Double Blind, Placebo Controlled Study of Safety and Efficacy of Leronlimab in Patients With "Long" COVID-19

A Phase 2, Randomized, Double Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Leronlimab in Patients Experiencing Prolonged Coronavirus Disease 2019 (COVID-19) Symptoms [Long-Haulers]

The purpose of this study is to assess the safety and efficacy of leronlimab (PRO 140) administered as weekly subcutaneous injections in subjects experiencing prolonged symptoms (> 12 weeks) of COVID-19.

Study Overview

• Status: Completed
• Conditions: Coronavirus Disease 2019
• Intervention / Treatment: Drug: Placebos; Drug: Leronlimab (700mg)

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 prolonged symptoms caused by Coronavirus Disease 2019 (COVID-19). 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. Total study duration is 91 days. The study will be conducted at up to 5 centers in the United States and planned number of subjects are 50 subjects.

Visit schedule:

Visit 1 - Screening assessment Visit 2 - baseline, first dose Visit 3 - no dose, baseline+3 days Visit 4 - second dose, baseline + 7 days Visit 5 - no dose, safety assessment/con med, baseline +10 days Visit 6 - third dose, baselines + 14 days Visit 7 - no dose, safety assessments, baseline + 17 days Visit 8 - fourth dose, baseline +21 days Visit 9 - no dose, safety assessment, baseline + 24 days Visit 10 - fifth dose, baseline + 28 days Visit 11 - no dose, safety assessment, baseline + 31 days Visit 12 - sixth dose, baseline + 35 days Visit 13 - no dose, safety assessment, baseline + 38 days Visit 14 - seventh dose, baseline + 42 days Visit 15 - no dose, safety assessment, baseline + 45 days Visit 16 - eighth and final dose, baseline + 49 days Visit 17 - End of treatment, baseline + 56 days

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Aventura, Florida, United States, 33180
      • Arthritis & Rheumatic Disease Specialties
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Center for Advanced Research & Education (CARE)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female adult ≥ 18 years of age at time of enrollment.
2. Prior confirmed COVID-19 diagnosis by standard reverse transcriptase-polymerase chain reaction (RT-PCR) assay or equivalent testing

3. Clinical Symptom Score of ≥6 AND at least two symptoms of moderate or higher severity as listed below at the time of Screening and currently experiencing two or more of the following symptoms consistent with COVID-19 infection for a prolonged period of time (>12 weeks).

   Clinical symptoms include the following:

   • Respiratory symptoms such as cough, sore throat, stuffy or runny nose, shortness of breath (difficulty breathing), tightness of chest.
   • Neurological symptoms such as difficulty in concentration (brain fog), sleep disturbance/insomnia, headache, dizziness, anxiety, tingling or numbness, loss of sense of smell or taste.
   • Cardiovascular and Gastrointestinal symptoms such as feeling of fast heartbeat, nausea, vomiting, diarrhea.
   • Musculoskeletal symptoms such as muscle aches/cramps, muscle weakness, joint pain/swelling.
   • General immune response symptoms such as fatigue (low energy or tiredness), chills or shivering, feeling hot or feverish, or exertional malaise (feeling of discomfort, illness, or lack of well-being after physical activity or mental stress).

   Note: Clinical Symptom Score is obtained from the patient diary (refer to Appendix 1 for scoring instructions).

4. Electrocardiogram (ECG) with no clinically significant findings as assessed by the Investigator.

   Note: Below are the examples of clinically significant and non-clinically significant ECG abnormalities:

   • ECG findings indicative of acute myocardial infarction or acute ischemic changes would be considered clinically significant abnormalities.
   • ECG finding such as atrial fibrillation, atrial flutter, paced rhythms in individuals who have undergone permanent pacemaker placement, evidence of prior infarction, unchanged stable conduction abnormalities e.g. right bundle branch block, or any other finding which does not significantly impact mortality would be considered non-clinically significant findings and subjects with these abnormal findings would be allowed to enroll in the study.
5. Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
6. Men and women of childbearing potential and their partner must agree to use two medically accepted methods of contraception (e.g., barrier contraceptives [male condom, female condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], or one of the following methods of birth control (intrauterine devices, bilateral tubal occlusion, or vasectomy) or must practice complete sexual abstinence for the duration of the study (excluding women who are not of childbearing potential and men who have been sterilized).
7. Females of child-bearing potential must have a negative urine pregnancy test at Screening Visit and prior to receiving the first dose of study drug; and Male participants must agree to use contraception and refrain from donating sperm for at least 90 days after the last dose of study intervention.
8. Subject is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures and study restrictions

Exclusion Criteria:

1. Exhibiting signs of moderate or severe pulmonary disease (such as Chronic Obstructive Pulmonary Disease (COPD), asthma, or pulmonary fibrosis)
2. Ongoing requirement of oxygen therapy
3. Pulse oxygen saturation (SpO2) of <94% on room air at the time of screening
4. History of splenectomy
5. Liver cirrhosis or patient showing signs of clinical jaundice at the time of screening
6. Chronic kidney disease stage 4 or requiring dialysis at the time of screening
7. New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF)
8. Exhibiting signs of uncontrolled hypo-or hyper- thyroidism at the time of Screening
9. Uncontrolled rheumatologic disorders at the time of screening
10. History of organ transplantation or are candidates for organ transplantation at the time of screening
11. History of Chronic Fatigue Syndrome prior to COVID-19 infection
12. History of fibromyalgia prior to COVID-19 infection
13. History of major psychiatric disorder including bipolar disorders, schizophrenia, schizoaffective disorder, major depression. Patients with major depression can be enrolled if patient has had no episode within the past year or is considered in remission or controlled by treatment.
14. Any malignancy within the past 5 years, excluding successfully treated basal cell carcinoma or squamous cell carcinoma without evidence of metastases.
15. Any other clinically significant serious systemic diseases which would interfere with study conduct or study results interpretation per the Investigator.
16. Treatment with immunosuppressive or immunomodulatory medications within 5 half-lives prior to screening. Patients on replacement therapy for adrenal insufficiency will be allowed. Patients on stable (> 3 months) low dose corticosteroid ≤ 5 mg Prednisone will be allowed.
17. History of allergic reactions attributed to compounds of similar chemical or biologic composition to leronlimab (PRO 140) are not eligible
18. Ongoing use of CCR5 antagonist
19. Inability to provide informed consent or to comply with test requirements
20. Consideration by the investigator, for safety reasons, that the subject is an unsuitable candidate to receive study treatment
21. Pregnancy or breast feeding
22. Participating in another study for an investigational treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Syringes containing normal saline for injection were prepared by an unblinded pharmacist at the clinical sites for use as the placebo.	Drug: Placebos; Placebos; Other Names: placebo
Experimental: 700mg Leronlimab; Each vial of active contains 350mg of leronlimab at a concentration of 175mg/ml (nominal 2mL 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 Names: Pro140

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes From Baseline in Daily COVID-19-related Symptom Severity Score Through Day 56.	Changes in common COVID-19-related symptoms were evaluated daily by the patient using a patient diary between start and end of treatment. The diary is shown in Appendix 17.1 in the protocol and covers patient-reported changes for symptoms (ranked as none = 0, mild = 1, moderate = 2 or severe = 3) of cough, sore throat, stuffy or runny nose, difficulty breathing, feeling tightness in chest, feeling fast heartbeat, fatigue, exertional malaise, muscle aches and cramps, muscle weakness, joint pain and swelling, shivering and chills, feeling hot or feverish, difficulty concentrating, insomnia, headache, dizziness, anxiety, tingling or numbness, nausea, vomiting, diarrhea, sense of smell, sense of taste. Maximum score could be 70 (22 parameters with scores up to 3, two parameters with scores up to 2), lowest score could be 0. A negative value shows improvement in symptoms. The lower the value, the greater the improvement (i.e., a score of -16 is greater improvement than a score of -8).	Changes in COVID-19 related symptoms from baseline (start of treatment) and day 56 (end of treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of COVID-19 Associated Symptoms From Start of Study Treatment (Day 0) Based on Self-assessment Using Daily Symptom Diary.	Number of days when any symptoms scored as moderate or severe at baseline (Day 0) are still scored as moderate or severe through day 56 (end of treatment) or symptoms scored as mild or absent at baseline are scored as mild or worse at day 56 (end of treatment).	Duration of symptoms from baseline (day 0, start of treatment) and day 56 (end of treatment)
Number of Days Free of Symptoms Associated With COVID-19 That Were Present at the Start of Study Treatment (Day 0) Based on Self-assessment Using Daily Symptom Diary.	Symptom-free days are defined as number of days when any symptoms scored as mild, moderate or severe at baseline are scored as absent (or none) through Day 56 (end of treatment) using a self-assessment diary.	Between start of treatment (day0) and day 56 (end of treatment)
Progression (or Worsening) of COVID-19-associated Symptoms Through Day 56 Compared to Baseline.	Progression or worsening of symptoms is defined as number of days when any symptoms scored as 2 at baseline scored as 3 through day 56 or 1 at baseline are scored as 2 or 3 through day 56 or scored 0 at study entry scored as 1, 2 or 3 through day 56. No change in symptoms would give a score of 0, symptom progression would give a positive number, symptom improvement would a negative number. Minimum baseline symptom score for eligibility for the study was 6. Maximum symptom score is 70, therefore if all symptoms progressed to the severest level the change in score would be +64. If all patients had a severe score for all symptoms at baseline and all improved to no symptoms at day 56, the maximum improvement in score would be -70.	Between start of treatment (day0) and day 56 (end of treatment)
Change From Baseline in PROMIS® Fatigue Score at Days 7,14, 21, 28, 35, 42 and End of Treatment (Day 56).	Change from baseline in physical and psychological fatigue measured using the PROMIS® scale. A decrease in the score compared to baseline shows an improvement in the symptom. PROMIS definition - Patient-Reported Outcomes Measurement Information System. The Fatigue Short Form (4a) was used (Section 17.3 Appendix 3 of protocol). Raw fatigue scores range from 4 to 20 and are converted to a T-score metric where the response from the general population is set at 50 with standard deviations at 10; a score of greater than 60 would be one std dev greater than the general population, meaning more fatigue. A link to the fatigue score maps is provided in the hyperlinks section. The minimum fatigue T-score is 33.7 (with a std error of 4.9) and a maximum score of 75.8 (with a std error of 3.9). The higher the score, the more fatigue. A decrease in the fatigue score from baseline to day 28 and day 56 would indicate decrease in fatigue.	Between Baseline (day 0), Visit 4 (day 7), Visit 6 (day 14), Visit 8 (day 21) Visit 10 (day 28), Visit 12 (day 35), Visit 14 (day 42), Visit 16 (Day 56) and Visit 17 (day 56, end of treatment).
Change From Baseline in PROMIS® Cognitive Function Score at Days 7, 14, 21, 28, 35, 42, 49 and End of Treatment (d56)	Change in cognitive function score between baseline, day 28 and day 56 were measured using the PROMIS Cognitive Function Assessment Short Form 4a. Higher scores on the PROMIS Cognitive Function Assessment indicate better perceived cognitive functioning. Answers to 4 questions with scores ranging from 1 (very often - several times a day) to 5 (never) provide raw scores that are then normalized T scores. A T score of 50 is the mean of the general population, with std devs of 10, therefore a score of 40 is one std dev lower than that of the general population. The lowest raw score (4) converts to a T score of 24.99 while the highest raw score (20) converts to a T score of 61.13. A link to the PROMIS scoring maps is provided in the hyperlinks section. An increase in score for cognitive function assessment represents an increase in cognitive function	Baseline (start of treatment), day 28 and day 56 (end of treatment)
Change From Baseline in PROMIS® Sleep Disturbance Score at Days 7,14, 21, 28, 35, 42, 49 and End of Treatment (Day 56).	Assessment of change in sleep disturbance between baseline, day 28 and day 56 used the PROMIS® Sleep Disturbance Short Form (see Appendix 5 in Section 17 of the protocol). Four questions are scored between 1 (best score for good quality sleep) and 5 (worst score) such that the lower the score, the better the sleep. Raw scores are converted to a T-score with a mean of 50 and a standard deviation (SD) of 10 for the general population. T-scores of 60 are one SD worse than average (worse quality sleep). By comparison, Sleep Disturbance T-scores of 40 are one SD better than average. The PROMIS Sleep Disturbance scoring manual shows the lowest sleep disturbance score of 4 converting to a T score of 32 with a std error of 5.2, while the highest score of 20 converts to a T score of 73.3 with a std error of 4.6. The change from baseline is based on patients with paired values.	Between Baseline (day 0), Visit 4 (day 7), Visit 6 (day 14), Visit 8 (day 21) Visit 10 (day 28), Visit 12 (day 35), Visit 14 (day 42), Visit 16 (Day 56) and Visit 17 (day 56, end of treatment).
Number of Participants Requiring Hospitalization During the Treatment Phase	Number of participants who required hospitalization during the treatment phase.	Between baseline (start of treatment) and day 56 (end of treatment)
Duration (Days) of Hospitalization During the Treatment Phase	Duration (in days) of hospitalization required during treatment phase	Between baseline (start of treatment) and day 56 (end of treatment)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Pulse Oxygen Saturation (SpO2) at Day 7, 14, 21, 28, 35, 42, 49, and 56	Exploratory Outcome - Change from baseline in pulse oxygen saturation (SpO2) at Day 7, 14, 21, 28, 35, 42, 49, and 56	Change between baseline (start of treatment) and Day 7, 14, 21, 28, 35, 42, 49, and 56 (end of treatment).
Change From Baseline in Serum Cytokine and Chemokine Levels on Days 28 and 56.	Exploratory Outcome - Change from baseline in serum cytokine and chemokine levels	Change between baseline (start of treatment) and days 28 and 56 (end of treatment)
Change From Baseline in CD4+ and CD8+ T Cell Count on Days 28 and 56.	Exploratory Outcome - Change from baseline in CD4+ and CD8+ T cell count	Change between baseline (start of treatment) and days 28 and 56 (end of treatment)
Change From Baseline in Transforming Growth Factor Beta 1 (TGF beta1) on Days 28 and 56	Exploratory Outcome - change in TGF-b1 from baseline to days 28 and 56 (end of treatment)	Change between baseline (start of treatment) and days 28 and 56 (end of treatment)
Change From Baseline in C-reactive Protein (CRP) on Days 28 and 56	Exploratory Outcome - Change in C-reactive Protein (CRP) from baseline to Days 28 and 56 (end of treatment)	Change between baseline (start of treatment) and days 28 and 56 (end of treatment)
Change From Baseline in CCR5 Receptor Occupancy on Days 28 and 56.	Exploratory Outcome - Change in CCR5 receptor occupancy from baseline and days 28 and 56 (end of treatment)	Change between baseline (start of treatment) and days 28 and 56 (end of treatment)
Exploration of Biomarkers That May Predict and/or Act as Pharmacodynamic Indicators of Pharmacologic Activity of Leronlimab.	Exploratory Outcome - Exploration of biomarkers that may predict and/or act as pharmacodynamic indicators of pharmacologic activity of leronlimab.	91 Days
Incidence of Treatment-related Adverse Events (TEAEs)	Safety Measurement - incidence of treatment emergent adverse events	Between baseline and day 91
Incidence and Severity of Treatment-emergent Adverse Events (TEAEs)	Safety Measures - Incidence and severity of treatment-emergent adverse events	Between baseline and day 91
Incidence of Serious Adverse Events (SAEs)	Safety Measures - incidence of severe adverse events	Between baseline and day 91
Incidence of TEAEs and SAEs Leading to Discontinuation of Study Medication.	Safety Measures - incidence of TEAEs and SAEs leading to discontinuation of study medication	Between baseline and day 56
Changes in Blood Chemistry, Hematology and Coagulation Parameter Results	Safety Measures - Changes in blood chemistry, hematology and coagulation parameter results	Between baseline and day 91
Changes in Vital Signs Including Temperature, Pulse, Respiratory Rate, Systolic and Diastolic Blood Pressure	Safety Measures - Changes in vital signs including temperature, pulse, respiratory rate, systolic and diastolic blood pressure	Between baseline and day 91
Changes in Physical Examination Results	Safety Measures - Changes in physical examination results	Between baseline and day 91
Changes in Electrocardiogram (ECG) Results	Safety Measures - changes in electrocardiogram results	Change between baseline and day 91

Collaborators and Investigators

• Sponsor: CytoDyn, Inc.
• Collaborators: Amarex Clinical Research
• Investigators: Principal Investigator: Norman Gaylis, MD, Arthritis and Rheumatic Disease Specialties Aventura Florida

Publications and helpful links

General Publications

• Gaylis NB, Ritter A, Kelly SA, Pourhassan NZ, Tiwary M, Sacha JB, Hansen SG, Recknor C, Yang OO. Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome. Clin Infect Dis. 2022 Sep 30;75(7):1232-1234. doi: 10.1093/cid/ciac226.
• Chang XL, Wu HL, Webb GM, Tiwary M, Hughes C, Reed JS, Hwang J, Waytashek C, Boyle C, Pessoa C, Sylwester AW, Morrow D, Belica K, Fischer M, Kelly S, Pourhassan N, Bochart RM, Smedley J, Recknor CP, Hansen SG, Sacha JB. CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab. Front Immunol. 2021 Nov 19;12:794638. doi: 10.3389/fimmu.2021.794638. eCollection 2021.

Helpful Links

• PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue Assessment
• PROMIS (Patient-Reported Outcomes Measurement Information System) Cognitive Function Assessment
• PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance Assessment guide
• PROMIS T-score maps

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): June 5, 2021
• Study Completion (Actual): July 8, 2021

Study Registration Dates

• First Submitted: December 14, 2020
• First Submitted That Met QC Criteria: December 18, 2020
• First Posted (Actual): December 22, 2020

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: COVID-19
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Leronlimab
• Other Study ID Numbers: CD15_COVID-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No