A Pragmatic Adaptive Randomized, Controlled Phase II/III Multicenter Study of IFX-1 in Patients With Severe COVID-19 Pneumonia

At a glance

Drugs Vilobelimab (Primary)
Indications COVID-19 pneumonia
Focus Registrational; Therapeutic Use
Acronyms PANAMO
Sponsors InflaRx

Most Recent Events

26 Jul 2022 According to an InflaRx media release, the company plans to submit a request for Emergency Use Authorization (EUA) following encouraging Type B meeting with US FDA. In the meeting with the FDA, the company discussed in detail the completed Phase III part of the PANAMO study in invasively mechanically ventilated, critically ill COVID-19 patients. Application for EUA planned to be submitted in Q3 2022
12 May 2022 According to an InflaRx media release, discussions with regulatory authorities are ongoing to determine next steps towards a potential approval in this indication.
31 Mar 2022 Primary endpoint (Phase III: Mortality) has not been met, according to an InflaRx media release.

Trial Overview

Outcome

Primary endpoint not met - negative

Purpose

Phase II & Phase III: This is a pragmatic, adaptive, randomized, multicenter phase II/III study evaluating IFX-1 for the treatment of COVID-19 related severe pneumonia. The study consists of two parts: Phase II, an open-label, randomized, 2-arm phase evaluating best supportive care (BSC) + IFX-1 (Arm A) and BSC alone (Arm B); and Phase III, a double-blind, placebo-controlled, randomized phase comparing standard of care (SOC) + IFX-1 (Arm A) versus SOC + placebo-to-match (Arm B)

Comments

According to an InflaRx media release, the company plans to submit a request for Emergency Use Authorization (EUA) following encouraging Type B meeting with US FDA. In the meeting with the FDA, the company discussed in detail the completed Phase III part of the PANAMO study in invasively mechanically ventilated, critically ill COVID-19 patients. Application for EUA planned to be submitted in Q3 2022

Primary Endpoints

Not met, 31 Mar 2022

Phase III: Mortality

description: 28-day all-cause mortality
Based on the preliminary interim analysis of efficacy data from Phase II, the primary endpoint chosen for Phase III is 28-day all-cause mortality.
time_frame: Day 28^[1]

Phase II

The primary endpoint in Phase II was the relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of randomization) in Oxygenation Index (PaO2 / FiO2) in supine position at day 5.

Other Endpoints

Treatment Emergent Adverse Events

description: Frequency, severity, and relatedness to study drug of serious and non-serious TEAEs
time_frame: Day1 to Day 60

Safety Parameters

description: Proportion of patients with an improvement in the 8-point ordinal scale
time_frame: Day 15, Day 28^[2]

Diseases Treated

Indication	Qualifiers	Patient Segments
COVID-19 pneumonia	treatment	severe

Subjects

Subject Type patients
Number
Planned: 390

Actual: 399
Sex male & female
Age Group ≥ 18 years; adult; elderly

Patient Inclusion Criteria

- At least 18 years of age or older - Clinically evident or otherwise confirmed severe pneumonia - SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization with locally available test system)

Patient Exclusion Criteria

- Known history of progressed COPD as evidenced by use of daily maintenance treatment with long-acting bronchodilators or inhaled/oral corticosteroids for > 2 months - Patient moribund or expected to die in next 24h according to the judgment of the investigator - Known severe congestive heart failure (New York Heart Association [NYHA] Class III- IV - Received organ or bone marrow transplantation in past 3 months - Known cardio-pulmonary mechanical resuscitation in past 14 days

Trial Details

Identifiers

Identifier	Owner
NCT04333420	ClinicalTrials.gov: US National Institutes of Health
EudraCT2020-001335-28	European Clinical Trials Database
IFX1P2-9	-

Organisations

Sponsors InflaRx
Affiliations InflaRx

Trial Dates

Initiation Dates
Actual : 31 Mar 2020
Primary Completion Dates
Planned : 30 Sep 2021

Actual : 31 Oct 2021
End Dates
Planned : 31 Dec 2021

Actual : 31 Dec 2021

Other Details

Design double-blind; multicentre; open; parallel; prospective; randomised
Phase of Trial Phase II/III
Location Belgium; Brazil; France; Germany; India; Latin America; Mexico; Netherlands; Peru; Russia; South Africa; USA
Focus Registrational; Therapeutic Use

Drug Name	Highest Phase	Originator
Vilobelimab - InflaRx	Phase III	InflaRx

Interventions

Drugs	Route	Formulation
VilobelimabPrimary Drug	Intravenous	Infusion

Arm A: SOC + IFX-1

Drug: SOC + IFX-1 (SOC + IFX-1)

Arm B : SOC + Placebo

Drug: SOC + Placebo (SOC + Placebo)

Results

Therapeutic efficacy

Results from phase II/III trial demonstrated that the vilobelimab treatment resulted in a relative reduction in 28-day all-cause mortality of 23.9% compared to placebo (vilobelimab 31.7% versus placebo 41.6%, p=0.094), which was not statistically significant using site-stratified cox regression analysis as pre-specified in the final statistical analysis plan. The original protocol-specified analysis would have resulted in a statistically significant p-value of 0.027. Additionally, logistic regression analyses of 28-day all-cause mortality resulted in p-values of <0.05 for 3 out of the 4 pre-specified analyses. Importantly, 60-day all-cause mortality, a key secondary endpoint, showed a continued reduction of mortality in the vilobelimab arm ^[3]. Efficacy data obtained from phase II/III trial indicated relative reduction in 28-day all cause mortality of 43% (vilobelimab 21.2% versus placebo 37.2%, p=0.014, hazard ratio: 0.5) in patients with severe acute respiratory distress syndrome (ARDS) and PaO2/FiO2 <100 (n=98, p=0.044); in intubated patients suffering from one or more additional organ support captured as baseline ordinal scale of 7 (n=237, p=0.028); and in patients with kidney impairment, captured by estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m² (n=108, p=0.036). As per site-stratified Cox regression analysis as pre-specified in the final statistical analysis plan of the study, this was not statistically significant. The statistical analysis method was changed from non-stratified to site-stratified as per the recommendation of the regulatory authorities. In pre-specified subgroup analysis in Western European patients, a 43% of relative reduction in 28-day all cause mortality was detected, when vilobelimab was compared with placebo treatment (n=209, p-value=0.014). The analysis was done in intubated patients suffering from one or more additional organ support. Earlier data from the part II of a phase II/III trials indicated twenty-eight-day all-cause mortality in the vilobelimab treatment group was 13% (2 out of 15) versus 27% (4 out of 15) in the control group. In a vilobelimab treatment group, a higher number of patients with 2 or more comorbidities associated with increased COVID-19 mortality were reported, compared to best supportive care group. In the vilobelimab treatment group fewer patients experienced renal impairment assessed by estimated glomerular filtration rates and more patients showed reversal of blood lymphocytopenia and a greater lowering of lactate dehydrogenase concentrations as a sign of reduction in tissue damage. A temporary, but statistically significant increase of D-dimer levels in the first days following vilobelimab administration was reported, as a potential signal for induction of blood clot lysis. No statistically significant group differences on the relative percentage change from baseline to day five in oxygenation index (defined as PaO2/FiO2 ratio) were detected^[1]^[4]^[5].

Adverse events

In a part II of a phase II/III trials, being conducted in patients with severely progressed pneumonia associated with COVID-2019 infections, vilobelimab treatment was well tolerated. There was one death in vilobelimab treatment arm after acute ventilator tube complication (leakage), the other death was due to pulmonary failure in patient with history of severe COPD. In the best supportive care group, there were four deaths due to COVID-2019 induced multi-organ failure. Three of these four were due to pulmonary embolisms as an SAE. Adverse events were comparatively lower in vilobelimab group^[5].

Publications

InflaRx. InflaRx Announces Encouraging Phase III Topline Results from PANAMO Trial of Vilobelimab in Severe COVID-19 Patients. Media-Rel 2022;.
Media Release
InflaRx. InflaRx Reports Encouraging Topline Results from the Exploratory Phase II Part of the Adaptive Randomized Phase II/III Trial of IFX-1 in COVID-19. Media-Rel 2020;.
Media Release

Authors

Author	Total Publications	First Author	Last Author
InflaRx	2	2	2

Trial Centres

Investigators

Download Data (CSV)

Investigator	Centre Name	Trial Centre Country
A Vlaar, MD	University Amsterdam	-
Clinical Research and Development Winzerlaer Strasse 2 Jena Postcode: 07745 Germany Telephone: +4989414 1897897 korinna.pilz@inflarx.de show details	InflaRX GmbH	Germany
Korinna Pilz, MD +49 89 4141 89 78 Ext: 0 korinna.pilz@inflarx.de show details	, InflaRx GmbH	-

Centres

Download Data (CSV)

Centre Name	Location	Trial Centre Country
-	-	-
Hospital Grenoble	Grenoble	France
Inflarx	Amsterdam	Netherlands
InflaRx GmbH	-	-
InflaRX GmbH	Jena	Germany
Inflarx Site	Aachen	Germany
Inflarx Site	Amsterdam	Netherlands
Inflarx Site	Barnaul	Russia
Inflarx Site	Callao	Peru
Inflarx Site	Campinas	Brazil
Inflarx site	Criciúma	Brazil
Inflarx site	Eindhoven	Netherlands
Inflarx Site	Enschede	Netherlands
Inflarx Site	Hannover	Germany
Inflarx Site	Jena	Germany
Inflarx Site	Maastricht	Netherlands
Inflarx Site	Nantes	France
Inflarx Site	Paris	France
Inflarx Site	São José	Brazil
Inflarx Site	Yvoir	Belgium
University Aachen	Aachen	Germany
University Amsterdam	-	-
University Augsburg	Augsburg	Germany
University Berlin- Charite	Berlin	Germany
University Brussels	Brussels	Belgium
University Culiacan	Culiacán	Mexico
University Dresden	Dresden	Germany
University Eindhoven	Eindhoven	Netherlands
University Greifswald	Greifswald	Germany
University Leuven	Leuven	Belgium
University Lima II	Lima	Peru
University Moscow	Moscow	Russia
University Nantes	Nantes	France
University Nice	Nice	France
University Nuevo Leon Monterrey	Nuevo León	Mexico
University of Chiuhuahua	Chihuahua	Mexico
University of Peru	Lima	Peru
University of Somerset West	Somerset West	South-Africa
University Paris 1	Paris	France
University Paris 2	Paris	France
University Paris 3	Paris	France
University Porto Alegre	Porto Alegre	Brazil
University Ryazan	Ryazan'	Russia
University Simon Campos	Mérida	Mexico
University St. Etienne	Saint-Étienne	France
University Suresnes	Suresnes	France

Trial History

Event Date	Event Type	Comment
26 Jul 2022	Other trial event	According to an InflaRx media release, the company plans to submit a request for Emergency Use Authorization (EUA) following encouraging Type B meeting with US FDA. In the meeting with the FDA, the company discussed in detail the completed Phase III part of the PANAMO study in invasively mechanically ventilated, critically ill COVID-19 patients. Application for EUA planned to be submitted in Q3 2022 Updated 27 Jul 2022
12 May 2022	Other trial event	According to an InflaRx media release, discussions with regulatory authorities are ongoing to determine next steps towards a potential approval in this indication. Updated 19 May 2022
25 Apr 2022	Other trial event	Last checked against the ClinicalTrials.gov record. ClinicalTrials.gov: US National Institutes of Health Updated 25 Apr 2022
31 Mar 2022	Endpoint not met	Primary endpoint (Phase III: Mortality) has not been met, according to an InflaRx media release. Updated 04 Apr 2022
31 Mar 2022	Other trial event	According to an InflaRx media release, the company plans to publish detailed results from this study in a peer-reviewed journal and present the findings at a medical meeting in the coming months. The Company plans to discuss data from the PANAMO study with regulatory authorities in due course. Updated 04 Apr 2022
31 Mar 2022	Other trial event	According to an InflaRx media release, the company will host a conference call to discuss the Phase III PANAMO study results today. Updated 04 Apr 2022
31 Mar 2022	Results	Results of Phase III part published in an InflaRx Media Release Updated 04 Apr 2022
24 Mar 2022	Other trial event	According to an InflaRx media release, topline data for the 28-day mortality primary endpoint is expected to be available by the end of March 2022. Updated 29 Mar 2022
06 Feb 2022	Status change - completed	Status changed from active, no longer recruiting to completed. ClinicalTrials.gov: US National Institutes of Health Updated 10 Feb 2022
13 Jan 2022	Other trial event	This trial has been completed in Belgium, according to European Clinical Trials Database record. European Clinical Trials Database Updated 13 Jan 2022
13 Jan 2022	Other trial event	Last checked against European Clinical Trials Database record. European Clinical Trials Database Updated 13 Jan 2022
11 Jan 2022	Other trial event	This trial has been completed in Netherlands, according to European Clinical Trials Database record. European Clinical Trials Database Updated 12 Jan 2022
22 Dec 2021	Other trial event	This trial has been completed in Germany, according to European Clinical Trials Database record. European Clinical Trials Database Updated 24 Dec 2021
12 Oct 2021	Other trial event	According to an InflaRx media release, topline results are expected to be available in Q1 2022. Updated 15 Oct 2021
12 Oct 2021	Status change - active, no longer recruiting	Status changed from recruiting to active, no longer recruiting, according to an InflaRx media release. Updated 15 Oct 2021
05 Aug 2021	Other trial event	According to an InflaRx media release, the option to potentially stop the study early on the basis of efficacy was removed from the interim analysis. Additional trial sites are expected to be added, including in the United States. Updated 12 Aug 2021
05 Aug 2021	Other trial event	According to an InflaRx media release, the trial enrollment reaches 299 patients and an independent data monitoring committee has recommended to continue the trial as planned after analyzing data from the first 180 evaluable patients. Updated 12 Aug 2021
12 May 2021	Other trial event	According to an InflaRx media release, trial enrollment reaches 178 patients and interim analysis is expected in Q3 2021. Updated 18 May 2021
11 May 2021	Completion date	Planned End Date changed from 31 Aug 2021 to 31 Dec 2021. ClinicalTrials.gov: US National Institutes of Health Updated 13 May 2021
11 May 2021	Other trial event	Planned primary completion date changed from 31 May 2021 to 30 Sep 2021. ClinicalTrials.gov: US National Institutes of Health Updated 13 May 2021
25 Mar 2021	Other trial event	According to an InflaRx media release, topline data from the trial are expected to be available by the end 2021. Updated 31 Mar 2021
29 Oct 2020	Results	According to an InflaRx media release, data from the Phase II part of the study were published in the peer-reviewed journal, The Lancet Rheumatology. Updated 03 Nov 2020
16 Sep 2020	Completion date	Planned End Date changed from 31 Dec 2020 to 31 Aug 2021. ClinicalTrials.gov: US National Institutes of Health Updated 21 Sep 2020
16 Sep 2020	Other trial event	Planned primary completion date changed from 31 Oct 2020 to 31 May 2021. ClinicalTrials.gov: US National Institutes of Health Updated 21 Sep 2020
14 Sep 2020	Other trial event	According to an InflaRx media release, Additional sites to be added in the US, EU and other regions Updated 17 Sep 2020
14 Sep 2020	Other trial event	According to an InflaRx media release, the phase II results have been accepted for publication in the peer-reviewed journal, The Lancet Rheumatology. Updated 15 Sep 2020
14 Sep 2020	Other trial event	According to an InflaRx media release, the company announced today the start of the global Phase III part of this Phase II/III trial with the initiation of the first clinical site in the Netherlands. And, German regulatory authority, the Paul-Ehrlich-Institut (PEI), has approved the Phase III clinical trial in Germany Updated 15 Sep 2020
04 Sep 2020	Other trial event	Planned number of patients changed from 130 to 390. European Clinical Trials Database Updated 04 Sep 2020
21 Jul 2020	Other trial event	According to an InflaRx media release, phase III part of this study is subject to regulatory approval. Updated 23 Jul 2020
21 Jul 2020	Other trial event	According to an InflaRx media release, other planned key endpoints for phase III part are assessments of organ support and assessment of disease improvement on the ordinal scale. Updated 23 Jul 2020
21 Jul 2020	Other trial event	According to an InflaRx media release, the Company plans to enroll approximately 360 early intubated, critically ill patients with COVID-19 induced pneumonia in phase III part. The company plans to conduct the study at sites in the US, Europe, South America and potentially other regions and an interim analysis is currently planned after enrollment of 180 patients, with the potential for an early stop for efficacy or futility. Updated 23 Jul 2020
21 Jul 2020	Other trial event	According to an InflaRx media release, the phase II results have been submitted for publication to a peer-reviewed medical journal along with a preprint server. Updated 23 Jul 2020
21 Jul 2020	Other trial event	According to an InflaRx media release, the company will initiate the phase III part in the coming months. Updated 23 Jul 2020
17 Jun 2020	Other trial event	According to an InflaRx media release, upon review of the safety data, the independent data safety monitoring board recommended continuation of the trial into the Phase III part. Updated 19 Jun 2020
17 Jun 2020	Other trial event	According to an InflaRx media release, data are being prepared for submission to a scientific journal. Updated 19 Jun 2020
17 Jun 2020	Interim results	Interim results (n=30) presented in an InflaRx Media Release. Updated 19 Jun 2020
29 Apr 2020	Other trial event	According to an InflaRx media release, after all patients have been treated in the first part of the trial, an interim analysis will be performed to assess the clinical benefit of the treatment using the assessed clinical parameters in order to potentially adapt the confirmatory second part of the study. Part 1 is fully enrolled with 30 patients as of April 24, 2020. Additional centers have been opened in the Netherlands, since March 2020. Updated 04 May 2020
08 Apr 2020	Other trial event	New source identified and integrated (European Clinical Trials Database; EudraCT2020-001335-28) European Clinical Trials Database Updated 08 Apr 2020
07 Apr 2020	New trial record	New trial record ClinicalTrials.gov: US National Institutes of Health Updated 07 Apr 2020
31 Mar 2020	Other trial event	According to an InflaRx media release, InflaRx has dosed the first patient this study. Updated 07 Apr 2020

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