Angiotensin 1-7 as a Therapy in the Treatment of COVID-19

Angiotensin 1-7 as a Therapy for Pneumonia Caused by Coronavirus 2(SARS-CoV-2)

Phase 2 ,double blind, randomized study of therapy with Angiotensin 1-7 in COVID-19 patients. 120 confirmed SARS-CoV-2 infected patients who exhibit moderate- clinical symptoms including dyspnea, cough and fever, hospitalized in the KETER department in several hospitals in Israel, will be enrolled. 60 patients will receive Ang 1-7 subcutaneously 500 mcg/kg /day. 60 patients will receive placebo : NaCl 0.9% 2 ml -control arm .

Treatment duration: 14 days or until clinical improvement that enables discharge from hospital.

(the shortest time will be the limiting factor in treatment duration). Follow-up-30 days. 14-30 days after discharge from hospital: we will contact the patient via phone to ask questions related to any possible adverse reaction to the drug and general health.

Study Overview

• Status: Recruiting
• Conditions: COVID-19
• Intervention / Treatment: Drug: Angiotensin 1-7

Detailed Description

The working hypothesis behind this study is that the deleterious effects of SARS-CoV-2 are largely attributed to the deprivation of the affected target cells from their advantageous ACE-2-Ang 1-7-MasR machinery on one hand, and to the use of ACE2 as a Trojan horse to infect and destroy these cells on the other in a vicious feed-forward cycle.

120 confirmed SARS-CoV-2 infected patients who exhibit moderate- clinical symptoms including dyspnea, cough and fever, hospitalized in the KETER department in several hospitals in Israel, will be enrolled. 60 patients will receive Ang 1-7 subcutaneously 500 mcg/kg /day. 60 patients will receive placebo : NaCl 0.9% 2 ml -control arm .

Treatment duration: 14 days or until clinical improvement that enables discharge from hospital.

All patients will be treated by Dexamethasone and Remdesivir, according to the published guidelines. Moreover, if other promising medications will be approved for COVID-19, the patients will also be treated by these medications. The current trial will not exclude promising COVID-19 treatments.

Each patient will be closely followed up, where routine physical sings, respiratory and hemodynamic parameters will be documented. In addition, the following complications will be monitored: thromboembolic events, myocarditis, impaired liver function and acute kidney injury. Allergic reactions will be treated by corticosteroids, antihistamines and adrenalin if needed. Patients experiencing allergic reactions will be excluded from continuing the trail.

In addition, biochemical (kidney function tests, electrolytes, liver enzymes, albumin, protein, ferritin, troponin- 5 ml) and hematological (CBC-(3 ml), and coagulation tests-(3 ml)) analysis will be performed on the day of enrollment and every 3 days . Other blood tests for immunophenotyping, cytokines, COVID-19 PCR, Angiotensin II (Ang II) levels, Angiotensin 1-7 (Ang 1-7) levels, ACE and ACE-2 will be collected at baseline and at days 6,15,21 and 30 days after enrollment. and every week ( 2 chemistry (10 ml) and 2 CBC tubes (10 ml)).

In addition chest X-ray will be performed at enrollment and at days 6,15,21 and 30 days after enrollment.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Etty Kruzel-Davila, Dr.; Phone Number: +972-53-276-6052; Email: e_kruzel@rambam.health.gov.il

Study Locations

• Israel
  • Haifa, Israel, 3525408
    • Recruiting
    • Rambam Medical Center
    • Contact: Etty Kruzel-Davila, DR; Phone Number: +972-53-276-6052; Email: e_kruzel@rambam.health.gov.il

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Respiratory specimen is positive for SARS-CoV-2 nucleic acid by RT-PCR
2. Fever: Temperature >37.8℃

3. Moderate lung disease, defined by the following respiratory variables (meets one of the following criteria): lung infiltrates (evident by chest X-ray) not attributable to other causes plus one of the following:

   • Respiratory rate: RR ≥25 breaths/min
   • Oxygen saturation ≤94 % at rest on room air
4. HBsAg negative, HCV negative; HIV negative

5. Informed consent

   -

   Exclusion Criteria:

   • Age <18 years
   • Pregnant or breast-feeding woman or with positive pregnancy test result
   • PaO2/FiO2 ≤100 mmHg / mechanical ventilation
   • Severe organ failure - not expected to survive for >7 days
   • Hemodynamically unstable in the preceding 10 hours (MAP ≤65 mmHg, or SAP <90 mmHg, DAP <60 mmHg, vasoactive agents are required)
   • Patient on ECMO
   • Patient in other therapeutic clinical trial within 30 days before enrolment
   • Chronic immunosuppression: current autoimmune diseases or patients who received immunotherapy within 30 days before enrolment
   • 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 congestive heart failure( NYHA class III or IV, EF less than 30%,) liver cirrhosis , chronic kidney disease stave IV, V(e GFR<30 ml/min), chronic obstructive lung disease: GOLD C,D : ≥2 exacerbations or ≥1 that required hospitalization, FEV1<50%, GOLD 3,4)
   • Atopic patients suffering from allergies

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: treatment group; Ang 1-7 subcutaneously 500 mcg/kg /day	Drug: Angiotensin 1-7; Ang 1-7 subcutaneously 500 mcg/kg /day
Placebo Comparator: control group; NaCl 0.9% subcutaneously 2.0 cc once a day	Drug: Angiotensin 1-7; Ang 1-7 subcutaneously 500 mcg/kg /day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for mechanical ventilation	Patient is intubated	Any time from randomization up to 30 days of last study treatment dose
Death	death certificate	Any time from randomization up to 30 days of last study treatment dose

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus
• Collaborators: Constant Therapeutics LLC

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2021
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: October 27, 2020
• First Submitted That Met QC Criteria: October 27, 2020
• First Posted (Actual): October 28, 2020

Study Record Updates

• Last Update Posted (Actual): January 22, 2021
• Last Update Submitted That Met QC Criteria: January 18, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Antihypertensive Agents; Vasodilator Agents; Angiotensin I (1-7)
• Other Study ID Numbers: 0328-20-RMB; MOH_2020-11-02_009463 (Other Identifier: Ministry Of Health Israel)

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