Pharmacokinetics & Tolerability Study of MAP0004 Co-administered With Ketoconazole

• Sponsor: Allergan (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01468558
• Collaborator: MAP Pharmaceuticals, Inc., a wholly owned subsidiary of Allergan (Industry)
• Enrollment: 24
• Location: 1
• Arm: 1
• Duration (Months): 1
• Patients Per Site Per Month: 23.6

Study Details

Study Description

Brief Summary

Compare the DHE pharmacokinetic profiles observed following administration of:

1. MAP0004 (oral inhalation DHE)

2. MAP0004 co-administered with oral Ketoconazole

3. Intravenous (IV) DHE (D.H.E.45®, the approved reference therapy)

Compare the tolerability of MAP0004, IV DHE, and MAP0004 with co-administration of Ketoconazole.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Evaluation of the Effect of Ketoconazole on the Pharmacokinetics and Safety of Dihydroergotamine Mesylate (DHE) Delivered by Oral Inhalation (MAP0004) in Healthy Volunteers Compared to DHE Delivered Intravenously (DHE 45®)
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Other: All subjects Subjects received MAP0004 on Day 1 of Visit 2, Ketoconazole on Days 3 through 6 of Visit 2, and MAP0004 again on Day 6 of Visit 2. Subjects then returned for Visit 3, 7-11 days from the end of Visit 2. At Visit 3 subjects received 1.0 mg IV DHE (Intravenous Dihydroergotamine Mesylate).	Drug: MAP0004; MAP0004 1.0mg via inhalation on Day 1 and Day 6 of Visit 2; Drug: IV DHE; IV DHE (Intravenous Dihydroergotamine Mesylate) administered at Visit 3; Other Names: D.H.E.45® ; Drug: Ketoconazole; Ketoconazole 400 mg administered once a day on days 3-6 of Visit 2; Other Names: Nizoral®

Outcome Measures

Primary Outcome Measures

1. Cmax of Dihydroergotamine After MAP0004, MAP0004 Co-administered With Ketoconazole, and IV DHE Administration [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, MAP0004 Co-administered With Ketoconazole, and IV DHE Administration [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:

• Able to provide written Informed Consent

• Male or Female subjects 18 to 45 years old

• Female subjects who are practicing adequate contraception or who are sterile

• Stable cardiac status

• Normal rhythm or arrhythmia deemed clinically insignificant on ECG

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 12 weeks 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

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: NCT01468558
• Other Study ID Numbers: MAP0004-CL-P104
• First Posted: Nov 9, 2011
• Last Update Posted: Jan 9, 2014
• Last Verified: Dec 1, 2013

• Keywords provided by Allergan: Drug Drug Interaction Study in Normal Healthy Volunteers
• Additional relevant MeSH terms: Ketoconazole

Study Results

Participant Flow

Pre-assignment Detail	All subjects received MAP0004 on Day 1 of Visit 2, Ketoconazole on Days 3 through 6 of Visit 2, and MAP0004 again on Day 6 of Visit 2. Subjects then returned for Visit 3, 7-11 days from the end of Visit 2. At Visit 3 subjects received 1.0 mg Intravenous (IV) Dihydroergotamine Mesylate (DHE).

Arm/Group Title	Overall Study
Arm/Group Description	Subjects first received MAP0004 1.0mg via oral inhalation followed by 48 hours of PK sampling, they then received Ketoconazole (400mg once a day for 4 days) followed by MAP0004 1.0mg and another 48 hours of PK sampling. After a 7-11 day washout, subjects returned to the clinic to receive 1.0mg IV DHE and 48 hours of PK sampling.
Period Title: Overall Study
STARTED	24
COMPLETED	22
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	All subjects that were enrolled in the study.
Overall Participants	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.58 (8.3)
Sex: Female, Male (Count of Participants)
Female	16 66.7%
Male	8 33.3%

Outcome Measures

1. Primary Outcome

Title	Cmax of Dihydroergotamine After MAP0004, MAP0004 Co-administered With Ketoconazole, and IV DHE Administration
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	MAP0004 1.0mg + Ketoconazole	IV DHE 1.0mg
Arm/Group Description	MAP0004 1.0mg via inhalation on Day 1 of Visit 2.	Ketoconazole 400mg once a day on Days 3-6 of Visit 2 and MAP0004 1.0mg via inhalation on Day 6 of Visit 2.	IV DHE 1.0mg on Day 1 of Visit 3.
Measure Participants	21	23	20
Geometric Mean (Standard Deviation) [pg/ml]	2582.507 (1137.829)	2495.100 (1130.850)	27771.234 (36191.528)

2. Primary Outcome

Title	AUC(0-48) of Dihydroergotamine After MAP0004, MAP0004 Co-administered With Ketoconazole, and IV DHE Administration
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	MAP0004 1.0mg + Ketoconazole	IV DHE 1.0mg
Arm/Group Description	MAP0004 1.0mg via inhalation on Day 1 of Visit 2.	Ketoconazole 400mg once a day on Days 3-6 of Visit 2 and MAP0004 1.0mg via inhalation on Day 6 of Visit 2.	IV DHE 1.0mg on Day 1 of Visit 3.
Measure Participants	23	23	20
Geometric Mean (Standard Deviation) [pg*h/ml]	3484.725 (1221.423)	4070.611 (1628.973)	9229.171 (3130.093)

Adverse Events

Adverse Event Reporting Description	All 24 subjects who received MAP0004 alone, 24 subjects who received MAP0004 with ketoconazole, and 22 subjects who received IV DHE are included in the adverse event analysis. Adverse events are presented by treatment arm, not necessarily by individual treatment (intervention) received.
Arm/Group Title	MAP0004 1.0mg		MAP0004 1.0mg + Ketoconazole		IV DHE 1.0mg
Arm/Group Description	MAP0004 1.0mg via inhalation on Day 1 of Visit 2.		Ketoconazole 400mg once a day on Days 3-6 of Visit 2 and MAP0004 1.0mg via inhalation on Day 6 of Visit 2.		IV DHE 1.0mg on Day 1 of Visit 3.
All Cause Mortality
	MAP0004 1.0mg		MAP0004 1.0mg + Ketoconazole		IV DHE 1.0mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MAP0004 1.0mg		MAP0004 1.0mg + Ketoconazole		IV DHE 1.0mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	MAP0004 1.0mg		MAP0004 1.0mg + Ketoconazole		IV DHE 1.0mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/24 (25%)		7/24 (29.2%)		11/22 (50%)
Gastrointestinal disorders
Diarrhea	1/24 (4.2%)		0/24 (0%)		2/22 (9.1%)
Nausea	0/24 (0%)		1/24 (4.2%)		11/22 (50%)
Vomiting	0/24 (0%)		0/24 (0%)		3/22 (13.6%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/24 (0%)		0/24 (0%)		4/22 (18.2%)
Nervous system disorders
Dizziness	1/24 (4.2%)		1/24 (4.2%)		4/22 (18.2%)
Headache	6/24 (25%)		7/24 (29.2%)		5/22 (22.7%)
Skin and subcutaneous tissue disorders
Rash	0/24 (0%)		2/24 (8.3%)		0/22 (0%)
Vascular disorders
Hot flush	0/24 (0%)		1/24 (4.2%)		3/22 (13.6%)

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.