Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19

• ClinicalTrials.gov Identifier: NCT04287686
• Recruitment Status: Withdrawn
• First Posted: February 27, 2020
• Last Update Posted: March 17, 2020
• Sponsor: The First Affiliated Hospital of Guangzhou Medical University
• Information provided by (Responsible Party): Yimin LI, The First Affiliated Hospital of Guangzhou Medical University

Tracking Information

• First Submitted Date: February 21, 2020
• First Posted Date: February 27, 2020
• Last Update Posted Date: March 17, 2020
• Estimated Study Start Date: February 2020
• Estimated Primary Completion Date: April 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 25, 2020)

• Time course of body temperature (fever) [ Time Frame: 14 days ]
  Compare the time course of body temperature (fever) between two groups over time.
• Viral load over time [ Time Frame: 14 days ]
  Compare viral load between two groups over time.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 25, 2020)

• P/F ratio over time [ Time Frame: 14 days ]
  PaO2/FiO2 ratio
• Sequential organ failure assessment score(SOFA score) over time [ Time Frame: 14 days ]
  SOFA, including assessment of respiratory, blood, liver, circulatory, nerve, kidney, from 0 to 4 scores in each systems, the higher scores mean a worse outcome.
• Pulmonary Severity Index (PSI) [ Time Frame: 14 days ]
• Image examination of chest over time [ Time Frame: 14 days ]
  Based on radiologist's assessment of inflammatory exudative disease, category as follows: significant improvement, partial improvement, no improvement, increase of partial exudation, significant increase in exudation, unable to judge.
• Proportion of subjects who progressed to critical illness or death [ Time Frame: 14 days ]
• Time from first dose to conversion to normal or mild pneumonia [ Time Frame: 14 days ]
• T-lymphocyte counts over time [ Time Frame: 14 days ]
• C-reactive protein levels over time [ Time Frame: 14 days ]
• Angiotensin II (Ang II) changes over time [ Time Frame: 14 days ]
• Angiotensin 1-7 (Ang 1-7) changes over time [ Time Frame: 14 days ]
• Angiotensin 1-5 (Ang 1-5) changes over time [ Time Frame: 14 days ]
• Renin changes over time [ Time Frame: 14 days ]
• Aldosterone changes over time [ Time Frame: 14 days ]
• Angiotensin-converting enzyme (ACE) changes over time [ Time Frame: 14 days ]
• Angiotensin-converting enzyme 2 (ACE2) changes over time [ Time Frame: 14 days ]
• Interleukin 6 (IL-6) changes over time [ Time Frame: 14 days ]
• Interleukin 8 (IL-8) changes over time [ Time Frame: 14 days ]
• Soluble tumor necrosis factor receptor type II (sTNFrII) changes over time [ Time Frame: 14 days ]
• Plasminogen activator inhibitor type-1 (PAI-1) changes over time [ Time Frame: 14 days ]
• Von willebrand factor (vWF) changes over time [ Time Frame: 14 days ]
• Tumor necrosis factor-α (TNF-α) changes over time [ Time Frame: 14 days ]
• Soluble receptor for advanced glycation end products (sRAGE) changes over time [ Time Frame: 14 days ]
• Surfactant protein-D (SP-D) changes over time [ Time Frame: 14 days ]
• Angiopoietin-2 changes over time [ Time Frame: 14 days ]
• Frequency of adverse events and severe adverse events [ Time Frame: 14 days ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19
• Official Title: A Randomized, Open Label, Controlled Clinical Study to Evaluate the Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) in Adult Patients With COVID-19
• Brief Summary: This is an open label, randomized, controlled, pilot clinical study in patients with COVID-19, to obtain preliminary biologic, physiologic, and clinical data in patients with COVID-19 treated with rhACE2 or control patients, to help determine whether a subsequent Phase 2B trial is warranted.

Detailed Description

This is a small pilot study investigating whether there is any efficacy signal that warrants a larger Phase 2B trial, or any harm that suggests that such a trial should not be done. It is not expected to produce statistically significant results in the major endpoints. The investigators will examine all of the biologic, physiological, and clinical data to determine whether a Phase 2B trial is warranted.

Primary efficacy analysis will be carried only on patients receiving at least 4 doses of active drug. Safety analysis will be carried out on all patients receiving at least one dose of active drug.

It is planned to enroll more than or equal to 24 subjects with COVID-19. It is expected to have at least 12 evaluable patients in each group.

Experimental group: 0.4 mg/kg rhACE2 IV BID and standard of care Control group: standard of care

Intervention duration: up to 7 days of therapy

No planned interim analysis.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

2-arm pilot study

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: COVID-19

Intervention

Drug: Recombinant human angiotensin-converting enzyme 2 (rhACE2)

In this study, the experimental group will receive 0.4 mg/kg rhACE2 IV BID for 7 days.

Study Arms

• Experimental: rhACE2 group
  0.4 mg/kg IV BID for 7 days (unblinded) + standard of care
  Intervention: Drug: Recombinant human angiotensin-converting enzyme 2 (rhACE2)
• No Intervention: Control group
  Standard of care; no placebo

• Publications *: Zhang X, Li S, Niu S. ACE2 and COVID-19 and the resulting ARDS. Postgrad Med J. 2020 Jul;96(1137):403-407. doi: 10.1136/postgradmedj-2020-137935. Epub 2020 Jun 10.

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: March 15, 2020): 0
• Original Estimated Enrollment (submitted: February 25, 2020): 24
• Estimated Study Completion Date: April 2020
• Estimated Primary Completion Date: April 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Laboratory diagnosis:

   • Respiratory specimen is positive for SARS-CoV-2 nucleic acid by RT-PCR; OR,
   • The viral gene sequencing of the respiratory specimen is highly homologous to known novel coronavirus.

2. Fever:

   Axillary temperature >37.3℃

3. Respiratory variables (meets one of the following criteria):

   • Respiratory rate: RR ≥25 breaths/min
   • Oxygen saturation ≤93% at rest on room air
   • PaO2/FiO2 ≤300 mmHg（1 mmHg=0.133 KPa）
   • Pulmonary imaging showed that the lesions progressed more than 50% within 24-48 hours, and the patients were managed as severe
4. HBsAg negative, or HBV DNA ≤10^4 copy/ml if HBsAg positive; anti-HCV negative; HIV negative two weeks prior to signed Informed Consent Form (ICF)
5. Appropriate ethics approval and
6. ICF

Exclusion Criteria:

• Age <18 years; Age >80 years
• Pregnant or breast feeding woman or with positive pregnancy test result
• P/F <100 mmHg
• Moribund condition (death likely in days) or not expected to survive for >7 days
• Refusal by attending MD
• Not hemodynamically stable in the preceding 4 hours (MAP ≤65 mmHg, or SAP <90 mmHg, DAP <60 mmHg, vasoactive agents are required)
• Patient on invasive mechanical ventilation or ECMO
• Patient in other therapeutic clinical trial within 30 days before ICF
• Receive any other ACE inhibitors (ACEI), angiotensin-receptor blockers (ARB) treatment within 7 days before ICF
• Chronic immunosuppression: current autoimmune diseases or patients who received immunotherapy within 30 days before ICF
• Hematologic malignancy (lymphoma, leukemia, multiple myeloma)
• Other patient characteristics (not thought to be related to underlying COVID-19) that portend a very poor prognosis (e.g, severe liver failure, and ect)
• Known allergy to study drug or its ingredients related to renin-angiotensin system (RAS), or frequent and/or severe allergic reactions with multiple medications
• Other uncontrolled diseases, as judged by investigators
• Body weight ≥85 kg

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04287686
• Other Study ID Numbers: GIRH-APN01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Yimin LI, The First Affiliated Hospital of Guangzhou Medical University
• Original Responsible Party: Same as current
• Current Study Sponsor: The First Affiliated Hospital of Guangzhou Medical University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Yimin Li, PhD, MD; The First Affiliated Hospital of Guangzhou Medical University

• PRS Account: The First Affiliated Hospital of Guangzhou Medical University
• Verification Date: March 2020