Acute Lung Injury (ALI) Associated With COVID-19, Lung Inflammation Associated With COVID-19
Conditions
Keywords
Acute lung injury, ALI, COVID-19, Coronavirus Disease 2019, inflammatory lung conditions, Inflammatory lung disease, ARDS, SARS-CoV-2, Pneumonia
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.
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.
Interventions
DRUGTD-0903
Study Drug to be administered by inhalation
DRUGPlacebo
Placebo to be administered by inhalation
Sponsors
Theravance Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Pharmacist & Sponsor are not blinded for Part 1. Sponsor is blinded for Part 2. Pharmacist is not blinded for Part 2.
Intervention model description
Parallel group, randomized, double-blind, placebo-controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
Countries
Brazil, Finland, Moldova, Romania, Ukraine, United Kingdom, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Matching Placebo Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system. | 6 |
| Part 1: TD-0903 - 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 1 mg. Participants were administered a 2 mg loading dose as the total dose on Day 1. | 6 |
| Part 1: TD-0903 - 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 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1. | 7 |
| Part 1: TD-0903 - 10 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. | 6 |
| Part 2: Matching Placebo Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system. | 104 |
| Part 2: TD-0903 - 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 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1. | 106 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 0 | 0 | 13 | 8 |
| Overall Study | Discontinued Prior to Treatment | 0 | 0 | 0 | 0 | 2 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Miscellaneous | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Part 1: TD-0903 - 1 mg | Part 1: TD-0903 - 3 mg | Part 1: TD-0903 - 10 mg | Part 1: Matching Placebo | Part 2: Matching Placebo | Part 2: TD-0903 - 3 mg |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 89 Participants | 3 Participants | 2 Participants | 1 Participants | 3 Participants | 34 Participants | 46 Participants |
| Age, Categorical Between 18 and 65 years | 146 Participants | 3 Participants | 5 Participants | 5 Participants | 3 Participants | 70 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 10 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 204 Participants | 6 Participants | 7 Participants | 6 Participants | 6 Participants | 90 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 230 Participants | 6 Participants | 7 Participants | 6 Participants | 5 Participants | 102 Participants | 104 Participants |
| Sex: Female, Male Female | 90 Participants | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 41 Participants | 41 Participants |
| Sex: Female, Male Male | 145 Participants | 5 Participants | 4 Participants | 5 Participants | 3 Participants | 63 Participants | 65 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 1 / 6 | 0 / 7 | 0 / 6 | 13 / 102 | 6 / 103 |
| other Total, other adverse events | 6 / 6 | 4 / 6 | 1 / 7 | 5 / 6 | 18 / 102 | 15 / 103 |
| serious Total, serious adverse events | 3 / 6 | 1 / 6 | 1 / 7 | 0 / 6 | 16 / 102 | 10 / 103 |
Outcome results
Primary
Part 2: Number of Respiratory Failure-free Days (RFDs) From 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).
Time frame: Randomization to Day 28
Population: ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2: Matching Placebo | Part 2: Number of Respiratory Failure-free Days (RFDs) From Randomization to Day 28 | 21.0 days |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Respiratory Failure-free Days (RFDs) From Randomization to Day 28 | 21.0 days |
Comparison: Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.p-value: 0.613795% CI: [0.706, 1.846]Van Elteren test
Secondary
Part 2: Change From Baseline in SaO2/FiO2 Ratio on Day 7
SaO2/FiO2 ratio was calculated as SaO2 divided by FiO2.
Time frame: Baseline and Day 7
Population: ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 2: Matching Placebo | Part 2: Change From Baseline in SaO2/FiO2 Ratio on Day 7 | 88.97 ratio measure | Standard Error 7.769 |
| Part 2: TD-0903 - 3 mg | Part 2: Change From Baseline in SaO2/FiO2 Ratio on Day 7 | 88.46 ratio measure | Standard Error 7.654 |
Comparison: Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Groupp-value: 0.96295% CI: [-21.95, 20.92]Mixed model repeated measures model
Secondary
Part 2: Number of Participants Alive and Respiratory Failure-free on 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.
Time frame: Day 28
Population: ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 2: Matching Placebo | Part 2: Number of Participants Alive and Respiratory Failure-free on Day 28 | 85 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants Alive and Respiratory Failure-free on Day 28 | 92 Participants |
Comparison: Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Groupp-value: 0.300595% CI: [-4.5, 14.63]Cochran-Mantel-Haenszel chi-square test
Secondary
Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on 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
Time frame: Days 7, 14, 21 and 28
Population: ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 1 | 57 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 2 | 12 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 3 | 1 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 4 | 25 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 5 | 42 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 6 | 7 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 7 | 7 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 8 | 2 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 1 | 6 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 2 | 6 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 3 | 2 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 4 | 14 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 5 | 10 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 6 | 1 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 7 | 6 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 8 | 6 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 1 | 72 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 2 | 4 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 3 | 4 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 4 | 4 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 5 | 3 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 6 | 1 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 7 | 2 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 8 | 12 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 1 | 79 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 2 | 5 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 3 | 0 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 4 | 1 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 5 | 3 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 6 | 0 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 7 | 1 Participants |
| Part 2: Matching Placebo | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 8 | 13 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 8 | 6 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 1 | 8 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 1 | 72 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 2 | 9 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 1 | 78 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 3 | 1 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 2 | 9 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 4 | 23 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 5 | 1 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 5 | 48 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 3 | 6 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 6 | 7 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 2 | 11 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 7 | 2 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 4 | 0 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 7 | Score 8 | 1 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 7 | 2 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 1 | 52 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 5 | 4 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 2 | 11 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 3 | 1 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 3 | 7 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 6 | 0 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 4 | 13 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 6 | 0 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 5 | 7 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 7 | 3 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 6 | 2 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 28 | Score 4 | 1 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 7 | 5 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 21 | Score 8 | 5 Participants |
| Part 2: TD-0903 - 3 mg | Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 | Day 14 | Score 8 | 2 Participants |
Comparison: Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group on Day 7p-value: 0.591895% CI: [0.692, 1.922]Van Elteren test
Comparison: Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group on Day 14p-value: 0.697895% CI: [0.651, 1.878]Van Elteren test
Comparison: Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group on Day 21p-value: 0.39995% CI: [0.702, 2.388]Van Elteren test
Comparison: Part 2: TD-0903 - Parallel-Group 3 mg versus Part 2: Matching Placebo - Parallel-Group on Day 28p-value: 0.644595% CI: [0.605, 2.299]Van Elteren test