TD-0903 for ALI Associated With COVID-19

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Lung Injury (ALI) Associated With COVID-19; Lung Inflammation Associated With COVID-19
• Intervention / Treatment: Drug: Placebo; Drug: TD-0903

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 Type: Interventional
• Enrollment (Actual): 235
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Bela Vista, Brazil, 01323-001
    • Theravance Biopharma Investigational Site
  • Botucatu, Brazil, 18618-686
    • Theravance Biopharma Investigational Site
  • Caxias Do Sul, Brazil, 95070-560
    • Theravance Biopharma Investigational Site
  • São José Do Rio Preto, Brazil, 15090-000
    • Theravance Biopharma Investigational Site
• Finland
  • Helsinki, Finland, 00290
    • Theravance Biopharma Investigational Site
  • Turku, Finland, 20520
    • Theravance Biopharma Investigational Site
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, MD-2025
    • Theravance Biopharma Investigational Site
• Romania
  • Bucharest, Romania, 21105
    • Theravance Biopharma Investigational Site
• Ukraine
  • Brovary, Ukraine, 07 400
    • Theravance Biopharma Investigational Site
  • Kyiv, Ukraine, 01 103
    • Theravance Biopharma Investigational Site
  • Kyiv, Ukraine, 01 601
    • Theravance Biopharma Investigational Site
• United Kingdom
  • Manchester, United Kingdom, M23 9QZ
    • Theravance Biopharma Investigational Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Theravance Biopharma Investigational Site
  • Colorado
    • Denver, Colorado, United States, 80220
      • Theravance Biopharma Investigational Site
  • Florida
    • Sebring, Florida, United States, 33870
      • Theravance Biopharma Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02135
      • Theravance Biopharma Investigational Site
    • Fall River, Massachusetts, United States, 02720
      • Theravance Biopharma Investigational Site
  • Montana
    • Kalispell, Montana, United States, 59901
      • Theravance Biopharma Investigational Site
  • New York
    • Glens Falls, New York, United States, 12801
      • Theravance Biopharma Investigational Site
    • Hyde Park, New York, United States, 11040
      • Theravance Biopharma
  • Ohio
    • Columbus, Ohio, United States, 43214
      • Theravance Biopharma Investigational Site
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Theravance Biopharma Investigational Site
    • Bethlehem, Pennsylvania, United States, 18015
      • Theravance Biopharma Investigational Site
  • Washington
    • Wenatchee, Washington, United States, 98801
      • Theravance Biopharma Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Theravance Biopharma

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2020
• Primary Completion (Actual): April 21, 2021
• Study Completion (Actual): April 21, 2021

Study Registration Dates

• First Submitted: May 22, 2020
• First Submitted That Met QC Criteria: May 22, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Actual): March 17, 2022
• Last Update Submitted That Met QC Criteria: March 15, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Pneumonia; COVID-19; ARDS; Coronavirus Disease 2019; ALI; Acute lung injury; inflammatory lung conditions; Inflammatory lung disease
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; Wounds and Injuries; Thoracic Injuries; COVID-19; Inflammation; Pneumonia; Acute Lung Injury; Lung Injury
• Other Study ID Numbers: 0188; 2020-001807-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.

Drug and device information, study documents

• 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