16.1%
Body Mass Index (BMI) ((kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [(kg/m^2)]	26.3 (4.08)

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetic (PK) Parameter: Maximum Measure Plasma Concentration (Cmax),
Description	Summary of Dose-Adjusted Diazepam and Nordiazepam PK parameter Cmax. The mean Cmax value was adjusted to a 20 mg dose.
Time Frame	Pre-dose, 10, 15, 30, and 45 mins, and 1, 1.5, 2, 4, 6, 9,and 12 hours

Outcome Measure Data

Analysis Population Description

PK Population: patients who had adequate concentration-time data to permit estimation of noncompartmental PK parameters. One patient was not included in the analysis of nordiazepam due to receiving clorazepate, which interfered with the analysis of nordiazepam from diazepam administration.

Arm/Group Title	Diazepam Nasal Spray	Nordiazepam
Arm/Group Description	Diazepam: single-dose; dosage in mg, based on patient body weight	Diazepam was slowly converted to nordiazepam following intranasal administration
Measure Participants	30	29
Mean (Standard Deviation) [nanogram/milliliter (ng/mL)]	208 (90.3)	23.9 (16.5)

2. Secondary Outcome

Title	Number of Patients With Treatment Emergent Adverse Events (TEAEs)
Description	TEAEs refer to adverse events with start dates occurring after dosing. Treatment-Related TEAEs refer to those 'possibly' or 'probably' related to study drug. Intensity definitions: Mild: Usually transient, required no special treatment, and did not interfere with the patient's daily activities. Moderate: Usually caused a low degree of inconvenience or concern to the patient, and may have interfered with daily activities, but was usually ameliorated by simple therapeutic measures. Severe: Interrupted a patient's usual daily activities, and generally required systemic drug therapy or other treatment.
Time Frame	Pre-dose to 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety Population (dosed with study drug)

Arm/Group Title	Diazepam Nasal Spray
Arm/Group Description	Diazepam: single-dose; dosage in mg, based on patient body weight
Measure Participants	31
Subjects with one or more TEAEs	28 90.3%
Total number of TEAEs	96 309.7%
Subjects with one or more Treatment-Related TEAEs	21 67.7%
Total number of Treatment-Related TEAEs	56 180.6%
Subjects with one or more Severe TEAEs	1 3.2%
Total number of Severe TEAEs	1 3.2%
Total number of Moderate TEAEs	24 77.4%
Total number of Mild TEAEs	71 229%

3. Primary Outcome

Title	Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax)
Description	Summary of Dose-Adjusted Diazepam and Nordiazepam PK parameter Tmax. The mean Tmax value was adjusted to a 20 mg dose.
Time Frame	Pre-dose, 10, 15, 30, and 45 mins, and 1, 1.5, 2, 4, 6, 9,and 12 hours

Outcome Measure Data

Analysis Population Description

PK Population: patients who had adequate concentration-time data to permit estimation of noncompartmental PK parameters. One patient was not included in the analysis of nordiazepam due to receiving clorazepate, which interfered with the analysis of nordiazepam from diazepam administration.

Arm/Group Title	Diazepam Nasal Spray	Nordiazepam
Arm/Group Description	Diazepam: single-dose; dosage in mg, based on patient body weight	Diazepam was slowly converted to nordiazepam following intranasal administration
Measure Participants	30	29
Mean (Standard Deviation) [hour (h)]	0.98 (0.86)	11.10 (2.14)

4. Primary Outcome

Title	Pharmacokinetic (PK) Parameter: Area Under The Concentration Curve From Time 0 to 12 Hours (AUC(0-12)) and AUC Time to Last Measurable Plasma Concentration
Description	Summary of Dose-Adjusted Diazepam and Nordiazepam PK parameter AUC(0-12) and AUC(last). The mean estimate of AUC(0-12) was adjusted to a 20 mg dose. AUC(last) was used for the calculation of AUC for nordiazepam. AUC(0-12) values could not be estimated for nordiazepam given that nordiazepam concentrations were rising between 6 and 12 hours.
Time Frame	Pre-dose, 10, 15, 30, and 45 mins, and 1, 1.5, 2, 4, 6, 9,and 12 hours

Outcome Measure Data

Analysis Population Description

PK Population: patients who had adequate concentration-time data to permit estimation of noncompartmental PK parameters. One patient was not included in the analysis of nordiazepam due to receiving clorazepate, which interfered with the analysis of nordiazepam from diazepam administration.

Arm/Group Title	Diazepam Nasal Spray	Nordiazepam
Arm/Group Description	Diazepam: single-dose; dosage in mg, based on patient body weight	Diazepam was slowly converted to nordiazepam following intranasal administration.
Measure Participants	30	29
AUC(0-12)	1227 (488)	NA (NA)
AUC(last)	NA (NA)	192 (148)

Adverse Events

Time Frame	Pre-dose to 48 hours post-dose
Adverse Event Reporting Description	TEAEs refer to AEs with start date and times occuring after dosing.
Arm/Group Title	Diazepam Nasal Spray
Arm/Group Description	Diazepam: single-dose; dosage in mg, based on patient body weight
All Cause Mortality
	Diazepam Nasal Spray
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Diazepam Nasal Spray
	Affected / at Risk (%)	# Events
Total	0/31 (0%)
Other (Not Including Serious) Adverse Events
	Diazepam Nasal Spray
	Affected / at Risk (%)	# Events
Total	28/31 (90.3%)
Eye disorders
Lacrimation increased	5/31 (16.1%)
Gastrointestinal disorders
Nausea	5/31 (16.1%)
Abdominal pain upper	1/31 (3.2%)
General disorders
Fatigue	2/31 (6.5%)
Catheter site pain	1/31 (3.2%)
Feeling hot	1/31 (3.2%)
Peripheral coldness	1/31 (3.2%)
Injury, poisoning and procedural complications
Tongue injury	4/31 (12.9%)
Investigations
Blood pressure increased	1/31 (3.2%)
Metabolism and nutrition disorders
Decreased appetite	1/31 (3.2%)
Musculoskeletal and connective tissue disorders
Myalgia	2/31 (6.5%)
Arthralgia	1/31 (3.2%)
Musculoskeletal discomfort	1/31 (3.2%)
Pain in extremity	1/31 (3.2%)
Nervous system disorders
Headache	16/31 (51.6%)
Dysgeusia	8/31 (25.8%)
Somnolence	5/31 (16.1%)
Dizziness	3/31 (9.7%)
Renal and urinary disorders
Urinary retention	1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Nasal discomfort	7/31 (22.6%)
Rhinorrhoea	5/31 (16.1%)
Oropharyngeal pain	4/31 (12.9%)
Paranasal sinus hypersecretion	4/31 (12.9%)
Nasal Congestion	3/31 (9.7%)
Parosmia	3/31 (9.7%)
Cough	2/31 (6.5%)
Throat irritation	2/31 (6.5%)
Dry throat	1/31 (3.2%)
Paranasal sinus discomfort	1/31 (3.2%)
Upper respiratory tract congestion	1/31 (3.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Sponsor has right to review at least forty-five (45) days prior to the date of submission for publication or of public disclosure. Multi-center trials; publication shall be delayed until a publication of the multi-center results or until twelve (12) months have elapsed since the completion of the study, whichever occurs first.