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

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

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: MAP0004
* Drug: IV Placebo (Saline)
* Drug: Placebo Inhaler
* Drug: IV Dihydroergotamine Mesylate (DHE)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide a signed, executed written informed consent Healthy non-smoking adult volunteers: Male or Female subjects 18 to 45 years old Female subjects who are practicing adequate contraception Stable cardiac status Normal hemoglobin values Normal Echocardiogram Normal or not clinically significant 12-lead Electrocardiogram Demonstrated ability to properly use the Tempo® Inhaler Subject has not donated blood in the last 56 days Exclusion Criteria: Contraindication to dihydroergotamine mesylate (DHE) Use of any excluded concomitant medications within the 10 days prior to Visit 1 History of hemiplegic or basilar migraine Participation in another investigational trial during the 30 days prior to Visit 1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Treatment A, then Treatment B, then Treatment C<br>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<br>* 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol<br>Drug: IV Placebo (Saline)<br>* IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol<br>Drug: Placebo Inhaler<br>* Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.<br>Drug: IV Dihydroergotamine Mesylate (DHE)<br>* IV DHE administered in Treatment A as per protocol<br>* Other names: D.H.E.45®;|
| Other: Treatment A, then Treatment C, then Treatment B<br>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<br>* 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol<br>Drug: IV Placebo (Saline)<br>* IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol<br>Drug: Placebo Inhaler<br>* Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.<br>Drug: IV Dihydroergotamine Mesylate (DHE)<br>* IV DHE administered in Treatment A as per protocol<br>* Other names: D.H.E.45®;|
| Other: Treatment B, then Treatment A, then Treatment C<br>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<br>* 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol<br>Drug: IV Placebo (Saline)<br>* IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol<br>Drug: Placebo Inhaler<br>* Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.<br>Drug: IV Dihydroergotamine Mesylate (DHE)<br>* IV DHE administered in Treatment A as per protocol<br>* Other names: D.H.E.45®;|
| Other: Treatment B, then Treatment C, then Treatment A<br>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<br>* 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol<br>Drug: IV Placebo (Saline)<br>* IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol<br>Drug: Placebo Inhaler<br>* Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.<br>Drug: IV Dihydroergotamine Mesylate (DHE)<br>* IV DHE administered in Treatment A as per protocol<br>* Other names: D.H.E.45®;|
| Other: Treatment C, then Treatment A, then Treatment B<br>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<br>* 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol<br>Drug: IV Placebo (Saline)<br>* IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol<br>Drug: Placebo Inhaler<br>* Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.<br>Drug: IV Dihydroergotamine Mesylate (DHE)<br>* IV DHE administered in Treatment A as per protocol<br>* Other names: D.H.E.45®;|
| Other: Treatment C, then Treatment B, then Treatment A<br>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<br>* 1.0 mg orally inhaled MAP0004 administered in Treatment B as per protocol<br>Drug: IV Placebo (Saline)<br>* IV Placebo (Saline) administered in Treatment B and Treatment C as per protocol<br>Drug: Placebo Inhaler<br>* Orally inhaled Placebo administered in Treatment A and Treatment C as per protocol.<br>Drug: IV Dihydroergotamine Mesylate (DHE)<br>* IV DHE administered in Treatment A as per protocol<br>* Other names: D.H.E.45®;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers