Pharmacodynamic Study to Compare Acute Effects of Dihydroergotamine Mesylate (DHE) on Pulmonary Arterial Pressure

• Sponsor: Allergan (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01089062
• Collaborator: MAP Pharmaceuticals, Inc., a wholly owned subsidiary of Allergan (Industry)
• Enrollment: 24
• Location: 1
• Arms: 6
• Duration (Months): 9
• Patients Per Site Per Month: 2.7

Study Details

Study Description

Brief Summary

Compare the acute effects and tolerability of Dihydroergotamine Mesylate (DHE) delivered by Oral Inhalation (MAP0004) versus by intravenous (IV) infusion in healthy adult volunteers.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: MAP0004; Drug: IV Placebo (Saline); Drug: Placebo Inhaler; Drug: IV Dihydroergotamine Mesylate (DHE)	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind, Placebo Controlled, Three-Period Crossover Study Comparing the Acute Effects of Intravenous Dihydroergotamine (DHE) and Orally Inhaled DHE (MAP0004) on Pulmonary Arterial Pressure and Tolerability in Healthy Adults
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Other: Treatment A, then Treatment B, then Treatment C The second dose in each treatment group (A,B,C) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 2. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 3. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 4.	Drug: MAP0004; 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol; Drug: IV Placebo (Saline); IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol; Drug: Placebo Inhaler; Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.; Drug: IV Dihydroergotamine Mesylate (DHE); IV DHE administered in Treatment A as per protocol; Other Names: D.H.E.45®
Other: Treatment A, then Treatment C, then Treatment B The second dose in each treatment group (A,C,B) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 2. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 3. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 4.	Drug: MAP0004; 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol; Drug: IV Placebo (Saline); IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol; Drug: Placebo Inhaler; Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.; Drug: IV Dihydroergotamine Mesylate (DHE); IV DHE administered in Treatment A as per protocol; Other Names: D.H.E.45®
Other: Treatment B, then Treatment A, then Treatment C The second dose in each treatment group (B,A,C) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 2. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 3. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 4.	Drug: MAP0004; 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol; Drug: IV Placebo (Saline); IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol; Drug: Placebo Inhaler; Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.; Drug: IV Dihydroergotamine Mesylate (DHE); IV DHE administered in Treatment A as per protocol; Other Names: D.H.E.45®
Other: Treatment B, then Treatment C, then Treatment A The second dose in each treatment group (B,C,A) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 2. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 3. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 4.	Drug: MAP0004; 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol; Drug: IV Placebo (Saline); IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol; Drug: Placebo Inhaler; Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.; Drug: IV Dihydroergotamine Mesylate (DHE); IV DHE administered in Treatment A as per protocol; Other Names: D.H.E.45®
Other: Treatment C, then Treatment A, then Treatment B The second dose in each treatment group (C,A,B) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 2. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 3. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 4.	Drug: MAP0004; 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol; Drug: IV Placebo (Saline); IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol; Drug: Placebo Inhaler; Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.; Drug: IV Dihydroergotamine Mesylate (DHE); IV DHE administered in Treatment A as per protocol; Other Names: D.H.E.45®
Other: Treatment C, then Treatment B, then Treatment A The second dose in each treatment group (C,B,A) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 2. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 3. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 4.	Drug: MAP0004; 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol; Drug: IV Placebo (Saline); IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol; Drug: Placebo Inhaler; Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.; Drug: IV Dihydroergotamine Mesylate (DHE); IV DHE administered in Treatment A as per protocol; Other Names: D.H.E.45®

Outcome Measures

Primary Outcome Measures

1. AUC(0-2hrs) of Pulmonary Arterial Systolic Pressure (PASP) Over Time Post 1st Dose [2 hours from time of first dose]

   AUC(0-2hrs) (Area Under the Curve, time 0-2 hours post-1st dose) in PASP millimeters of mercury times minutes (mmHg*min). PASP is the highest pressure exerted on the walls of the pulmonary artery.

Secondary Outcome Measures

1. Percent of Subjects With an Increase in PASP Greater Than 10mmHg From Baseline to 2 Hours From the First Dose [baseline and 2 hours from the time of first dose]

   Pulmonary artery systolic pressure (PASP) is the highest pressure exerted on the walls of the pulmonary artery.

2. Maximum Change in PASP From Baseline to the Two Hour Period Following the First Dose [baseline and 2 hours from the time of first dose]

   Pulmonary artery systolic pressure (PASP) is the highest pressure exerted on the walls of the pulmonary artery.

3. AUC(0-4hrs) of Pulmonary Arterial Systolic Pressure (PASP) From the Start of the First Dose to Two Hours After the Second Dose [4 hours from the time of first dose]

   AUC(0-4hrs) (Area Under the Curve, time 0-4 hours post-1st dose) in PASP millimeters of mercury times minutes (mmHg*min). PASP is the highest pressure exerted on the walls of the pulmonary artery.

4. Change in Blood Pressure From Baseline After the Two 2-hour Post Dosing Periods [baseline, 10 minutes post 1st dose, 10 minutes post 2nd dose]

   Systolic and diastolic blood pressure measure the lowest and highest pressures against the walls of the arteries. Changes were calculated from 30 minutes pre dose (baseline) to 10 minutes post first and second dose. A positive change from baseline indicates an increase in blood pressure and a negative change indicates a decrease in blood pressure.

5. Change From Baseline in QTc Interval at 14 Minutes After the 1st and 2nd Dose [baseline, 14 minutes from time of 1st dose, 14 minutes from time of 2nd dose]

   The corrected QT interval (QTc) is a measurement of the electrical impulses through the largest part of the heart muscle. A negative change is a shortening of the QTc interval, a positive change is a lengthening of the QTc interval.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Able to provide a signed, executed written informed consent

2. Healthy non-smoking adult volunteers: Male or Female subjects 18 to 45 years old

3. Female subjects who are practicing adequate contraception

4. Stable cardiac status

5. Normal hemoglobin values

6. Normal Echocardiogram

7. Normal or not clinically significant 12-lead Electrocardiogram

8. Demonstrated ability to properly use the Tempo® Inhaler

9. Subject has not donated blood in the last 56 days

Exclusion Criteria:

1. Contraindication to dihydroergotamine mesylate (DHE)

2. Use of any excluded concomitant medications within the 10 days prior to Visit 1

3. History of hemiplegic or basilar migraine

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke Clinical Research Unit	Durham	North Carolina	United States	27710

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Robert J Noveck, M.D., Ph.D., Duke Clinical Research Unit

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT01089062
• Other Study ID Numbers: MAP0004-CL-P102
• First Posted: Mar 18, 2010
• Last Update Posted: Jan 9, 2014
• Last Verified: Dec 1, 2013

• Keywords provided by Allergan: Healthy volunteers
• Additional relevant MeSH terms: Dihydroergotamine

Study Results

Participant Flow

Pre-assignment Detail	This is a 3-treatment, 3-period, 6-sequence crossover study. Each subject received all 3 treatments in a randomly assigned order: treatments A, B, and C, the sequences were ABC, ACB, BAC, BCA, CAB, and CBA.

Arm/Group Title	Treatment A, Then B, Then C	Treatment A, Then C, Then B	Treatment B, Then A, Then C	Treatment B, Then C, Then A	Treatment C, Then A, Then B	Treatment C, Then B, Then A
Arm/Group Description	The second dose in each treatment group (A,B,C) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment A = inhaler placebo and Intravenous (IV) Dihydroergotamine (DHE) for first dose, inhaler placebo for second dose at Visit 2. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 3. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 4.	The second dose in each treatment group (A,C,B) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 2. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 3. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 4.	The second dose in each treatment group (B,A,C) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 2. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 3. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 4.	The second dose in each treatment group (B,C,A) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 2. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 3. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 4.	The second dose in each treatment group (C,A,B) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 2. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 3. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 4.	The second dose in each treatment group (C,B,A) was given two hours from the time of the first dose. There were 7-11 days between each treatment visit. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose at Visit 2. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose at Visit 3. Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose at Visit 4.
Period Title: Visit 2 (Randomization)
STARTED	4	4	4	4	4	4
COMPLETED	3	3	3	4	3	3
NOT COMPLETED	1	1	1	0	1	1
Period Title: Visit 2 (Randomization)
STARTED	3	3	3	4	3	3
COMPLETED	3	3	3	3	3	3
NOT COMPLETED	0	0	0	1	0	0
Period Title: Visit 2 (Randomization)
STARTED	3	3	3	3	3	3
COMPLETED	3	3	3	3	3	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Visit 2 (Randomization)
STARTED	3	3	3	3	3	3
COMPLETED	3	3	3	3	3	3
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Treatment A, Then B, Then C	Treatment A, Then C, Then B	Treatment B, Then A, Then C	Treatment B, Then C, Then A	Treatment C, Then A, Then B	Treatment C, Then B, Then A	Total
Arm/Group Description	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose. Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose. Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.	Total of all reporting groups
Overall Participants	4	4	4	4	4	4	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.6 (9.2)	23.4 (3.9)	28.2 (8.2)	30.3 (4.7)	26.5 (7.4)	24.8 (7.2)	26.6 (6.6)
Sex: Female, Male (Count of Participants)
Female	2 50%	4 100%	2 50%	4 100%	1 25%	3 75%	16 66.7%
Male	2 50%	0 0%	2 50%	0 0%	3 75%	1 25%	8 33.3%

Outcome Measures

1. Primary Outcome

Title	AUC(0-2hrs) of Pulmonary Arterial Systolic Pressure (PASP) Over Time Post 1st Dose
Description	AUC(0-2hrs) (Area Under the Curve, time 0-2 hours post-1st dose) in PASP millimeters of mercury times minutes (mmHg*min). PASP is the highest pressure exerted on the walls of the pulmonary artery.
Time Frame	2 hours from time of first dose

Outcome Measure Data

Analysis Population Description

Patients with available data at the required time point were included in the analysis population.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose.	Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose.	Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.
Measure Participants	18	18	18
Mean (Standard Deviation) [mmHg*min]	2794.93 (476.66)	2580.06 (389.06)	2497.71 (384.29)

2. Secondary Outcome

Title	Percent of Subjects With an Increase in PASP Greater Than 10mmHg From Baseline to 2 Hours From the First Dose
Description	Pulmonary artery systolic pressure (PASP) is the highest pressure exerted on the walls of the pulmonary artery.
Time Frame	baseline and 2 hours from the time of first dose

Outcome Measure Data

Analysis Population Description

Patients with available data at the required time point were included in the analysis population.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose.	Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose.	Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.
Measure Participants	24	24	24
Number [percentage of participants]	4.2 105%	0.0 0%	0.0 0%

3. Secondary Outcome

Title	Maximum Change in PASP From Baseline to the Two Hour Period Following the First Dose
Description	Pulmonary artery systolic pressure (PASP) is the highest pressure exerted on the walls of the pulmonary artery.
Time Frame	baseline and 2 hours from the time of first dose

Outcome Measure Data

Analysis Population Description

Patients with available data at the required time point were included in the analysis population.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose.	Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose.	Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.
Measure Participants	24	24	24
Baseline	22.8 (4.4)	19.2 (4.6)	21.2 (3.3)
Max Change from Baseline over 2 hrs from 1st dose	7.8 (2.4)	6.1 (2.8)	4.0 (1.7)

4. Secondary Outcome

Title	AUC(0-4hrs) of Pulmonary Arterial Systolic Pressure (PASP) From the Start of the First Dose to Two Hours After the Second Dose
Description	AUC(0-4hrs) (Area Under the Curve, time 0-4 hours post-1st dose) in PASP millimeters of mercury times minutes (mmHg*min). PASP is the highest pressure exerted on the walls of the pulmonary artery.
Time Frame	4 hours from the time of first dose

Outcome Measure Data

Analysis Population Description

Patients with available data at the required time point were included in the analysis population.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose 2 hours from time of first dose.	Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose.	Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.
Measure Participants	24	24	24
Mean (Standard Deviation) [mmHg*min]	5700.11 (1016.86)	5336.38 (823.51)	4907.03 (773.11)

5. Secondary Outcome

Title	Change in Blood Pressure From Baseline After the Two 2-hour Post Dosing Periods
Description	Systolic and diastolic blood pressure measure the lowest and highest pressures against the walls of the arteries. Changes were calculated from 30 minutes pre dose (baseline) to 10 minutes post first and second dose. A positive change from baseline indicates an increase in blood pressure and a negative change indicates a decrease in blood pressure.
Time Frame	baseline, 10 minutes post 1st dose, 10 minutes post 2nd dose

Outcome Measure Data

Analysis Population Description

Patients with available data at the required time point were included in the analysis population.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose.	Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose.	Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.
Measure Participants	20	20	20
Baseline Systolic	112.5 (11.3)	113.3 (15.3)	113.2 (12.3)
Change at 10 min in Systolic after 1st dose	10.4 (10.0)	4.7 (8.5)	0.4 (7.9)
Change at 10 min in Systolic after 2nd dose	0.2 (7.8)	1.2 (9.9)	-0.5 (5.2)
Baseline Diastolic	65.8 (7.3)	67.2 (9.1)	64.4 (6.7)
Change at 10 min in Diastolic after 1st dose	7.0 (7.2)	2.0 (8.0)	1.1 (5.1)
Change at 10 min in Diastolic after 2nd dose	-1.5 (11.2)	-2.0 (9.4)	0.1 (4.9)

6. Secondary Outcome

Title	Change From Baseline in QTc Interval at 14 Minutes After the 1st and 2nd Dose
Description	The corrected QT interval (QTc) is a measurement of the electrical impulses through the largest part of the heart muscle. A negative change is a shortening of the QTc interval, a positive change is a lengthening of the QTc interval.
Time Frame	baseline, 14 minutes from time of 1st dose, 14 minutes from time of 2nd dose

Outcome Measure Data

Analysis Population Description

Patients with available data at the required time point were included in the analysis population.

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose.	Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose.	Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.
Measure Participants	20	20	20
Baseline	403.9 (15.8)	402.3 (19.0)	399.9 (16.4)
Change from baseline at 14 mins post 1st dose	-5.8 (12.2)	-0.8 (5.6)	2.4 (10.8)
Change from baseline at 14 mins post 2nd dose	1.5 (10.7)	-0.8 (13.4)	4.1 (9.6)

Adverse Events

Adverse Event Reporting Description	All subjects who were randomized and received at least one dose of study drug were included in the adverse event analysis. Adverse events are presented by treatment arm, not by individual treatment (intervention) received.
Arm/Group Title	Treatment A		Treatment B		Treatment C
Arm/Group Description	Treatment A = inhaler placebo and IV DHE for first dose, inhaler placebo for second dose.		Treatment B = MAP0004 1.0mg and IV placebo for first dose, MAP0004 1.0mg for second dose.		Treatment C = inhaler placebo and IV placebo for first dose, inhaler placebo for second dose.
All Cause Mortality
	Treatment A		Treatment B		Treatment C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Treatment A		Treatment B		Treatment C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Treatment A		Treatment B		Treatment C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/20 (95%)		10/20 (50%)		6/20 (30%)
Eye disorders
Vision blurred	1/20 (5%)		0/20 (0%)		0/20 (0%)
Gastrointestinal disorders
Nausea	10/20 (50%)		1/20 (5%)		0/20 (0%)
Vomiting	2/20 (10%)		0/20 (0%)		0/20 (0%)
Abdominal pain	1/20 (5%)		0/20 (0%)		0/20 (0%)
Abdominal pain lower	1/20 (5%)		0/20 (0%)		0/20 (0%)
Abdominal pain upper	0/20 (0%)		1/20 (5%)		0/20 (0%)
Dysphagia	1/20 (5%)		0/20 (0%)		0/20 (0%)
Stomach discomfort	1/20 (5%)		0/20 (0%)		0/20 (0%)
General disorders
Feeling hot	8/20 (40%)		0/20 (0%)		0/20 (0%)
Chest discomfort	2/20 (10%)		0/20 (0%)		0/20 (0%)
Asthenia	1/20 (5%)		0/20 (0%)		0/20 (0%)
Fatigue	1/20 (5%)		0/20 (0%)		0/20 (0%)
Infusion site pain	0/20 (0%)		1/20 (5%)		0/20 (0%)
Sensation of pressure	1/20 (5%)		0/20 (0%)		0/20 (0%)
Infections and infestations
Upper respiratory tract infection	0/20 (0%)		0/20 (0%)		1/20 (5%)
Investigations
Heart rate increased	1/20 (5%)		0/20 (0%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/20 (0%)		1/20 (5%)		0/20 (0%)
Musculoskeletal stiffness	1/20 (5%)		0/20 (0%)		0/20 (0%)
Pain in jaw	0/20 (0%)		1/20 (5%)		0/20 (0%)
Sensation of heaviness	1/20 (5%)		0/20 (0%)		0/20 (0%)
Nervous system disorders
Headache	6/20 (30%)		5/20 (25%)		1/20 (5%)
Dizziness	3/20 (15%)		2/20 (10%)		1/20 (5%)
Burning sensation	4/20 (20%)		0/20 (0%)		0/20 (0%)
Paraesthesia	3/20 (15%)		0/20 (0%)		0/20 (0%)
Head discomfort	2/20 (10%)		0/20 (0%)		0/20 (0%)
Somnolence	1/20 (5%)		1/20 (5%)		0/20 (0%)
Sensory Disturbance	1/20 (5%)		0/20 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/20 (5%)		0/20 (0%)		1/20 (5%)
Oropharyngeal pain	1/20 (5%)		1/20 (5%)		0/20 (0%)
Nasal discomfort	1/20 (5%)		0/20 (0%)		0/20 (0%)
Nasal dryness	1/20 (5%)		0/20 (0%)		0/20 (0%)
Throat irritation	1/20 (5%)		0/20 (0%)		0/20 (0%)
Social circumstances
Pharmaceutical product complaint	4/20 (20%)		2/20 (10%)		1/20 (5%)
Vascular disorders
Flushing	2/20 (10%)		0/20 (0%)		1/20 (5%)
Hot flush	0/20 (0%)		0/20 (0%)		1/20 (5%)

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.