Coronavirus Disease 2019
Conditions
Keywords
COVID-19
Brief summary
The purpose of this study was assess the safety and efficacy of leronlimab (PRO 140) administered as weekly subcutaneous injection in subjects with severe or critical COVID-19 disease.
Detailed description
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.
Interventions
DRUGPlacebo
Placebo
Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5)
Sponsors
CytoDyn, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Unblinded pharmacists at clinical sites were notified of the arm to which the subjects were enrolled for the randomized portion of the study in order to prepare the appropriate treatment. There was no masking for the open-label portion of the study.
Intervention model description
There were 394 participants randomized to the blinded portion of the study using an Interactive Response Technology (IRT) system. A separate cohort of 90 new participants were enrolled in the open label portion of the study after completion of enrollment of the blinded portion. None of the participants involved in the blinded portion of the study were included in the open label portion.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality at Day 28 | Mortality at day 28 (Visit 2, start of treatment = day 0) | Incidence of mortality at day 28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. First patient was enrolled into Part 1 of the study (blinded portion) on 16-April-2020. Data submitted represent analysis performed on data collected after all patients completed the Follow Up period.
Participants by arm
| Arm | Count |
|---|---|
| 700mg Leronlimab Two syringes, each containing 350mg of leronlimab in 2mL, allowed administration of the 700mg dose, subcutaneously.
Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5) | 259 |
| Placebo Two syringes each containing 2mL of normal saline for injection were prepared by an unblinded pharmacist at the clinical sites for use as the placebo. | 125 |
| 700mg Leronlimab - open label Two syringes, each containing 350mg of leronlimab in 2mL, allowed administration of the 700mg dose, subcutaneously. | 89 |
| Total | 473 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Blinded Portion | Pt randomized to study but withdrew consent before treatment with investigational product | 6 | 0 | 4 |
| Open Label | Pt enrolled but withdrew consent prior to dosing | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | 700mg Leronlimab | Placebo | 700mg Leronlimab - open label |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 149 Participants | 88 Participants | 29 Participants | 32 Participants |
| Age, Categorical Between 18 and 65 years | 324 Participants | 171 Participants | 96 Participants | 57 Participants |
| Age, Continuous | 58.72 years | 58.82 years | 58.51 years | 59.18 years |
| COVID SYMPTOM SCORE | 3.2 units on a scale | 3.2 units on a scale | 3.2 units on a scale | 3.3 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 11 Participants | 7 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 69 Participants | 29 Participants | 23 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 110 Participants | 85 Participants | 25 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 0 Participants | 0 Participants | 17 Participants |
| Race (NIH/OMB) White | 257 Participants | 133 Participants | 70 Participants | 54 Participants |
| Region of Enrollment United States | 473 participants | 259 participants | 125 participants | 89 participants |
| Sex: Female, Male Female | 157 Participants | 90 Participants | 42 Participants | 25 Participants |
| Sex: Female, Male Male | 316 Participants | 169 Participants | 83 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 31 / 125 | 60 / 259 | 23 / 89 |
| other Total, other adverse events | 77 / 125 | 142 / 259 | 29 / 89 |
| serious Total, serious adverse events | 47 / 125 | 99 / 259 | 35 / 89 |
Outcome results
Primary
All-cause Mortality at Day 28
Incidence of mortality at day 28
Time frame: Mortality at day 28 (Visit 2, start of treatment = day 0)
Population: Modified Intent to Treat (mITT) population was used for the analysis. The mITT population is defined as the set of subjects who randomized and have received at least one dose of leronlimab (PRO 140) or placebo. This population was used for the primary efficacy endpoint.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 700mg Leronlimab | All-cause Mortality at Day 28 | Mortality | 52 Participants |
| 700mg Leronlimab | All-cause Mortality at Day 28 | Survival | 207 Participants |
| Placebo | All-cause Mortality at Day 28 | Mortality | 27 Participants |
| Placebo | All-cause Mortality at Day 28 | Survival | 98 Participants |
| 700mg Open Label | All-cause Mortality at Day 28 | Mortality | 23 Participants |
| 700mg Open Label | All-cause Mortality at Day 28 | Survival | 66 Participants |
Secondary
All-cause Mortality at Day 14
Day 0 refers to the data of randomization/first treatment.
Time frame: Mortality at day 14 (initiation of treatment = day 0)
Population: Modified Intent to Treat (mITT) population was used for the analysis. The mITT population is defined as the set of subjects who randomized and have received at least one dose of leronlimab (PRO 140) or placebo. This population was used for the secondary outcome endpoint analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 700mg Leronlimab | All-cause Mortality at Day 14 | 25 Participants |
| Placebo | All-cause Mortality at Day 14 | 13 Participants |
| 700mg Open Label | All-cause Mortality at Day 14 | 17 Participants |
Secondary
Change in Clinical Status of Subjects at Day 28 (on a 7 Point Ordinal Scale)
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.
Time frame: Change from start of treatment (baseline) to day 28
Population: Rank ANCOVA model adjusted for stratification factor and age based on non-missing observed data. Change from baseline is based on patients with paired values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 700mg Leronlimab | Change in Clinical Status of Subjects at Day 28 (on a 7 Point Ordinal Scale) | 1.5 score on a scale | Standard Deviation 2.25 |
| Placebo | Change in Clinical Status of Subjects at Day 28 (on a 7 Point Ordinal Scale) | 1.4 score on a scale | Standard Deviation 2.18 |
| 700mg Open Label | Change in Clinical Status of Subjects at Day 28 (on a 7 Point Ordinal Scale) | 1.0 score on a scale | Standard Deviation 2.1 |
Secondary
Length of Hospital Stay
Length of Hospital Stay measured in days
Time frame: Timeframe is from screening visit to end of treatment (visit 5)
Population: Modified Intent to Treat (mITT) population was used for the analysis. The mITT population is defined as the set of subjects who randomized and have received at least one dose of leronlimab (PRO 140) or placebo. Patients with incomplete data were excluded from the analysis. This population was used for the secondary outcome endpoint analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 700mg Leronlimab | Length of Hospital Stay | 15 Days |
| Placebo | Length of Hospital Stay | 14 Days |
| 700mg Open Label | Length of Hospital Stay | 14 Days |
Secondary
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).
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.
Time frame: Change from baseline to days 14 and 28
Population: Responders refer to subjects who achieved a category of 6 or higher at Day 14 and/or Day 28. Note: Proportions are based on the result of multiple imputation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 700mg Leronlimab | 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). | Non-responders at d14 | 0.62 Proportion of patients |
| 700mg Leronlimab | 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). | Responders at d14 | 0.38 Proportion of patients |
| 700mg Leronlimab | 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). | Missing at D14 | 0 Proportion of patients |
| 700mg Leronlimab | 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). | Non-responders at d28 | 0.41 Proportion of patients |
| 700mg Leronlimab | 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). | Responders at d28 | 0.58 Proportion of patients |
| 700mg Leronlimab | 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). | Missing at d28 | 0 Proportion of patients |
| Placebo | 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). | Responders at d28 | 0.55 Proportion of patients |
| Placebo | 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). | Non-responders at d14 | 0.58 Proportion of patients |
| Placebo | 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). | Non-responders at d28 | 0.45 Proportion of patients |
| Placebo | 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). | Missing at d28 | 0 Proportion of patients |
| Placebo | 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). | Missing at D14 | 0 Proportion of patients |
| Placebo | 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). | Responders at d14 | 0.42 Proportion of patients |
| 700mg Open Label | 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). | Missing at D14 | 0.13 Proportion of patients |
| 700mg Open Label | 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). | Non-responders at d28 | 0.47 Proportion of patients |
| 700mg Open Label | 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). | Responders at d28 | 0.46 Proportion of patients |
| 700mg Open Label | 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). | Missing at d28 | 0.07 Proportion of patients |
| 700mg Open Label | 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). | Responders at d14 | 0.39 Proportion of patients |
| 700mg Open Label | 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). | Non-responders at d14 | 0.47 Proportion of patients |
Other Pre-specified
All-Cause Mortality at Day 14 in the Critically Ill Population
All-cause mortality at day 14 in the critically ill population. Day 0 refers to the date of randomization/first treatment.
Time frame: Mortality at day 14 (initiation of treatment = day 0)
Population: There were 62 patients in the critically ill population. Critically ill was defined as patients that were hospitalized, on invasive ventilation or extracorporeal membrane oxygenation (ECMO). Critically ill subjects were a subgroup of the Modified Intent to Treat population used for this analysis. As defined in the SAP, subgroup analysis was performed on predefined stratification factors including the subgroup of patients identified as critically ill and defined as above.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 700mg Leronlimab | All-Cause Mortality at Day 14 in the Critically Ill Population | 2 Participants |
| Placebo | All-Cause Mortality at Day 14 in the Critically Ill Population | 5 Participants |