TD-0903 for ALI Associated With COVID-19

• Sponsor: Theravance Biopharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04402866
• Collaborator: (none)
• Enrollment: 235
• Locations: 24
• Arms: 6
• Actual Duration (Months): 9.9
• Patients Per Site: 9.8
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This Phase 2 study will evaluate the efficacy, safety, pharmacodynamics and pharmacokinetics of inhaled TD-0903 compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with confirmed COVID-19 associated acute lung injury and impaired oxygenation.

Condition or Disease	Intervention/Treatment	Phase
Acute Lung Injury (ALI) Associated With COVID-19; Lung Inflammation Associated With COVID-19	Drug: TD-0903; Drug: Placebo	Phase 2

Detailed Description

Part 1 of the study includes up to 3 ascending dose cohorts, each comprised of 8 subjects (6 receiving TD-0903 and 2 receiving placebo).

Part 2 of the study will evaluate one dose of TD-0903 (selected based on the data from Part

1. as compared with placebo. Part 2 is targeting 198 subjects total.

Study Design

• Study Type: Interventional
• Actual Enrollment: 235 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Parallel group, randomized, double-blind, placebo-controlledParallel group, randomized, double-blind, placebo-controlled
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Pharmacist & Sponsor are not blinded for Part 1. Sponsor is blinded for Part 2. Pharmacist is not blinded for Part 2.
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-group, Multi-center Study of an Inhaled Pan-Janus Kinase Inhibitor, TD-0903, to Treat Symptomatic Acute Lung Injury Associated With COVID-19
• Actual Study Start Date: Jun 24, 2020
• Actual Primary Completion Date: Apr 21, 2021
• Actual Study Completion Date: Apr 21, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: TD-0903 - MAD Dose A 6 out of 8 subjects per cohort will be randomized to receive TD-0903 MAD Dose A	Drug: TD-0903; Study Drug to be administered by inhalation
Experimental: Part 1: TD-0903 - MAD Dose B 6 out of 8 subjects per cohort will be randomized to receive TD-0903 MAD Dose B	Drug: TD-0903; Study Drug to be administered by inhalation
Experimental: Part 1: TD-0903 - MAD Dose C 6 out of 8 subjects per cohort will be randomized to receive TD-0903 MAD Dose C	Drug: TD-0903; Study Drug to be administered by inhalation
Experimental: Part 1: Placebo for MAD 2 out of 8 subjects per cohort (up to 3 cohorts) will be randomized to receive placebo	Drug: Placebo; Placebo to be administered by inhalation
Experimental: Part 2: TD-0903 99 subjects will be randomized to receive TD-0903	Drug: TD-0903; Study Drug to be administered by inhalation
Experimental: Part 2: Placebo 99 subjects will be randomized to receive Placebo	Drug: Placebo; Placebo to be administered by inhalation

Outcome Measures

Primary Outcome Measures

1. Part 2: Number of Respiratory Failure-free Days (RFDs) From Randomization to Day 28 [Randomization to Day 28]

   An RFD was defined as a day that a participant was alive and did not require the use of any respiratory support (invasive mechanical ventilation, non-invasive positive pressure ventilation, high-flow oxygen devices, or oxygen supplementation) from randomization through Day 28. The number of RFDs was 0 for participants who used respiratory support for 28 days or longer or for participants who died on or before Day 28. A clinical status score of ≤ 4 on a given day was equivalent to an RFD. The clinical status categories and associated scores ranged from 1-8 where a higher score represented a worse outcome. A clinical status score of 4 was defined as a participant who was hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care (whether or not related to COVID-19).

Secondary Outcome Measures

1. Part 2: Change From Baseline in SaO2/FiO2 Ratio on Day 7 [Baseline and Day 7]

   SaO2/FiO2 ratio was calculated as SaO2 divided by FiO2.

2. Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 [Days 7, 14, 21 and 28]

   The clinical status categories and associated scores ranged from 1-8 where a higher score represented a worse outcome. The scale was as follows: Score 1: Not hospitalized, no limitations on activities Score 2: Not hospitalized, but with limitations on activities and/or requiring home oxygen Score 3: Hospitalized, not requiring supplemental oxygen, and no longer requiring ongoing medical care Score 4: Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care (whether or not related to COVID-19) Score 5: Hospitalized, requiring supplemental oxygen Score 6: Hospitalized, on non-invasive ventilation or high-flow oxygen devices Score 7: Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation Score 8: Death

3. Part 2: Number of Participants Alive and Respiratory Failure-free on Day 28 [Day 28]

   Defined as participants who were alive and did not require the use of any respiratory support (invasive mechanical ventilation, non-invasive positive pressure ventilation, high-flow oxygen devices, or oxygen supplementation) on Day 28.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Willing and able to provide written informed consent on their own prior to performing study procedures. In the U.K., subject assent or proxy consent as per local site procedures, may also be acceptable if both a clinician and second health professional attest that the subject understands the risks and potential benefits of the study and elects to proceed. Outside the U.K., written informed consent may only be obtained from the subject or legally authorized representative. In the event the subject loses capacity during the study, the subject consents to continued participation, except where this is not clinically indicated.

• Willing and able to comply with study-related procedures/assessments

• Age 18 to 80 years old

• Hospitalized (or documentation of a plan to admit to the hospital if the subject is in an emergency department) and requiring supplemental oxygen to maintain saturation > 90%

• A diagnosis of symptomatic COVID-19 defined as a positive test for SARS-CoV-2 RNA detected by RT-PCR on a sample from the upper respiratory tract (e.g., nasopharyngeal, nasal, or oropharyngeal swab) collected < 72 hours prior to randomization

• Onset of COVID-19 -related symptoms > 2 days and </= 10 days prior to hospital admission

Exclusion Criteria:

• Subjects currently receiving invasive mechanical ventilation

• Presence or suspicion of active malignancy with the exception of cancer in situ (e.g., skin cancer)

• Evidence of serious active infection other than COVID-19

• Current diagnosis of human immunodeficiency virus, hepatitis B or C

• In the opinion of the investigator, unlikely to survive for > 24 hours from enrollment

• Women who are pregnant or might be pregnant, or who are currently breast-feeding. Subjects must agree to not donate ova or sperm through 30 days after the last dose of study medication

• Presence of significant comorbidity that, in the opinion of the investigator, predisposes the subject to mortality. Such conditions might include: a. New York Heart Association class IV Heart Failure b. Hepatic dysfunction (i.e., AST or ALT >3x upper limit of normal) c. Renal dysfunction (i.e., estimated glomerular filtration rate (eGFR) < 50mL/min) or receiving renal replacement therapy

• Presence of septic shock at time of enrollment

• Hemoglobin < 80 g/L

• Evidence of neutropenia (i.e., absolute neutrophil count < 1000 cells/uL), lymphopenia (i.e., absolute lymphocyte count < 200 cells/uL) or thrombocytopenia (i.e.Platelets < 50×10^9/L)

• Hypersensitivity to TD-0903 or its components, or to other JAK inhibitors

• Treatment with anti-IL 6 (e.g., tocilizumab, sarilumab), anti-IL-6R antagonists (e.g., abatacept), JAK inhibitors (e.g., baricitinib, tofacitinib) supplemental interferon therapy, or tyrosine kinase inhibitors (e.g., erlotinib, gefinitib) in the past 30 days, or plans to receive a JAK inhibitor during the study period

• Current treatment with conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs)/immunosuppressive agents including:

1. Methotrexate, cyclosporine, mycophenolate, tacrolimus, penicillamine, or sulfasalazine within 2 weeks prior to enrollment

2. Azathioprine or cyclophosphamide within 12 weeks prior to enrollment

3. Monoclonal antibodies targeting B cells (e.g., rituximab) within 12 weeks prior to enrollment

4. Tumor necrosis factor-alpha (TNFα)) inhibitors within 4 weeks prior to enrollment

• Participating in other clinical trials involving any other experimental treatment for COVID-19, except in the context of a single-arm antiviral or convalescent plasma compassionate-use protocol

• Subjects with active or incompletely treated pulmonary tuberculosis, or known history of non-tuberculosis mycobacterium over past 12 months

• Subject requires continuous oxygen supplementation for underlying cardio-respiratory history in the past 90 days

• Body Mass Index ≥40 kg/m2

• Receipt of live vaccine (i.e., live attenuated) in the 4 weeks prior to visit 1 or plans to receive a live vaccine (or live attenuated) during the study period. Note: Use of non-live (inactivated) vaccinations is allowed for all subjects

• History of venous thromboembolism (VTE), deep venous thrombosis (DVT), Pulmonary Embolism (PE) or known hypercoagulable disorder (e.g., factor V Leiden, antiphospholipid antibody syndrome, protein C or S deficiency)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Theravance Biopharma Investigational Site	Duarte	California	United States	91010
2	Theravance Biopharma Investigational Site	Denver	Colorado	United States	80220
3	Theravance Biopharma Investigational Site	Sebring	Florida	United States	33870
4	Theravance Biopharma Investigational Site	Boston	Massachusetts	United States	02135
5	Theravance Biopharma Investigational Site	Fall River	Massachusetts	United States	02720
6	Theravance Biopharma Investigational Site	Kalispell	Montana	United States	59901
7	Theravance Biopharma Investigational Site	Glens Falls	New York	United States	12801
8	Theravance Biopharma	Hyde Park	New York	United States	11040
9	Theravance Biopharma Investigational Site	Columbus	Ohio	United States	43214
10	Theravance Biopharma Investigational Site	Allentown	Pennsylvania	United States	18103
11	Theravance Biopharma Investigational Site	Bethlehem	Pennsylvania	United States	18015
12	Theravance Biopharma Investigational Site	Wenatchee	Washington	United States	98801
13	Theravance Biopharma Investigational Site	Bela Vista		Brazil	01323-001
14	Theravance Biopharma Investigational Site	Botucatu		Brazil	18618-686
15	Theravance Biopharma Investigational Site	Caxias Do Sul		Brazil	95070-560
16	Theravance Biopharma Investigational Site	São José Do Rio Preto		Brazil	15090-000
17	Theravance Biopharma Investigational Site	Helsinki		Finland	00290
18	Theravance Biopharma Investigational Site	Turku		Finland	20520
19	Theravance Biopharma Investigational Site	Chisinau		Moldova, Republic of	MD-2025
20	Theravance Biopharma Investigational Site	Bucharest		Romania	21105
21	Theravance Biopharma Investigational Site	Brovary		Ukraine	07 400
22	Theravance Biopharma Investigational Site	Kyiv		Ukraine	01 103
23	Theravance Biopharma Investigational Site	Kyiv		Ukraine	01 601
24	Theravance Biopharma Investigational Site	Manchester		United Kingdom	M23 9QZ

Sponsors and Collaborators

• Theravance Biopharma

Investigators

• Study Director: Medical Monitor, Theravance Biopharma

Study Documents (Full-Text)

• Study Protocol - Sep 18, 2020
• Statistical Analysis Plan - Dec 22, 2020

More Information

Publications

None provided.

• Responsible Party: Theravance Biopharma
• ClinicalTrials.gov Identifier: NCT04402866
• Other Study ID Numbers: 0188; 2020-001807-18
• First Posted: May 27, 2020
• Last Update Posted: Mar 17, 2022
• Last Verified: Mar 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
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Theravance Biopharma: Acute lung injury; ALI; COVID-19; Coronavirus Disease 2019; inflammatory lung conditions; Inflammatory lung disease; ARDS; SARS-CoV-2; Pneumonia
• Additional relevant MeSH terms: COVID-19; Pneumonia; Lung Injury; Acute Lung Injury; Inflammation

Study Results

Participant Flow

Recruitment Details

235 participants were enrolled across 24 sites in the United States, Brazil, Finland, the Republic of Moldova, Romania, Ukraine and the United Kingdom.

Pre-assignment Detail

235 participants were enrolled and 230 participants were randomized and treated with study drug. Within each cohort in Part 1 (multiple-ascending dose design), participants were randomized 3:1, TD-0903 to placebo. During Part 2 (parallel-group design), participants were stratified by baseline age (≤ 60 versus > 60 years), and by concurrent use of antiviral medications (yes or no) at baseline. Within each stratum, participants were randomized 1:1 to receive either TD-0903 or placebo.

Arm/Group Title	Part 1: Matching Placebo	Part 1: TD-0903 - 1 mg	Part 1: TD-0903 - 3 mg	Part 1: TD-0903 - 10 mg	Part 2: Matching Placebo	Part 2: TD-0903 - 3 mg
Arm/Group Description	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 1 mg. Participants were administered a 2 mg loading dose as the total dose on Day 1.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 10 mg.	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.
Period Title: Overall Study
STARTED	6	6	7	6	104	106
Randomized and Treated With Study Drug	6	6	7	6	102	103
COMPLETED	4	5	6	6	89	92
NOT COMPLETED	2	1	1	0	15	14

Baseline Characteristics

Arm/Group Title	Part 1: Matching Placebo	Part 1: TD-0903 - 1 mg	Part 1: TD-0903 - 3 mg	Part 1: TD-0903 - 10 mg	Part 2: Matching Placebo	Part 2: TD-0903 - 3 mg	Total
Arm/Group Description	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 1 mg. Participants were administered a 2 mg loading dose as the total dose on Day 1.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 10 mg.	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.	Total of all reporting groups
Overall Participants	6	6	7	6	104	106	235
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 50%	3 50%	5 71.4%	5 83.3%	70 67.3%	60 56.6%	146 62.1%
>=65 years	3 50%	3 50%	2 28.6%	1 16.7%	34 32.7%	46 43.4%	89 37.9%
Sex: Female, Male (Count of Participants)
Female	3 50%	1 16.7%	3 42.9%	1 16.7%	41 39.4%	41 38.7%	90 38.3%
Male	3 50%	5 83.3%	4 57.1%	5 83.3%	63 60.6%	65 61.3%	145 61.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	10 9.6%	14 13.2%	24 10.2%
Not Hispanic or Latino	6 100%	6 100%	7 100%	6 100%	90 86.5%	89 84%	204 86.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	4 3.8%	3 2.8%	7 3%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 16.7%	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.4%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	2 1.9%	2 0.9%
White	5 83.3%	6 100%	7 100%	6 100%	102 98.1%	104 98.1%	230 97.9%
More than one race	0 0%	0 0%	0 0%	0 0%	1 1%	0 0%	1 0.4%
Other	0 0%	0 0%	0 0%	0 0%	1 1%	0 0%	1 0.4%

Outcome Measures

1. Primary Outcome

Title	Part 2: Number of Respiratory Failure-free Days (RFDs) From Randomization to Day 28
Description	An RFD was defined as a day that a participant was alive and did not require the use of any respiratory support (invasive mechanical ventilation, non-invasive positive pressure ventilation, high-flow oxygen devices, or oxygen supplementation) from randomization through Day 28. The number of RFDs was 0 for participants who used respiratory support for 28 days or longer or for participants who died on or before Day 28. A clinical status score of ≤ 4 on a given day was equivalent to an RFD. The clinical status categories and associated scores ranged from 1-8 where a higher score represented a worse outcome. A clinical status score of 4 was defined as a participant who was hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care (whether or not related to COVID-19).
Time Frame	Randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.

Arm/Group Title	Part 2: Matching Placebo	Part 2: TD-0903 - 3 mg
Arm/Group Description	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.
Measure Participants	102	100
Median (Inter-Quartile Range) [days]	21.0	21.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Matching Placebo, Part 2: TD-0903 - 3 mg
	Comments	Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6137
	Comments
	Method	Van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Common Odds Ratio
	Estimated Value	1.142
	Confidence Interval	(2-Sided) 95%; 0.706 to 1.846
	Parameter Dispersion	Type: Value:
	Estimation Comments	Common Odds Ratio (TD-0903 vs. placebo) and corresponding 95% Wald confidence interval (CI) were obtained from the proportional odds regression model of RFD adjusting for baseline age strata (≤ 60 years vs. > 60 years).

2. Secondary Outcome

Title	Part 2: Change From Baseline in SaO2/FiO2 Ratio on Day 7
Description	SaO2/FiO2 ratio was calculated as SaO2 divided by FiO2.
Time Frame	Baseline and Day 7

Outcome Measure Data

Analysis Population Description

ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.

Arm/Group Title	Part 2: Matching Placebo	Part 2: TD-0903 - 3 mg
Arm/Group Description	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.
Measure Participants	86	90
Least Squares Mean (Standard Error) [ratio measure]	88.97 (7.769)	88.46 (7.654)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Matching Placebo, Part 2: TD-0903 - 3 mg
	Comments	Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group
	Type of Statistical Test	Other
	Comments	Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
Statistical Test of Hypothesis	p-Value	0.962
	Comments
	Method	Mixed model repeated measures model
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 95%; -21.95 to 20.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28
Description	The clinical status categories and associated scores ranged from 1-8 where a higher score represented a worse outcome. The scale was as follows: Score 1: Not hospitalized, no limitations on activities Score 2: Not hospitalized, but with limitations on activities and/or requiring home oxygen Score 3: Hospitalized, not requiring supplemental oxygen, and no longer requiring ongoing medical care Score 4: Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care (whether or not related to COVID-19) Score 5: Hospitalized, requiring supplemental oxygen Score 6: Hospitalized, on non-invasive ventilation or high-flow oxygen devices Score 7: Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation Score 8: Death
Time Frame	Days 7, 14, 21 and 28

Outcome Measure Data

Analysis Population Description

ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.

Arm/Group Title	Part 2: Matching Placebo	Part 2: TD-0903 - 3 mg
Arm/Group Description	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.
Measure Participants	102	100
Score 1	6 100%	8 133.3%
Score 2	12 200%	9 150%
Score 3	1 16.7%	1 16.7%
Score 4	25 416.7%	23 383.3%
Score 5	42 700%	48 800%
Score 6	7 116.7%	7 116.7%
Score 7	7 116.7%	2 33.3%
Score 8	2 33.3%	1 16.7%
Score 1	57 950%	52 866.7%
Score 2	6 100%	11 183.3%
Score 3	2 33.3%	7 116.7%
Score 4	14 233.3%	13 216.7%
Score 5	10 166.7%	7 116.7%
Score 6	1 16.7%	2 33.3%
Score 7	6 100%	5 83.3%
Score 8	6 100%	2 33.3%
Score 1	72 1200%	72 1200%
Score 2	4 66.7%	9 150%
Score 3	4 66.7%	6 100%
Score 4	4 66.7%	0 0%
Score 5	3 50%	4 66.7%
Score 6	1 16.7%	0 0%
Score 7	2 33.3%	3 50%
Score 8	12 200%	5 83.3%
Score 1	79 1316.7%	78 1300%
Score 2	5 83.3%	11 183.3%
Score 3	0 0%	1 16.7%
Score 4	1 16.7%	1 16.7%
Score 5	3 50%	1 16.7%
Score 6	0 0%	0 0%
Score 7	1 16.7%	2 33.3%
Score 8	13 216.7%	6 100%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Matching Placebo, Part 2: TD-0903 - 3 mg
	Comments	Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group on Day 7
	Type of Statistical Test	Other
	Comments	Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
Statistical Test of Hypothesis	p-Value	0.5918
	Comments
	Method	Van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.153
	Confidence Interval	(2-Sided) 95%; 0.692 to 1.922
	Parameter Dispersion	Type: Value:
	Estimation Comments	Between-group comparisons analyzed using a proportional odds model adjusting for baseline age strata (≤ 60 years vs. > 60 years).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part 2: Matching Placebo, Part 2: TD-0903 - 3 mg
	Comments	Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group on Day 14
	Type of Statistical Test	Other
	Comments	Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
Statistical Test of Hypothesis	p-Value	0.6978
	Comments
	Method	Van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.105
	Confidence Interval	(2-Sided) 95%; 0.651 to 1.878
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Between-group comparisons analyzed using a proportional odds model adjusting for baseline age strata (≤ 60 years vs. > 60 years).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part 2: Matching Placebo, Part 2: TD-0903 - 3 mg
	Comments	Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group on Day 21
	Type of Statistical Test	Other
	Comments	Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
Statistical Test of Hypothesis	p-Value	0.3990
	Comments
	Method	Van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.295
	Confidence Interval	(2-Sided) 95%; 0.702 to 2.388
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Between-group comparisons analyzed using a proportional odds model adjusting for baseline age strata (≤ 60 years vs. > 60 years).

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part 2: Matching Placebo, Part 2: TD-0903 - 3 mg
	Comments	Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group on Day 28
	Type of Statistical Test	Other
	Comments	Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
Statistical Test of Hypothesis	p-Value	0.6445
	Comments
	Method	Van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.180
	Confidence Interval	(2-Sided) 95%; 0.605 to 2.299
	Parameter Dispersion	Type: Value:
	Estimation Comments	Between-group comparisons analyzed using a proportional odds model adjusting for baseline age strata (≤ 60 years vs. > 60 years).

4. Secondary Outcome

Title	Part 2: Number of Participants Alive and Respiratory Failure-free on Day 28
Description	Defined as participants who were alive and did not require the use of any respiratory support (invasive mechanical ventilation, non-invasive positive pressure ventilation, high-flow oxygen devices, or oxygen supplementation) on Day 28.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.

Arm/Group Title	Part 2: Matching Placebo	Part 2: TD-0903 - 3 mg
Arm/Group Description	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.	TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.
Measure Participants	104	106
Count of Participants [Participants]	85 1416.7%	92 1533.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Matching Placebo, Part 2: TD-0903 - 3 mg
	Comments	Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group
	Type of Statistical Test	Other
	Comments	Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
Statistical Test of Hypothesis	p-Value	0.3005
	Comments	The p-value was calculated using the Cochran-Mantel-Haenszel chi-square test stratified by baseline age group (≤ 60 years vs. > 60 years)
	Method	Cochran-Mantel-Haenszel chi-square test
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	5.06
	Confidence Interval	(2-Sided) 95%; -4.50 to 14.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Day 1 to Day 28
Adverse Event Reporting Description	Safety analysis set - all participants who received at least one dose of study drug.
Arm/Group Title	Part 1: Matching Placebo		Part 1: TD-0903 - 1 mg		Part 1: TD-0903 - 3 mg		Part 1: TD-0903 - 10 mg		Part 2: Matching Placebo		Part 2: TD-0903 - 3 mg
Arm/Group Description	Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.		TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 1 mg.		TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg.		TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 10 mg.		Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.		TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system. Participants were administered the recommended dose of 3 mg based on the data from Part 1.
All Cause Mortality
	Part 1: Matching Placebo		Part 1: TD-0903 - 1 mg		Part 1: TD-0903 - 3 mg		Part 1: TD-0903 - 10 mg		Part 2: Matching Placebo		Part 2: TD-0903 - 3 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		13/102 (12.7%)		6/103 (5.8%)
Serious Adverse Events
	Part 1: Matching Placebo		Part 1: TD-0903 - 1 mg		Part 1: TD-0903 - 3 mg		Part 1: TD-0903 - 10 mg		Part 2: Matching Placebo		Part 2: TD-0903 - 3 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		1/6 (16.7%)		1/7 (14.3%)		0/6 (0%)		16/102 (15.7%)		10/103 (9.7%)
Cardiac disorders
Cardiac arrest	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/102 (2%)		0/103 (0%)
Ventricular fibrillation	0/6 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
General disorders
Multiple organ dysfunction syndrome	1/6 (16.7%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		1/102 (1%)		3/103 (2.9%)
Sudden death	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/102 (1%)		0/103 (0%)
Infections and infestations
COVID-19	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Bacterial sepsis	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/102 (1%)		1/103 (1%)
Septic shock	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/102 (1%)		0/103 (0%)
Systemic bacterial infection	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		1/103 (1%)
Investigations
Alanine aminotransferase increased	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		1/103 (1%)
Aspartate aminotransferase increased	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		1/103 (1%)
Nervous system disorders
Ischaemic stroke	0/6 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		0/102 (0%)		1/103 (1%)
Syncope	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/102 (1%)		0/103 (0%)
Renal and urinary disorders
Acute kidney injury	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		3/102 (2.9%)		0/103 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	2/6 (33.3%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		3/103 (2.9%)
Acute respiratory failure	0/6 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		3/102 (2.9%)		0/103 (0%)
Pulmonary embolism	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		4/102 (3.9%)		0/103 (0%)
Respiratory failure	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		5/102 (4.9%)		3/103 (2.9%)
Pneumothorax	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/102 (1%)		1/103 (1%)
Vascular disorders
Shock	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/102 (2%)		1/103 (1%)
Other (Not Including Serious) Adverse Events
	Part 1: Matching Placebo		Part 1: TD-0903 - 1 mg		Part 1: TD-0903 - 3 mg		Part 1: TD-0903 - 10 mg		Part 2: Matching Placebo		Part 2: TD-0903 - 3 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		4/6 (66.7%)		1/7 (14.3%)		5/6 (83.3%)		18/102 (17.6%)		15/103 (14.6%)
Blood and lymphatic system disorders
Lymphopenia	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Cardiac disorders
Bradycardia	0/6 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Sinus tachycardia	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		1/103 (1%)
Gastrointestinal disorders
Abdominal pain	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Diarrhoea	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		7/102 (6.9%)		3/103 (2.9%)
Nausea	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		1/102 (1%)		0/103 (0%)
Vomiting	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
General disorders
Pyrexia	1/6 (16.7%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Hepatobiliary disorders
Hepatic failure	0/6 (0%)		0/6 (0%)		1/7 (14.3%)		0/6 (0%)		2/102 (2%)		1/103 (1%)
Hypertransaminasaemia	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/102 (0%)		0/103 (0%)
Infections and infestations
Oropharyngeal candidiasis	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/102 (0%)		0/103 (0%)
Vascular device infection	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Investigations
Alanine aminotransferase increased	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		6/102 (5.9%)		5/103 (4.9%)
Metabolism and nutrition disorders
Hyperglycaemia	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		2/102 (2%)		3/103 (2.9%)
Hypokalaemia	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Nervous system disorders
Dysgeusia	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		1/102 (1%)		1/103 (1%)
Headache	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		1/103 (1%)
Tremor	0/6 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Psychiatric disorders
Depressed mood	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Depression	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Insomnia	0/6 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		1/103 (1%)
Renal and urinary disorders
Chronic kidney disease	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/6 (0%)		0/6 (0%)		0/7 (0%)		3/6 (50%)		1/102 (1%)		3/103 (2.9%)
Oropharyngeal pain	0/6 (0%)		1/6 (16.7%)		0/7 (0%)		1/6 (16.7%)		1/102 (1%)		0/103 (0%)
Pulmonary hypertension	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Upper-airway cough syndrome	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		0/102 (0%)		0/103 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/6 (16.7%)		0/6 (0%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		0/103 (0%)
Vascular disorders
Hypertension	0/6 (0%)		1/6 (16.7%)		0/7 (0%)		0/6 (0%)		0/102 (0%)		4/103 (3.9%)
Hypotension	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/6 (16.7%)		1/102 (1%)		1/103 (1%)

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.