First-In-Human Study To Evaluate Safety, Tolerability, And Pharmacokinetics Following Single Ascending And Multiple Ascending Doses of PF-07304814 In Hospitalized Participants With COVID-19.

Study Overview
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Brief Summary
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It is Phase 1b, 2-part, double-blind, placebo-controlled study to evaluate safety, tolerability, and pharmacokinetics of PF-07304814, in patients hospitalized with SARS-CoV-2 virus infection.

Detailed Description
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It is a 2-part study in hospitalized COVID-19 patients. Part 1 is to evaluate safety, tolerability, PK and markers of clinical activity of escalating doses of PF-07304814 given as 24-hour IV infusion. 2 planned and 3 optional cohorts with 8 participants each are planned. Part 2 is to evaluate safety, tolerability, PK and markers of clinical activity of escalating doses of PF- 07304814 given as 120-hour infusion. 2 planned and 2 optional cohorts with 8 participants each are planned

Official Title
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A PHASE 1B, 2-PART, DOUBLE-BLIND, PLACEBO-CONTROLLED, SPONSOR-OPEN STUDY, TO EVALUATE THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF SINGLE ASCENDING (24-HOUR, PART 1) AND MULTIPLE ASCENDING (120-HOUR, PART 2) INTRAVENOUS INFUSIONS OF PF-07304814 IN HOSPITALIZED PARTICIPANTS WITH COVID-19

Conditions
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Viral Disease

Intervention / Treatment
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* Drug: PF-07304814
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants between the ages of 18 and 79 years. Confirmed SARS-CoV-2 infection. Hospitalized for COVID-19. Symptoms consistent with COVID-19 indicated by at least 1 of the following: fever, cough, sore throat, malaise, headache, muscle pain, shortness of breath, new loss of taste and smell, nausea, chills, fatigue, rhinorrhea, diarrhea, vomiting or radiographic infiltrates by imaging consistent with COVID-19 Total body weight >=50 kg (110 lb), BMI <40 kg/m2; BMI <35 kg/m2 for 76- 79 years. Exclusion Criteria: Evidence of critical illness, defined by at least one of the following: Respiratory failure, Multi-organ dysfunction/failure, Cardiac failure or septic shock Participants that are anticipated by the study Investigator to progress to critical disease, including mechanical ventilation, within 24 hours of enrolment Participants with pre-existing moderate to severe cardiovascular disease, uncontrolled diabetes, or severe asthma or severe COPD. 3.Participants with a known medical history of recent acute or chronic liver disease (other than NASH), chronic or active hepatitis B or C infection, or primary biliary cirrhosis. 4.Participants with a known medical history of ischemic heart disease, heart failure, dysrhythmia or other pre-existing cardiac condition. 5. Participants with known HIV infection, acute or chronic history of hepatitis B or C. 6.Participants with a known medical history of recurrent seizures. 7. Participants with history of venous thromboembolic event, including deep venous thrombosis or pulmonary embolism 8.Confirmed concurrent active systemic infection other than COVID-19. 9.Current diagnosis of cancer, unless in remission and untreated. 10.Other medical or psychiatric condition including recent or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation 11.Females who are pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Part 1 will have 2 planned cohorts. Each escalating cohort will be initiated for enrollment after assessment of safety, tolerability and PK data from previous cohorts by an independent IRC and is deemed acceptable. Part 2 will have 2 planned cohort and each escalating cohort will be initiated after all safety, tolerability and PK data from previous cohort is evaluated and is deemed acceptable by a competent regulatory authority.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-07304814<br>Part 1: Cohort 1-5 Part 2: Cohort 6-9 | Drug: PF-07304814<br>* PF-07304814 is an anti-viral, formulated for intravenous delivery<br>|
| Placebo Comparator: Placebo<br>Part 1: Cohort 1-5 Part 2: Cohort 6-9 | Drug: Placebo<br>* Placebo will be formulated for intravenous delivery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With TEAEs, SAEs, and Severe TEAEs - Part 1: SAD | An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. An adverse event was considered a Treatment-Emergent Adverse Event (TEAE) if the event started during the effective duration of treatment. | Day 1 to 37 days | 
| Number of Participants With TEAEs, SAEs, and Severe TEAEs - Part 2: MAD | An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. An adverse event was considered a treatment-emergent adverse event (TEAE) if the event started during the effective duration of treatment. | Day 1 to 41 days | 
| Number of Participants With Discontinuations From Study/Study Drug or Dose Reduction Due to TEAEs - Part 1: SAD | An AE was any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE was considered a TEAE if the event started during the effective duration of treatment. | Day 1 up to 37 days | 
| Number of Participants With Discontinuations From Study/Study Drug or Dose Reduction Due to TEAEs - Part 2: MAD | An adverse event (AE) was any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE was considered a Treatment-Emergent Adverse Event (TEAE) if the event started during the effective duration of treatment. | Day 1 to 41 days | 
| Number of Participants With Laboratory Abnormality Without Regard to Baseline Abnormality - Part 1: SAD | Laboratory abnormalities reported in at least 1 participant are presented in this OM, including: Hematology - lymphocytes, basophiles; Clinical Chemistry - aspartate aminotransferase, alanine aminotransferase, calcium, bicarbonate, glucose, glucose -FASTING; Urinalysis - urine glucose, urine hemoglobin, urobilinogen and urine erythrocytes (per high power field). Baseline was the last pre-dose measurement. LLN = lower limit of normal, ULN = upper limit of normal. | Day 1 up to 6 days | 
| Number of Participants With Laboratory Abnormality Without Regard to Baseline Abnormality - Part 2: MAD | Laboratory abnormalities reported in at least 1 participant are presented in this OM, including: Hematology - lymphocytes hemoglobin, hematocrit, erythrocytes, ery. mean corpuscular volume, ery. mean corpuscular, hemoglobin; Clinical Chemistry - alanine aminotransferase, protein, albumin, urea nitrogen, creatinine, HDL cholesterol, triglycerides, calcium, phosphate, bicarbonate, glucose; Urinalysis - urine glucose, ketones, urine hemoglobin, urobilinogen, nitrite, leukocyte esterase, urine erythrocytes (per high power field), urine leukocytes (Scalar). Baseline was the last pre-dose measurement. LLN = lower limit of normal, ULN = upper limit of normal | Day 1 up to 41 days | 
| Summary of Baseline and Change From Baseline in Systolic and Diastolic Blood Pressure at Day 1 (30 Minutes, 2 Hours, 6 Hour, and 12 Hours; 24 Hours [End of Treatment]), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) - Part 1: SAD | Absolute baseline values and changes from baseline in supine systolic and diastolic blood pressure were summarized by treatment and time post-dose. Blood pressure was assessed in the supine position after at least 5 minutes of rest in a quiet setting without distractions. Baseline was defined as the last pre-dose measurement. | Baseline (pre-dose Day 1), Day 1-30 minutes, 2 hours, 6 hour, and 12 hours; 24 hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2). | 
| Summary of Baseline and Change From Baseline in Systolic and Diastolic Blood Pressure at Day2,3,4,5, and 6 (120 Hours), Day7 (Follow-up 1), Day10 (Follow-up 2), Day14 (Follow-up 3), Between Day34-41 (Follow-up 4), and/or Early Termination - Part 2: MAD | Absolute baseline values and changes from baseline in supine systolic and diastolic blood pressure were summarized by treatment and time post-dose. Blood pressure was assessed in the supine position after at least 5 minutes of rest in a quiet setting without distractions. Baseline was defined as the last pre-dose measurement. | Baseline (pre-dose Day 1), Day 2, 3, 4, 5; 120 hours (End of Treatment), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (between Day 34-41) and/or early termination (ET) . | 
| Summary of Baseline and Change From Baseline in Pulse Rate at Day 1 (30 Minutes, 2 Hours, 6 Hour, and 12 Hours; 24 Hours [End of Treatment]), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) - Part 1: SAD | Absolute baseline values and changes from baseline in pulse rate were summarized by treatment and time post-dose. Baseline was defined as the last pre-dose measurement. | Baseline (pre-dose Day 1), 30 minutes, 2 hours, 6 hour, and 12 hours (post-dose Day 1); 24 hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2). | 
| Summary of Baseline and Change From Baseline in Pulse Rate at Day 2, 3, 4, 5, and 6 (120 Hours), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Between Day 34-41 (Follow-up 4), and/or Early Termination - Part 2: MAD | Absolute baseline values and changes from baseline in pulse rate were summarized by treatment and time post-dose. Baseline was defined as the last pre-dose measurement. | Baseline (pre-dose Day 1); Day 2, 3, 4, 5; 120 hours (End of Treatment), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (between Day 34-41) and/or early termination (ET). | 
| Summary of Baseline and Change From Baseline in Temperature at Day 1 (30 Minutes, 2 Hours, 6 Hour, and 12 Hours; 24 Hours [End of Treatment]), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) - Part 1: SAD | Absolute baseline values and changes from baseline in temperature were summarized by treatment and time post-dose. Baseline was defined as the last pre-dose measurement. | Baseline (pre-dose Day 1); 30 minutes, 2 hours, 6 hour, and 12 hours (post-dose Day1); 24 hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2). | 
| Summary of Baseline and Change From Baseline in Temperature at Day 2, 3, 4, 5, and 6 (120 Hours), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Between Day 34-41 (Follow-up 4), and/or Early Termination - Part 2: MAD | Absolute baseline values and changes from baseline in temperature were summarized by treatment and time post-dose. Baseline was defined as the last pre-dose measurement. | Baseline (pre-dose Day 1); Day 2, 3, 4, 5; 120 hours (End of Treatment), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (between Day 34-41) and/or early termination (ET). | 
| Summary of Baseline and Change From Baseline in Respiratory Rate at Day 1 (30 Minutes, 2 Hours, 6 Hour, and 12 Hours; 24 Hours [End of Treatment]), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) - Part 1: SAD | Absolute baseline values and changes from baseline in respiratory rate were summarized by treatment and time post-dose. Baseline was defined as the last pre-dose measurement. | Baseline (pre-dose Day 1); 30 minutes, 2 hours, 6 hour, and 12 hours (post-dose Day1); 24 hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2). | 
| Summary of Baseline and Change From Baseline in Respiratory Rate at Day 2, 3, 4, 5, and 6 (120 Hours), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Between Day 34-41 (Follow-up 4), and/or Early Termination - Part 2: MAD | Absolute baseline values and changes from baseline in respiratory rate were summarized by treatment and time post-dose. Baseline was defined as the last pre-dose measurement. | Baseline (pre-dose Day 1); Day 2, 3, 4, 5; 120 hours (End of Treatment), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (between Day 34-41) and/or early termination (ET). | 
| Summary of Baseline and Change From Baseline in Pulse Oximetry/SpO2 at 24 Hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) - Part 1: SAD | Percent SpO2 values at baseline and changes from baseline were summarized for participants in 3 categories: (1) participants who received supplemental oxygen throughout, (2) participants who received supplemental oxygen at some point during the study, and (3) participants who never received supplemental oxygen. Baseline of pulse oximetry/SpO2 was defined as the last pre-dose measurement. SpO2 = arterial oxygen saturation. | Baseline (pre-dose Day 1); Day1-24 hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) | 
| Summary of Baseline and Change From Baseline in Pulse Oximetry/SpO2 at Day 2, 3, 4, 5; 6 (120hours), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (Between Day 34-41), and/or Early Termination-Part 2: MAD | Percent SpO2 values at baseline and changes from baseline were summarized for participants in 3 categories: (1) participants who received supplemental oxygen throughout, (2) participants who received supplemental oxygen at some point during the study, and (3) participants who never received supplemental oxygen. Baseline of pulse oximetry/SpO2 was defined as the last pre-dose measurement. SpO2 = arterial oxygen saturation. | Baseline (pre-dose Day 1); Day 2, 3, 4, 5; 120 hours (End of Treatment), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (between Day 34-41), and/or early termination (ET). | 
| Summary of Baseline and Change From Baseline in ECG Mean Heart Rate at Day 1 (30 Minutes, 2 Hours, 6 Hour, and 12 Hours; 24 Hours [End of Treatment]), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) - Part 1: SAD | The average of the triplicate readings collected at each assessment time was calculated for each ECG parameter. Baseline was defined as the average (if possible) of the triplicate pre-dose recordings on Day 1. Only centrally read ECG data was used. | Baseline (pre-dose Day 1); 30 minutes, 2 hours, 6 hour, and 12 hours (post-dose Day1); 24 hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) | 
| Summary of Baseline and Change From Baseline in ECG Mean Heart Rate at Day 2, 3, 5, 6 (120 Hours), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (Between Day 34-41) and/or Early Termination- Part 2: MAD | The average of the triplicate readings collected at each assessment time was calculated for each ECG parameter. Baseline was defined as the average (if possible) of the triplicate pre-dose recordings on Day 1. Only centrally read ECG data was used. | Baseline (pre-dose Day 1); Day 2, 3, 5; 120 hours (End of Treatment), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (between Day 34-41), and/or early termination(ET) | 
| Summary of Baseline and Change From Baseline in PR, QRS, QT and QTcF Intervals at Day 1 (30 Minutes, 2 Hours, 6 Hour, and 12 Hours; 24 Hours [End of Treatment]), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) - Part 1: SAD | The average of the triplicate readings collected at each assessment time was calculated for each ECG parameter. Baseline was defined as the average (if possible) of the triplicate pre-dose recordings on Day 1. Only centrally read ECG data was used. | Baseline (pre-dose Day 1); 30 minutes, 2 hours, 6 hour, and 12 hours (post-dose Day1); 24 hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2) | 
| Summary of Baseline and Change From Baseline in PR, QRS, QT and QTcF Intervals at Day 2, 3, 5, 6 (120 Hours), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (Between Day 34-41) and/or Early Termination- Part 2: MAD | The average of the triplicate readings collected at each assessment time was calculated for each ECG parameter. Baseline was defined as the average (if possible) of the triplicate pre-dose recordings on Day 1. Only centrally read ECG data was used. | Baseline (pre-dose Day 1); Day 2, 3, 5; 120 hours (End of Treatment), Day 7 (Follow-up 1), Day 10 (Follow-up 2), Day 14 (Follow-up 3), Follow-up 4 (between Day 34-41), and/or early termination(ET) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameters: Concentration at 24 Hours (End of Infusion) - Part 1: SAD | C24 was defined as concentration at 24 hours. 24-hour PK draw was approximately 4 hours post end of infusion which corresponded to 28 hours. | Pre-dose and 6 hours post-dose on Day 1; 24 hours; 48 hours; and/or early termination. | 
| PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameter: Concentration at 120 Hours (End of Infusion) - Part 2: MAD | C120 was defined as concentration at 120 hours. Blood sample collection at approximately at 2 and 6 hours post the end of the infusion, which correspond to approximately 122 hours and 126 hours post the start of infusion. | Pre-dose on Day1; Day 2, 3, 5 and 6 (end of treatment day), 7 (Follow-up 1), and/or early termination. | 
| PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameters: Maximum Observed Concentration (Cmax) - Part 2: MAD | Cmax was defined as maximum observed concentration. Blood sample collection at approximately 2 and 6 hours post the end of the infusion, which correspond to approximately 122 hours and 126 hours post the start of infusion. | Pre-dose on Day1; Day 2, 3, 5 and 6 (end of treatment day), 7 (Follow-up 1), and/or early termination. | 
| PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameters: t½ - Part 2: MAD | t½ was defined as terminal half-life. Blood sample collection at approximately within 30 minutes before end of infusion ( 120 hours), and at 2 and 6 hours post the end of the infusion, which correspond to approximately 122h and 126h post the start of infusion. | Pre-dose on Day1; Day 2, 3, 5 and 6 (end of treatment day), 7 (Follow-up 1), and/or early termination. | 
| PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameters: Concentration at Steady State (Css) - Part 2: MAD | Css was defined as concentration at steady state. Blood sample collection at approximately 2 and 6 hours post the end of the infusion, which correspond to approximately 122 hours and 126 hours post the start of infusion. | Pre-dose on Day1; Day 2, 3, 5 and 6 (end of treatment day), 7 (Follow-up 1), and/or early termination. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-COV-2