LSALT Peptide vs. Placebo to Prevent ARDS and Acute Kidney Injury in Patients Infected With SARS-CoV-2 (COVID-19)

• ClinicalTrials.gov Identifier: NCT04402957
• Recruitment Status: Active, not recruiting
• First Posted: May 27, 2020
• Last Update Posted: May 6, 2021
• Sponsor: Arch Biopartners Inc.
• Information provided by (Responsible Party): Arch Biopartners Inc.

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
COVID; Severe Acute Respiratory Syndrome; Sars-CoV2; Acute Kidney Injury	Drug: LSALT peptide; Drug: Placebo	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:

1. 100 mL of 5 mg IV LSALT peptide infusion over 2 hours daily
2. 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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: October 14, 2020
• Estimated Primary Completion Date: May 31, 2021
• Estimated Study Completion Date: June 30, 2021

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 Name: Metablok

Outcome Measures

Primary Outcome Measures :

1. Development of Acute Respiratory Distress Syndrome (ARDS) and Other Organ Injuries [ Time Frame: 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 :

1. Ventilation-free days [ Time Frame: 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.
2. Time on nasal cannula or oxygen masks [ Time Frame: 28 days ]
   Oxygen therapy provided as non-invasive therapy for ARDS patients.
3. 28 day mortality - all cause and attributable [ Time Frame: 28 days ]
   28 day mortality - all cause and attributable
4. ICU and hospitalization length of stay (days) [ Time Frame: 28 days ]
   ICU and hospitalization length of stay (days)
5. SARS-CoV2 testing [ Time Frame: 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
6. Need and duration for extracorporeal membrane oxygenation (ECMO) [ Time Frame: 28 days ]
   Extracorporeal membrane oxygenation (ECMO) is often used for severe ARDS to allow lung healing/repair and reverse respiratory failure.
7. Vasopressor free days [ Time Frame: 28 days ]
   Vasopressor free days
8. Radiographic pulmonary assessments [ Time Frame: 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.
9. Change in modified Medical Research Council (mMRC) dyspnea and Sequential Organ Failure Assessment (SOFA) scores [ Time Frame: 28 days ]
   Change in daily mMRC dyspnea and SOFA scores (0 to 4) with 4 being the most severe outcome
10. Incidence of non-lung disorders [ Time Frame: 28 days ]
    Incidence of other organ (non-lung) disorders
11. Measures of liver dysfunction [ Time Frame: 28 days ]
    Change in liver function tests (ALT, AST, and total bilirubin levels) from baseline
12. Measures of kidney dysfunction [ Time Frame: 28 days ]
    Change in SCr and eGFR from baseline
13. Measures of cardiac dysfunction [ Time Frame: 28 days ]
    Change in highly-sensitive troponin (hs-troponin) from baseline
14. Measures of coagulopathies [ Time Frame: 28 days ]
    Change from baseline ACT, aPTT, and/or PT/INR levels
15. Changes in immunogenic responses [ Time Frame: 28 days ]
    Change in baseline antiviral immunoglobulins (IgG, IgM) at EOS.
16. Healthcare outcomes [ Time Frame: 28 days ]
    Changes in total healthcare costs from admission to discharge between treatment groups.
17. Molecular changes in pro-inflammatory pathways [ Time Frame: 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
18. Pharmacokinetics of LSALT peptide [ Time Frame: 28 days ]
    Pharmacokinetics of LSALT peptide over the study period.

Eligibility Criteria

• Ages Eligible for Study: 45 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male and female hospitalized patients between 45 and 80 years of age at time of consent.

2. 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:

   • Fever (oral temperature ≥ 100.4 °F [> 38 °C]) with or without chills
   • Dyspnea or difficulty breathing (≤ 2 on mMRC dyspnea scale)
   • Nonproductive cough

3. Patients must present with moderate to severe illness as defined below:

   • 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
   • 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%.
4. APACHE II score < 20
5. 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
6. 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.
7. 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:

1. Known sensitivity, allergy, or previous exposure to LSALT peptide.
2. Exposure to any investigational drug or device <90 days prior to entry into study.
3. 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.
4. Anticipated transfer to another hospital or medical center within 72 hours, which is not a study site.

5. 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:

   • HBV low viral load defined as <20,000 IU/mL
   • HepC low viral load defined as <800,000 IU/mL
   • HIV low viral load defined as <5000 copies/mL

6. Participation in another drug or device study at any time during this study, for example:

   • Ulinastatin 200,000 IU or greater
   • High dose intravenous Vitamin C
   • Budesonide and formoterol
   • Bevacizumab to prevent ARDS
   • Dornase alfa to reduce hypoxemia in ventilated trauma patients.
7. As indicated in the inclusion criteria, pregnant female patients are excluded from study. Further, female patients who are nursing are excluded from study.

8. Has any medical condition considered to be clinically significant and could potentially affect patient safety or study outcome, including but not limited to:

   • Acute or chronic kidney disease (stage-4 or -5 renal impairment; eGFR<30 mL/min/1.73 m2 or hemodialysis)
   • End-stage malignancy undergoing treatment
   • Immunocompromised patients or those with medical/surgical conditions (e.g., solid organ transplantation) which require chronic immunosuppression
   • Chronic hematologic disease which, in the opinion of the PI, prohibits the patient from entering into study
   • Acute liver injury with AST and/or ALT levels greater than 3x ULN
   • 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
   • End-stage lung disease, acute lung injury, severe chronic obstructive pulmonary disease (COPD), or mechanical ventilation.

Contacts and Locations

Locations

United States, California

VA San Diego Healthcare System

San Diego, California, United States, 92161

United States, Florida

Broward Health Medical Center

Fort Lauderdale, Florida, United States, 33316

United States, Louisiana

LSU Health Shreveport

Shreveport, Louisiana, United States, 71103

Canada, Alberta

University of Calgary - Foothills Medical Centre

Calgary, Alberta, Canada

University of Calgary - Peter Lougheed Centre

Calgary, Alberta, Canada

Turkey

Ankara City Hospital

Ankara, Turkey

Istanbul University Cerrahpasa

Istanbul, Turkey, 34098

Sponsors and Collaborators

Arch Biopartners Inc.

More Information

• Responsible Party: Arch Biopartners Inc.
• ClinicalTrials.gov Identifier: NCT04402957
• Other Study ID Numbers: AB002
• First Posted: May 27, 2020
• Last Update Posted: May 6, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Severe Acute Respiratory Syndrome; Acute Kidney Injury; Syndrome; Wounds and Injuries; Disease; Pathologic Processes; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Respiratory Tract Infections; Infections; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases