A Study of Brexanolone for Acute Respiratory Distress Syndrome (ARDS) Due to Coronavirus Disease 2019 (COVID-19)

• Sponsor: Sage Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04537806
• Collaborator: (none)
• Enrollment: 29
• Locations: 9
• Arms: 2
• Actual Duration (Months): 6.4
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the efficacy and safety of brexanolone in participants on ventilator support for acute respiratory distress syndrome (ARDS) due to COVID-19.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome; COVID-19	Drug: Brexanolone; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Study of Brexanolone for Acute Respiratory Distress Syndrome Due to COVID-19
• Actual Study Start Date: Dec 18, 2020
• Actual Primary Completion Date: Jul 1, 2021
• Actual Study Completion Date: Jul 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous intravenous (IV) infusion of brexanolone-matching placebo.	Drug: Placebo; Administered as IV infusion.
Experimental: Brexanolone Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone at 70 micrograms per kilogram per hour (mcg/kg/h) for 58 hours followed by a 2-hour taper of brexanolone at 35 mcg/kg/h.	Drug: Brexanolone; Administered as IV infusion.; Other Names: Allopregnanolone Zulresso SAGE-547

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Are Alive and Free of Respiratory Failure at Day 28 [Day 28]

   Respiratory failure is defined based on resource utilization, requiring at least one of the following: Endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (heated, humidified oxygen delivered via reinforced nasal cannula at flow rates >20 liter/minute with fraction of delivered oxygen >=0.5), noninvasive positive pressure ventilation, and extracorporeal membrane oxygenation (ECMO). Percentage of participants who were alive and free of respiratory failure at Day 28 were reported in this outcome measure.

Secondary Outcome Measures

1. Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) [From first dose of investigational product up to end of study (up to Day 40)]

   An adverse event (AE) is any untoward medical occurrence in a participant administered with a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. A TEAE is defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study.

2. Number of Participants Who Died Through Day 28 [From screening up to Day 28]

   All cause mortality was reported up to Day 28 in this outcome measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant was confirmed positive for the novel coronavirus responsible for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection as determined by polymerase chain reaction (PCR) at Screening

• Participant had a presumptive diagnosis of ARDS at Screening and partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen [PF ratio]) less than (<) 300 prior to randomization

• Participant was intubated and receiving mechanical ventilation prior to randomization

• Participants must had initiated mechanical ventilation within 48 hours prior to screening, or had an immediate clinical plan for such intervention at time of screening

• Participant was likely to survive, in the opinion of the investigator, for at least 72 hours from the time of screening

Exclusion Criteria:

• Participant had fulminant hepatic failure at Screening

• Participant had end stage renal disease at Screening

• Participant had a known allergy to progesterone, allopregnanolone, or any excipients in the brexanolone injection

• Participant was concurrently participating in another clinical trial for an investigational product or device at screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sage Investigational Site	Fresno	California	United States	93701
2	Sage Investigational Site	Augusta	Georgia	United States	30912
3	Sage Investigational Site	Boston	Massachusetts	United States	02115
4	Sage Investigational Site	Burlington	Massachusetts	United States	01805
5	Sage Investigational Site	Lansing	Michigan	United States	48912
6	Sage Investigational Site	Las Vegas	Nevada	United States	89102
7	Sage Investigational Site	Charlotte	North Carolina	United States	28203
8	Sage Investigational Site	Richmond	Virginia	United States	23298
9	Sage Investigational Site	Seattle	Washington	United States	98122

Sponsors and Collaborators

• Sage Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 26, 2021
• Statistical Analysis Plan - Nov 23, 2021

More Information

Publications

None provided.

• Responsible Party: Sage Therapeutics
• ClinicalTrials.gov Identifier: NCT04537806
• Other Study ID Numbers: 547-ARD-301
• First Posted: Sep 3, 2020
• Last Update Posted: Aug 19, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: COVID-19; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome; Pregnanolone; Brexanolone

Study Results

Participant Flow

Recruitment Details	Participants were enrolled in the study at 9 centers in the United States from 18 December 2020 to 01 July 2021.
Pre-assignment Detail	A total of 33 participants were screened of which 29 were randomized and 28 were dosed. This study consisted of up to a 2-day screening period, a 60-hour treatment period plus an additional follow-up of up to 23 days.

Arm/Group Title	Placebo	Brexanolone
Arm/Group Description	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous intravenous (IV) infusion of brexanolone-matching placebo.	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone at 70 micrograms per kilogram per hour (mcg/kg/h) for 58 hours followed by a 2-hour taper of brexanolone at 35 mcg/kg/h.
Period Title: Overall Study
STARTED	15	14
Safety Analysis Set	14	14
Full Analysis Set	14	14
COMPLETED	13	13
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Placebo	Brexanolone	Total
Arm/Group Description	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone-matching placebo.	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone at 70 mcg/kg/h for 58 hours followed by a 2-hour taper of brexanolone at 35 mcg/kg/h.	Total of all reporting groups
Overall Participants	14	14	28
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.6 (9.81)	58.2 (12.79)	60.4 (11.40)
Sex: Female, Male (Count of Participants)
Female	6 42.9%	8 57.1%	14 50%
Male	8 57.1%	6 42.9%	14 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 21.4%	4 28.6%	7 25%
Not Hispanic or Latino	11 78.6%	10 71.4%	21 75%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 7.1%	1 7.1%	2 7.1%
Black or African American	2 14.3%	1 7.1%	3 10.7%
White	10 71.4%	11 78.6%	21 75%
Other	1 7.1%	1 7.1%	2 7.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Are Alive and Free of Respiratory Failure at Day 28
Description	Respiratory failure is defined based on resource utilization, requiring at least one of the following: Endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (heated, humidified oxygen delivered via reinforced nasal cannula at flow rates >20 liter/minute with fraction of delivered oxygen >=0.5), noninvasive positive pressure ventilation, and extracorporeal membrane oxygenation (ECMO). Percentage of participants who were alive and free of respiratory failure at Day 28 were reported in this outcome measure.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who initiated IP (brexanolone or placebo). Here, "Overall number of participants analyzed" signifies the number of participants with available data for analysis.

Arm/Group Title	Placebo	Brexanolone
Arm/Group Description	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone-matching placebo.	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone at 70 mcg/kg/h for 58 hours followed by a 2-hour taper of brexanolone at 35 mcg/kg/h.
Measure Participants	13	13
Number [percentage of participants]	23.1 165%	23.1 165%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brexanolone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Proc Genmod
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -31.8 to 31.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates for treatment, and the corresponding 95% confidence interval (CI) were estimated using Proc Genmod method, with treatment as a factor and age groups as a covariate variable.

2. Secondary Outcome

Title	Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)
Description	An adverse event (AE) is any untoward medical occurrence in a participant administered with a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom or disease temporally associated with the use of an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. A TEAE is defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study.
Time Frame	From first dose of investigational product up to end of study (up to Day 40)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who initiated IP (brexanolone or placebo).

Arm/Group Title	Placebo	Brexanolone
Arm/Group Description	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone-matching placebo.	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone at 70 mcg/kg/h for 58 hours followed by a 2-hour taper of brexanolone at 35 mcg/kg/h.
Measure Participants	14	14
Count of Participants [Participants]	13 92.9%	14 100%

3. Secondary Outcome

Title	Number of Participants Who Died Through Day 28
Description	All cause mortality was reported up to Day 28 in this outcome measure.
Time Frame	From screening up to Day 28

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who initiated IP (brexanolone or placebo).

Arm/Group Title	Placebo	Brexanolone
Arm/Group Description	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone-matching placebo.	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone at 70 mcg/kg/h for 58 hours followed by a 2-hour taper of brexanolone at 35 mcg/kg/h.
Measure Participants	14	14
Count of Participants [Participants]	6 42.9%	8 57.1%

Adverse Events

Time Frame	From screening up to end of study (up to Day 40)
Adverse Event Reporting Description	Safety analysis set included all participants who initiated IP (brexanolone or placebo).
Arm/Group Title	Placebo		Brexanolone
Arm/Group Description	Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone-matching placebo.		Participants receiving mechanical ventilation as standard of care were randomized to receive a 60-hour single continuous IV infusion of brexanolone at 70 mcg/kg/h for 58 hours followed by a 2-hour taper of brexanolone at 35 mcg/kg/h.
All Cause Mortality
	Placebo		Brexanolone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/14 (50%)		8/14 (57.1%)
Serious Adverse Events
	Placebo		Brexanolone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/14 (57.1%)		8/14 (57.1%)
Cardiac disorders
Atrial fibrillation	1/14 (7.1%)		1/14 (7.1%)
Acute myocardial infarction	0/14 (0%)		1/14 (7.1%)
Cardiac arrest	1/14 (7.1%)		0/14 (0%)
Gastrointestinal disorders
Intra-abdominal haematoma	1/14 (7.1%)		0/14 (0%)
General disorders
Multiple organ dysfunction syndrome	1/14 (7.1%)		1/14 (7.1%)
Infections and infestations
COVID-19	0/14 (0%)		1/14 (7.1%)
Pneumonia serratia	0/14 (0%)		1/14 (7.1%)
Septic shock	2/14 (14.3%)		0/14 (0%)
Pneumonia	1/14 (7.1%)		0/14 (0%)
Sepsis	1/14 (7.1%)		0/14 (0%)
Nervous system disorders
Encephalopathy	0/14 (0%)		2/14 (14.3%)
Cerebellar infarction	0/14 (0%)		1/14 (7.1%)
Cerebral infarction	0/14 (0%)		1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	3/14 (21.4%)		4/14 (28.6%)
Acute respiratory failure	3/14 (21.4%)		3/14 (21.4%)
Hypoxia	0/14 (0%)		1/14 (7.1%)
Pneumothorax	0/14 (0%)		1/14 (7.1%)
Acute respiratory distress syndrome	1/14 (7.1%)		0/14 (0%)
Surgical and medical procedures
Endotracheal intubation	2/14 (14.3%)		0/14 (0%)
Vascular disorders
Deep vein thrombosis	1/14 (7.1%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Brexanolone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/14 (78.6%)		11/14 (78.6%)
Blood and lymphatic system disorders
Anaemia	1/14 (7.1%)		1/14 (7.1%)
Thrombocytopenia	0/14 (0%)		1/14 (7.1%)
Cardiac disorders
Bradycardia	0/14 (0%)		1/14 (7.1%)
Tachyarrhythmia	0/14 (0%)		1/14 (7.1%)
Atrial fibrillation	1/14 (7.1%)		0/14 (0%)
Defect conduction intraventricular	1/14 (7.1%)		0/14 (0%)
Extrasystoles	1/14 (7.1%)		0/14 (0%)
Tachycardia	1/14 (7.1%)		0/14 (0%)
Ear and labyrinth disorders
Hypoacusis	0/14 (0%)		1/14 (7.1%)
Gastrointestinal disorders
Constipation	2/14 (14.3%)		2/14 (14.3%)
Haematochezia	0/14 (0%)		1/14 (7.1%)
Mouth ulceration	0/14 (0%)		1/14 (7.1%)
Nausea	0/14 (0%)		1/14 (7.1%)
Dysphagia	1/14 (7.1%)		0/14 (0%)
General disorders
Pyrexia	1/14 (7.1%)		1/14 (7.1%)
Hypothermia	1/14 (7.1%)		0/14 (0%)
Infections and infestations
Septic shock	0/14 (0%)		4/14 (28.6%)
Candida infection	0/14 (0%)		1/14 (7.1%)
Clostridium difficile infection	0/14 (0%)		1/14 (7.1%)
Enterococcal bacteraemia	0/14 (0%)		1/14 (7.1%)
Escherichia sepsis	0/14 (0%)		1/14 (7.1%)
Pseudomonas infection	0/14 (0%)		1/14 (7.1%)
Staphylococcal infection	0/14 (0%)		1/14 (7.1%)
Urinary tract infection enterococcal	0/14 (0%)		1/14 (7.1%)
Bacterial disease carrier	1/14 (7.1%)		0/14 (0%)
Pneumonia	1/14 (7.1%)		0/14 (0%)
Injury, poisoning and procedural complications
Lip injury	0/14 (0%)		1/14 (7.1%)
Penis injury	0/14 (0%)		1/14 (7.1%)
Product administration interrupted	0/14 (0%)		1/14 (7.1%)
Scrotal injury	0/14 (0%)		1/14 (7.1%)
Skin laceration	0/14 (0%)		1/14 (7.1%)
Ear injury	1/14 (7.1%)		0/14 (0%)
Mechanical ventilation complication	1/14 (7.1%)		0/14 (0%)
Overdose	1/14 (7.1%)		0/14 (0%)
Investigations
Staphylococcus test positive	0/14 (0%)		1/14 (7.1%)
Alanine aminotransferase increased	2/14 (14.3%)		0/14 (0%)
Aspartate aminotransferase increased	2/14 (14.3%)		0/14 (0%)
Blood alkaline phosphatase increased	1/14 (7.1%)		0/14 (0%)
Blood bilirubin increased	1/14 (7.1%)		0/14 (0%)
Metabolism and nutrition disorders
Metabolic alkalosis	0/14 (0%)		1/14 (7.1%)
Hypernatraemia	3/14 (21.4%)		0/14 (0%)
Hypophosphataemia	2/14 (14.3%)		0/14 (0%)
Acidosis	1/14 (7.1%)		0/14 (0%)
Dehydration	1/14 (7.1%)		0/14 (0%)
Hyperkalaemia	1/14 (7.1%)		0/14 (0%)
Hypervolaemia	1/14 (7.1%)		0/14 (0%)
Hypoglycaemia	1/14 (7.1%)		0/14 (0%)
Hypokalaemia	1/14 (7.1%)		0/14 (0%)
Metabolic acidosis	1/14 (7.1%)		0/14 (0%)
Nervous system disorders
Encephalopathy	1/14 (7.1%)		0/14 (0%)
Psychiatric disorders
Delirium	0/14 (0%)		3/14 (21.4%)
Anxiety	1/14 (7.1%)		0/14 (0%)
Intensive care unit delirium	1/14 (7.1%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/14 (0%)		1/14 (7.1%)
Skin and subcutaneous tissue disorders
Blister	0/14 (0%)		2/14 (14.3%)
Decubitus ulcer	0/14 (0%)		1/14 (7.1%)
Rash	1/14 (7.1%)		0/14 (0%)
Surgical and medical procedures
Tracheostomy	1/14 (7.1%)		1/14 (7.1%)
Endotracheal intubation	1/14 (7.1%)		0/14 (0%)
Vascular disorders
Hypertension	3/14 (21.4%)		1/14 (7.1%)
Hypotension	2/14 (14.3%)		1/14 (7.1%)

Limitations/Caveats

The study was terminated early due to sponsor's decision and there were no safety concerns.

More Information

Certain Agreements

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

The PI can either be a party and subject to the same restrictions as the institution, or if not a party, the restrictions are described on the face of the contract (i.e., PI is a contractor of the institution; PI is part of a larger group of study personnel; institution has contracted with or otherwise bound all study personnel under confidentiality obligations and requirements to vest intellectual property to the institution).