A Phase 2 Study of MP-376 to Prevent Acute Exacerbations in Chronic Obstructive Pulmonary Disease (COPD) Patients

• Sponsor: Horizon Pharma USA, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00739648
• Collaborator: (none)
• Enrollment: 322
• Locations: 39
• Arms: 2
• Duration (Months): 18
• Patients Per Site: 8.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Patients with Chronic Obstructive Pulmonary Disease (COPD) suffer from frequent and recurrent acute exacerbations (AECB) which are associated with enormous healthcare expenditures and significant morbidity, specifically an increased risk of death, a decline in pulmonary function and a significant change in quality of life. Bacteria appear to have an important role in acute exacerbations in chronic bronchitis and COPD. Studies of acute exacerbations in COPD have shown a reduction in bacterial load with prolonged exacerbation-free interval. In addition, recent studies indicate that acquisition of a new strain of H. influenzae, M. catarrhalis, S. pneumoniae or P. aeruginosa are responsible for many of these exacerbations. Chronic inflammation and bacterial infection predispose many patients to frequent and recurrent acute exacerbations.

Mpex believes that intermittent administration of inhaled MP-376 in high risk patients will decrease the incidence of acute exacerbations by both by lowering the organism burden, and resultant inflammation, as well as pre-emptive eradication of any newly acquired bacterial strains.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: MP-376; Drug: Placebo	Phase 2

Detailed Description

This study will be a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of MP-376 inhalation solution given daily for 5 days in a 28 day treatment cycle to COPD patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 322 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety, Tolerability and Efficacy of MP-376 Inhalation Solution Administered for 5 Days Every 28 Days to Prevent Acute Exacerbations in High Risk COPD Patients
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo inhaled twice daily via the PARI eFlow nebulizer for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles	Drug: Placebo; same frequency as study drug using the same method of delivery; Other Names: MP-376 color-matched placebo
Experimental: MP-376 240 mg Twice Daily (BID) MP-376 240 mg BID inhaled via the PARI eFlow nebulizer for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles	Drug: MP-376; MP-376 administered via inhalation for 5 consecutive days within 28-day treatment cycles for up to 12 cycles; Other Names: Levofloxacin inhalation solution Aeroquin

Outcome Measures

Primary Outcome Measures

1. Exacerbation Rate [From randomization to the patients final study visit (up to 12 months)]

   The number of acute exacerbations per patient-year of study participation, where an acute exacerbation was defined as a deterioration in respiratory symptoms that required treatment with antibiotics, corticosteroids, hospitalization or a combination of those treatments.

Secondary Outcome Measures

1. Duration of Acute Exacerbation [from randomization to the patient's final study visit (up to 12 months)]

   From the beginning of antibiotics and/or systemic corticosteroids to the end of antibiotics and/or systemic corticosteroids, whichever was longer, for treatment of the first acute exacerbation

2. Percent Change in Forced Vital Capacity (FVC) [from baseline to the conclusion of the fourth 28-day treatment cycle (4 months)]

   The percent change in the amount of air a patient can inhale

3. Percent Change in Forced Expiratory Volume in 1 Second (FEV1) [from baseline to the conclusion of the fourth 28-day treatment cycle (4 months)]

   The percent change in the amount of air a patient can exhale in 1 second

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria (selected):

• 40 years of age

• History of COPD

• Forced expiratory volume in 1 second (FEV1) </= 70% of predicted and FEV1/Forced vital capacity (FVC) </= 0.7 value at screening

• Have at least two acute exacerbation episodes in the proceeding year

• Clinically stable with no changes in health status within the last 30 days

• Lifetime smoking history of at least 10 pack-years

• Willing and able to use a daily electronic diary

Exclusion Criteria (selected):

• Use of any systemic or inhaled antibiotics within 30 days prior to baseline

• History of hypersensitivity to fluoroquinolones or intolerance with aerosol medication

• Creatinine clearance < 40 mg/ml/min, AST, ALT >/= 5 x upper limit of normal (ULN) or total bilirubin >/= 3 x ULN at Screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Haleyville	Alabama	United States	35565
2		Hueytown	Alabama	United States	35023
3		Mobile	Alabama	United States	36608
4		Montgomery	Alabama	United States	36117
5		Glendale	Arizona	United States	85306
6		Phoenix	Arizona	United States	85006
7		Chula Vista	California	United States	91911
8		Lomita	California	United States	90717
9		Long Beach	California	United States	90822
10		Mission Viejo	California	United States	92691
11		Oceanside	California	United States	92056
12		Palo Alto	California	United States	94304
13		Riverside	California	United States	92506
14		San Diego	California	United States	92117
15		San Jose	California	United States	95124
16		Wheat Ridge	Colorado	United States	80033
17		Clearwater	Florida	United States	33765
18		DeBary	Florida	United States	32713
19		DeLand	Florida	United States	32720
20		Orlando	Florida	United States	32806
21		Savannah	Georgia	United States	31406
22		New Orleans	Louisiana	United States	70115
23		Taylor	Michigan	United States	48180
24		Omaha	Nebraska	United States	68198
25		Buffalo	New York	United States	14215
26		Ithaca	New York	United States	14850
27		Greenville	North Carolina	United States	27834
28		Columbus	Ohio	United States	43210
29		Maumee	Ohio	United States	43537
30		Toledo	Ohio	United States	43614
31		Medford	Oregon	United States	97504
32		Johnston	Rhode Island	United States	02919
33		Easley	South Carolina	United States	29640
34		Gaffney	South Carolina	United States	29340
35		Spartanburg	South Carolina	United States	29303
36		Union	South Carolina	United States	29379
37		San Antonio	Texas	United States	78212
38		Richmond	Virginia	United States	23225
39		Salem	Virginia	United States	24153

Sponsors and Collaborators

• Horizon Pharma USA, Inc.

Investigators

• Principal Investigator: Sanjay Sethi, M.D., University at Buffalo

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Horizon Pharma USA, Inc.
• ClinicalTrials.gov Identifier: NCT00739648
• Other Study ID Numbers: Mpex-302
• First Posted: Aug 22, 2008
• Last Update Posted: Jan 19, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Horizon Pharma USA, Inc.: COPD; Patients
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Levofloxacin

Study Results

Participant Flow

Arm/Group Title	Placebo	MP-376 240 mg BID
Arm/Group Description	Placebo inhaled twice daily via the eFlow nebulizer for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles	MP-376 240 mg inhaled twice daily via the PARI eFlow nebulizer for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles
Period Title: Overall Study
STARTED	108	214
COMPLETED	82	161
NOT COMPLETED	26	53

Baseline Characteristics

Arm/Group Title	Placebo	MP-376 240 mg BID	Total
Arm/Group Description	Placebo inhaled twice daily via the eFlow nebulizer for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles	MP-376 240 mg inhaled twice daily via the PARI eFlow nebulizer for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles	Total of all reporting groups
Overall Participants	108	214	322
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.4 (9.06)	64.0 (9.14)	63.8 (9.10)
Sex: Female, Male (Count of Participants)
Female	52 48.1%	101 47.2%	153 47.5%
Male	56 51.9%	113 52.8%	169 52.5%

Outcome Measures

1. Primary Outcome

Title	Exacerbation Rate
Description	The number of acute exacerbations per patient-year of study participation, where an acute exacerbation was defined as a deterioration in respiratory symptoms that required treatment with antibiotics, corticosteroids, hospitalization or a combination of those treatments.
Time Frame	From randomization to the patients final study visit (up to 12 months)

Outcome Measure Data

Analysis Population Description

modified intent to treat (MITT; patients who received at least one dose of study drug)

Arm/Group Title	Placebo	MP-376 240 mg BID
Arm/Group Description	Placebo inhaled twice daily (BID) via PARI eFlow nebulizer for 5 consecutive days in each 28-day treatment cycle for up to 12 cycles	MP-376 240 mg inhaled twice daily (BID)via PARI eFlow nebulizer for 5 consecutive days in each 28-day treatment cycle for up to 12 cycles
Measure Participants	108	214
Mean (Standard Error) [exacerbation per patient year]	1.20 (0.15)	1.31 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, MP-376 240 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7282
	Comments
	Method	Regression, Linear
	Comments	negative binomial regression model
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 90%; 0.86 to 1.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Duration of Acute Exacerbation
Description	From the beginning of antibiotics and/or systemic corticosteroids to the end of antibiotics and/or systemic corticosteroids, whichever was longer, for treatment of the first acute exacerbation
Time Frame	from randomization to the patient's final study visit (up to 12 months)

Outcome Measure Data

Analysis Population Description

MITT

Arm/Group Title	Placebo	MP-376 240 mg BID
Arm/Group Description	Placebo inhaled BID via nebulization for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles	MP-376 240 mg inhaled BID via nebulization for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles
Measure Participants	108	214
Mean (Standard Deviation) [Days]	12.9 (12.11)	11.6 (7.98)

3. Secondary Outcome

Title	Percent Change in Forced Vital Capacity (FVC)
Description	The percent change in the amount of air a patient can inhale
Time Frame	from baseline to the conclusion of the fourth 28-day treatment cycle (4 months)

Outcome Measure Data

Analysis Population Description

MITT

Arm/Group Title	Placebo	MP-376 240 mg BID
Arm/Group Description	Placebo inhaled BID via nebulization for 5 consecutive days in a 28-day cycle for up to 12 cycles	MP-376 240 mg inhaled BID via nebulization for 5 consecutive days in a 28-day cycle for up to 12 cycles
Measure Participants	108	214
Least Squares Mean (Standard Error) [Percent]	14.46 (6.18)	-0.77 (4.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, MP-376 240 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9768
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-15.2
	Confidence Interval	(2-Sided) 90%; -27.8 to -2.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Change in Forced Expiratory Volume in 1 Second (FEV1)
Description	The percent change in the amount of air a patient can exhale in 1 second
Time Frame	from baseline to the conclusion of the fourth 28-day treatment cycle (4 months)

Outcome Measure Data

Analysis Population Description

MITT

Arm/Group Title	Placebo	MP-376 240 mg BID
Arm/Group Description	Placebo inhaled BID via nebulization for 5 consecutive days in a 28-day cycle for up to 12 cycles	MP-376 240 mg inhaled BID via nebulization for 5 consecutive days in a 28-day cycle for up to 12 cycles
Measure Participants	108	214
Least Squares Mean (Standard Error) [Percent]	14.76 (6.21)	2.42 (4.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, MP-376 240 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9464
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.3
	Confidence Interval	(2-Sided) 90%; -24.9 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	1 year
Arm/Group Title	Placebo		MP-376 240 mg BID
Arm/Group Description	Placebo inhaled twice daily via the eFlow nebulizer for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles		MP-376 240 mg inhaled twice daily via the PARI eFlow nebulizer for 5 consecutive days within a 28-day treatment cycle for up to 12 cycles
All Cause Mortality
	Placebo		MP-376 240 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		MP-376 240 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/108 (29.6%)		72/214 (33.6%)
Blood and lymphatic system disorders
Anemia	1/108 (0.9%)	1	0/214 (0%)	0
Cardiac disorders
Coronary artery disease	0/108 (0%)	0	3/214 (1.4%)	3
Atrial fibrillation	1/108 (0.9%)	1	1/214 (0.5%)	1
Myocardial infarction	1/108 (0.9%)	1	1/214 (0.5%)	1
Angina pectoris	0/108 (0%)	0	1/214 (0.5%)	1
Angina unstable	0/108 (0%)	0	1/214 (0.5%)	1
Atrial tachycardia	0/108 (0%)	0	1/214 (0.5%)	1
Cardiac failure	1/108 (0.9%)	1	0/214 (0%)	0
Coronary artery stenosis	0/108 (0%)	0	1/214 (0.5%)	1
Stress cardiomyopathy	1/108 (0.9%)	1	0/214 (0%)	0
Tachyarrhythmia	1/108 (0.9%)	1	0/214 (0%)	0
Gastrointestinal disorders
Pancreatitis	1/108 (0.9%)	2	1/214 (0.5%)	1
Colitis ulcerative	0/108 (0%)	0	1/214 (0.5%)	1
Gastritis	1/108 (0.9%)	1	0/214 (0%)	0
Ileus	0/108 (0%)	0	1/214 (0.5%)	1
Intestinal obstruction	1/108 (0.9%)	1	0/214 (0%)	0
Large intestinal obstruction	0/108 (0%)	0	1/214 (0.5%)	1
Large intestine perforation	0/108 (0%)	0	1/214 (0.5%)	1
Upper gsatrointestinal hemorrhage	1/108 (0.9%)	1	0/214 (0%)	0
General disorders
Condition Aggravated	22/108 (20.4%)	31	39/214 (18.2%)	53
Chest pain	3/108 (2.8%)	4	4/214 (1.9%)	4
Catheter site hematoma	0/108 (0%)	0	1/214 (0.5%)	1
Multi-organ failure	1/108 (0.9%)	1	0/214 (0%)	0
Non-cardiac chest pain	0/108 (0%)	0	1/214 (0.5%)	1
Edema	0/108 (0%)	0	1/214 (0.5%)	1
Hepatobiliary disorders
Cholecystitits	0/108 (0%)	0	1/214 (0.5%)	1
Infections and infestations
Pneumonia	1/108 (0.9%)	1	10/214 (4.7%)	10
Cellulitis	0/108 (0%)	0	2/214 (0.9%)	2
Gastroenteritis viral	0/108 (0%)	0	2/214 (0.9%)	2
Septic shock	1/108 (0.9%)	1	1/214 (0.5%)	1
Bursitis infective staphylococcal	1/108 (0.9%)	1	0/214 (0%)	0
Gastroenteritis	0/108 (0%)	0	1/214 (0.5%)	1
Hepatitis C	0/108 (0%)	0	1/214 (0.5%)	1
Herpes zoster	1/108 (0.9%)	1	0/214 (0%)	0
Kidney infection	1/108 (0.9%)	1	0/214 (0%)	0
Nocardiosis	0/108 (0%)	0	1/214 (0.5%)	1
Staphylococcal bacteremia	1/108 (0.9%)	1	0/214 (0%)	0
Streptococcal bacteremia	0/108 (0%)	0	1/214 (0.5%)	1
Injury, poisoning and procedural complications
Cervical vertebral fracture	0/108 (0%)	0	1/214 (0.5%)	1
Foot fracture	0/108 (0%)	0	1/214 (0.5%)	1
Post procedureal hematoma	1/108 (0.9%)	1	0/214 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/108 (0%)	0	1/214 (0.5%)	1
Hyperglycemia	0/108 (0%)	0	1/214 (0.5%)	1
Hypoglycemia	1/108 (0.9%)	1	0/214 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	1/108 (0.9%)	1	0/214 (0%)	0
Musculoskeletal chest pain	1/108 (0.9%)	1	0/214 (0%)	0
Osteoarthritis	1/108 (0.9%)	1	0/214 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	0/108 (0%)	0	2/214 (0.9%)	2
Breast cancer	0/108 (0%)	0	1/214 (0.5%)	1
Nervous system disorders
Syncope	1/108 (0.9%)	1	1/214 (0.5%)	1
Carotid artery stenosis	0/108 (0%)	0	1/214 (0.5%)	1
Cerebrovascular accident	0/108 (0%)	0	1/214 (0.5%)	1
Dementia	0/108 (0%)	0	1/214 (0.5%)	1
Paresis	1/108 (0.9%)	1	0/214 (0%)	0
Psychiatric disorders
Alcohol withdrawal syndrome	0/108 (0%)	0	1/214 (0.5%)	1
Confusional state	0/108 (0%)	0	1/214 (0.5%)	1
Depression	0/108 (0%)	0	1/214 (0.5%)	2
Mental status change	0/108 (0%)	0	1/214 (0.5%)	1
Renal and urinary disorders
Renal failure acute	1/108 (0.9%)	1	0/214 (0%)	0
Reproductive system and breast disorders
Vaginal prolapse	0/108 (0%)	0	1/214 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	2/108 (1.9%)	2	4/214 (1.9%)	4
Acute respiratory failure	1/108 (0.9%)	1	1/214 (0.5%)	1
Pulmonary embolism	0/108 (0%)	0	2/214 (0.9%)	2
Respiratory depression	0/108 (0%)	0	1/214 (0.5%)	1
Vascular disorders
Aoritic stenosis	0/108 (0%)	0	1/214 (0.5%)	1
Deep vein thrombosis	0/108 (0%)	0	1/214 (0.5%)	1
Hypertension	1/108 (0.9%)	1	0/214 (0%)	0
Hypertensive crisis	0/108 (0%)	0	1/214 (0.5%)	1
Hypertensive emergency	1/108 (0.9%)	1	0/214 (0%)	0
Hypotension	0/108 (0%)	0	1/214 (0.5%)	1
Malignant hypertension	0/108 (0%)	0	1/214 (0.5%)	1
Peripheral vascular disorder	0/108 (0%)	0	1/214 (0.5%)	1
Venous thrombosis limb	1/108 (0.9%)	1	0/214 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		MP-376 240 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	94/108 (87%)		197/214 (92.1%)
Gastrointestinal disorders
Nausea	13/108 (12%)	113	24/214 (11.2%)	28
Diarrhea	7/108 (6.5%)	7	13/214 (6.1%)	14
Vomiting	3/108 (2.8%)	3	11/214 (5.1%)	12
General disorders
Condition aggravated	58/108 (53.7%)	120	114/214 (53.3%)	247
Edema peripheral	7/108 (6.5%)	8	16/214 (7.5%)	16
Chest pain	6/108 (5.6%)	7	13/214 (6.1%)	14
Chest discomfort	6/108 (5.6%)	6	11/214 (5.1%)	11
Infections and infestations
Sinusititis	13/108 (12%)	13	11/214 (5.1%)	13
Pneumonia	5/108 (4.6%)	6	17/214 (7.9%)	24
Urinary tract infection	8/108 (7.4%)	10	10/214 (4.7%)	11
Metabolism and nutrition disorders
Hyperglycemia	4/108 (3.7%)	4	12/214 (5.6%)	18
Nervous system disorders
Dysgeusia	3/108 (2.8%)	3	62/214 (29%)	91
Headache	11/108 (10.2%)	11	16/214 (7.5%)	18
Psychiatric disorders
Insomnia	6/108 (5.6%)	6	14/214 (6.5%)	15
Anxiety	6/108 (5.6%)	6	6/214 (2.8%)	6
Respiratory, thoracic and mediastinal disorders
Dyspenea	18/108 (16.7%)	21	29/214 (13.6%)	42
Cough	12/108 (11.1%)	16	24/214 (11.2%)	25
Sinus congestion	6/108 (5.6%)	6	9/214 (4.2%)	9
Pharynlaryngeal pain	6/108 (5.6%)	6	8/214 (3.7%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.