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

Primary Purpose

COVID-19 Pneumonia, Impaired Respiratory Function

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

DFV890

Standard of Care (SoC)

About this trial

This is an interventional treatment trial for COVID-19 Pneumonia, Impaired Respiratory Function focused on measuring COVID-19 pneumonia, SARS-CoV-2, APACHE II, DFV890, inflammasome

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

DFV890 + SoC

Standard of Care (SoC)

Arm Description

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.

SoC was used as an active comparator arm.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

Full Information

NCT ID

NCT04382053

First Posted

May 8, 2020

Last Updated

June 27, 2022

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT04382053

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Completed

Study Start Date

May 27, 2020 (Actual)

Primary Completion Date

December 10, 2020 (Actual)

Study Completion Date

December 24, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

COVID-19 Pneumonia, Impaired Respiratory Function

Keywords

COVID-19 pneumonia, SARS-CoV-2, APACHE II, DFV890, inflammasome

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

143 (Actual)

8. Arms, Groups, and Interventions

Arm Title

DFV890 + SoC

Arm Type

Experimental

Arm Description

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.

Arm Title

Standard of Care (SoC)

Arm Type

Active Comparator

Arm Description

SoC was used as an active comparator arm.

Intervention Type

Drug

Intervention Name(s)

DFV890

Intervention Description

DFV890 25 mg tablets orally/nasogastrically administered 50 mg b.i.d for 14 days in addition to SoC.

Intervention Type

Drug

Intervention Name(s)

Standard of Care (SoC)

Intervention Description

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.

Primary Outcome Measure Information:

Title

APACHE II Severity of Disease Score on Day 15 or on the Day of Discharge (Whichever is Earlier)

Description

Time Frame

up to Day 15

Secondary Outcome Measure Information:

Title

Serum C-reactive Protein (CRP) Levels

Description

Time Frame

Days 2, 4, 6, 8, 10, 12, 14 and 15

Title

Clinical Status Over Time

Description

Time Frame

Baseline, days 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27 and 29

Title

Number of Participants Not Requiring Mechanical Ventilation for Survival

Description

Time Frame

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)

Title

Number of Participants With at Least One-point Improvement From Baseline in Clinical Status

Description

Time Frame

Baseline, Day 15 and Day 29

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Caba

State/Province

Buenos Aires

ZIP/Postal Code

C1180AAX

Country

Argentina

Facility Name

Novartis Investigative Site

City

Buenos Aires

ZIP/Postal Code

B1846BMF

Country

Argentina

Facility Name

Novartis Investigative Site

City

Porto Alegre

State/Province

ZIP/Postal Code

90020-090

Country

Brazil

Facility Name

Novartis Investigative Site

City

Sao Paulo

State/Province

ZIP/Postal Code

04029-000

Country

Brazil

Facility Name

Novartis Investigative Site

City

Hvidovre

ZIP/Postal Code

2650

Country

Denmark

Facility Name

Novartis Investigative Site

City

Regensburg

State/Province

Bavaria

ZIP/Postal Code

93053

Country

Germany

Facility Name

Novartis Investigative Site

City

Hannover

ZIP/Postal Code

30625

Country

Germany

Facility Name

Novartis Investigative Site

City

Wuerzburg

ZIP/Postal Code

97080

Country

Germany

Facility Name

Novartis Investigative Site

City

Budapest

ZIP/Postal Code

1121

Country

Hungary

Facility Name

Novartis Investigative Site

City

Coimbatore

State/Province

Tamil Nadu

ZIP/Postal Code

641028

Country

India

Facility Name

Novartis Investigative Site

City

Kolkata

State/Province

West Bengal

ZIP/Postal Code

700099

Country

India

Facility Name

Novartis Investigative Site

City

New Delhi

ZIP/Postal Code

110029

Country

India

Facility Name

Novartis Investigative Site

City

New Delhi

ZIP/Postal Code

110075

Country

India

Facility Name

Novartis Investigative Site

City

Ciudad de Mexico

State/Province

Mexico CP

ZIP/Postal Code

14080

Country

Mexico

Facility Name

Novartis Investigative Site

City

Monterrey

State/Province

Nuevo Leon

ZIP/Postal Code

64460

Country

Mexico

Facility Name

Novartis Investigative Site

City

Harderwijk

ZIP/Postal Code

3840 AC

Country

Netherlands

Facility Name

Novartis Investigative Site

City

San Martin de Porres

State/Province

Lima

ZIP/Postal Code

Country

Peru

Facility Name

Novartis Investigative Site

City

San Miguel

State/Province

Lima

ZIP/Postal Code

Country

Peru

Facility Name

Novartis Investigative Site

City

Barnaul

ZIP/Postal Code

656045

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Chelyabinsk

ZIP/Postal Code

454021

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Ekaterinburg

ZIP/Postal Code

620035

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Krasnoyarsk

ZIP/Postal Code

660049

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Moscow

ZIP/Postal Code

119991

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Ryazan

ZIP/Postal Code

390039

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Saint Petersburg

ZIP/Postal Code

193079

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

St Petersburg

ZIP/Postal Code

199106

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

George

State/Province

Western Cape

ZIP/Postal Code

6529

Country

South Africa

Facility Name

Novartis Investigative Site

City

Barcelona

State/Province

Catalunya

ZIP/Postal Code

08036

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28006

Country

Spain

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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.

Citations:

PubMed Identifier

36104613

Citation

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. 2023 Jun;51(3):641-654. doi: 10.1007/s15010-022-01904-w. Epub 2022 Sep 14.

Results Reference

derived

Learn more about this trial

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

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

COVID-19 Pneumonia, Impaired Respiratory Function

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial