The Safety and Effectiveness of MK0476 (Montelukast) in Patients With Chronic Asthma - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Crossover Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Chronic Asthma
Interventions:	Drug: Comparator: montelukast Drug: Comparator: placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patients were recruited from 6 centers in the United States between July and December 2008.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
117 participants were screened; 49 were excluded. Randomized patients met the following criteria during the prestudy period: FEV1 (Forced expiratory volume in one second) 50-85% predicted while withholding short-acting beta agonist (SABA) and reversibility of airway obstruction >12% following SABA at Visits 1 and 2.

Reporting Groups

	Description
Placebo	Patients are randomized to receive placebo for montelukast on either Intervention I (Visit 3), Intervention II (Visit 5), Intervention III (Visit 7) or Intervention IV (Visit 9). At all interventions, either albuterol or placebo for albuterol is administered 4 hours after placebo for montelukast. During the washout periods separating the intervention periods, patients received no study treatment (i.e., patients did not receive montelukast or placebo treatment).
25 Mcg Montelukast	Patients are randomized to receive montelukast 25 mcg (microgram) on either Intervention I (Visit 3), Intervention II (Visit 5), Intervention III (Visit 7) or Intervention IV (Visit 9). At all interventions either albuterol or placebo for albuterol is administered 4 hours after montelukast 25 mcg. During the washout periods separating the intervention periods, patients received no study treatment (i.e., patients did not receive montelukast or placebo treatment).
100 Mcg Montelukast	Patients are randomized to receive montelukast 100 mcg on either Intervention I (Visit 3), Intervention II (Visit 5), Intervention III (Visit 7) or Intervention IV (Visit 9). At all interventions either albuterol or placebo for albuterol is administered 4 hours after montelukast 100 mcg. During the washout periods separating the intervention periods, patients received no study treatment (i.e., patients did not receive montelukast or placebo treatment).
250 Mcg Montelukast	Patients are randomized to receive montelukast 250 mcg on either Intervention I (Visit 3), Intervention II (Visit 5), Intervention III (Visit 7) or Intervention IV (Visit 9). At all interventions either albuterol or placebo for albuterol is administered 4 hours after montelukast 250 mcg. During the washout periods separating the intervention periods, patients received no study treatment (i.e., patients did not receive montelukast or placebo treatment).
500 Mcg Montelukast	Patients are randomized to receive montelukast 500 mcg on either Intervention I (Visit 3), Intervention II (Visit 5), Intervention III (Visit 7) or Intervention IV (Visit 9). At all interventions either albuterol or placebo for albuterol is administered 4 hours after montelukast 500 mcg. During the washout periods separating the intervention periods, patients received no study treatment (i.e., patients did not receive montelukast or placebo treatment).
1000 Mcg Montelukast	Patients are randomized to receive montelukast 1000 mcg on either Intervention I (Visit 3), Intervention II (Visit 5), Intervention III (Visit 7) or Intervention IV (Visit 9). At all interventions either albuterol or placebo for albuterol is administered 4 hours after montelukast 1000 mcg. During the washout periods separating the intervention periods, patients received no study treatment (i.e., patients did not receive montelukast or placebo treatment).
Total	Consistent with the "incomplete-block" design of this study, 6 treatments (placebo and 5 active-dose levels) were administered during only 4 treatment periods. In other words, in this 4-period crossover design, no patient received all 6 treatments and thus some treatments were not received by all of the patients. Therefore, the TOTAL number of participants across ALL the dose levels provides the best metric to follow the consistency of patient flow from one treatment period to the next treatment period.

Participant Flow for 7 periods

Period 1: First Intervention (Visit 3 to Visit 4)

	Placebo	25 Mcg Montelukast	100 Mcg Montelukast	250 Mcg Montelukast	500 Mcg Montelukast	1000 Mcg Montelukast	Total
STARTED	17	11	6	19	6	9	68
COMPLETED	17	11	6	19	6	9	68
NOT COMPLETED	0	0	0	0	0	0	0

Period 2: First Washout Period of 4-7 Days

	Placebo	25 Mcg Montelukast	100 Mcg Montelukast	250 Mcg Montelukast	500 Mcg Montelukast	1000 Mcg Montelukast	Total
STARTED	17	11	6	19	6	9	68
COMPLETED	17	11	6	17	6	9	66
NOT COMPLETED	0	0	0	2	0	0	2
Adverse Event	0	0	0	2	0	0	2

Period 3: Second Intervention (Visit 5 to Visit 6)

	Placebo	25 Mcg Montelukast	100 Mcg Montelukast	250 Mcg Montelukast	500 Mcg Montelukast	1000 Mcg Montelukast	Total
STARTED	18	8	10	14	6	10	66
COMPLETED	18	8	10	14	6	10	66
NOT COMPLETED	0	0	0	0	0	0	0

Period 4: Second Washout Period of 4-7 Days

	Placebo	25 Mcg Montelukast	100 Mcg Montelukast	250 Mcg Montelukast	500 Mcg Montelukast	1000 Mcg Montelukast	Total
STARTED	18	8	10	14	6	10	66
COMPLETED	18	8	10	14	6	10	66
NOT COMPLETED	0	0	0	0	0	0	0

Period 5: Third Intervention (Visit 7 to Visit 8)

	Placebo	25 Mcg Montelukast	100 Mcg Montelukast	250 Mcg Montelukast	500 Mcg Montelukast	1000 Mcg Montelukast	Total
STARTED	16	12	6	18	6	8	66
COMPLETED	16	12	6	18	6	8	66
NOT COMPLETED	0	0	0	0	0	0	0

Period 6: Third Washout Period of 4-7 Days

	Placebo	25 Mcg Montelukast	100 Mcg Montelukast	250 Mcg Montelukast	500 Mcg Montelukast	1000 Mcg Montelukast	Total
STARTED	16	12	6	18	6	8	66
COMPLETED	16	12	6	18	6	8	66
NOT COMPLETED	0	0	0	0	0	0	0

Period 7: Fourth Intervention(Visit 9 to Visit 10)

	Placebo	25 Mcg Montelukast	100 Mcg Montelukast	250 Mcg Montelukast	500 Mcg Montelukast	1000 Mcg Montelukast	Total
STARTED	16	11	8	15	7	9	66
COMPLETED	16	11	8	15	7	8	65
NOT COMPLETED	0	0	0	0	0	1	1
Patient unable to attend last visit	0	0	0	0	0	1	1

Baseline Characteristics

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Reporting Groups

	Description
All Participants	Combined participants from all arms.

Baseline Measures

	All Participants
Number of Participants [units: participants]	68
Age [units: years] Mean ± Standard Deviation	39.1 ± 12.6
Gender [units: participants]
Female	32
Male	36
FEV1 (Forced Expiratory Volume in One Second) [units: L (Liter)] Mean ± Standard Deviation	2.44 ± 0.63

Outcome Measures

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1. Primary:

Change From Baseline in FEV1 Over 4 Hours [ Time Frame: 0 (=baseline) to 4 hours after treatment with montelukast ]

Show Outcome Measure 1

2. Secondary:

Change From Baseline in FEV1 Over 90 Minutes After Albuterol/Placebo Administration [ Time Frame: 4 hours (equals time point at which albuterol or albuterol placebo is administered) to 5.5 hours after treatment with montelukast ]

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Measure Type	Secondary
Measure Title	Change From Baseline in FEV1 Over 90 Minutes After Albuterol/Placebo Administration
Measure Description	FEV1 measurements taken at 0 (=baseline), 15, 30, 60, and 90 minutes after albuterol/placebo administration contributed to the average change from baseline over 90 minutes. The number of minutes between consecutive measurements was used as weighting factor. The time-weighted average change was standardized by dividing by the time associated with the last measurement.
Time Frame	4 hours (equals time point at which albuterol or albuterol placebo is administered) to 5.5 hours after treatment with montelukast
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (FAS) population which included all randomized patients who took at least one dose of post randomization study drug (albuterol or matching placebo) 4 hours after treatment with montelukast at either of the intervention visits and had a measurement for analysis available in at least one treatment period of the cross-over design.

Reporting Groups

	Description
Montelukast+Albuterol	Montelukast (data for each patient are pooled across all 3 of the active doses received by that patient) +Albuterol (data for each patient are pooled across all 3 administrations of active albuterol, as added to active montelukast)
Montelukast+ Placebo	Montelukast (data for each patient are pooled across all 3 of the active doses received by that patient) +Placebo for Albuterol (data for each patient are pooled across all 3 administrations of placebo for albuterol, as added to active montelukast)

Measured Values

	Montelukast+Albuterol	Montelukast+ Placebo
Number of Participants Analyzed [units: participants]	26	41
Change From Baseline in FEV1 Over 90 Minutes After Albuterol/Placebo Administration [units: L] Least Squares Mean ( 95% Confidence Interval )	0.34 ( 0.22 to 0.45 )	0.15 ( 0.06 to 0.24 )

Statistical Analysis 1 for Change From Baseline in FEV1 Over 90 Minutes After Albuterol/Placebo Administration

Groups ^[1]	All groups
Difference in Least-Squares Means ^[2]	0.19
95% Confidence Interval	( 0.04 to 0.34 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant estimation information:
	Repeated measures model with terms for treatment (Albuterol/Placebo), dose, treatment-by-dose interaction and baseline FEV1

3. Other Pre-specified:

Change From Baseline in FEV1 at 8 Hours After Treatment With Montelukast [ Time Frame: 0 (baseline) and 8 hours after treatment with montelukast ]

Show Outcome Measure 3

4. Other Pre-specified:

Change From Baseline in FEV1 at 24 Hours After Treatment With Montelukast [ Time Frame: 0 (baseline) and 24 hours after treatment with montelukast ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only 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 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only 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 more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372

No publications provided by Merck

Publications automatically indexed to this study:

Philip G, Pedinoff A, Vandormael K, Tymofyeyev Y, Smugar SS, Reiss TF, Korenblat PE. A phase I randomized, placebo-controlled, dose-exploration study of single-dose inhaled montelukast in patients with chronic asthma. J Asthma. 2010 Dec;47(10):1078-84. Epub 2010 Nov 3.

Responsible Party:	Executive Vice President, Clinical and Quantitative Sciences, Merck Sharp & Dohme Corp
ClinicalTrials.gov Identifier:	NCT00739297 History of Changes
Other Study ID Numbers:	2008_542, MK0476-388
Study First Received:	August 19, 2008
Results First Received:	January 14, 2010
Last Updated:	April 21, 2010
Health Authority:	United States: Food and Drug Administration