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: Completed
• First Posted: May 27, 2020
• Last Update Posted: April 25, 2023
• 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; Acute Respiratory Distress Syndrome	Drug: LSALT peptide; Drug: Placebo	Phase 2

Detailed Description:

This study is a parallel group, randomized, third-party blinded, multicenter study to assess safety and efficacy of LSALT peptide versus placebo in hospitalized patients with confirmed infection or recent confirmed infection with complications associated with 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. This study will be third-party blind with only the Pharmacist at the site unblinded for the purpose of preparing drug/placebo for injection.

Patients will be followed for safety and efficacy up to Day 28, with Day 1 being the day of randomization to assess safety. After assessing the risk of ARDS and satisfying all inclusion and exclusion criteria, the patient will be randomized to 5 mg LSALT peptide or blinded placebo to be given intravenously once daily for a maximum of 14 days. Physical and respiratory examinations, vital signs, and adverse events will be recorded throughout the study, including Day 28 (EOS). Blood chemistries, hematology, coagulation, urinalysis, ECG, SARS-CoV-2 tests, eGFR, and chest x-ray (CXR) will be assessed at Day 1 (Screening/Baseline) prior to initiation of study drug, and on Day 3, EOT, and at EOS, as well as when clinically indicated. The ECG at EOS will only be obtained if clinically indicated. An additional CXR will be obtained at time of clinical improvement. Cytokines/biomarkers and pharmacokinetics (PK) will be assessed at Day 1 (Screening/Baseline) prior to initiation of study drug, at 1 (mid-dose) and 2 hours (end of infusion) of drug therapy on Days 1, 3, EOT, and a single blood sample at EOS for cytokines/biomarkers only. Where applicable, a urinary pregnancy test will be obtained at Screening in women of childbearing potential. Questionnaires (APACHE II, SOFA) will be obtained at Baseline, Day 3, EOT, and EOS; venous blood gas (VBG) or HCO3 (bicarbonate) levels may be substituted for arterial blood gas (ABG) if it is considered standard-of-care (SOC) or in the patient's best interest, and results in comparable APACHE II and SOFA scores. Other questionnaires (Berlin Definition and modified Medical Research Council Dyspnea Scale) will be assessed at Baseline, Day 3, EOT, and EOS. IgG, IgA, and IgM antiviral antibodies will be collected at Baseline and EOS. Patients will be maintained on the SOC per institutional guidelines, including prophylaxis or treatment of VTE, throughout the study.

A Data and Safety Monitoring Board (DSMB) will evaluate patients on a continuing basis for primarily safety assessments. Per the DSMB Charter, the DSMB will meet at least monthly if not more frequently based upon enrollment throughout the study period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 61 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
• Actual Primary Completion Date: May 27, 2021
• Actual Study Completion Date: June 2, 2022

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. 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.; Other Name: Metablok

Outcome Measures

Primary Outcome Measures :

1. To evaluate the proportion of subjects alive and free of respiratory failure and free of the need for continued renal replacement therapy (RRT) on Day 28 (as per Protocol AB002 - Version 1, dated 09JUNE2020) [ Time Frame: 28 days ]
   Respiratory failure is defined as the need for non-invasive or invasive mechanical ventilation, high flow oxygen [≥ 6 L/minute], or ECMO. 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.

Secondary Outcome Measures :

1. All-cause mortality [ Time Frame: 28 days ]
2. The presence of and severity of ARDS as an ordinal outcome of the proportion of patients who have none, mild, moderate, or severe ARDS [ Time Frame: 28 days ]
3. Time to each of mild, moderate, or severe ARDS [ Time Frame: 28 days ]
4. The number of ventilation-free days and ECMO-free days [ Time Frame: 28 days ]
5. Time on nasal cannula or oxygen mask [ Time Frame: 28 days ]
6. Length of stay in ICU and hospital (admission to discharge) [ Time Frame: 28 days ]
7. Virologic clearance rate [ Time Frame: 28 days ]
   SARS-CoV2 testing by swab (nasopharyngeal, nasal, throat, sputum, or lower respiratory tract) at baseline (Day 1) and every 3 days thereafter until eradication
8. Worst PaO2/FiO2 ratio following enrollment [ Time Frame: 28 days ]
9. Change in PaO2/FiO2 ratio [ Time Frame: 28 days ]
10. Vasopressor-free days [ Time Frame: 28 days ]
11. Change from maximal radiographic damage to EOT [ Time Frame: 28 days ]
12. Change in baseline modified Medical Research Council (mMRC) score [ Time Frame: 28 days ]
    Change in mMRC score (0 to 4) with 4 being the most severe outcome
13. Change in Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score [ Time Frame: 28 days ]
    Change in APACHE II score (0 to 71) with 71 being the most severe outcome
14. Proportion of patients with extrapulmonary organ dysfunction using the daily Sequential Organ Failure Assessment (SOFA) score [ Time Frame: 28 days ]
    Change in SOFA score (0 to 4) with 4 being the most severe outcome
15. Change in liver function by Alanine Aminotransferase (ALT) test [ Time Frame: 28 days ]
    ALT measured in IU/L
16. Change in liver function by Aspartate Transferase (AST) test [ Time Frame: 28 days ]
    AST measured in IU/L
17. Change in liver function by total bilirubin test [ Time Frame: 28 days ]
    Total bilirubin measured in mg/dL
18. Change in renal function by serum creatinine (SCr) test [ Time Frame: 28 days ]
    SCr measured in mg/dL
19. Change in renal function by estimated Glomerular Filtration Rate (eGFR) test [ Time Frame: 28 days ]
    eGFR measured in ml/min/1.73m2
20. Change in hs-troponin levels [ Time Frame: 28 days ]
21. Change in Activated Coagulation Time (ACT) [ Time Frame: 28 days ]
    ACT measured in seconds
22. Change in activated Partial Thromboplastin Time (aPTT) [ Time Frame: 28 days ]
    aPTT measured in seconds
23. Change in Prothrombin Time (PT)/International Normalized Ratio (INR) [ Time Frame: 28 days ]
    PT measured in seconds
24. Change in antiviral IgG, IgA, and IgM levels [ Time Frame: 28 days ]
    Immunoglobulins measured in mg/dL
25. Total healthcare costs from admission to discharge between treatment groups [ Time Frame: 28 days ]
26. Change in serum cytokines including IL-1a, IL-1b, and ferritin levels as well as other exploratory biomarkers drawn at the same time as LSALT peptide concentrations [ Time Frame: 28 days ]
    Fold change from baseline cytokines measured in ng/mL
27. Change in baseline antiviral immunoglobulins (IgG, IgM, IgA) at EOS [ Time Frame: 28 days ]
    Immunoglobulins measured in mg/dL

Eligibility Criteria

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

Criteria

Inclusion Criteria (Amendment 3, 15FEB2021):

1. Male and female hospitalized patients between 18 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 or have an existing complication secondary to SARS-CoV-2 infection which was positive within 2 weeks of entry into the study. Further, patients must have at least 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
   • Or other signs and symptoms of established complications to SARS-CoV-2 infection (e.g. coagulopathy, cardiomyopathy, acute kidney injury, and/or acute liver injury) within the limits of Exclusion Criteria 8

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 or establishment of survivability of the patient beyond 48 hours following randomization
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, or institutional guidelines) 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. Further, low-dose oral prednisone (<20 mg/day) and inhaled steroids (e.g. treatment of asthma) are allowed in the study.
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 unless recent injury (within 2 weeks) likely due to COVID-19 infection
   • 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 currently present at screening, and/or
   • End-stage lung disease, acute lung injury, severe chronic obstructive pulmonary disease (COPD) as assessed by the GOLD criteria (GOLD Stage IV), 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: April 25, 2023
• Last Verified: April 2023

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; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Acute Kidney Injury; Syndrome; Wounds and Injuries; Disease; Pathologic Processes; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Respiratory Tract Infections; Infections; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases