Safety, Tolerability and Pharmacokinetics of Inhaled Nanoparticle Formulation of Remdesivir (GS-5734) and NA-831 (NEUROSIVIR)

• ClinicalTrials.gov Identifier: NCT04480333
• Recruitment Status: Unknown
• First Posted: July 21, 2020
• Last Update Posted: July 21, 2020
• Sponsor: NeuroActiva, Inc.
• Information provided by (Responsible Party): NeuroActiva, Inc.

Study Description

Brief Summary:

The clinical study is designed to evaluate the safety, tolerability and pharmacokinetics of inhaled nanoparticle nanoparticle formulation of Remdesivir (GS-5734) alone and in combination with NA-831 in 48 healthy volunteers.

Condition or disease	Intervention/treatment	Phase
Covid19; Corona Virus Infection; Severe Acute Respiratory Syndrome; Severe Acute Respiratory Infection; Severe Acute Respiratory Syndrome (SARS) Pneumonia; Severe Acute Respiratory Syndrome of Upper Respiratory Tract; Neurodegeneration; Neuroinflammatory Response	Drug: Drug: NA-831 - 0.10 mg/kg; Drug: Placebo- 0.10 mg/kg; Drug: Drug: NA-831 - 0.20 mg/kg; Drug: Placebo- 0.20 mg/kg; Drug: Drug: GS-5734 - 1.00 mg/kg; Drug: Placebo- 1.00 mg/kg; Drug: Drug: GS-5734 - 2.00 mg/kg; Drug: Placebo- 2.00 mg/kg; Combination Product: Drugs: NA-831 (0.10 mg/kg) plus GS-5734 (1.00 mg/kg); Combination Product: Placebo 0.10 mg + 1.00 mg/kg; Combination Product: Drugs: NA-831 (0.20 mg/kg) plus GS-5734 (2.00 mg/kg); Combination Product: Placebo 0.20 mg + 2.00 mg/kg	Phase 1

Detailed Description:

It has been discovered that SARS-CoV-2 viruses (Covid-19) can directly invade the nervous system of patients, instead of injuring the nervous system through the immune response. Neurotropism is one common feature of Covid-19. Such neuro-invasive propensity of Covid-19 has been documented almost for all the Beta-coronaviruses including SARS-CoV and MERS-CoV.

Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. It was observed that patients surviving COVID-19 are at high risk for subsequent development of neurological disease and in particular Alzheimer's disease.

NA-831 is a new neuroprotective and neurogenesis drug that has been demonstrated its promising safety and efficacy in Phase 2A for the treatment of early onset of Alzheimer's disease. NA-831 in oral formulation is well tolerated NA-831 with no adverse effects. NA-831 in oral formulation exhibits predictable pharmacokinetics including dose-dependent exposure linearity and low variability.

Based on animal studies, NA-831 can provide effective interventions during the severe acute respiratory syndrome, and provide appropriate rehabilitation measures afterwards.

Remdesivir (GS-5734) intravenous formulation has been approved by the FDA under the emergency use authorization for potential treatment of severe cases of Covid-19.

It was found the upper respiratory tract is the most prevalent site of SARS-CoV-2 infection early in disease. Delivering drugs directly to the primary site of infection with a nebulizer, inhaled nanoparticle formulation may enable more targeted and accessible administration in non-hospitalized patients and potentially lower systemic exposure to the drug.

The study is designed to evaluate the safety, tolerability and pharmacokinetics of a new nanoparticle formulation of Remdesivir (GS-5734) and combination therapy with NA-831 in healthy volunteers.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment

Intervention Model Description

The dose escalation given to healthy volunteers across the following cohorts:

NA-831 cohorts:

0.1 mg/kg NA-831, number of subjects N=2 and 2 subjects on placebos 0.2 mg/kg NA-831, number of subjects N=4 and 2 subjects on placebos 0.5 mg/kg NA-831, number of subjects N=4 and 2 subjects on placebos

GS-5734 cohorts:

1. mg/kg GS-5734, number of subjects N=2 and 2 subjects on placebos
2. mg/kg GS-5734, number of subjects N=4 and 2 subjects on placebos

4 mg/kg GS-5734, number of subjects N=4 and 2 subjects on placebos

NA-831 plus GS-5734 cohorts:

0.1 mg/kg NA-831 plus 1 mg/kg GS-5734, number of subjects N=2 and 2 subjects on placebos 0.2 mg/kg NA-831 plus 2 mg/kg GS-5734, number of subjects N=4 and 2 subjects on placebos 0.5 mg/kg NA-831 plus 4 mg/kg GS-5734, number of subjects N=4 and 2 subjects on placebos.

• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-controlled Study of the Safety, Tolerability and Pharmacokinetics of Inhaled Nanoparticle Formulation of Remdesivir (GS-5734) and in Combination With NA-831 in Healthy Volunteers
• Estimated Study Start Date: September 15, 2020
• Estimated Primary Completion Date: December 31, 2020
• Estimated Study Completion Date: March 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Drug: NA-831 - 0.10 mg/kg; 3 Subjects will take inhaled formulation of NA-831 once a day for 5 days	Drug: Drug: NA-831 - 0.10 mg/kg; NA-831 in nanoparticle inhalation formulation; Other Name: NA-831 is a neuroprotective and neurogenesis drug
Placebo Comparator: Comparable Placebo- 0.10 mg/kg; 3 subjects will take inhaled formulation of placebo once a day for 5 days	Drug: Placebo- 0.10 mg/kg; Placebo in nanoparticle inhalation formulation; Other Name: Placebo Comparator
Experimental: Drug: NA-831 - 0.20 mg/kg; 6 Subjects will take inhaled formulation of NA-831 once a day for 5 days	Drug: Drug: NA-831 - 0.20 mg/kg; NA-831 in nanoparticle inhalation formulation; Other Name: NA-81 is a neuroprotective drug
Placebo Comparator: Comparable Placebo- 0.20 mg/kg; 3 subjects will take inhaled formulation of placebo once a day for 5 days	Drug: Placebo- 0.20 mg/kg; Placebo in nanoparticle inhalation formulation; Other Name: Placebo Comparator
Experimental: Drug: GS-5734 - 1.00 mg/kg; 3 Subjects will take inhaled formulation of GS-5734 once a day for 5 days	Drug: Drug: GS-5734 - 1.00 mg/kg; GS-5734 in nanoparticle inhaled formulation; Other Name: GS-5734 (Remdesivir) is an antiviral drug
Placebo Comparator: Comparable Placebo- 1.00 mg.kg; 3 Subjects will take inhaled formulation of GS-5734 once a day for 5 days	Drug: Placebo- 1.00 mg/kg; Placebo in nanoparticle inhalation formulation; Other Name: Placebo Comparator
Experimental: Drug: GS-5734 - 2.00 mg/kg; 6 Subjects will take inhaled formulation of GS-5734 once a day for 5 days	Drug: Drug: GS-5734 - 2.00 mg/kg; GS-5734 in nanoparticle inhaled formulation; Other Name: GS-5734 (Remdesivir) is an anti-viral drug
Placebo Comparator: Comparable Placebo - 2.00 mg/kg; 3 Subjects will take inhaled formulation of GS-5734 once a day for 5 days	Drug: Placebo- 2.00 mg/kg; Placebo in nanoparticle inhaled formulation; Other Name: Placebo Comparator
Experimental: Drugs: NA-831 (0.10 mg/kg) plus GS-5734 (1.00 mg/kg); 3 Subjects- will take inhaled formulation NA-831 (0.10 mg/kg) plus GS-5734 (1.00 mg/kg) once/day for 5 days	Combination Product: Drugs: NA-831 (0.10 mg/kg) plus GS-5734 (1.00 mg/kg); The combined NA-831 and GS-5734 are in nanoparticle inhaled formulation; Other Name: Combination therapy of NA-831 a neuroprotective drug and GS-5734 an antiviral drug
Placebo Comparator: Placebo- 0.10- mg/kg placebo+1.00 mg mg/kg; 3 Subjects - inhaled formulation of placebo once/day for 5 days	Combination Product: Placebo 0.10 mg + 1.00 mg/kg; The combined placebo are in nanoparticle inhaled formulation; Other Name: Placebo Comparator
Experimental: Drugs: NA-831( 0.20 mg/kg) + GS-5734 (2.00 mg/kg); 6 Subjects- inhaled formulation of NA-831 (0.20 mg/kg) + GS-5734 (2.00 mg/kg) once/day for 5 days	Combination Product: Drugs: NA-831 (0.20 mg/kg) plus GS-5734 (2.00 mg/kg); The combined NA-831 and GS-5734 are in nanoparticle inhaled formulation; Other Name: Combination therapy of NA-831, a neuroprotective drug and GS-5734, an antiviral drug
Placebo Comparator: Placebo- 0.20 mg/kg + 2.00mg/kg; 3 Subjects- inhaled formulation of placebo once/day for 5 days	Combination Product: Placebo 0.20 mg + 2.00 mg/kg; Placebo 0.10 mg + 1.00 mg/kg; Other Name: Placebo Comparator

Outcome Measures

Primary Outcome Measures :

1. Proportion of Participants Experiencing any Treatment-Emergent Adverse Events [ Time Frame: First dose date up to Day 30 Follow-up Assessment ]
   AEs will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) V5.0
2. Proportion of Participants Experiencing any Treatment-Emergent Graded Laboratory Abnormalities [ Time Frame: First dose date up to Day 30 Follow-up Assessment ]
   This will be assessed at various time points by clinical laboratory tests and vital signs.

Secondary Outcome Measures :

1. Maximum Concentration (Cmax) - Pharmacokinetic Assessment [ Time Frame: 7 days ]
   Monitoring of the levels of drugs in subject sera at various time points to elucidate the maximum concentration (Cmax) of NA-831 and GS-5734 in human serum.
2. Time to Maximum Concentration (Tmax) - Pharmacokinetic Assessment [ Time Frame: 7 days ]
   Monitoring of the levels of drugs in subject sera at various time points to elucidate the time to maximum concentration (Tmax) of NA-831 and GS-5734 in human serum
3. AUC calculated from time of administration to the last measurable concentration (AUC0-last) - Pharmacokinetic Assessment [ Time Frame: 7 days ]
   Monitoring of the levels of drugs in subject sera at various time points to elucidate the area under the curve from time of administration to the last measurable of NA-831 and GS-5734
4. Area Under the Curve Extrapolated to Infinity (AUC0-∞) [ Time Frame: 7 days ]
   Monitoring of the levels of drugs in subject sera at various time points to elucidate the area under the curve extrapolated to infinity (AUC0-∞) of NA-831 and GS-5734
5. Half-Life (t1/2) - Pharmacokinetic Assessment [ Time Frame: 7 days ]
   Monitoring of the levels of drugs in subject sera at various time points to elucidate the half-life (t1/2) of NA-831 and GS-5734 in human serum.
6. Volume of Distribution (Vd) - Pharmacokinetic Assessment [ Time Frame: 7 days ]
   Monitoring of the levels of drugs in subject sera through various time points to elucidate the volume of distribution (Vd) of NA-831 and GS-5734 in human serum.
7. Clearance [CL] - Pharmacokinetic Assessment [ Time Frame: 7 days ]
   Monitoring of the levels of drugs in subject sera through at various time points to elucidate clearance [CL] of NA-831 and GS-5734 in human serum.

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

INCLUSION CRITERIA:

1. Healthy adult volunteers, aged 21 to 50 years old, men or women.
2. Subjects negative for human immunodeficiency virus (HIV antibody screen), Hepatitis B virus surface Antigen (HBsAg) and Hepatitis C virus (HCV antibody screen).
3. Subjects who are willing to comply with the requirements of the study protocol, attend scheduled visits and make themselves available for the duration of the study with access to a consistent means of telephone contact.
4. Subjects who give written informed consent approved by the Internal Review Board governing the site.
5. Satisfactory baseline medical assessment as assessed by physical examination and a stable health status. Normal laboratory values must be within normal range of the assessing site or show minor variations that are deemed not clinically significant as judged by the Investigator and acceptable for study entry.
6. Accessible vein in the forearm for blood collection.
7. Female subjects of childbearing potential may be enrolled in the study if they have negative urine pregnancy tests on the day of screening and day of admission.
8. Female subjects of non-childbearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause.
9. Both male (if he has a partner of childbearing potential) and female subjects (of childbearing potential) must agree to use adequate and reliable contraceptive measures (e.g. spermicides, condoms, contraceptive pills, etc.) or practice abstinence throughout the duration of the study (up to 30 days post-dosing).

EXCLUSION CRITERIA:

1. Subject previously diagnosed with COVID-19 or had been issued with a quarantine order by the Center of Disease Control (CDC).
2. Presence of acute infection in the preceding 14 days, or presence of a temperature ≥ 100.0 ˚F (oral or tympanic temperature assessment), or acute symptoms of any severity on the scheduled date of admission.
3. History of severe drug and / or food allergies and / or known allergies to the trial product or its components.
4. Female subject who is pregnant or breast-feeding.
5. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, , or immunosuppressive disorders.
6. Any neurological disease or history of significant neurological disorder (e.g. meningitis, seizures, multiple sclerosis, vasculitis, migraines, Guillain-Barré syndrome [genetic/congenital or acquired]).
7. Evidence of clinically significant anemia (HB < 10 g/dL) or any other significant active hematological disease, or having donated > 450 mL of blood within the past three (3) months.
8. Participation or planned participation in a study involving the administration of an investigational compound within the past four (4) months or during this study period.
9. Receipt of immunoglobulins and/or any blood products within nine (9) months of study enrolment or planned administration of any of these products during the study period.
10. Evidence of Hepatitis B or C or HIV by laboratory testing.
11. A positive test result for drugs of abuse (except a positive test result associated with prescription medication that has been reviewed and approved by the investigator) or alcohol at screening.
12. Administration of any licensed vaccine within 30 days before the first study vaccine dose.
13. Both male (if he has a partner of childbearing potential) and female subjects (of childbearing potential) who are unwilling to use adequate contraception or practice abstinence throughout the duration of the study (up to 84 days post-dosing).

14. Any condition that, in the opinion of the Investigator, would complicate or compromise the study or well-being of the subject.

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Contacts and Locations

Contacts

Contact: Brian Tran, MD; 1-415-941-3133; BTran@neuroactiva.com

Contact: Markku Kurkinen, PhD; 1-415-941-3133; MKurkinen@neuroactiva.com

Locations

United States, California

Coronavirus Research Institute; Recruiting

Sunnyvale, California, United States, 94086

Contact: David Nguyen, MD research@covri.org

Contact: Lloyd Tran, PhD LTran@neuroactiva.com

Sub-Investigator: Markku Kurkinen, PhD

Sponsors and Collaborators

NeuroActiva, Inc.

Investigators

• Study Director: Lloyd Tran, PhD; NeuroActiva, Inc.

More Information

• Responsible Party: NeuroActiva, Inc.
• ClinicalTrials.gov Identifier: NCT04480333
• Other Study ID Numbers: NEUROSIVIR
• First Posted: July 21, 2020
• Last Update Posted: July 21, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: We plan to share the Study Protocol
• Supporting Materials: Study Protocol
• Time Frame: 90 days after the completion of the study
• Access Criteria: to be determined

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by NeuroActiva, Inc.:

Covid-19; Corona Virus Infection; Severe Acute Respiratory Syndrome; Severe Acute Respiratory Infection; Severe Acute Respiratory Syndrome (SARS) Pneumonia; Severe Acute Respiratory Syndrome of Upper Respiratory Tract; Neurodegeneration; Neuroinflammation; Cognitive decline

Additional relevant MeSH terms:

Remdesivir; Infections; Communicable Diseases; COVID-19; Pneumonia; Virus Diseases; Respiratory Tract Infections; Severe Acute Respiratory Syndrome; Coronavirus Infections; Syndrome; Nerve Degeneration; Disease; Pathologic Processes; Disease Attributes; Pneumonia, Viral; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Antiviral Agents; Neuroprotective Agents; Anti-Infective Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs