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: Not yet recruiting
• First Posted: May 27, 2020
• Last Update Posted: June 16, 2020
• 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.

The study will have staggered enrolment in that a cohort of 6 patients will be enrolled into the study during the first wave. Further cohorts of 6 patients will be enrolled only after the Data and Safety Monitoring Board (DSMB; refer to the DSMB Charter) has assessed 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 additional cohorts of 6 patients to be studied as planned in this 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.

Patients will be physically examined throughout the study period, including respiratory assessments. Vital signs, adverse events (AE), routine blood chemistries, coagulation, hematology, and urinalysis will be assessed throughout the study. LSALT peptide and metabolite concentrations and cytokine levels will be assessed daily at the mid-point (1 hour) and immediately at the end of the 2-hour study drug infusion. An ECG will be recorded at Baseline prior to drug therapy, Day 3, and at EOS. A chest x-ray will be obtained at Baseline and Day 3 as well as at time of clinical improvement, EOT, and EOS. Questionnaires (APACHE II, Berlin Definition, SOFA, and modified Medical Research Council Dyspnea Scale) will be assessed each morning and when indicated by the PI.

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).

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)
• Estimated Study Start Date: July 1, 2020
• Estimated Primary Completion Date: December 31, 2020
• 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. Use of hydroxychloroquine, chloroquine, azithromycin, remdesivir, or Kaletra® (lopinavir/-ritonavir) is allowed if not part of another investigational study.
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.
4. Anticipated transfer to another hospital or medical center within 72 hours, which is not a study site.
5. Known history of hepatitis B (HBV), hepatitis C (HepC), HIV, SARS, or MERS infection.

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

Contacts

Contact: Daniel A Muruve, MD; 403-220-2418; info@archbiopartners.com

Contact: Richard Muruve; 647-428-7031; info@archbiopartners.com

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: June 16, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:

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