LSALT Peptide vs. Placebo to Prevent ARDS and Acute Kidney Injury in Patients Infected With SARS-CoV-2 (COVID-19)
Study Details
Study Description
Brief Summary
To evaluate the proportion of subjects alive and free of respiratory failure (e.g. need for non-invasive or invasive mechanical ventilation, high flow oxygen, or ECMO) and free of the need for continued renal replacement therapy (RRT) on Day 28. The need for continued RRT at Day 28 will be defined as either dialysis in the past 3 days (Day 26, 27, or 28) or an eGFR on Day 28 <10 mL/min/1.73 m2.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This is a global, multicenter, randomized, double-blind, placebo-controlled, proof of concept study of LSALT peptide as prevention of acute respiratory distress syndrome (ARDS) and acute kidney injury in patients infected with SARS-CoV-2 (COVID-19). Following screening and after establishing baseline parameters such as lung and renal function, clinical chemistries, coagulation, hematology, and urinalysis, and satisfying all inclusion and exclusion criteria, patients will be randomized to one of two blinded treatment regimens:
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100 mL of 5 mg IV LSALT peptide infusion over 2 hours daily
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100 mL drug-free IV saline infusion over 2 hours daily.
Thirty (30) patients will be randomized to active drug (LSALT peptide) and 30 patients will be randomized to matching placebo. Patients and, if necessary, the Legal Authorized Representative (LAR), the Investigational Staff, and the Sponsor and its representatives will not know the randomization schemata. The Pharmacist at the site will be unblinded and prepare drug/placebo for injection.
This double-blind, placebo-controlled, proof-of-concept Phase 2 study is designed to evaluate LSALT peptide compared with placebo in a defined number of adult hospitalized patients with the diagnosis of COVID-19. This is a 1:1 randomization comparing 5 mg LSALT peptide daily with matching placebo. LSALT peptide or drug-free saline will begin immediately once the patient meets all inclusion/exclusion criteria at the start of hospitalization and followed with daily physical exams, blood chemistries, coagulation, and hematology; ECGs will be recorded at Baseline, Day 3, and EOS. Patients will be maintained on standard of care, including prophylaxis or treatment for VTE, per institutional guidelines throughout the study. Questionnaires (APACHE II, SOFA, Berlin Definition, and modified Medical Research Council Dyspnea Scale) will be assessed at Baseline, when clinically indicated, and at EOT and EOS. Dosing will end on Day 14, or at cure or increasing severity of ARDS, or at death. Patients will be followed clinically, and safety and efficacy measures will be recorded at end of study (EOS; Day 28) or death, whichever occurs first.
Duration of therapy will be a maximum of 14 days. Patients will be maintained on the standard of care for the treatment of COVID-19 as defined by the institutional guidelines. Co-morbidities and concomitant medications will be reviewed daily and documented in the patient's eCRF. The risk of venous thromboembolism (VTE), a potential consequence of SARS-CoV-2 infection, will be assessed daily and prophylaxis will be included as standard of care for every patient. Please refer to antithrombotic therapy in patients with COVID-19 (COVID-19 Treatment Guidelines Panel, 12-May-2020).
A Data and Safety Monitoring Board (refer to the DSMB Charter) will evaluate patients on a continuing basis for primarily safety assessments but also the adequacy of treatment based upon clinical data of the patient, target drug concentrations, and data obtained from the AB001 PK study in healthy subjects to offer recommendations to the Sponsor. In the absence of adverse events or any safety issues during the course of study, the DSMB may recommend continuance or suspension of the study due to futility or safety issues. The DSMB will meet at least monthly if not more frequently based upon enrollment throughout the study period. Per protocol, at no time will patients be dosed for more than 14 days of therapy. The DSMB Charter will outline all processes for changes to the protocol and protocol design prior to the first patient being enrolled into study.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo 100 mL drug-free IV saline infusion over 2 hours daily |
Drug: Placebo
0.9% saline solution
|
| Experimental: LSALT 100 mL of 5 mg IV LSALT peptide infusion over 2 hours daily |
Drug: LSALT peptide
LSALT, a peptide drug with the sequence NH3-LSALTPSPSWLKYKAL-COOH, binds to dipeptidase-1 (DPEP-1) but does not inhibit its biologic enzymatic activity, potentially minimizing off-target or other adverse effects. LSALT peptide inhibits leukocyte recruitment in multiple experimental disease models through the direct inhibition of leukocyte adhesion to DPEP-1 present in lungs, kidney, and liver. DPEP-1 represents a new molecular pathway for leukocyte adhesion discovered by Arch Biopartners scientists.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Development of Acute Respiratory Distress Syndrome (ARDS) and Other Organ Injuries [28 days]
To evaluate the efficacy of intravenous LSALT peptide plus standard of care to prevent the progression of COVID-19 to mild, moderate or severe ARDS, acute kidney injury, cardiomyopathy, acute liver injury, coagulopathy, or death in patients infected with SARS-CoV-2 compared with placebo plus standard of care.
Secondary Outcome Measures
- Ventilation-free days [28 days]
High-frequency oscillatory ventilation, with its rapid delivery of low tidal volumes and a respiratory rate in the range of 60 to 900 breaths/minute, has also been utilized in ARDS patients.
- Time on nasal cannula or oxygen masks [28 days]
Oxygen therapy provided as non-invasive therapy for ARDS patients.
- 28 day mortality - all cause and attributable [28 days]
28 day mortality - all cause and attributable
- ICU and hospitalization length of stay (days) [28 days]
ICU and hospitalization length of stay (days)
- SARS-CoV2 testing [28 days]
Swab (nasopharyngeal, nasal, throat, sputum, or lower respiratory tract) at baseline (Day 1) and every 3 days thereafter until eradication → virologic clearance rate
- Need and duration for extracorporeal membrane oxygenation (ECMO) [28 days]
Extracorporeal membrane oxygenation (ECMO) is often used for severe ARDS to allow lung healing/repair and reverse respiratory failure.
- Vasopressor free days [28 days]
Vasopressor free days
- Radiographic pulmonary assessments [28 days]
Chest X-rays performed at Baseline, Day 3, at clinical improvement, and end-of-treatment (EOT) and study (EOS) to determine presence of bilateral opacities.
- Change in modified Medical Research Council (mMRC) dyspnea and Sequential Organ Failure Assessment (SOFA) scores [28 days]
Change in daily mMRC dyspnea and SOFA scores (0 to 4) with 4 being the most severe outcome
- Incidence of non-lung disorders [28 days]
Incidence of other organ (non-lung) disorders
- Measures of liver dysfunction [28 days]
Change in liver function tests (ALT, AST, and total bilirubin levels) from baseline
- Measures of kidney dysfunction [28 days]
Change in SCr and eGFR from baseline
- Measures of cardiac dysfunction [28 days]
Change in highly-sensitive troponin (hs-troponin) from baseline
- Measures of coagulopathies [28 days]
Change from baseline ACT, aPTT, and/or PT/INR levels
- Changes in immunogenic responses [28 days]
Change in baseline antiviral immunoglobulins (IgG, IgM) at EOS.
- Healthcare outcomes [28 days]
Changes in total healthcare costs from admission to discharge between treatment groups.
- Molecular changes in pro-inflammatory pathways [28 days]
Change in serum cytokines including IL-1α, IL-1ß, IL-1ra, IL-5, IL-6, IL-8, IL-12, TNFα, CXCL10/IP10, MCP-3, and ferritin drawn at the same time as LSALT peptide levels
- Pharmacokinetics of LSALT peptide [28 days]
Pharmacokinetics of LSALT peptide over the study period.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male and female hospitalized patients between 45 and 80 years of age at time of consent.
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Clinical and laboratory diagnosis of COVID-19 infection. Patients must be positive for the SARS-CoV-2 by Real-Time Reverse Transcriptase (RT)-PCR
Diagnostic Panel as well as two of the following three symptoms:
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Fever (oral temperature ≥ 100.4 °F [> 38 °C]) with or without chills
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Dyspnea or difficulty breathing (≤ 2 on mMRC dyspnea scale)
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Nonproductive cough
- Patients must present with moderate to severe illness as defined below:
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Moderate illness: Patients who have evidence of lower respiratory disease by clinical assessment or imaging and an oxygen saturation (SpO2) > 93% on room air at sea level
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Severe illness: Patients who have a respiratory frequency > 30 breaths per minute (bpm), SpO2 ≤ 93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300, or lung infiltrates > 50%.
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APACHE II score < 20
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Therapies which have been shown to be beneficial and are included in standard COVID-19 treatment guidelines (e.g. those of WHO or NIH) are permitted
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Sexually active women of child-bearing potential (WCBP) must be using a medically acceptable method of birth control throughout the study and for at least 1 day following the end of study, and have a negative urine pregnancy test at the Screening visit. A WCBP is defined as a female who is biologically capable of becoming pregnant. A medically acceptable method of birth control includes intrauterine devices in place for at least 3 months, surgical sterilization, or the implant. In patients who are not sexually active, abstinence is an acceptable form of birth control and urine will be tested per protocol. Women who are of nonchild-bearing potential, i.e., post-menopause, must have this condition captured in their medical history. Pregnant women and nursing mothers are excluded from this study.
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Patient or LAR is available and willing to give written informed consent, after being properly informed of the nature and risks of the study and prior to engaging in any study-related procedures.
Exclusion Criteria:
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Known sensitivity, allergy, or previous exposure to LSALT peptide.
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Exposure to any investigational drug or device <90 days prior to entry into study.
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Treatment with immunomodulators or immunosuppressant drugs, including but not limited to IL-6 inhibitors, TNF inhibitors, anti-IL-1 immunomodulators, and JAK inhibitors within five half-lives or 30 days (whichever is longer) prior to randomization and throughout the study period. However, should any of these treatments become standard-of-care and incorporated into clinical treatment guidelines (e.g. those of WHO or NIH), the treatment is permitted.
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Anticipated transfer to another hospital or medical center within 72 hours, which is not a study site.
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Uncontrolled of poorly treated active hepatitis B (HBV), hepatitis C (HepC), or HIV infection. Those subjects who are positive for HBV, HepC, or HIV but are well-controlled with low viral loads are allowed to participate in this study:
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HBV low viral load defined as <20,000 IU/mL
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HepC low viral load defined as <800,000 IU/mL
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HIV low viral load defined as <5000 copies/mL
- Participation in another drug or device study at any time during this study, for example:
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Ulinastatin 200,000 IU or greater
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High dose intravenous Vitamin C
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Budesonide and formoterol
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Bevacizumab to prevent ARDS
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Dornase alfa to reduce hypoxemia in ventilated trauma patients.
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As indicated in the inclusion criteria, pregnant female patients are excluded from study. Further, female patients who are nursing are excluded from study.
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Has any medical condition considered to be clinically significant and could potentially affect patient safety or study outcome, including but not limited to:
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Acute or chronic kidney disease (stage-4 or -5 renal impairment; eGFR<30 mL/min/1.73 m2 or hemodialysis)
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End-stage malignancy undergoing treatment
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Immunocompromised patients or those with medical/surgical conditions (e.g., solid organ transplantation) which require chronic immunosuppression
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Chronic hematologic disease which, in the opinion of the PI, prohibits the patient from entering into study
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Acute liver injury with AST and/or ALT levels greater than 3x ULN
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History of coagulopathy within the last year as defined by abnormal ACT, aPTT, and/or PT/INR values at least 2-fold outside normal limits, and/or
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End-stage lung disease, acute lung injury, severe chronic obstructive pulmonary disease (COPD), or mechanical ventilation.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | VA San Diego Healthcare System | San Diego | California | United States | 92161 |
| 2 | Broward Health Medical Center | Fort Lauderdale | Florida | United States | 33316 |
| 3 | LSU Health Shreveport | Shreveport | Louisiana | United States | 71103 |
| 4 | University of Calgary - Foothills Medical Centre | Calgary | Alberta | Canada | |
| 5 | University of Calgary - Peter Lougheed Centre | Calgary | Alberta | Canada | |
| 6 | Ankara City Hospital | Ankara | Turkey | ||
| 7 | Istanbul University Cerrahpasa | Istanbul | Turkey | 34098 |
Sponsors and Collaborators
- Arch Biopartners Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AB002