Study to Evaluate the Efficacy and Safety of Leronlimab for Mild to Moderate COVID-19

• ClinicalTrials.gov Identifier: NCT04343651
• Recruitment Status: Completed
• First Posted: April 13, 2020
• Results First Posted: January 4, 2023
• Last Update Posted: January 4, 2023
• Sponsor: CytoDyn, Inc.
• Information provided by (Responsible Party): CytoDyn, Inc.

Study Description

Brief Summary:

This is a Phase 2, two-arm, randomized, double blind, placebo controlled multicenter study to evaluate the safety and efficacy of leronlimab (PRO 140) in patients with mild-to-moderate symptoms of respiratory illness caused by coronavirus 2019 infection.

Condition or disease	Intervention/treatment	Phase
Coronavirus Disease 2019	Drug: Placebo; Drug: Leronlimab (700mg)	Phase 2

Detailed Description:

This is a Phase 2, two-arm, randomized, double blind, placebo controlled multicenter study to evaluate the safety and efficacy of leronlimab (PRO 140) in patients with mild-to-moderate symptoms of respiratory illness caused by coronavirus 2019 infection. Patients will be randomized to receive weekly doses of 700 mg leronlimab (PRO 140), or placebo. Leronlimab (PRO 140) and placebo will be administered via subcutaneous injection.

The study will have three phases: Screening Period, Treatment Period, and Follow-Up Period.

A total of 75 subjects will be randomized 2:1 in this study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 86 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Leronlimab for Mild to Moderate Coronavirus Disease 2019 (COVID-19)
• Actual Study Start Date: April 1, 2020
• Actual Primary Completion Date: July 21, 2020
• Actual Study Completion Date: September 20, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; The placebo comparator consists of the formulation buffer for leronlimab, i.e., the placebo is the same as the active arm without leronimab. The placebo is presented in the same container closure at the same fill volume as the active (nominal 1mL fill volume). The formulation buffer contains histidine, glycine, sodium chloride, sorbitol, polysorbate 20 and sterile water for injections.	Drug: Placebo; Placebo
Experimental: 700mg Leronlimab; Each vial of active contains 175mg of leronlimab at a concentration of 175mg/ml (nominal 1mL fill volume) in formulation buffer containing histidine, glycine, sodium chloride, sorbitol, polysorbate 20 and sterile water for injections.	Drug: Leronlimab (700mg); Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5); Other Name: PRO 140

Outcome Measures

Primary Outcome Measures :

1. Mean Change From Baseline in Total Symptom Score [ Time Frame: Clinical Improvement will be assessed at baseline and at EOT (day 14). ]

   Clinical Improvement as assessed by change in total symptom score (for fever, myalgia, dyspnea and cough) by count of patients showing improvement, no change or worsened.

   Note: The total score per patient ranges from 0 to 12 points. Each symptom is graded from 0 to 3. [0=none, 1=mild, 2=moderate, and 3=severe]. Higher scores mean a worse outcome. A negative change from baseline shows an improvement in symptom score.

Secondary Outcome Measures :

1. Time to Clinical Resolution (TTCR) [ Time Frame: Time (in days) from initiation of study treatment until resolution of clinical symptoms (fever, myalgia, dyspnea and cough). ]

   Defined as the time from initiation of study treatment to the resolution of clinical symptoms (fever, myalgia, dyspnea, cough).

   Data presented how the number of days at which a certain percentage of patients achieve resolution of symptoms, i.e., 50% of patients on placebo saw resolution of symptoms in 15 days, and 15 days for patients on leronlimab.

   The hazard ratio was 0.781, 95% Confidence Interval 0.43, 1.41 and the p-value was 0.4138.

   TTCR is defined as the duration from date of first exposure to treatment to the first occurrence of total symptom score equals 0.

2. Incidence of Hospitalization [ Time Frame: From visit 2 (day 0) through day 14 (in days) ]
   Number of patients requiring hospitalization
3. Duration (Days) of Hospitalization [ Time Frame: Total duration of hospitalization between visit 2 (day 0) in days and end of treatment ]
   Duration of hospitalization in days
4. Incidence of Mechanical Ventilation [ Time Frame: Total duration of mechanical ventilation since visit 2 (day 0) (days) ]
   Incidence of mechanical ventilation supply
5. Duration of Mechanical Ventilation Supply [ Time Frame: Duration of mechanical ventilation since visit 2 (day 0) (days ]
   Duration (days) of mechanical ventilation supply
6. Incidence of Oxygen Use [ Time Frame: Use of oxygen since visit 2 (day 0) to end of treatment ]
   Incidence of oxygen use over course of treatment
7. Duration of Oxygen Use [ Time Frame: Total duration of oxygen use since visit 2 (day 0) to EOT (day 14) (days) ]
   Duration of oxygen use in days
8. Mortality at Day 14 [ Time Frame: Mortality at EOT (day 14) ]
   Incidence of mortality at day 14
9. Time to Return to Normal Activity [ Time Frame: Date of first exposure to treatment to the first occurrence of ordinal scale equals "not hospitalized, no limitations of activities" ]
   Time to return to normal activity from initiation of study treatment defined as duration from date of first exposure to treatment to the first occurrence of ordinal scale equals "not hospitalized, no limitations of activities"
10. Change From Baseline in National Early Warning Score 2 (NEWS2) to Day 3, 7 and 14 [ Time Frame: Baseline to Day 3, 7 and 14 ]

    NEWS2 is an assessment based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness) developed by the Royal College of Physicians (https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2). Respiratory rate (bpm) scores 0-3; Sp02 (on room air or suppl) scores 0-3; SpO2 (hypercapnic resp failure) scores 0-3; room air or supplemental O2 scores 0 (room) or 2 (suppl); temperature - scores 0-3; systolic BP scores 0-3; pulse (bpm) scores 0-3; consciousness - alert (score 0) vs. new onset confusion (score 3). The total possible score ranges from 0 to 20. The higher the score the greater the clinical risk. Higher scores indicate the need for escalation, medical review and possible clinical intervention and more intensive monitoring.

    Change shown is positive or negative from baseline, with a negative number indicating improvement (i.e., a decrease in total score).

11. Mean Change in Percent Oxygen Saturation From Baseline to Days 3, 7 and 14 [ Time Frame: Mean change in percent oxygen saturation from baseline to Days 3, 7 and 14 ]
    Mean change in percent oxygen saturation from baseline to Days 3, 7 and 14 for patients with paired values
12. Change From Baseline in the Patient's Health Status on a 7-category Ordinal Scale on Days 3, 7 and 14 [ Time Frame: Assessments performed Day 0 (first treatment is Visit 2, day 0), Visit 3 (3+/- 1 day after first treatment) Visit 4 (second treatment, 7+/- 1 day from V2, day7) and end of treatment (7+/- 1 day from V4, day 14) ]

    A 7-category ordinal scale of patient health status ranges from: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

    Lower scores mean a worse outcome.

Other Outcome Measures:

1. Change in Size of Lesion Area by Chest Radiograph or CT [ Time Frame: Day 14 ]
   Change in size of lesion area by chest radiograph or CT - exploratory endpoint
2. Change From Baseline in Serum Cytokine and Chemokine Levels [ Time Frame: Days 3, 7, and 14 ]
   Change from baseline in serum cytokine and chemokine levels at day 3, day 7 and day 14
3. Change From Baseline in CCR5 Receptor Occupancy Levels for Tregs and Macrophages [ Time Frame: Days 3, 7, and 14 ]
   Change from baseline in CCR5 receptor occupancy levels for Tregs and macrophages at day3, day 7 and day 14
4. Change From Baseline in CD3+, CD4+ and CD8+ T Cell Count [ Time Frame: Days 3, 7, and 14 ]
   Change from baseline in CD3+, CD4+ and CD8+ T cell count at day 3, day 7 and day 14

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female adult ≥ 18 years of age at time of enrollment.

2. Subjects with mild-to-moderate symptoms of respiratory illness caused by coronavirus 2019 infection as defined below:

   Mild (uncomplicated) Illness:

   • Diagnosed with COVID-19 by a standardized RT-PCR assay AND
   • Mild symptoms, such as fever, rhinorrhea, mild cough, sore throat, malaise, headache, muscle pain, or malaise, but with no shortness of breath AND
   • No signs of a more serious lower airway disease AND
   • RR<20, HR <90, oxygen saturation (pulse oximetry) > 93% on room air

   Moderate Illness:

   • Diagnosed with COVID-19 by a standardized RT-PCR assay AND
   • In addition to symptoms above, more significant lower respiratory symptoms, including shortness of breath (at rest or with exertion) OR
   • Signs of moderate pneumonia, including RR ≥ 20 but <30, HR ≥ 90 but less than 125, oxygen saturation (pulse oximetry) > 93% on room air AND
   • If available, lung infiltrates based on X-ray or CT scan < 50% present
3. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator.
4. Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
5. Understands and agrees to comply with planned study procedures.
6. Women of childbearing potential must agree to use at least one medically accepted method of contraception (e.g., barrier contraceptives [condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], or intrauterine devices) for the duration of the study.

Exclusion Criteria:

1. Subjects showing signs of acute respiratory distress syndrome (ARDS) or respiratory failure necessitating mechanical ventilation at the time of screening;
2. History of severe chronic respiratory disease and requirement for long-term oxygen therapy;
3. Subjects showing signs of clinical jaundice at the time of screening;
4. History of moderate and severe liver disease (Child-Pugh score >12);
5. Subjects requiring Renal Replacement Therapy (RRT) at the time of screening;
6. History of severe chronic kidney disease or requiring dialysis;

7. Any uncontrolled active systemic infection requiring admission to an intensive care unit (ICU); Note: Subjects infected with chronic hepatitis B virus or hepatitis C virus will be eligible for the study if they have no signs of hepatic decompensation.

   Note: Subjects infected with HIV-1 will be eligible for the study with undetectable viral load and are on a stable ART regimen. Investigators are required to review the subjects' medical records to confirm HIV-1 RNA suppression within the previous 3 months.

   Note: Empirical antibiotic treatment for secondary bacterial infections is allowed during the course of study.

8. Patients with malignant tumor, or other serious systemic diseases;
9. Patients who are participating in other clinical trials;
10. Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to leronlimab (PRO 140) are not eligible; and
11. Inability to provide informed consent or to comply with test requirements

Contacts and Locations

Locations

United States, California

University of California, Los Angeles

Los Angeles, California, United States, 90095

Palmtree Clinical Research, Inc.

Palm Springs, California, United States, 92262-4871

Eisenhower Health

Rancho Mirage, California, United States, 92270

United States, Connecticut

Yale

New Haven, Connecticut, United States, 06510

United States, Georgia

Center for Advanced Research & Education (CARE)

Gainesville, Georgia, United States, 30501

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, New Jersey

Atlantic Health System Hospital

Morristown, New Jersey, United States, 07962-1905

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10467

White Plains Hospital

White Plains, New York, United States, 10601

United States, North Carolina

Novant Health

Charlotte, North Carolina, United States, 27103

United States, Ohio

Ohio Health

Columbus, Ohio, United States, 43215

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

Sponsors and Collaborators

CytoDyn, Inc.

Investigators

• Principal Investigator: Angela Ritter, MD; Center for Advanced Research and Education

  Study Documents (Full-Text)

Documents provided by CytoDyn, Inc.:

Study Protocol  [PDF] March 30, 2020

Statistical Analysis Plan  [PDF] April 26, 2020

More Information

Additional Information:

NEWS2 Score 

• Responsible Party: CytoDyn, Inc.
• ClinicalTrials.gov Identifier: NCT04343651
• Other Study ID Numbers: CD10_COVID-19
• First Posted: April 13, 2020
• Results First Posted: January 4, 2023
• Last Update Posted: January 4, 2023
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by CytoDyn, Inc.:

COVID-19

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Leronlimab; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents