Evaluate the Efficacy & Safety of Leronlimab in Patients With Severe or Critical COVID-19

This was a Phase 2b/3, two-arm, randomized, double blind, placebo controlled, adaptive design multicenter study to evaluate the safety and efficacy of leronlimab (PRO 140) in patients with severe or critical 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.

A single arm, non-randomized, open-label phase was added to the protocol after completion of enrollment in the randomized phase of the study.

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

• Placebo (Drug): Placebo
• Leronlimab (700mg) (Drug), also known as PRO 140: Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5)

Primary outcomes

• All-cause Mortality at Day 28 [Mortality at day 28 (Visit 2, start of treatment = day 0)]: Incidence of mortality at day 28

Secondary outcomes

• All-cause Mortality at Day 14 [Mortality at day 14 (initiation of treatment = day 0)]: Day 0 refers to the data of randomization/first treatment.
• Proportion of Patients Achieving a Category of 6 or Higher on the Ordinal Scale at Days 14 and 28 (on a 7 Point Ordinal Scale). [Change from baseline to days 14 and 28]: Evaluation of the clinical status of participants at Day 28 was assessed with a 7-level ordinal scale (OS) (with higher score indicating better outcome). The OS of patient health status ranged 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. The study enrolled hospitalized patients with an OS Score of 2, 3, or 4 at baseline. The OS score of 6 refers to a participant who is not hospitalized with limitation on activities and 7 refers to not hospitalized with no limitations on activities.
• Change in Clinical Status of Subjects at Day 28 (on a 7 Point Ordinal Scale) [Change from start of treatment (baseline) to day 28]: Evaluation of the clinical status of participants at Day 28 was assessed with a 7-level ordinal scale (OS) (with higher score indicating better outcome). The OS of patient health status ranged 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. The study enrolled hospitalized patients with an OS Score of 2, 3, or 4 at baseline. Baseline is last available value before treatment. Change from baseline is based on patients with paired values. The p value is from rank ANCOVA model adjusted for stratification factor and age using imputed data. All results and change from baseline are based on the result of multiple imputation.
• Length of Hospital Stay [Timeframe is from screening visit to end of treatment (visit 5)]: Length of Hospital Stay measured in days

Other outcomes

• All-Cause Mortality at Day 14 in the Critically Ill Population [Mortality at day 14 (initiation of treatment = day 0)]: All-cause mortality at day 14 in the critically ill population. Day 0 refers to the date of randomization/first treatment.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Male or female adult ≥ 18 years of age at time of screening.
2. Subjects hospitalized with severe or critical illness caused by coronavirus 2019 infection as defined below:

   A. Severe Illness:

   \- Diagnosed with COVID-19 by standard reverse transcriptase polymerase chain reaction (RT-PCR) assay or equivalent testing within 5 days of screening

   AND

   Symptoms of severe systemic illness/infection with COVID-19:

   \- At least 1 of the following: fever, cough, sore throat, malaise, headache, muscle pain, shortness of breath at rest or with exertion, confusion, or symptoms of severe lower respiratory symptoms including dyspnea at rest or respiratory distress

   AND

   Clinical signs indicative of severe systemic illness/infection with COVID-19, with at least 1 of the following:

   \- respiration rate (RR) ≥ 30, heart rate (HR) ≥ 125, saturated oxygen (SaO2) <93% on room air or requires > 2L oxygen by nasal canula (NC) in order maintain SaO2 ≥93%, PaO2/FiO2 <300 (ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen)

   AND

   \- None of the following: Respiratory failure (defined by endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula, noninvasive positive pressure ventilation, or clinical diagnosis of respiratory failure in setting of resource limitations), Septic shock (defined by systolic blood pressure (SBP) < 90 mm Hg, or Diastolic BP < 60 mm Hg), Multiple organ dysfunction/failure

   B. Critical Illness:

   \- Diagnosed with COVID-19 by standard RT-PCR assay or equivalent testing within 5 days of screening

   AND

   Evidence of critical illness, defined by at least 1 of the following:

   \- Respiratory failure defined based on resource utilization requiring at least 1 of the following: Endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula, noninvasive positive pressure ventilation, extracorporeal membrane oxygenation (ECMO), or clinical diagnosis of respiratory failure (in setting of resource limitation)

   OR

   \- Shock (defined by SBP < 90 mm Hg, or Diastolic BP < 60 mm Hg or requiring vasopressors)

   OR

   -Multiple organ dysfunction/failure
3. Subject, if intubated, positive end expiratory pressure (PEEP) <15 cmH2O with PaO2/FiO2 >150 mmHg.
4. Electrocardiogram (ECG) with no clinically significant findings as assessed by the Investigator
5. Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
6. Understands and agrees to comply with planned study procedures.
7. Women of childbearing potential and their partner must agree to use at least one highly effective method of contraception (e.g., hormonal contraceptives \[implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings\], intrauterine devices, bilateral tubal occlusion, or sexual abstinence) for the duration of the study.

Exclusion Criteria:

1. Subjects with do-not-resuscitate (DNR) and/or do-not-intubate (DNI) orders or expected to be made DNR/DNI in setting of resource limitations or family wishes.
2. Not a candidate for dialysis or continuation of care (or full medical support) in setting of resource limitations.
3. Subject on continuous vasopressors (at the dose of norepinephrine >20μg/min and/or vasopressin >0.04 units/kg/min) for >48 hours at time of screening.
4. Subjects who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to leronlimab (PRO 140) are not eligible.
5. Inability to provide informed consent or to comply with test requirements
6. Consideration by the investigator, for safety reasons, that the subject is an unsuitable candidate to receive study treatment
7. Pregnancy or breast feeding
8. Subject participating in another study with for an investigational treatment for COVID-19.

Note: Subject who were prescribed (1) hydroxychloroquine or chloroquine with or without azithromycin, (2) Remdesivir, (3) convalescent plasma therapy, or (4) immunomodulatory treatments (including but not limited to sarilumab, clazakizumab, tocilizumab, and anakinra) for the off-label treatment of COVID-19 prior to study enrollment may be included and may continue to receive these agents as part of standard-of-care.

Participant flow

Outcome results

• All-cause Mortality at Day 28 (Primary), Count of participants, Participants: 700mg Leronlimab 52; Placebo 27; 700mg Open Label 23
• All-cause Mortality at Day 14 (Secondary), Count of participants, Participants: 700mg Leronlimab 25; Placebo 13; 700mg open label 17
• Proportion of Patients Achieving a Category of 6 or Higher on the Ordinal Scale at Days 14 and 28 (on a 7 Point Ordinal Scale). (Secondary), Number, Proportion of patients: 700mg Leronlimab 0.58; Placebo 0.55; 700mg Open Label 0.46
• Change in Clinical Status of Subjects at Day 28 (on a 7 Point Ordinal Scale) (Secondary), Mean, score on a scale: 700mg Leronlimab 1.5 +/- 2.25; Placebo 1.4 +/- 2.18; 700mg Open Label 1.0 +/- 2.1
• Length of Hospital Stay (Secondary), Median, Days: 700mg Leronlimab 15 (1 to 45); Placebo 14 (1 to 46); 700mg Open Label 14 (1 to 45)
• All-Cause Mortality at Day 14 in the Critically Ill Population (Other pre specified), Count of participants, Participants: 700mg Leronlimab 2; Placebo 5

Adverse events

Time frame: Study drug was administered at Visit 2 (day 0) and visit 4 (day 7). Adverse events and medications were monitored throughout the study from Visit 2 (day 0, first treatment) through completion of follow up which is Visit 7, (4 weeks after the End of Treatment visit) for a total of 42 days.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The outcome and safety data came from a report from the contract research organization that oversaw the study. A review of 64 Case Report Forms for the open label portion of the study indicated that over 70% contained no information about adverse events, therefore the adverse events for the open label portion of the study may be underreported.

• Welch J, Dean J, Hartin J. Using NEWS2: an essential component of reliable clinical assessment. Clin Med (Lond). 2022 Nov;22(6):509-513. doi: 10.7861/clinmed.2022-0435. PMID 36427875

• Study Protocol (PDF, 2020-12-28)
• Statistical Analysis Plan (PDF, 2021-02-15)
• Informed Consent Form (PDF, 2020-12-28)

• Jacob Lalezari, MD, Study director, CytoDyn, Inc.