Double Blind, Placebo Controlled Study of Safety and Effi... | NCT04678830

Name	Class
Amarex Clinical Research	OTHER

Description Module

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

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	Syringes containing normal saline for injection were prepared by an unblinded pharmacist at the clinical sites for use as the placebo.	Drug: Placebos
700mg Leronlimab	Experimental	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)

Name	Type	Description	Arm Group Labels	Other Names
Placebos	Drug	Placebos	Placebo	placebo

Outcomes Module

Primary Outcomes

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 Outcomes

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)

Other Outcomes

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).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male or female adult ≥ 18 years of age at time of enrollment.
Prior confirmed COVID-19 diagnosis by standard reverse transcriptase-polymerase chain reaction (RT-PCR) assay or equivalent testing
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).
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.
Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
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).
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.
Subject is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures and study restrictions

Exclusion Criteria:

Exhibiting signs of moderate or severe pulmonary disease (such as Chronic Obstructive Pulmonary Disease (COPD), asthma, or pulmonary fibrosis)
Ongoing requirement of oxygen therapy
Pulse oxygen saturation (SpO2) of <94% on room air at the time of screening
History of splenectomy
Liver cirrhosis or patient showing signs of clinical jaundice at the time of screening
Chronic kidney disease stage 4 or requiring dialysis at the time of screening
New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF)
Exhibiting signs of uncontrolled hypo-or hyper- thyroidism at the time of Screening
Uncontrolled rheumatologic disorders at the time of screening
History of organ transplantation or are candidates for organ transplantation at the time of screening
History of Chronic Fatigue Syndrome prior to COVID-19 infection
History of fibromyalgia prior to COVID-19 infection
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.
Any malignancy within the past 5 years, excluding successfully treated basal cell carcinoma or squamous cell carcinoma without evidence of metastases.
Any other clinically significant serious systemic diseases which would interfere with study conduct or study results interpretation per the Investigator.
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.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to leronlimab (PRO 140) are not eligible
Ongoing use of CCR5 antagonist
Inability to provide informed consent or to comply with test requirements
Consideration by the investigator, for safety reasons, that the subject is an unsuitable candidate to receive study treatment
Pregnancy or breast feeding
Participating in another study for an investigational treatment

Name	Affiliation	Role
Norman Gaylis, MD	Arthritis and Rheumatic Disease Specialties Aventura Florida	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Arthritis & Rheumatic Disease Specialties		Aventura	Florida	33180	United States
Center for Advanced Research & Education (CARE)

PubMed Identifier	Type	Citation	Retractions
35452519	Derived	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.
34868084	Derived

Label	URL
PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue Assessment	View source

ID	Title	Description
FG000	Placebo	Syringes containing normal saline for injection were prepared by an unblinded pharmacist at the clinical sites for use as the placebo. Placebos: Placebos
FG001	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 Leronlimab (700mg): Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5)

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	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 Leronlimab (700mg): Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5)

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	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).	The Modified Intent-to-Treat (mITT) population was defined as the set of subjects who received at least one dose of leronlimab (PRO 140) or placebo. This population was to be used for the analysis of efficacy parameters or measurements. Fifty six (56) patients received at least one dose of leronlimab or placebo.	Posted		Mean	Standard Deviation	units on a scale		Changes in COVID-19 related symptoms from baseline (start of treatment) and day 56 (end of treatment)

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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 Leronlimab (700mg): Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5)

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Seizures and seizure disorders	Nervous system disorders	MedDRA v 24.0	Systematic Assessment	Worsening seizures

ID	Term
D011024	Pneumonia, Viral
D011014	Pneumonia
D012141	Respiratory Tract Infections
D007239	Infections