TD-0903 for ALI Associated With COVID-19

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Lung Injury (ALI) Associated With COVID-19, Lung Inflammation Associated With COVID-19

Intervention / Treatment
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* Drug: TD-0903
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: Methotrexate, cyclosporine, mycophenolate, tacrolimus, penicillamine, or sulfasalazine within 2 weeks prior to enrollment Azathioprine or cyclophosphamide within 12 weeks prior to enrollment Monoclonal antibodies targeting B cells (e.g., rituximab) within 12 weeks prior to enrollment 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel group, randomized, double-blind, placebo-controlled
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Randomization to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Change From Baseline in SaO2/FiO2 Ratio on Day 7 | SaO2/FiO2 ratio was calculated as SaO2 divided by FiO2. | Baseline and Day 7 | 
| 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 | Days 7, 14, 21 and 28 | 
| 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. | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, Acute lung injury, ALI, COVID-19, Coronavirus Disease 2019, inflammatory lung conditions, Inflammatory lung disease, SARS-CoV-2, Pneumonia