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Safety and Efficacy of NP-120 (Ifenprodil) for the Treatment of Hospitalized Patient With Confirmed COVID-19 Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04382924
Recruitment Status : Recruiting
First Posted : May 11, 2020
Last Update Posted : September 9, 2020
Sponsor:
Collaborator:
Novotech (Australia)
Information provided by (Responsible Party):
Algernon Pharmaceuticals

Study Description
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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 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.


Condition or disease Intervention/treatment Phase
COVID Drug: NP-120 (Ifenprodil) Phase 2 Phase 3

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

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 682 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 5, 2020
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : February 2022
Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment Arm A
NP-120 (Ifenprodil) 20 mg TID + Standard of Care
 Drug: NP-120 (Ifenprodil)
Ifenprodil, 20 mg TID Ifenprodil, 40 mg TID
No Intervention: Control Arm
Standard of Care only
Experimental: Treatment Arm B
NP-120 (Ifenprodil) 40 mg TID + Standard of Care
 Drug: NP-120 (Ifenprodil)
Ifenprodil, 20 mg TID Ifenprodil, 40 mg TID


Outcome Measures
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Primary Outcome Measures :
  1. Patient clinical status (on the WHO 7-point ordinal scale) at day 15 in IP versus SOC control group patients: [ Time Frame: Day 15 ]
    1. Not hospitalized, no limitations on activities
    2. Not hospitalized, limitation on activities
    3. Hospitalized, not requiring supplemental oxygen
    4. Hospitalized, requiring supplemental oxygen
    5. Hospitalized, on non-invasive ventilation or high flow oxygen devices
    6. Hospitalized, on invasive mechanical ventilation or ECMO
    7. Death


Secondary Outcome Measures :
  1. Status on an ordinal scale assessed daily while hospitalized and on days 15 and 28 in IP versus control group patients [ Time Frame: Days 1 through 28 ]
  2. NEWS assessed days 3, 5, 8 ,11 daily while hospitalized and on days 15 and 29 in IP versus control group patients [ Time Frame: Days 3, 5, 8, 11, 25, 29 ]
  3. Rate of mechanical ventilation in IP versus control group patients [ Time Frame: Day 15, 28 ]
  4. Duration of mechanical ventilation (if applicable) in IP versus control group patients [ Time Frame: Day 15, 28 ]
  5. Duration of supplemental oxygen in IP versus control group patients [ Time Frame: Day 15, 28 ]
  6. Time to return to room pressure (SpO2 > 94%) on room air [ Time Frame: Day 15, 28 ]
  7. Duration in ICU (if applicable) in IP versus control group patients [ Time Frame: Day 15, 28 ]
  8. Rate of Mortality in IP versus control group patients [ Time Frame: Day 15, 28 ]
  9. Duration of hospitalization in IP versus control group patients [ Time Frame: Day 15, 28 ]
  10. Time to discharge in IP versus control group patients [ Time Frame: Day 15, 28 ]
  11. 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 [ Time Frame: Up to day 15, day 28 ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04382924


Contacts
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Contact: Nancy Stewart, Ph.D. 204-928-7905 nstewart@gvicds.com
Contact: Mark Williams, Ph.D. 431-777-7759 mark@algernonpharmaceuticals.com

Locations
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United States, Florida
Westchester Research Center Recruiting
Miami, Florida, United States, 33155
Contact: Aimee Gonzalez         
United States, Illinois
Affinity Health - Loretto Hospital Recruiting
Chicago, Illinois, United States, 60644
Contact: Maria Iliescu-Levine         
United States, Missouri
Heartland Regional Medical Center Recruiting
Saint Joseph, Missouri, United States, 64507
Contact: Gautam Balakrishnan         
United States, Ohio
Promedica Health: Toledo Hospital and BayPark Hospital Recruiting
Toledo, Ohio, United States, 43606
Contact: Maria Matal         
Australia, Queensland
Princess Alexandra Hospital Recruiting
Woolloongabba, Queensland, Australia, 4102
Contact: Andrew Henderson         
Australia, Victoria
Royal Melbourne Hospital Recruiting
Parkville, Victoria, Australia, 3050
Contact: Adam Deane         
Philippines
Makati Medical Center Recruiting
Manila, Philippines
Contact: Maria Tarcela Gler         
Philippine General Hospital Recruiting
Manila, Philippines
Contact: Joel Santiaguel         
Lung Center of the Philippines Recruiting
Quezon City, Philippines
Romania
National Institute of Infectious Diseases Recruiting
Bucharest, Romania, 021105
Contact: Adrien Streinu-Cercel         
Sponsors and Collaborators
Algernon Pharmaceuticals
Novotech (Australia)
More Information
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Responsible Party: Algernon Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04382924    
Other Study ID Numbers: AGN120-3
First Posted: May 11, 2020    Key Record Dates
Last Update Posted: September 9, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Ifenprodil
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
 Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Vasodilator Agents
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents