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

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

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: MAP0004; Drug: IV Placebo (Saline); Drug: Placebo Inhaler; Drug: IV Dihydroergotamine Mesylate (DHE)

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Clinical Research Unit

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / 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®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-2hrs) of Pulmonary Arterial Systolic Pressure (PASP) Over Time Post 1st 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.	2 hours from time of first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Subjects With an Increase in PASP Greater Than 10mmHg From Baseline to 2 Hours From the First Dose	Pulmonary artery systolic pressure (PASP) is the highest pressure exerted on the walls of the pulmonary artery.	baseline and 2 hours from the time of first dose
Maximum Change in PASP From Baseline to the Two Hour Period Following the First Dose	Pulmonary artery systolic pressure (PASP) is the highest pressure exerted on the walls of the pulmonary artery.	baseline and 2 hours from the time of first dose
AUC(0-4hrs) of Pulmonary Arterial Systolic Pressure (PASP) From the Start of the First Dose to Two Hours After the Second 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 hours from the time of first dose
Change in Blood Pressure From Baseline After the Two 2-hour Post Dosing Periods	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.	baseline, 10 minutes post 1st dose, 10 minutes post 2nd dose
Change From Baseline in QTc Interval at 14 Minutes After the 1st and 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.	baseline, 14 minutes from time of 1st dose, 14 minutes from time of 2nd dose

Collaborators and Investigators

• Sponsor: Allergan
• Collaborators: MAP Pharmaceuticals, Inc., a wholly owned subsidiary of Allergan
• Investigators: Principal Investigator: Robert J Noveck, M.D., Ph.D., Duke Clinical Research Unit

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: March 17, 2010
• First Submitted That Met QC Criteria: March 17, 2010
• First Posted (Estimate): March 18, 2010

Study Record Updates

• Last Update Posted (Estimate): January 9, 2014
• Last Update Submitted That Met QC Criteria: December 9, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Healthy volunteers
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Dopamine Agonists; Dopamine Agents; Vasoconstrictor Agents; Dihydroergotamine
• Other Study ID Numbers: MAP0004-CL-P102