Clinical trial NCT04535167: 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.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Viral Disease
Keywords: COVID-19
SARS-COV-2
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2020-09-01
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: * Inclusion Criteria:

  1. Male or female participants between the ages of 18 and 79 years.
  2. Confirmed SARS-CoV-2 infection.
  3. Hospitalized for COVID-19.
  4. 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
  5. Total body weight \>=50 kg (110 lb), BMI \<40 kg/m2; BMI \<35 kg/m2 for 76- 79 years.
* Exclusion Criteria:

  1. Evidence of critical illness, defined by at least one of the following: Respiratory failure, Multi-organ dysfunction/failure, Cardiac failure or septic shock
  2. Participants that are anticipated by the study Investigator to progress to critical disease, including mechanical ventilation, within 24 hours of enrolment
  3. 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.

Primary outcomes:
measure: Number of Participants With TEAEs, SAEs, and Severe TEAEs - Part 1: SAD
timeFrame: Day 1 to 37 days
measure: Number of Participants With TEAEs, SAEs, and Severe TEAEs - Part 2: MAD
timeFrame: Day 1 to 41 days
measure: Number of Participants With Discontinuations From Study/Study Drug or Dose Reduction Due to TEAEs - Part 1: SAD
timeFrame: Day 1 up to 37 days
measure: Number of Participants With Discontinuations From Study/Study Drug or Dose Reduction Due to TEAEs - Part 2: MAD
timeFrame: Day 1 to 41 days
measure: Number of Participants With Laboratory Abnormality Without Regard to Baseline Abnormality - Part 1: SAD
timeFrame: Day 1 up to 6 days
measure: Number of Participants With Laboratory Abnormality Without Regard to Baseline Abnormality - Part 2: MAD
timeFrame: Day 1 up to 41 days
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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) .
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: 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
timeFrame: Baseline (pre-dose Day 1); Day1-24 hours (End of Treatment), Day 3 (Follow-up 1) and Day 6 (Follow-up 2)
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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 outcomes:
measure: PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameters: Concentration at 24 Hours (End of Infusion) - Part 1: SAD
timeFrame: Pre-dose and 6 hours post-dose on Day 1; 24 hours; 48 hours; and/or early termination.
measure: PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameter: Concentration at 120 Hours (End of Infusion) - Part 2: MAD
timeFrame: Pre-dose on Day1; Day 2, 3, 5 and 6 (end of treatment day), 7 (Follow-up 1), and/or early termination.
measure: PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameters: Maximum Observed Concentration (Cmax) - Part 2: MAD
timeFrame: Pre-dose on Day1; Day 2, 3, 5 and 6 (end of treatment day), 7 (Follow-up 1), and/or early termination.
measure: PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameters: t½ - Part 2: MAD
timeFrame: Pre-dose on Day1; Day 2, 3, 5 and 6 (end of treatment day), 7 (Follow-up 1), and/or early termination.
measure: PF-07304814 (Prodrug) and PF-00835231 (Active Moiety) Plasma PK Parameters: Concentration at Steady State (Css) - Part 2: MAD
timeFrame: Pre-dose on Day1; Day 2, 3, 5 and 6 (end of treatment day), 7 (Follow-up 1), and/or early termination.
Other outcomes:
Locations:
city: Mountain View
country: United States
facility: El Camino Health
state: California
city: Mountain View
country: United States
facility: Palo Alto Medical Foundation
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Sacramento
country: United States
facility: UC Davis Health Investigational Drug Pharmacy
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital Translational and Clinical Research Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital, Clinical Trials Pharmacy
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Memphis
country: United States
facility: Regional One Health
state: Tennessee
city: Brussels
country: Belgium
facility: University Hospital Brugmann
city: Belo Horizonte
country: Brazil
facility: Santa Casa De Misericórdia de Belo Horizonte
state: Minas Gerais
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Del Rocio
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Crosas-Molist E, Samain R, Kohlhammer L, Orgaz JL, George SL, Maiques O, Barcelo J, Sanz-Moreno V. Rho GTPase signaling in cancer progression and dissemination. Physiol Rev. 2022 Jan 1;102(1):455-510. doi: 10.1152/physrev.00045.2020. Epub 2021 Sep 20.