Clinical trial NCT04382924: Safety and Efficacy of NP-120 (Ifenprodil) for the Treatment of Hospitalized Patient With Confirmed COVID-19 Disease
Official title: A Randomized Open Label Phase 2b/3 Study of the Safety and Efficacy of NP-120 (Ifenprodil) for the Treatment of Hospitalized Patient With Confirmed COVID-19 Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID
Lead sponsor: Algernon Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Novotech (Australia)
First posted: 2020-05-11
Enrollment: 168
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this adaptive trial is to determine the clinical efficacy of Ifenprodil in the treatment of patients infected with COVID-19. This Protocol is largely based on the recommendations of the World Health Organization (WHO) R\&D Blueprint Clinical Trials Expert Group COVID-19 Therapeutic Trial Synopsis, and associated Master Protocol.

The choice of the primary outcome measure will be determined by a pilot study of the first 150 subjects. Subject clinical status (on a 7-point ordinal scale) at day 15 in treatment versus the control group is the default primary endpoint.

Detailed description: NP-120 (Ifenprodil) is an N-methyl-D-Aspartate (NDMA) inhibitor that is specific for the NR2B subunit of the NMDA Receptor. The NMDA receptor, and specifically the NR2B subunit, is involved in glutamate signaling, and is expressed on both neutrophils and T cells. In the case of neutrophils, activation of the NMDA receptor can (1) result in expression of CD11b which targets neutrophils via ICAM-1 to areas of inflammation, and (2) trigger the autocrine release of glutamate. In the case of T-cells, activation of T cells via glutamate can cause (1) T cell proliferation and, (2) the release of cytokines. The activation of T cells and cytokine release can be blocked in vitro by the addition of Ifenprodil. As such it could be a potent anti-inflammatory agent.

Ifenprodil was discovered by a genome wide RNAi assay to uncover gene targets associated with cytoprotective activity against highly pathogenic H5N1 influenza, specifically by preserving cell viability in vitro. When tested in a murine model of H5N1, the drug at clinically relevant doses: (1) improved survivability from 0% at day 6 to 40% day 14 post-infection, (2) the drug significantly reduced edema and lung injury score and (3) reduced infiltrating T cells, neutrophils and NK cells and attenuated the 'cytokine storm'. The mortality rate of H5N1 in humans is \>50%, whereas the mortality rate of COVID-19 infected patients is \< 5%, and both viruses cause acute lung injury and share similar pulmonary pathologies. NP-120 has also been shown to mediate anti-inflammatory responses and reduce pulmonary fibrosis in a murine model of idiopathic pulmonary fibrosis, a complication which can occur after a respiratory virus infection.

Based on the fact that H5N1 has a significantly higher mortality rate than COVID-19 but still shares similar lung pathologies, Algernon Pharmaceuticals believes Ifenprodil could reduce lung injury associated with COVID-19 infection, thereby improving lung function and accelerating patient recovery.

The purpose of this Phase 2b/3 trial is to determine the safety and efficacy of NP-120 in the treatment of COVID-19 infection.

Eligibility criteria: Inclusion Criteria:

1. Male and female subjects aged ≥18 years of age
2. Confirmed coronavirus infection

   1. Positive real-time fluorescence polymerase chain reaction of the patient's respiratory or blood specimens for COVID-19 nucleic acid
   2. Viral gene sequences in respiratory or blood specimens that are highly homologous to COVID-19
   3. Any other diagnostic test accepted by local regulatory authorities
3. Must be hospitalized and requiring supplemental oxygen, or on non-invasive ventilation or high flow oxygen devices (Score of 4 or 5 on WHO Ordinal Clinical Scale)
4. Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must use at least 1 highly effective method of contraception (e.g. oral contraceptives, intrauterine device, diaphragm plus spermicide) from the time of screening and must agree to continue using such precautions for 90 days after the final dose of study drug(s)
5. Non-sterilized males who are sexually active with a female partner of childbearing potential must use condom plus spermicide from day 1 through 90 days after receipt of the last dose of study drug(s)
6. Subjects (or reasonable legal designate) must have the capacity to understand, sign and date a written, informed consent form and any required authorization prior to initiation of any study procedures

Exclusion Criteria:

1. Patients with vasodilatory shock, orthostatic hypotension, hypotension, or tachycardia at screening/baseline
2. Patients experiencing cerebral hemorrhage or cerebral infarction at baseline
3. ALT/AST \> 5 times the upper limit of normal; Child-Pugh Score 10 to 15
4. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR \< 30)
5. Patients on mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
6. Patients taking droxidopa
7. Pregnant and lactating women and those planning to get pregnant
8. Known or suspected allergy to the trial drug or the relevant drugs given in the trial
9. Presence of other disease that may interfere with testing procedures or in the judgement of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial
10. Know inability of patient to comply with the protocol for the duration of the study
11. Involvement in a clinical research study within 4 weeks prior to screening and/or prior enrollment in the study or plan to participate in another interventional clinical trial during the study period. Participation in observational registry studies is permitted.

Primary outcomes:
measure: Patient Clinical Status (on the WHO 7-point Ordinal Scale) at Day 15 in IP Versus SOC Control Group Patients:
timeFrame: Day 15
Secondary outcomes:
measure: Status on an Ordinal Scale Assessed Daily While Hospitalized and on Days 15 and 28 in IP Versus Control Group Patients
timeFrame: Days 1 through 28
measure: NEWS Assessed Days 3, 5, 8 ,11 Daily While Hospitalized and on Days 15 and 29 in IP Versus Control Group Patients
timeFrame: Days 3, 5, 8, 11, 25, 29
measure: Rate of Mechanical Ventilation in IP Versus Control Group Patients
timeFrame: Up to Day 28
measure: Duration of Mechanical Ventilation (if Applicable) in IP Versus Control Group Patients
timeFrame: Up to day 28
measure: Duration of Supplemental Oxygen in IP Versus Control Group Patients
timeFrame: Up to Day 29
measure: Time to Return to Room Pressure (SpO2 > 94%) on Room Air
timeFrame: Up to Day 29
measure: Duration in ICU (if Applicable) in IP Versus Control Group Patients
timeFrame: Up to Day 29
measure: Rate of Mortality in IP Versus Control Group Patients
timeFrame: Up to Day 29
measure: Duration of Hospitalization in IP Versus Control Group Patients
timeFrame: Day 15, 28
measure: Time to Discharge in IP Versus Control Group Patients
timeFrame: Day 15, 28
measure: Effect on the Rate of Change of Partial Pressure of Oxygen (PaO2) and PaO2/FiO2 Ratio Taken at Baseline and Measured Once Daily up to 2 Weeks of Treatment in IP Versus Control Group Patients
timeFrame: Up to day 15, day 28
Other outcomes:
Locations:
city: Miami
country: United States
facility: Westchester Research Center
state: Florida
city: Chicago
country: United States
facility: Affinity Health - Loretto Hospital
state: Illinois
city: Saint Joseph
country: United States
facility: Heartland Regional Medical Center
state: Missouri
city: Toledo
country: United States
facility: Promedica Health: Toledo Hospital and BayPark Hospital
state: Ohio
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Manila
country: Philippines
facility: Makati Medical Center
city: Manila
country: Philippines
facility: Philippine General Hospital
city: Quezon City
country: Philippines
facility: Lung Center of the Philippines
city: Bucharest
country: Romania
facility: National Institute of Infectious Diseases
Study officials:
References: