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.
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.
Drug: NP-120 (Ifenprodil)
Ifenprodil, 20 mg TID Ifenprodil, 40 mg TID
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.
Westchester Research Center
Miami, Florida, United States
Affinity Health - Loretto Hospital
Chicago, Illinois, United States
Heartland Regional Medical Center
Saint Joseph, Missouri, United States
Promedica Health: Toledo Hospital and BayPark Hospital
Toledo, Ohio, United States
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia
Royal Melbourne Hospital
Parkville, Victoria, Australia
Makati Medical Center
Manila, Philippines
Philippine General Hospital
Manila, Philippines
Lung Center of the Philippines
Quezon City, Philippines
National Institute of Infectious Diseases
Bucharest, Romania