Asthma, Status Asthmaticus
Conditions
Keywords
Asthma, Dose-Escalation, Controlled, MN-221
Brief summary
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.
Detailed description
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.
Interventions
DRUGDose Group 1
IV infusion of MN-221 16 mcg/min for 15 min; total dose of 240 mcg
DRUGMN-221 placebo
i.v. infusion of placebo for 15 minutes
DRUGDose Group 2
i.v. infusion of MN-221 30 mcg/min for 15 minutes (total dose of 450 mcg)
DRUGDose Group 3
i.v. infusion of MN-221 16 mcg/min for 15 minutes followed by 8 mcg/min for 105 minutes (total dose = 1,080 mcg)
Sponsors
MediciNova
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of FEV1 (Forced Expiratory Volume in 1 Second) Expressed as Percent of Predicted After Two Doses of Albuterol (5 mg Each) and Ipratropium (0.5 mg Each) When Compared to FEV1 at Hour 2 After the Start of the Infusion of MN-221 or Placebo. | Baseline and Hour 2 | The primary efficacy summary was change from Baseline in FEV1 (percent predicted), at Hour 2. Baseline was defined as FEV1 (percent predicted) after two doses of albuterol (5 mg each) and ipratropium (0.5 mg each) and FEV1 (percent predicted) FEV1 at Hour 2 was defined as the FEV1 (percent predicted) at 2 hours after the start of the infusion of MN-221 or placebo. Change from Baseline in FEV1 (percent predicted), was summarized by treatment group at Hour 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 (L) The Forced Expiratory Volume in One Second as Measured in Liters Per Second. | Baseline to Hour 2 | FEV1 (L) was determined over time using a spirometer. Measure the mean change in FEV1 (L) from Baseline. |
| Hospital Admission Rate During Visit 1 | Hour -1.5 through Hour 5 | After a patient in the emergency department (ED) presents with an acute exacerbation of asthma, the hospital proceeds with SOC procedures for this condition. Despite treatment in the ED, it is sometimes necessary to admit the patient into the hospital. In the study described here, the rate of hospital admissions was recorded. |
Countries
United States
Participant flow
Recruitment details
Upon presentation to the Emergency Department (ED) at a hospital participating in the study with an acute exacerbation of asthma, the Principal Investigator (ED physician) discussed the study with the potential subject.
Pre-assignment details
Some subjects were consented for the study, but upon screening, failed to meet the inclusion and exclusion criteria, had an FEV1 \> 50%, or refused to participate.
Participants by arm
| Arm | Count |
|---|---|
| 240 μg MN-221 i.v. (Intravenous) Infusion for 15 Minutes Initial dose: 16 μg/min of MN-221 for 15 minutes (total 240 μg). After safety data review meeting, chose escalation doses: 1) 30 μg/min for 15 minutes (total 450 μg), and 2) 16 μg/min for 15 minutes plus 8 μg/min for 105 minutes (total dose of 1,080 μg).Until the subject's FEV1 reached ≥ 70% predicted, the subject continued to receive the following standard treatment and assessment during the study treatment period:
* Assessment of subject's signs and symptoms
* Completion of 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 and/or Ipratropium (0.5 mg) via nebulizer may have been given up to every 20 minutes and every hour, respectively, 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 subj | 5 |
| MN-221 Placebo i.v. Infusion MN-221 Placebo i.v. infusion. Until the subject's FEV1 reached ≥ 70% predicted, the subject continued to receive the following standard treatment and assessment during the study treatment period: Assessment of subject's signs and symptoms,Completion of 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 have been given up to every 20 minutes if deemed to be indicated by the Investigator.
* Ipratropium (0.5 mg) via nebulizer may have been 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 did not improve to FEV1 ≥70% of predicted during the study treatment period, the subject may have continued to receive further treatment, including hospital admission, at the discretion of the Investigator. | 13 |
| 1,000-1,080 μg MN-221 i.v. 16 μg/minute for 15 minutes followed by 8 μg/minute for 105 minutes (total dose of 1,080 μg). Among the subjects in the 1,000 - 1,080 μg group, per protocol instructions, the two subjects originally randomized to receive 1,080 μg MN-221 were infused with study drug over a 120-minute period and the 1 subject originally randomized to receive 450 μg who actually received 1,000 μg was infused with study drug over a 15-minute period. Although there was this difference in infusion time, it was deemed appropriate to group these 3 subjects in the same dose group. | 3 |
| 450 μg MN-221 i.v. for 15 Minutes 30 μg/minute for 15 minutes (total dose of 450 μg) administered i.v. | 6 |
| 1,995 μg MN-221 i.v. Over 15 Minutes and 25 Minutes Two subjects were randomized to receive 450 μg dose i.v. Instead, Subject 0010015 received 1,995 μg i.v. over 15 minutes infusion; Subject 0010016 received 1,995 μg i.v. over 25 minutes infusion. | 2 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | MN-221 Placebo i.v. Infusion | 1,000-1,080 μg MN-221 i.v. | 450 μg MN-221 i.v. for 15 Minutes | 1,995 μg MN-221 i.v. Over 15 Minutes and 25 Minutes | Total | 240 μg MN-221 i.v. (Intravenous) Infusion for 15 Minutes |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 3 Participants | 6 Participants | 2 Participants | 29 Participants | 5 Participants |
| Age Continuous | 42.6 years STANDARD_DEVIATION 9.7 | 22.3 years STANDARD_DEVIATION 3.21 | 39.2 years STANDARD_DEVIATION 9.77 | 45 years STANDARD_DEVIATION 0 | 37.83 years STANDARD_DEVIATION 11.31 | 30.2 years STANDARD_DEVIATION 11.56 |
| Region of Enrollment United States | 13 participants | 3 participants | 6 participants | 2 participants | 29 participants | 5 participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 6 Participants | 2 Participants | 21 Participants | 3 Participants |
| Sex: Female, Male Male | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 5 | 6 / 13 | 0 / 3 | 1 / 6 | 2 / 2 |
| serious Total, serious adverse events | 0 / 5 | 4 / 13 | 0 / 3 | 1 / 6 | 1 / 2 |
Outcome results
Primary
Change of FEV1 (Forced Expiratory Volume in 1 Second) Expressed as Percent of Predicted After Two Doses of Albuterol (5 mg Each) and Ipratropium (0.5 mg Each) When Compared to FEV1 at Hour 2 After the Start of the Infusion of MN-221 or Placebo.
The primary efficacy summary was change from Baseline in FEV1 (percent predicted), at Hour 2. Baseline was defined as FEV1 (percent predicted) after two doses of albuterol (5 mg each) and ipratropium (0.5 mg each) and FEV1 (percent predicted) FEV1 at Hour 2 was defined as the FEV1 (percent predicted) at 2 hours after the start of the infusion of MN-221 or placebo. Change from Baseline in FEV1 (percent predicted), was summarized by treatment group at Hour 2.
Time frame: Baseline and Hour 2
Population: The analysis was performed on the Intention-to-Treat (ITT) population. Twenty-nine subjects met the study entry criteria, provided written informed consent, and were enrolled in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 240 μg MN-221 i.v. (Intravenous) Infusion for 15 Minutes | Change of FEV1 (Forced Expiratory Volume in 1 Second) Expressed as Percent of Predicted After Two Doses of Albuterol (5 mg Each) and Ipratropium (0.5 mg Each) When Compared to FEV1 at Hour 2 After the Start of the Infusion of MN-221 or Placebo. | 16.57 FEV1 (percent of predicted) | Full Range 11.17 |
| MN-221 Placebo i.v. Infusion | Change of FEV1 (Forced Expiratory Volume in 1 Second) Expressed as Percent of Predicted After Two Doses of Albuterol (5 mg Each) and Ipratropium (0.5 mg Each) When Compared to FEV1 at Hour 2 After the Start of the Infusion of MN-221 or Placebo. | 3.88 FEV1 (percent of predicted) | Full Range 7.79 |
| 1,000-1,080 μg MN-221 i.v. | Change of FEV1 (Forced Expiratory Volume in 1 Second) Expressed as Percent of Predicted After Two Doses of Albuterol (5 mg Each) and Ipratropium (0.5 mg Each) When Compared to FEV1 at Hour 2 After the Start of the Infusion of MN-221 or Placebo. | 3.03 FEV1 (percent of predicted) | — |
| 450 μg MN-221 i.v. for 15 Minutes | Change of FEV1 (Forced Expiratory Volume in 1 Second) Expressed as Percent of Predicted After Two Doses of Albuterol (5 mg Each) and Ipratropium (0.5 mg Each) When Compared to FEV1 at Hour 2 After the Start of the Infusion of MN-221 or Placebo. | 4.27 FEV1 (percent of predicted) | — |
| 1,995 μg MN-221 i.v. Over 15 Minutes and 25 Minutes | Change of FEV1 (Forced Expiratory Volume in 1 Second) Expressed as Percent of Predicted After Two Doses of Albuterol (5 mg Each) and Ipratropium (0.5 mg Each) When Compared to FEV1 at Hour 2 After the Start of the Infusion of MN-221 or Placebo. | -0.82 FEV1 (percent of predicted) | — |
Secondary
FEV1 (L) The Forced Expiratory Volume in One Second as Measured in Liters Per Second.
FEV1 (L) was determined over time using a spirometer. Measure the mean change in FEV1 (L) from Baseline.
Time frame: Baseline to Hour 2
Population: 29 subjects experiencing an acute exacerbation of asthma were at approximately 8 ED sites. The sample size was based on feasibility and precedent for this type of study, rather than statistical considerations.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 240 μg MN-221 i.v. (Intravenous) Infusion for 15 Minutes | FEV1 (L) The Forced Expiratory Volume in One Second as Measured in Liters Per Second. | 0.60 liters per second |
| MN-221 Placebo i.v. Infusion | FEV1 (L) The Forced Expiratory Volume in One Second as Measured in Liters Per Second. | 0.10 liters per second |
| 1,000-1,080 μg MN-221 i.v. | FEV1 (L) The Forced Expiratory Volume in One Second as Measured in Liters Per Second. | 0.12 liters per second |
| 450 μg MN-221 i.v. for 15 Minutes | FEV1 (L) The Forced Expiratory Volume in One Second as Measured in Liters Per Second. | 0.10 liters per second |
| 1,995 μg MN-221 i.v. Over 15 Minutes and 25 Minutes | FEV1 (L) The Forced Expiratory Volume in One Second as Measured in Liters Per Second. | -0.02 liters per second |
Secondary
Hospital Admission Rate During Visit 1
After a patient in the emergency department (ED) presents with an acute exacerbation of asthma, the hospital proceeds with SOC procedures for this condition. Despite treatment in the ED, it is sometimes necessary to admit the patient into the hospital. In the study described here, the rate of hospital admissions was recorded.
Time frame: Hour -1.5 through Hour 5
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 240 μg MN-221 i.v. (Intravenous) Infusion for 15 Minutes | Hospital Admission Rate During Visit 1 | 0 participants |
| MN-221 Placebo i.v. Infusion | Hospital Admission Rate During Visit 1 | 7 participants |
| 1,000-1,080 μg MN-221 i.v. | Hospital Admission Rate During Visit 1 | 0 participants |
| 450 μg MN-221 i.v. for 15 Minutes | Hospital Admission Rate During Visit 1 | 3 participants |
| 1,995 μg MN-221 i.v. Over 15 Minutes and 25 Minutes | Hospital Admission Rate During Visit 1 | 1 participants |