Study Evaluating the Safety and Effects of MN-221 in Subjects Experiencing an Acute Exacerbation of Asthma

A Phase II, Randomized, Modified Single-Blind, Placebo-Controlled Dose Escalation Study to Evaluate the Safety and Efficacy of MN-221 When Administered Intravenously as an Adjunct to Standard Therapy to Adults With an Acute Exacerbation of Asthma

The objective of this clinical study is to examine the safety and effectiveness of intravenous MN-221 compared to placebo when administered as an adjunct to standard therapy in subjects experiencing an acute exacerbation of asthma.

This is a randomized, modified single-blind, placebo-controlled dose escalation, multi-center Emergency Department (ED) study. Each subject will receive MN-221 or placebo administered through a continuous intravenous infusion in addition to the standardized care treatment for an acute exacerbation of asthma. The study is a modified single-blind design where the subject and the Investigator will be blinded.

Upon presentation to the ED for assessment and treatment for an acute exacerbation of asthma the subject should receive standardized care consistent with the National Asthma Education and Prevention Program (NAEPP) guidelines.

Once the subject has received the standardized initial treatment regimen and has been assessed for response to that treatment (signs and symptoms of acute asthma exacerbation), an informed consent to participate in the study will be obtained, study entry criteria will be reviewed, a 12-lead ECG will be performed, a dyspnea index scale assessment will be conducted, and spirometry will be performed. If the subject's FEV1 is ≤ 55% of predicted and the subject meets all other study entry criteria the subject will be randomized to receive either MN-221 or placebo. Throughout the screening process the subject will continue to receive the appropriate medical care consistent with the NAEPP guidelines for the treatment of acute exacerbations of asthma.

There will be up to three dose groups with generally twelve subjects in each group. Subjects enrolled in the study will receive an intravenous infusion of MN-221 study drug or placebo. Generally six subjects will be randomized to receive MN-221 and generally six subjects will be randomized to receive placebo in each dose group.

The initial dose group will be randomized to receive:

• 16 μg/min of MN-221 for 15 minutes (total dose of 240 μg) or placebo.

Subsequent dose groups will receive the following proposed doses:

• 30 μg/min for 15 minutes (total dose of 450 μg) or placebo, and
• 16 μg/min for 15 minutes followed by 8 μg/min for 105 minutes (total dose of 1,080 μg) or placebo.

During the study treatment period, the subject will continue to receive the following standard treatment and assessment until the subject's FEV1 reaches ≥ 70% of predicted:

• Assessment of subject's signs and symptoms;
• Complete a dyspnea index scale;
• Supplemental oxygen to maintain oxygen saturation as measured by pulse oximetry of ≥ 90%;
• Albuterol (2.5 mg) via nebulizer given hourly; NOTE: Albuterol (2.5 mg) via nebulizer may be given up to every 20 minutes if deemed to be indicated by the Investigator.
• Ipratropium (0.5 mg) via nebulizer may be given every hour if deemed to be indicated by the Investigator.
• Spirometry completed within 10 minutes of nebulizer treatments; followed by,
• Reassessment of signs and symptoms. If the subject does not improve to FEV1 ≥ 70% of predicted during the study treatment period, the subject may continue to receive further treatment including hospital admission at the discretion of the Investigator. The study will be approximately 6.5 hours in length (Hour -1.5 to Hour 5) while the subject remains in the ED. Safety, efficacy and PK parameters will be monitored throughout the treatment period. An initial 24-hour post-randomization follow-up visit will be completed to evaluate the subject's health status as well as for safety and PK parameters. A second follow-up contact will be completed by telephone seven days post-randomization for safety purposes and to evaluate the subject's health status.

A risk/benefit evaluation will be performed by the study's Safety Review Committee at each dose level. The occurrence of clinical signs, symptoms, laboratory abnormalities, ECG abnormalities suggesting toxicity, or results of efficacy analyses (FEV1, dyspnea index scale), may result in a decision to modify the proposed planned dose escalations, to repeat a dose level, or to not evaluate any additional dose(s) of MN-221.

Inclusion Criteria:

1. Male or female;

2. Have self-reported history of physician-diagnosed and treated asthma for ≥ 3 months;

3. Have a diagnosis of an acute exacerbation of asthma upon presentation at the ED as defined by dyspnea and evidence of bronchospasm in an individual with a known history of asthma;

4. Upon presentation to the ED the treatment provided included:

   • A brief history and physical examination that includes vital signs, auscultation, assessments of accessory respiratory muscle usage and the level of dyspnea the subject is experiencing;
   • Supplemental oxygen given to maintain oxygen saturation as measured by pulse oximetry of ≥ 90%;
   • Two doses of inhaled beta2-agonist (defined as albuterol 5 mg) via nebulizer (each dose given sequentially up to approximately every 20 minutes); simultaneously with
   • Two doses of an inhaled anti-cholinergic agent (defined as ipratropium 0.5 mg) via nebulizer (each dose given sequentially up to approximately every20 minutes);
   • One dose of corticosteroid of at least 60 mg given orally (prednisone) or intravenously (methylprednisolone); and

5. Have a FEV1 ≤ 55% within 10 minutes of completing the treatment described in Inclusion Criterion #4;

6. Have a negative urine pregnancy test if you are females of childbearing potential;

7. Have ECG with no dysrhythmias (except sinus tachycardia);

8. Have no clinical or electrocardiographic signs of ischemic heart disease as determined by the Investigator; and

9. Have signed the informed consent obtained prior to starting any study procedures.

Exclusion criteria:

1. Have a current or prior diagnosis or suspected diagnosis of COPD or other chronic lung disease other than asthma;
2. Have presence of pneumonia;
3. Have presence of significant other respiratory dysfunction such as pneumothorax, pneumomediastinum, or pulmonary edema;
4. Have known or suspected vocal cord dysfunction syndrome;
5. Have presence of aspirated foreign body (known or suspected);
6. Have a history or any current clinical evidence suggesting cardiomyopathy or congestive heart failure;
7. Have a history or presence of tachyarrhythmias, with the exception of sinus tachycardia;
8. Have a heart rate ≥ maximum heart rate: (maximum predicted HR [220-age]-30); OR Heart rate ≥ 150 bpm;
9. Have hypokalemia, defined as a potassium level ≤ 3.0 mg/dL according to the point-of-care device level obtained at Screening;
10. Have significant cardiac, renal, hepatic, endocrine, metabolic, neurologic or other systemic disease. A significant disease will be defined as one which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or may influence the results of the study or the subject's ability to participate in the trial;
11. Have a self-reported history of greater than 15 pack-yr smoking history;
12. Have a fever ≥ 101.5º F;
13. Have uncontrolled hypertension defined as a blood pressure ≥ 170/100 mm Hg;
14. Have the need for immediate intubation as determined by the Investigator;
15. Are a pregnant or lactating female;
16. Have participated in another clinical study with an investigational drug within 30 days of randomization;
17. Have a positive urine drug screen for cocaine, methamphetamine or PCP;
18. Have a known allergy to MN-221 or any of the other components of the MN-221 drug product ;
19. Have a known allergy to other beta agonists;
20. Have had previous exposure to MN-221; or
21. Have used of theophylline, beta blockers, diuretics, digoxin, MAO inhibitors, or tricyclic antidepressants within 2 weeks prior to randomization.