Pharmacokinetics & Tolerability Study of MAP0004 in Smoking and Non-Smoking Adult Volunteers

• Sponsor: Allergan (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01199965
• Collaborator: MAP Pharmaceuticals, Inc., a wholly owned subsidiary of Allergan (Industry)
• Enrollment: 47
• Location: 1
• Arms: 2
• Duration (Months): 3
• Patients Per Site Per Month: 15.9

Study Details

Study Description

Brief Summary

Compare the pharmacokinetics of Dihydroergotamine Mesylate (DHE) delivered by oral inhalation (MAP0004) or Intravenous (IV) DHE in smokers versus non-smokers.

Identify whether there are clinically significant differences in the tolerability of MAP0004 between smokers and non-smokers.

Condition or Disease	Intervention/Treatment	Phase
Healthy Subjects	Drug: MAP0004; Drug: IV DHE	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, 2-Period, Crossover Phase 2 Study Comparing the Pharmacokinetics and Tolerability of Dihydroergotamine Mesylate (DHE) Delivered Intravenously (DHE 45) and by Oral Inhalation (MAP0004) in Smoking and Non-Smoking Adult Volunteers
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Other: IV DHE then MAP0004 Smokers and non-smokers received Intravenous Dihydroergotamine Mesylate (IV DHE) at Visit 2 followed by MAP0004 7-11 days later at Visit 3.	Drug: MAP0004; 1.0mg MAP0004 via inhalation at Visit 2 or 3 as per protocol; Drug: IV DHE; IV DHE administered at Visit 2 or 3 as per protocol; Other Names: D.H.E.45®
Other: MAP0004 then IV DHE Smokers and non-smokers received MAP0004 at Visit 2 followed by Intravenous Dihydroergotamine Mesylate (IV DHE) 7-11 days later at Visit 3.	Drug: MAP0004; 1.0mg MAP0004 via inhalation at Visit 2 or 3 as per protocol; Drug: IV DHE; IV DHE administered at Visit 2 or 3 as per protocol; Other Names: D.H.E.45®

Outcome Measures

Primary Outcome Measures

1. Cmax of Dihydroergotamine After MAP0004 and IV DHE Administration in Smokers Versus Non-smokers [48 hours]

   The maximum concentration (Cmax) is the highest concentration of a drug measured in the plasma. Plasma is the clear portion of the blood. The Cmax of Dihydroergotamine is reported in picograms per milliliter (pg/ml).

2. AUC(0-48) of Dihydroergotamine After MAP0004 and IV DHE Administration in Smokers and Non-smokers [48 hours]

   The AUC(0-48) is the area under the plot of plasma concentration of drug against time after drug administration. Dihydroergotamine AUC(0-48) is reported in picograms times hour per milliliter (pg*h/ml).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Major Inclusion Criteria:

1. Able to provide written informed consent

2. Male or Female subjects 18 to 45 years old

3. Female subjects who are practicing adequate contraception or who are sterile

4. Stable cardiac status

5. Normal rhythm or arrhythmia deemed clinically insignificant on ECG

Major Exclusion Criteria:

1. Contraindication to dihydroergotamine mesylate (DHE)

2. Use of any excluded concomitant medications within the 10 days prior to Visit 1 (See Section 5.5)

3. History of hemiplegic or basilar migraine

4. Participation in another investigational trial during the 30 days prior to Visit 1 or during this trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Simbec Research Limited	Merthyr Tydfil		United Kingdom	CF48 4DR

Sponsors and Collaborators

• Allergan
• MAP Pharmaceuticals, Inc., a wholly owned subsidiary of Allergan

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT01199965
• Other Study ID Numbers: MAP0004-CL-P203
• First Posted: Sep 13, 2010
• Last Update Posted: Jan 9, 2014
• Last Verified: Dec 1, 2013

• Additional relevant MeSH terms: Dihydroergotamine

Study Results

Participant Flow

Pre-assignment Detail	All smoking and non-smoking subjects received both MAP0004 and Intravenous (IV) Dihydroergotamine (DHE).

Arm/Group Title	Smokers	Non-smokers
Arm/Group Description	Currently smoking at least 10 cigarettes/day for at least 1 year with a positive urinary cotinine result.	Never smoked or total exposure <1 pack year and at least 12 months since last cigarette with a negative urinary cotinine result at screening.
Period Title: Overall Study
STARTED	23	24
COMPLETED	22	24
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Smokers	Non-smokers	Total
Arm/Group Description	Currently smoking at least 10 cigarettes/day for at least 1 year with a positive urinary cotinine result.	Never smoked or total exposure <1 pack year and at least 12 months since last cigarette with a negative urinary cotinine result at screening.	Total of all reporting groups
Overall Participants	23	24	47
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.91 (7.1)	30.71 (8.8)	31.79 (8)
Sex: Female, Male (Count of Participants)
Female	15 65.2%	16 66.7%	31 66%
Male	8 34.8%	8 33.3%	16 34%

Outcome Measures

1. Primary Outcome

Title	Cmax of Dihydroergotamine After MAP0004 and IV DHE Administration in Smokers Versus Non-smokers
Description	The maximum concentration (Cmax) is the highest concentration of a drug measured in the plasma. Plasma is the clear portion of the blood. The Cmax of Dihydroergotamine is reported in picograms per milliliter (pg/ml).
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Patients with available data at specified time points are included in the analysis population.

Arm/Group Title	MAP0004 1.0mg Smokers	MAP0004 1.0mg Non-smokers	IV DHE 1.0mg Smokers	IV DHE 1.0mg Non-smokers
Arm/Group Description	Currently smoking at least 10 cigarettes/day for at least 1 year with a positive urinary cotinine result and receiving MAP0004 at either Visit 2 or 3.	Never smoked or total exposure <1 pack year and at least 12 months since last cigarette with a negative urinary cotinine result at screening and receiving MAP0004 at either Visit 2 or 3.	Currently smoking at least 10 cigarettes/day for at least 1 year with a positive urinary cotinine result and receiving IV DHE at either Visit 2 or 3.	Never smoked or total exposure <1 pack year and at least 12 months since last cigarette with a negative urinary cotinine result at screening and receiving IV DHE at either Visit 2 or 3.
Measure Participants	22	24	22	24
Geometric Mean (Standard Deviation) [pg/ml]	1282.059 (636.138)	2550.727 (1297.097)	60046.128 (49580.385)	48428.635 (43894.253)

2. Primary Outcome

Title	AUC(0-48) of Dihydroergotamine After MAP0004 and IV DHE Administration in Smokers and Non-smokers
Description	The AUC(0-48) is the area under the plot of plasma concentration of drug against time after drug administration. Dihydroergotamine AUC(0-48) is reported in picograms times hour per milliliter (pg*h/ml).
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Patients with available data at specified time points are included in the analysis population.

Arm/Group Title	MAP0004 1.0mg Smokers	MAP0004 1.0mg Non-smokers	IV DHE 1.0mg Smokers	IV DHE 1.0mg Non-smokers
Arm/Group Description	Currently smoking at least 10 cigarettes/day for at least 1 year with a positive urinary cotinine result and receiving MAP0004 at Visit 2 or 3.	Never smoked or total exposure <1 pack year and at least 12 months since last cigarette with a negative urinary cotinine result at screening and receiving MAP0004 at Visit 2 or 3.	Currently smoking at least 10 cigarettes/day for at least 1 year with a positive urinary cotinine result and receiving IV DHE at Visit 2 or 3.	Never smoked or total exposure <1 pack year and at least 12 months since last cigarette with a negative urinary cotinine result at screening and receiving IV DHE at Visit 2 or 3.
Measure Participants	23	24	22	24
Geometric Mean (Standard Deviation) [pg*h/ml]	3014.968 (1136.162)	4148.750 (1533.861)	11049.027 (3744.094)	11731.639 (3167.828)

Adverse Events

Adverse Event Reporting Description	All 24 non-smoking subjects who received MAP0004 and IV DHE and 23 smoking subjects who received MAP0004 and 22 of the 23 smoking subjects received IV DHE were included in the adverse event analysis.
Arm/Group Title	MAP0004 1.0mg Smokers		MAP0004 1.0mg Non-smokers		IV DHE 1.0mg Smokers		IV DHE 1.0mg Non-smokers
Arm/Group Description	Currently smoking at least 10 cigarettes/day for at least 1 year with a positive urinary cotinine result and receiving MAP0004 at either Visit 2 or 3.		Never smoked or total exposure <1 pack year and at least 12 months since last cigarette with a negative urinary cotinine result at screening and receiving MAP0004 at either Visit 2 or 3.		Currently smoking at least 10 cigarettes/day for at least 1 year with a positive urinary cotinine result and receiving IV DHE at either Visit 2 or 3.		Never smoked or total exposure <1 pack year and at least 12 months since last cigarette with a negative urinary cotinine result at screening and receiving IV DHE at either Visit 2 or 3.
All Cause Mortality
	MAP0004 1.0mg Smokers		MAP0004 1.0mg Non-smokers		IV DHE 1.0mg Smokers		IV DHE 1.0mg Non-smokers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MAP0004 1.0mg Smokers		MAP0004 1.0mg Non-smokers		IV DHE 1.0mg Smokers		IV DHE 1.0mg Non-smokers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)		0/22 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	MAP0004 1.0mg Smokers		MAP0004 1.0mg Non-smokers		IV DHE 1.0mg Smokers		IV DHE 1.0mg Non-smokers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/23 (17.4%)		8/24 (33.3%)		15/22 (68.2%)		22/24 (91.7%)
Gastrointestinal disorders
Diarrhoea	0/23 (0%)		0/24 (0%)		1/22 (4.5%)		2/24 (8.3%)
Nausea	1/23 (4.3%)		0/24 (0%)		5/22 (22.7%)		9/24 (37.5%)
Vomiting	0/23 (0%)		0/24 (0%)		2/22 (9.1%)		5/24 (20.8%)
General disorders
Chest discomfort	0/23 (0%)		0/24 (0%)		2/22 (9.1%)		3/24 (12.5%)
Fatigue	0/23 (0%)		1/24 (4.2%)		2/22 (9.1%)		0/24 (0%)
Feeling hot	0/23 (0%)		0/24 (0%)		0/22 (0%)		2/24 (8.3%)
Infections and infestations
Rhinitis	0/23 (0%)		2/24 (8.3%)		0/22 (0%)		1/24 (4.2%)
Musculoskeletal and connective tissue disorders
Back pain	1/23 (4.3%)		1/24 (4.2%)		2/22 (9.1%)		0/24 (0%)
Neck pain	0/23 (0%)		2/24 (8.3%)		1/22 (4.5%)		4/24 (16.7%)
Pain in extremity	0/23 (0%)		0/24 (0%)		3/22 (13.6%)		2/24 (8.3%)
Nervous system disorders
Dizziness	1/23 (4.3%)		1/24 (4.2%)		6/22 (27.3%)		2/24 (8.3%)
Headache	2/23 (8.7%)		2/24 (8.3%)		6/22 (27.3%)		10/24 (41.7%)
Paraesthesia	0/23 (0%)		2/24 (8.3%)		1/22 (4.5%)		2/24 (8.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/23 (0%)		0/24 (0%)		0/22 (0%)		2/24 (8.3%)
Vascular disorders
Flushing	0/23 (0%)		0/24 (0%)		2/22 (9.1%)		5/24 (20.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.