Clinical trial NCT04382053: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19 Pneumonia, Impaired Respiratory Function
Keywords: COVID-19 pneumonia
SARS-CoV-2
APACHE II
DFV890
inflammasome
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-05-11
Enrollment: 143
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: APACHE II Severity of Disease Score on Day 15 or on the Day of Discharge (Whichever is Earlier)
timeFrame: up to Day 15
Secondary outcomes:
measure: Serum C-reactive Protein (CRP) Levels
timeFrame: Days 2, 4, 6, 8, 10, 12, 14 and 15
measure: Clinical Status Over Time
timeFrame: Baseline, days 2, 4, 6, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27 and 29
measure: Number of Participants Not Requiring Mechanical Ventilation for Survival
timeFrame: 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)
measure: Number of Participants With at Least One-point Improvement From Baseline in Clinical Status
timeFrame: Baseline, Day 15 and Day 29
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Hvidovre
country: Denmark
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Coimbatore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Kolkata
country: India
facility: Novartis Investigative Site
state: West Bengal
city: New Delhi
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Ciudad de Mexico
country: Mexico
facility: Novartis Investigative Site
state: Mexico CP
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo Leon
city: Harderwijk
country: Netherlands
facility: Novartis Investigative Site
city: San Martin de Porres
country: Peru
facility: Novartis Investigative Site
state: Lima
city: San Miguel
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Barnaul
country: Russian Federation
facility: Novartis Investigative Site
city: Chelyabinsk
country: Russian Federation
facility: Novartis Investigative Site
city: Ekaterinburg
country: Russian Federation
facility: Novartis Investigative Site
city: Krasnoyarsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Ryazan
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: George
country: South Africa
facility: Novartis Investigative Site
state: Western Cape
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis pharmaceuticals
role: STUDY_DIRECTOR
References:
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.