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

• ClinicalTrials.gov Identifier: NCT01089062
• Recruitment Status: Completed
• First Posted: March 18, 2010
• Results First Posted: October 22, 2013
• Last Update Posted: January 9, 2014
• Sponsor: Allergan
• Collaborator: MAP Pharmaceuticals, Inc., a wholly owned subsidiary of Allergan
• Information provided by (Responsible Party): Allergan

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 (Clinical Trial)
• 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: March 2010
• Actual Primary Completion Date: September 2010
• Actual Study Completion Date: December 2010

Arms and Interventions

Arm	Intervention/treatment
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 Name: D.H.E.45®
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 Name: D.H.E.45®
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 Name: D.H.E.45®
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 Name: D.H.E.45®
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 Name: D.H.E.45®
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 Name: D.H.E.45®

Outcome Measures

Primary Outcome Measures :

1. AUC(0-2hrs) of Pulmonary Arterial Systolic Pressure (PASP) Over Time Post 1st Dose [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

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

Criteria

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

United States, North Carolina

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Noveck RJ, Douglas PS, Chow SC, Mangum B, Kori S, Kellerman DJ. Assessing acute systemic effects of an inhaled drug with serial echocardiography: a placebo-controlled comparison of inhaled and intravenous dihydroergotamine. Drug Des Devel Ther. 2013 Jul 24;7:619-25. doi: 10.2147/DDDT.S44093. Print 2013.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT01089062
• Other Study ID Numbers: MAP0004-CL-P102
• First Posted: March 18, 2010
• Results First Posted: October 22, 2013
• Last Update Posted: January 9, 2014
• Last Verified: December 2013

Keywords provided by Allergan:

Healthy volunteers

Additional relevant MeSH terms:

Dihydroergotamine; Vasoconstrictor Agents; Dopamine Agonists; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents