STAIRS: Study of Varespladib in Patients Hospitalized With Severe COVID-19
Study Details
Study Description
Brief Summary
This is a 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability, and efficacy of oral varespladib, in addition to standard of care, in patients hospitalized with severe COVID-19 caused by SARS-CoV-2.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
The goals of this 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 study are to define a safe dose for the population and to assess the safety, tolerability, and efficacy of orally dosed varespladib to improve survival without respiratory failure in patients hospitalized with severe coronavirus disease 2019 (COVID-19), when given in addition to the institutional standard of care therapy.
Mortality rates of COVID-19 are strongly linked to acute respiratory distress syndrome (ARDS) which may be, additionally, correlated with elevations of secretory phospholipase 2 (sPLA2) and widespread loss of functioning lung tissue. Upregulation of sPLA2 is thought to be involved in the dysregulated inflammatory cascade pathways (increased markers of immune activation, also known as cytokine release syndrome) and enzymatic degradation of lung surfactant linked to the development of ARDS. It is believed that treatment with varespladib, a potent inhibitor of sPLA2, might prevent or mitigate progression of pulmonary dysfunction in COVID-19 patients by two mechanisms: suppression of sPLA2-induced inflammation and, uniquely, preservation of pulmonary surfactant by direct inhibition of the enzyme responsible for surfactant phospholipid degradation: sPLA2.
Data from previous phase 2 clinical trials of varespladib suggested it had potential to reduce mortality in severely septic patients with ARDS, particularly when treatment was initiated within 18 hours of identification of organ failure.
The study will be conducted in two parts. Both parts will be randomized and double-blind. Part 1 will be dose-finding in four parallel treatment groups randomized to treatment with varespladib (at 250 mg once daily [QD], twice daily [BID], or three times daily [TID] [250, 500, or 750 mg/day]) or placebo in a 5:5:5:3 ratio. After all participants in Part 1 have completed Day 28, a data safety monitoring board (DSMB) will review the safety results from Part 1, including all available safety data through Day 60, and will recommend the dose regimen to be used in Part 2. Part 2 will randomize an additional 72 participants to the dose regimen selected from Part 1 or placebo in a 1:1 ratio.
In both parts of the study, eligible participants will be enrolled and randomized to receive active varespladib or placebo in addition to institutional standard of care for 7 days.
Participants will be assessed daily per standard of care while hospitalized and on a regular basis after discharge. The Day 1, 4, 7, 14, and 28 visits will be performed in person (either at the hospital/site or via a home health provider) to assess safety, obtain blood and urine samples for laboratory tests, and obtain clinical outcome data. The Day 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 45, and 60 visits for discharged participants may be conducted by phone or via electronic patient-reported outcome (ePRO) devices.
Efficacy will be assessed by respiratory failure-free survival at Day 28. Safety will be assessed by evaluating adverse events (AEs), vital sign measurements, use of oxygen therapies, changes in levels of biomarkers, clinical laboratory test results, electrocardiograms (ECGs), physical examination findings, and concomitant medications and therapies. A DSMB will evaluate safety data at specified intervals during both parts of the trial.
Pharmacokinetic (PK) samples will be drawn from all participants in Part 1 and in a subset of approximately 14 participants in Part 2 in order to enable estimation of PK parameters in approximately 22 participants receiving active treatment with varespladib.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Varespladib: 250 mg QD For 7 days, and in addition to institutional standard of care, participants will take 250 mg varespladib in the morning. In order to maintain the blind, they will also take 1 placebo tablet in the afternoon and 1 placebo tablet in the evening. |
Drug: Varespladib
250 mg immediate-release oblong, white, film-coated tablet for oral administration
Other Names:
|
| Experimental: Varespladib: 250 mg BID For 7 days, and in addition to institutional standard of care, participants will take 250 mg varespladib in the morning and in the evening. In order to maintain the blind, they will also take 1 placebo tablet in the afternoon. |
Drug: Varespladib
250 mg immediate-release oblong, white, film-coated tablet for oral administration
Other Names:
|
| Experimental: Varespladib: 250 mg TID For 7 days, and in addition to institutional standard of care, participants will take 250 mg varespladib in the morning, in the afternoon, and in the evening. |
Drug: Varespladib
250 mg immediate-release oblong, white, film-coated tablet for oral administration
Other Names:
|
| Placebo Comparator: Placebo For 7 days, and in addition to institutional standard of care, participants will take 1 placebo tablet in the morning, in the afternoon, and in the evening. |
Drug: Placebo
Oral formulation matched to the oral varespladib tablet
|
Outcome Measures
Primary Outcome Measures
- Proportion of participants alive and free of respiratory failure at Day 28 [Baseline to Day 28]
The proportion of respiratory failure-free surviving participants in each Part 2 treatment group at Day 28 will be analyzed using the Mantel-Haenszel stratum-weighted estimator with treatment as a factor. 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 ([HFNC] heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) Noninvasive positive pressure ventilation ECMO, or Clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting because of resource limitation)
Secondary Outcome Measures
- Proportion of subjects using HFNC within the first 28 days after randomization [From randomization through Day 28]
The proportion of subjects using HFNC within the first 28 days after randomization.
- Time to initiation of use of HFNC within the first 28 days after randomization [From randomization through Day 28]
Number of days to initiation of use of HFNC within the first 28 days after randomization.
- Duration of use of HFNC within the first 28 days after randomization [From randomization through Day 28]
Number of days of use of HFNC within the first 28 days after randomization.
- Proportion of subjects using noninvasive respiratory support within the first 28 days after randomization [From randomization through Day 28]
Proportion of subjects using noninvasive respiratory support within the first 28 days after randomization.
- Time to initiation of noninvasive respiratory support within the first 28 days after randomization [From randomization through Day 28]
Number of days to initiation of noninvasive respiratory support within the first 28 days after randomization.
- Duration of noninvasive respiratory support within the first 28 days after randomization [From randomization through Day 28]
Number of days of noninvasive respiratory support within the first 28 days after randomization.
- Proportion of subjects using mechanical ventilation within the first 28 days after randomization [From randomization through Day 28]
Proportion of subjects using mechanical ventilation within the first 28 days after randomization.
- Time to initiation of subjects using mechanical ventilation within the first 28 days after randomization [From randomization through Day 28]
Number of days to initiation of subjects using mechanical ventilation within the first 28 days after randomization.
- Duration of use by subjects of mechanical ventilation within the first 28 days after randomization [From randomization through Day 28]
Number of days of use by subjects of mechanical ventilation within the first 28 days after randomization.
- Number of days of oxygen support through Day 28 after randomization [From randomization through Day 28]
Number of days of oxygen support through Day 28 after randomization.
- SpO₂ through Day 28 after randomization [From randomization through Day 28]
Changes in SpO₂ (percentage) from randomization through Day 28.
- Proportion of participants remaining free of mechanical ventilation or ECMO throughout the 28 days after randomization [From randomization through Day 28]
Proportion of participants remaining free of mechanical ventilation or ECMO throughout the 28 days after randomization.
- Number of ventilator-free days through Day 28 after randomization [From randomization through Day 28]
Number of ventilator-free days through Day 28 after randomization.
- Number of hospitalization days through Day 28 after randomization [From randomization through Day 28]
Number of hospitalization days through Day 28 after randomization.
- Clinical status as measured by the World Health Organization (WHO) 9-point ordinal scale from baseline through Day 60 [From baseline through Day 60]
Changes from baseline in clinical status as measured by the WHO 9-point ordinal scale, where 0 = no clinical or virological evidence of infection and 8 = death
- Number of vasopressor-free days through Day 28 after randomization [From randomization through Day 28]
Number of vasopressor-free days through Day 28 after randomization.
- Number of days without renal stabilization and/or replacement through Day 28 after randomization [From randomization through Day 28]
Number of days without renal stabilization and/or replacement through Day 28 after randomization.
- Number of days at elevated level of care (ICU) through Day 28 after randomization [From randomization through Day 28]
Number of days at elevated level of care (ICU) through Day 28 after randomization.
- Number of healthcare encounters through Day 28 after randomization [From randomization through Day 28]
Number of healthcare encounters through Day 28 after randomization.
- Proportion of subjects with all-cause mortality through Day 60 [From randomization through Day 60]
Proportion of subjects who experience all-cause mortality from randomization through Day 60.
- Time to all-cause mortality through Day 60 [From randomization through Day 60]
Time to all-cause mortality for all subjects who experience the event from randomization through Day 60.
- Number of organ failure-free days through Day 28 after randomization [From randomization through Day 28]
Number of organ failure-free days through Day 28 after randomization.
- Incidence and severity of AEs, SAEs, and AEs leading to discontinuation of IP [From providing informed consent through Day 60]
- Changes in vital signs: SpO₂ [From providing informed consent through Day 60]
Changes in SpO₂ (percentage) from providing informed consent through Day 60.
- Changes in vital signs: respiratory rate [From providing informed consent through Day 60]
Changes in respiratory rate (breaths per minute) from providing informed consent through Day 60.
- Changes in vital signs: body temperature [From providing informed consent through Day 60]
Changes in body temperature (degrees Celsius) from providing informed consent through Day 60.
- Changes in vital signs: heart rate [From providing informed consent through Day 60]
Changes in heartrate (beats per minute) from providing informed consent through Day 60.
- Changes in vital signs: blood pressure [From providing informed consent through Day 60]
Changes in blood pressure (systolic and diastolic blood pressure; mmHg) from providing informed consent through Day 60.
- Changes in levels of biomarkers: cardiac troponin [From providing informed consent through Day 28]
Changes in levels of cardiac troponin
- Changes in levels of biomarkers: C-reactive protein (CRP) [From providing informed consent through Day 28]
Changes in levels of CRP
- Changes in levels of biomarkers: D-dimer [From providing informed consent through Day 28]
Changes in levels of D-dimer
- Changes in levels of biomarkers: ferritin [From providing informed consent through Day 28]
Changes in levels of ferritin
- Changes in clinical laboratory evaluations: chemistry [From providing informed consent through Day 28]
The percentage of subjects with at least 1 post-baseline potentially clinically significant abnormality.
- Changes in clinical laboratory evaluations: coagulation [From providing informed consent through Day 28]
The percentage of subjects with at least 1 post-baseline potentially clinically significant abnormality.
- Changes in clinical laboratory evaluations: hematology [From providing informed consent through Day 28]
The percentage of subjects with at least 1 post-baseline potentially clinically significant abnormality.
- Changes in clinical laboratory evaluations: urinalysis [From providing informed consent through Day 28]
The percentage of subjects with at least 1 post-baseline potentially clinically significant abnormality.
- Changes in 12-lead ECGs [From providing informed consent through Day 28]
The percentage of subjects with an investigator interpretation of ECG results as abnormal clinically significant.
Other Outcome Measures
- Participant-reported quality-of-life assessment using the 12-item Short Form Survey (SF-12) at Day 28 after randomization [Day 28]
Changes from baseline to Day 28 in SF-12 scores, which range from 0 to 100, with higher scores indicating better physical and mental health functioning.
- Activity of sPLA2 within blood samples collected as clinically required from treatment initiation to Day 28 after randomization [From treatment initiation through Day 28]
Changes in observed sPLA2 values
- Changes in PK parameters: area-under-the-curve (AUC) [Day 1 through Day 3]
Change in AUC from Day 1 through Day 3
- Changes in PK parameters: maximum concentration (Cmax) [Day 1 through Day 3]
Change in Cmax from Day 1 through Day 3
- Changes in PK parameters: time of Cmax (Tmax) [Day 1 through Day 3]
Change in Tmax from Day 1 through Day 3
Eligibility Criteria
Criteria
Inclusion Criteria:
- Participant is hospitalized with severe COVID-19 illness, defined in accordance with the Food and Drug Administration (FDA) Guidance for Industry - COVID-19: Developing
Drugs and Biological Products for Treatment or Prevention (May 2020):
-
Severe illness:
-
Symptoms suggestive of severe systemic illness with COVID-19, which could include any symptom of moderate illness or shortness of breath at rest, or respiratory distress
- Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory rate ≥30 per minute, heart rate ≥125 per minute, SpO₂ ≤93% on room air at sea level or partial pressure of oxygen PaO₂/fraction of inspired oxygen FiO₂ <300.
-
Participant has a positive virologic nucleic acid amplification test (NAAT) indicating SARS-CoV-2 infection in a sample collected <72 hours prior to randomization.
-
Participant is between the ages of 18 and 80 years at the time of enrollment.
-
Participant provides informed consent prior to initiation of any study procedures.
-
Participant agrees to not participate in another clinical trial for the treatment of COVID 19 or SARS-CoV-2 through Day 28.
-
Participant has adequate hematologic status (in the absence of transfusion and growth factor support for at least 28 days), defined as follows:
-
Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L
-
Platelet count ≥75 × 10⁹/L
-
Hemoglobin ≥9 g/dL.
-
Participant has an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
Exclusion Criteria:
- Participant has mild, moderate, or critical COVID-19 defined in accordance with the
FDA Guidance for Industry:
-
Mild COVID-19:
-
Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnea
- No clinical signs indicative of moderate, severe, or critical severity
-
Moderate COVID-19:
-
Symptoms of moderate illness with COVID-19, which could include any symptom of mild illness (fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms) or shortness of breath with exertion
-
Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥20 breaths per minute, peripheral oxygen saturation (SpO₂) >93% on room air at sea level, heart rate ≥90 beats per minute
-
No clinical signs indicative of severe or critical illness
-
Critical COVID-19:
-
Respiratory failure defined based on resource utilization requiring at least one of the following:
-
Endotracheal intubation and mechanical ventilation
-
Oxygen delivered by high-flow nasal cannula ([HFNC] heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5)
-
Noninvasive positive pressure ventilation
-
ECMO, or
-
Clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation)
-
Shock (defined by systolic blood pressure <90 mmHg, or diastolic blood pressure <60 mmHg or requiring vasopressors)
-
Multi-organ dysfunction/failure.
-
Participant has taken investigational medications within 7 days or 5 half-lives prior to enrollment, whichever is shorter.
-
Participant has required any new form of sedation, anxiolysis or central nervous system (CNS) depressant within the 48 hours prior to enrollment that would interfere with neurologic assessments at enrollment.
-
Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension.
-
Participant has chronic respiratory failure not associated with COVID-19, defined as prior need for home oxygen, need for home noninvasive positive-pressure ventilation (NIPPV) for reasons other than isolated sleep apnea, or other signs of chronic respiratory failure, in the investigator's judgment.
-
Upper gastrointestinal (GI) bleed evidenced by hematemesis, "coffee-ground" emesis or nasogastric aspirate, or hematochezia thought to originate from upper GI tract.
-
Participant has abnormal liver function defined as any 2 of the following at screening:
-
Total bilirubin ≥2 × ULN
-
Alanine aminotransferase (ALT) ≥3 × ULN
-
Aspartate aminotransferase (AST) ≥3 × ULN
-
Alkaline phosphatase (ALP) >3 × ULN
-
Gamma-glutamyl transferase (GGT) >3 × ULN
-
Participant has an estimated glomerular filtration rate (eGFR) <60 mL/min.
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Participant has a known allergy or significant adverse reaction to varespladib-methyl or related compounds.
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Participant is considered by the investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns; or has any serious medical condition or clinically significant laboratory, ECG, vital sign, or physical examination abnormality that would prevent study participation or place the participant at significant risk, as judged by the Investigator.
-
Participant is breast-feeding, pregnant, has a positive serum hCG pregnancy test, or is not willing to use a highly effective method of contraception for 14 days after treatment. Highly effective methods of contraception are as follows:
-
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
-
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
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Intrauterine device, intrauterine hormone-releasing system
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Bilateral tubal occlusion
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Vasectomized partner
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Sexual abstinence
-
Double-barrier method (condoms, sponge, diaphragm, with spermicidal jellies, or cream).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ventura Clinical Trials | Ventura | California | United States | 93003 |
| 2 | University of Miami Miller School of Medicine | Miami | Florida | United States | 33136 |
| 3 | Cordova Research Institute | Miami | Florida | United States | 33155 |
| 4 | Westchester Research Center at Westchester General Hospital | Miami | Florida | United States | 33155 |
| 5 | Franciscan Alliance | Munster | Indiana | United States | 46321 |
| 6 | The Brigham and Women's Hospital Emergency Medicine | Boston | Massachusetts | United States | 02115 |
| 7 | Cooper University Hospital | Camden | New Jersey | United States | 08103 |
| 8 | Ascension St. John Clinical Research Institute | Tulsa | Oklahoma | United States | 74104 |
Sponsors and Collaborators
- Ophirex, Inc.
- Premier Research Group plc
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Additional Information:
- In patients of COVID-19, what are the symptoms and clinical features of mild and moderate cases?
- Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19)
Publications
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- Englert JA, Bobba C, Baron RM. Integrating molecular pathogenesis and clinical translation in sepsis-induced acute respiratory distress syndrome. JCI Insight. 2019 Jan 24;4(2). pii: 124061. doi: 10.1172/jci.insight.124061. [Epub ahead of print] Review.
- Food and Drug Administration. Guidance for Industry on COVID-19: Developing Drugs and Biological Products for Treatment or Prevention, May 2020.
- Gandhi RT, Lynch JB, Del Rio C. Mild or Moderate Covid-19. N Engl J Med. 2020 Oct 29;383(18):1757-1766. doi: 10.1056/NEJMcp2009249. Epub 2020 Apr 24. Review.
- Griffiths MJD, McAuley DF, Perkins GD, Barrett N, Blackwood B, Boyle A, Chee N, Connolly B, Dark P, Finney S, Salam A, Silversides J, Tarmey N, Wise MP, Baudouin SV. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Respir Res. 2019 May 24;6(1):e000420. doi: 10.1136/bmjresp-2019-000420. eCollection 2019.
- Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum in: Lancet. 2020 Jan 30;:.
- Mirastschijski U, Dembinski R, Maedler K. Lung Surfactant for Pulmonary Barrier Restoration in Patients With COVID-19 Pneumonia. Front Med (Lausanne). 2020 May 22;7:254. doi: 10.3389/fmed.2020.00254. eCollection 2020.
- Rezoagli E, Fumagalli R, Bellani G. Definition and epidemiology of acute respiratory distress syndrome. Ann Transl Med. 2017 Jul;5(14):282. doi: 10.21037/atm.2017.06.62. Review.
- Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585. Erratum in: JAMA. 2021 Mar 16;325(11):1113.
- Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996 Mar;34(3):220-33.
- Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-481. doi: 10.1016/S2213-2600(20)30079-5. Epub 2020 Feb 24. Erratum in: Lancet Respir Med. 2020 Apr;8(4):e26.
- OPX-PR-02
- W81XWH20C0066