Study of Efficacy and Safety of DV890 in Patients With COVID-19 Pneumonia

Phase 2, Randomized, Controlled, Open Label Multi-center Study to Assess Efficacy and Safety of DFV890 for the Treatment of SARS-CoV-2 Infected Patients With COVID-19 Pneumonia and Impaired Respiratory Function

This clinical study was designed to assess the efficacy and safety of DFV890 for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infected patients with coronavirus disease 2019 (COVID-19) pneumonia and impaired respiratory function.

Study Overview

• Status: Completed
• Conditions: COVID-19 Pneumonia, Impaired Respiratory Function
• Intervention / Treatment: Drug: DFV890; Drug: Standard of Care (SoC)

Detailed Description

This was a Phase II, randomized, controlled, open label multi-center study to assess the efficacy and safety of DFV890 for the treatment of SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired respiratory function.

The study consisted of four distinct study periods:

Screening / Baseline visit (Day -1 to 1): lasted up to a maximum of 24 hours and comprised a screening / baseline assessment. This visit was used to confirm that the study inclusion and exclusion criteria were met and served as baseline assessment prior to randomization.

Treatment period (Day 1-15): Participants were randomized as soon as possible, but within a maximum of 24 hours after screening in a 1:1 ratio receiving either DFV890 in addition to standard of care (SoC) or SoC alone. Participants in the investigational treatment arm received DFV890 administered for a total of 14 days in addition to SoC. Participants in the control arm received SoC alone. Study assessments were conducted every 2 days for hospitalized participants.

The End of Treatment (EOT) visit took place on Day 15. If participants were discharged from the hospital prior to Day 15, assessments on the day of discharge were performed according to the schedule listed under Day 15; participants continued to take the investigational treatment at home to complete the 14-day treatment period and the participants returned to the site for the Day 15/EOT assessment. If a hospital visit was not possible at Day 15, then home nursing services were used to support the last visit.

Follow-up (Day 16-29): After completion of the treatment period, participants were observed until Day 29 or discharged from hospital, whichever was sooner. Study assessments were conducted every 2 days for hospitalized participants. If participants were discharged from hospital prior to Day 29, a study visit conducted by telephone was performed on Day 29.

30-day safety follow-up assessment (Day 45): A follow-up visit for safety was conducted by telephone.

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1846BMF
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1180AAX
      • Novartis Investigative Site
• Brazil
  • RS
    • Porto Alegre, RS, Brazil, 90020-090
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 04029-000
      • Novartis Investigative Site
• Denmark
  • Hvidovre, Denmark, 2650
    • Novartis Investigative Site
• Germany
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1121
    • Novartis Investigative Site
• India
  • New Delhi, India, 110029
    • Novartis Investigative Site
  • New Delhi, India, 110075
    • Novartis Investigative Site
  • Tamil Nadu
    • Coimbatore, Tamil Nadu, India, 641028
      • Novartis Investigative Site
  • West Bengal
    • Kolkata, West Bengal, India, 700099
      • Novartis Investigative Site
• Mexico
  • Mexico CP
    • Ciudad de Mexico, Mexico CP, Mexico, 14080
      • Novartis Investigative Site
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Novartis Investigative Site
• Netherlands
  • Harderwijk, Netherlands, 3840 AC
    • Novartis Investigative Site
• Peru
  • Lima
    • San Martin de Porres, Lima, Peru, 31
      • Novartis Investigative Site
    • San Miguel, Lima, Peru, 32
      • Novartis Investigative Site
• Russian Federation
  • Barnaul, Russian Federation, 656045
    • Novartis Investigative Site
  • Chelyabinsk, Russian Federation, 454021
    • Novartis Investigative Site
  • Ekaterinburg, Russian Federation, 620035
    • Novartis Investigative Site
  • Krasnoyarsk, Russian Federation, 660049
    • Novartis Investigative Site
  • Moscow, Russian Federation, 119991
    • Novartis Investigative Site
  • Ryazan, Russian Federation, 390039
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 193079
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 199106
    • Novartis Investigative Site
• South Africa
  • Western Cape
    • George, Western Cape, South Africa, 6529
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28006
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female patients aged 18-80 years inclusive at screening.
• Clinically diagnosed with the SARS-CoV-2 virus by polymerase chain reaction (PCR) or by other approved diagnostic methodology within 7 days prior to randomization.
• Hospitalized with COVID-19-induced pneumonia evidenced by chest X-ray, computed tomography scan (CT scan) or magnetic resonance scan (MR scan), taken within 5 days prior to randomization (within 24 hours in patients in the Netherlands).
• Impaired respiratory function, defined as peripheral oxygen saturation (SpO2) ≤93% on room air or partial pressure of oxygen (PaO2) / fraction of inspired oxygen (FiO2) <300 millimeter of mercury (mmHg) at screening. For cities located at altitudes greater than 2500 m above sea level, these will be substituted with SpO2 <90% and PaO2/FiO2 <250 mmHg.
• APACHE II score of ≥10 at screening.
• C-reactive protein (CRP) ≥20 mg/L and/or ferritin level ≥600 μg/L at screening.
• Body mass index of ≥18 to <40kg/m2 at screening.

Exclusion Criteria:

• Suspected active or chronic bacterial (including Mycobacterium tuberculosis), fungal, viral, or other infection (besides SARS-CoV-2).
• In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatment.
• Intubated prior to randomization.
• Previous treatment with anti-rejection and immunomodulatory drugs within the past 2 weeks, or within the past 30 days or 5 half-lives (whichever is the longer) for immunomodulatory therapeutic antibodies or prohibited drugs, with the exception of hydroxychloroquine, chloroquine or corticosteroids:

For COVID-19 infection, ongoing corticosteroid treatment is permitted at doses as per local SoC.For non-COVID-19 disorders, ongoing corticosteroid treatment is permitted at doses up to and including prednisolone 10 mg daily or equivalent.

In patients in the Netherlands only, the use of hydroxychloroquine and/or chloroquine in the past 2 weeks are exclusionary.

• Serum alanine transaminase (ALT) or aspartate transaminase (AST) >5 times upper limit of normal detected within 24 hours at screening or at baseline (according to local laboratory reference ranges) or other evidence if severe hepatic impairment (Child-Pugh Class C).
• Absolute peripheral blood neutrophil count of ≤1000/mm3.
• Estimated GFR (eGFR) ≤30 mL/min/1.73m2 (based on CKD-EPI formula).
• Patients currently being treated with drugs known to be strong or moderate inducers of isoenzyme CYP2C9 and/or strong inhibitors of CYP2C9 and/or strong inducers of cytochrome P450, family 3, subfamily A (CYP3A) and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
• Patients with innate or acquired immunodeficiencies.
• Patients who have undergone solid organ or stem cell transplantation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DFV890 + SoC; DFV890 50 mg was administered orally or nasogastrically twice per day (b.i.d) approximately 12 hours apart (morning and evening) for 14 days in addition to SoC.	Drug: DFV890; DFV890 25 mg tablets orally/nasogastrically administered 50 mg b.i.d for 14 days in addition to SoC.; Drug: Standard of Care (SoC); SoC included a variety of supportive therapies that ranged from the administration of supplementary oxygen to full intensive care support, alongside the use of antiviral treatment, convalescent plasma, corticosteroids, antibiotics or other agents.
Active Comparator: Standard of Care (SoC); SoC was used as an active comparator arm.	Drug: Standard of Care (SoC); SoC included a variety of supportive therapies that ranged from the administration of supplementary oxygen to full intensive care support, alongside the use of antiviral treatment, convalescent plasma, corticosteroids, antibiotics or other agents.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
APACHE II Severity of Disease Score on Day 15 or on the Day of Discharge (Whichever is Earlier)	The APACHE II ("Acute Physiology And Chronic Health Evaluation II") is a severity-of-disease classification system. An integer score from 0 to 71 is computed based on several measurements; higher scores correspond to more severe disease and a higher risk of death. In practice, it is rare for any participant to accumulate more than 55 points. APACHE II score was measured on Day 15 or on the day of discharge (whichever was earlier). Participants who died on Day 15 or earlier were assigned the highest observed APACHE II score of any of the participants at any time during the trial (worst case imputation for deaths). Missing data values of the parameters required for the derivation of the APACHE II score were replaced by the last available assessment.	up to Day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum C-reactive Protein (CRP) Levels	C-reactive protein (CRP) is a blood test marker for inflammation in the body. It was analyzed on a log-scale fitting a repeated measures mixed model including treatment group, study day, the three stratification factors and log transformed baseline CRP as a covariate. Values reported were back-transformed to original scale.	Days 2, 4, 6, 8, 10, 12, 14 and 15
Clinical Status Over Time	Clinical status was measured with World Health Organization (WHO) 9-point ordinal scale. The scoring is - Uninfected patients have a score 0. - Ambulatory patients can have a score 1 (no limitation of activities) or 2 (limitation of activities). - Hospitalized patients with mild disease can have score 3 (no oxygen therapy) or 4 (oxygen by mask or nasal prongs). - Hospitalized patients with severe disease can have score 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support - pressors, renal replacement therapy, extracorporeal membrane oxygenation). - Patients who die have a score 8. Missing data values were handled as follows: For participants who died prior to Day 29, the score for death was imputed for all following visits up to and including day 29. For all the other participants, last observation carried forward was applied up to and including Day 29.	Baseline, days 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27 and 29
Number of Participants Not Requiring Mechanical Ventilation for Survival	Number of participants not requiring mechanical ventilation for survival until Day 15 and Day 29: defined by WHO 9-point ordinal scale score of < 6 points at all time points assessments. The scoring is - Uninfected patients have a score 0. - Ambulatory patients can have a score 1 (no limitation of activities) or 2 (limitation of activities). - Hospitalized patients with mild disease can have score 3 (no oxygen therapy) or 4 (oxygen by mask or nasal prongs). - Hospitalized patients with severe disease can have score 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support). - Patients who die have a score 8. Missing data values were handled as follows: For participants who died prior to Day 29, the score for death was imputed for all following visits up to and including day 29. For all the other participants, last observation carried forward was applied up to and including Day 29.	Until Day 15 (Assessments on Days 2, 4, 6, 8, 10, 12, 14 and 15) and until Day 29 (Assessments on Days 17, 19, 21, 23, 25, 27 and 29)
Number of Participants With at Least One-point Improvement From Baseline in Clinical Status	Number of participants with at least one-point improvement from baseline in clinical status, which was measured with WHO 9-point ordinal scale. The scoring is - Uninfected patients have a score 0. - Ambulatory patients can have a score 1 (no limitation of activities) or 2 (limitation of activities). - Hospitalized patients with mild disease can have score 3 (no oxygen therapy) or 4 (oxygen by mask or nasal prongs). - Hospitalized patients with severe disease can have score 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support). - Patients who die have a score 8. Missing data values were handled as follows: For participants who died prior to Day 29, the score for death was imputed for all following visits up to and including day 29. For all the other participants, last observation carried forward was applied up to and including Day 29.	Baseline, Day 15 and Day 29

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Madurka I, Vishnevsky A, Soriano JB, Gans SJ, Ore DJS, Rendon A, Ulrik CS, Bhatnagar S, Krishnamurthy S, Mc Harry K, Welte T, Fernandez AA, Mehes B, Meiser K, Gatlik E, Sommer U, Junge G, Rezende E; Study group. DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function. Infection. 2022 Sep 14:1-14. doi: 10.1007/s15010-022-01904-w. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2020
• Primary Completion (Actual): December 10, 2020
• Study Completion (Actual): December 24, 2020

Study Registration Dates

• First Submitted: May 8, 2020
• First Submitted That Met QC Criteria: May 8, 2020
• First Posted (Actual): May 11, 2020

Study Record Updates

• Last Update Posted (Actual): July 26, 2022
• Last Update Submitted That Met QC Criteria: June 27, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; inflammasome; COVID-19 pneumonia; DFV890; APACHE II
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Lung Diseases; COVID-19; Respiratory Insufficiency; Pneumonia
• Other Study ID Numbers: CDFV890D12201; 2020-001870-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes