Inhaled Aviptadil for the Treatment of COVID-19 in Patients at High Risk for ARDS

Inhaled Aviptadil for the Treatment of COVID-19 in Patients at High Risk for ARDS: A Randomized, Placebo Controlled, Multicenter Trial

The world is currently experiencing a coronavirus (CoV-2) pandemic. A new (SARS)-CoV infection epidemic began in Wuhan, Hubei, China, in late 2019; originally called 2019- nCoV the virus is now known as SARSCoV- 2 and the disease it causes COVID-19. Previous CoV epidemics included severe acute respiratory syndrome (SARS)-CoV, which started in China in 2003 and Middle East respiratory syndrome (MERS)-CoV in the Middle East, which started in 2012. The mortality rates were >10% for SARS and >35% for MERS. The direct cause of death is generally due to ensuing severe atypical pneumonia and ensuing acute respiratory distress syndrome (ARDS). Pneumonia also is generally the cause of death for people who develop influenza, although the mortality rate is lower (1%-3% for the influenza A H5N1 pandemic of 1918-1919 in the United States). Risk factors for a poor outcome of SARS-CoV-2 infection have so far been found to include older age and co-morbidities including chronic cardiovascular and respiratory conditions and current smoking status. In May 2020, the FDA authorized the emergency use of remdesivir for treatment of COVID-19 disease based on topline date of two clinical trials, even though an underpowered clinical trial did not find significant improvement in COVID- 19 patients treated with remdesivir. Nevertheless, remdesivir is the first and so far, only approved treatment for COVID-19. Additionally further trials and clinical observations have not found a significant benefit of other antiviral drugs. Although the results of several studies are still pending, there is still a desperate need for an effective, safe treatment for COVID-19. Aviptadil, which is a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP), might be beneficial in patients at risk of developing ARDS. Nonclinical studies demonstrate that VIP is highly concentrated in the lung, where it reduces inflammation.

Study Overview

• Status: Terminated
• Conditions: Covid19; Corona Virus Infection; ARDS; Aviptadil
• Intervention / Treatment: Drug: Aviptadil 67μg; Drug: Placebo 0.9% NaCl solution

Detailed Description

About 20% of individuals with Corona Virus disease (COVID-19) experience more severe disease characterized by significant respiratory symptoms including acute respiratory distress syndrome (ARDS). ARDS is a known lethal complication due to its low blood oxygenation levels and may result in organ failure. Until now, there are no specific vaccines or therapeutic drugs targeting SARS-CoV-2, alternative therapeutic interventions are needed to prevent and ameliorate respiratory conditions associated with COVID-19 to effectively reduce mortality and prevent ICU admissions. Aviptadil, which is a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP), might be beneficial in patients at risk of developing ARDS. Nonclinical studies demonstrate that VIP is highly concentrated in the lung, where it prevents N-methyl-D-aspartate (NMDA)-induced caspase-3 activation, inhibits IL-6 and TNFa production and protects against HCl-induced pulmonary edema. Further, in animal model systems of lung injury in mice, rats, guinea pigs, sheep, swine and dogs, Aviptadil was shown to restore barrier function at the endothelial/alveolar interface and to protect the lung and other organs from failure. In Europe, Aviptadil is approved for human use and has been shown to be safe in phase II trials for sarcoidosis, pulmonary fibrosis, bronchospasm, erectile dysfunction as well as in a phase I trial in ARDS in the past two decades. In the US, VIP has been given FDA Orphan Drug Designation for the treatment of ARDS and was admitted to the FDA Corona Virus Technology Accelerator Program. In a phase I trial of Aviptadil performed by Sami Said in the early 2000s, eight patients with severe ARDS on mechanical ventilation were treated with ascending doses of intravenous VIP. Seven patients (88%) were successfully extubated and were alive at the five day time point. Six (75%) left the hospital and one (13%) died of an unrelated cardiac event. A phase II clinical trial using intravenous Aviptadil in patients with COVID-19 infection and ARDS has begun. Further, a phase II/III clinical trial will study the effect of inhaled Aviptadil for the treatment of non-acute lung injury in COVID- 19 and begins in June 2020. In Europe, two phase II trials of Aviptadil have been conducted. Further, studies with healthy volunteers have shown that inhaled Aviptadil is well tolerated with few adverse effects.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • St.Gallen, Switzerland, 9007
    • Cantonal Hospital St.Gallen
  • BL
    • Liestal, BL, Switzerland, 4410
      • Cantonal Hospital Baselland Liestal

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• COVID-19 infection diagnosed
• Risk factors for the development of an ARDS according to an adapted EALI (early acute lung injury score) ≥ 2 Points (with at least one point from the EALI score)

EALI Score:

• 2-6l O2 supplementation to achieve a SaO2>90%: 1 point
• >6l O2 supplementation to achieve a SaO2>90%: 2 points
• Respiratory rate ≥ 30/min: 1 point
• Immunosuppression: 1 Point

Modification (for adapting for risk factors for ARDS in SARS-CoV-2 affected patients

• Arterial hypertension: 1 point
• Diabetes: 1 point

• Fever > 39°C: 1 point

  • Age > 18 years
  • Ability to adequate compliance with the inhalation manoeuvre
  • Ability to sign the informed consent

Exclusion Criteria:

• Known or highly suspected bacterial infection (antibiotic treatment to avoid bacterial superinfection may be allowed)
• PCT ≥ 1μg/l
• Mechanical ventilation
• Inability to conduct inhalation therapy
• Hemodynamic instability with requirement of vasopressor therapy
• Severe comorbidities interfering with the safe participation at the trial according to the treating physician
• Pregnancy
• Systemic immunosuppression

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aviptadil Treatment; Participants will receive standard care plus a dose of 67μg nebulized Aviptadil three times a day for ten days.	Drug: Aviptadil 67μg; Participants will receive standard care plus a dose of 67μg nebulized Aviptadil three times a day for ten days.
Placebo Comparator: Placebo Treatment; Participants in the control group will receive an Inhalation of 0.9% NaCl solution three times a day for 10 days	Drug: Placebo 0.9% NaCl solution; Patiens will receive Standard care plus 0.9% NaCl solution three times a day for ten days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to clinical improvement	Time to clinical improvement of a decrease of at least two points on a seven-point ordinal scale of clinical status or discharged alive from hospital. The seven-point scale consists of the following categories: not hospitalized;; hospitalized, not requiring supplemental oxygen;; hospitalized, requiring supplemental oxygen;; hospitalized, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both;; hospitalized, intubation and mechanical ventilation;; ventilation and additional organ support - pressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO);; death	Randomization until discharge from hospital but up to maximum 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of mechanical ventilation	Frequency of Patient who need mechanical ventilation during hospital stay	Randomization until discharge from hospital up to maximum 28 days
Oxygen supplementation	Time requiring oxygen supplementation	Randomization until discharge from hospital up to maximum 28 days
SaO2	Slope in SaO2	Randomization until discharge from hospital up to maximum 28 days
FiO2	Slope in FiO2	Randomization until discharge from hospital but up to maximum 28 days
C-reactive Protein	Slope in C-reactive Protein	measured at baseline, at least every 7 days and at discharge up to maximum 28 days
Neutrophile	Neutrophile ratio	measured at baseline, at least every 7 days and at discharge up to maximum 28 days
lymphocyte	lymphocyte ratio	measured at baseline, at least every 7 days and at discharge up to maximum 28 days
Interleukine 6	Interleukine 6 level	measured at baseline, at least every 7 days and at discharge up to maximum 28 days
Procalcitonin	Procalcitonin level	measured at baseline, at least every 7 days and at discharge up to maximum 28 days
Frequency of Multi organ dysfunction Syndrome (MODS)	Frequency of Patient who showed a multi organ dysfunction Syndrome during Hospital stay	Randomization until discharge from hospital up to maximum 28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospitalization	duration of hospitalization in survivors	randomization till discharge of hospital up to 28 days
treatment initiation to death	Time from treatment initiation to death	Treatment initiation to death up to maximum 28 days
Blood pressure	Blood pressure will be assessed daily in mmHg	Daily until discharge up to maximum 28 days
Heart rate	Heart rate will be assessed daily in bpm	Daily until discharge up to maximum 28 days
Respiratory rate	Respiratory rate will be assessed daily in Counts per minute	Daily until discharge up to maximum 28 days
Body temperature (auricular) in °C	Body temperature (auricular) will be assessed daily in °C	Daily until discharge up to maximum 28 days
Pulse oximetry	Pulse oximetry will be assessed daily in %	Daily until discharge up to maximum 28 days
Glasgow Coma Scale	Glasgow Coma Scale will be assessed daily The lowes possible score is 3 = deep coma or death The highest possible score is 15 = Fully awake	Daily until discharge up to maximum 28 days
Dispnea and caugh	Visual analogue scale for dyspnea and cough as patient-related outcome parameter	Randomization until discharge from hospital up to maximum 28 days

Collaborators and Investigators

• Sponsor: Prof. Dr. Jörg Leuppi
• Investigators: Principal Investigator: Jörg D Leuppi, Professor, Cantonal Hosptal, Baselland

Publications and helpful links

General Publications

• Boesing M, Abig K, Brandle M, Brutsche M, Burri E, Frye BC, Giezendanner S, Grutters JC, Haas P, Heisler J, Jaun F, Leuppi-Taegtmeyer AB, Luthi-Corridori G, Muller-Quernheim J, Nuesch R, Pohl W, Rassouli F, Leuppi JD. Inhaled aviptadil for the possible treatment of COVID-19 in patients at high risk for ARDS: study protocol for a randomized, placebo-controlled, and multicenter trial. Trials. 2022 Sep 20;23(1):790. doi: 10.1186/s13063-022-06723-w.

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2021
• Primary Completion (Actual): June 14, 2023
• Study Completion (Actual): June 14, 2023

Study Registration Dates

• First Submitted: August 21, 2020
• First Submitted That Met QC Criteria: September 1, 2020
• First Posted (Actual): September 2, 2020

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 16, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Covid 19; Corona Virus Infection; acute respiratory distress syndrome (ARDS); Aviptadil; Faster recovery
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Virus Diseases
• Other Study ID Numbers: 2020-01902

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