The primary objective is to assess the clinical efficacy of dapansutrile versus placebo in subjects presenting with moderate COVID-19 respiratory symptoms and evidence of early cytokine release syndrome.Secondary objectives are to assess:* Complete…
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- Viral infectious disorders
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Intervention
Outcome measures
Primary outcome
The primary efficacy-related endpoint will be to compare the dapansutrile and
placebo arms by the following measure:
Clinical deterioration, or lack of improvement, by Day 15, defined as either
having any COVID-19-related hospitalization after enrollment OR meeting both
criteria of (1) worsening or persistence of shortness of breath AND (2) oxygen
saturation less than 92% on room air at sea level or need for supplemental
oxygen to achieve oxygen saturation of 92% or greater . Note: If the PI has
chosen to treat the subject for COVID-19 on an in-patient basis (e.g., the
subject is elderly or frail), hospitalization is not considered clinical
deterioration unless the other criteria have been met or hospitalization is
prolonged through Day 15.
Secondary outcome
The secondary efficacy-related endpoints will be to compare the dapansutrile
and placebo arms by the following measures:
* Complete resolution of fever symptoms (feeling feverish, chills, shivering
and/or sweating) and shortness of breath
* Proportion of subjects with complete resolution by study visits on Days 8,
15, 29, and 45
* Time to complete resolution;
* WHO Ordinal Scale for Clinical Improvement
* Clinical status at Day 8, Day 15, and Day 29
* Mean change from baseline at Day 8, Day 15, and Day 29;
* Oxygenation
* Oxygenation-free days from Day 1 through Day 15
* Incidence, timing and duration of new oxygen use through Day 45;
* Mechanical ventilation
* Mechanical ventilator-free days from Day 1 through Day 15
* Incidence, timing and duration of mechanical ventilation use through Day
45;
* Hospitalization
* Duration of hospital stay (days) due to COVID-19 (note: if the PI has
chosen to treat the subject for COVID-19 on an in-patient basis, this is not
applicable);
* Mortality
* Incidence of death through Day 45;
* Fever
* Number of days with fever (> 38*C / 100.4*F);
* Diarrhea
* Severity and frequency through Day 15;
* Vomiting
* Severity and frequency through Day 15;
* Loss of taste and Loss of smell
* Severity through Day 15;
* All symptoms relevant to COVID-19
* Severity and frequency through Day 15;
* Immunological and inflammatory labs, COVID-19 biomarkers, and cytokine
biomarkers
* Mean change from baseline through Day 15 in the following:
ALT, AST, Creatinine, C3a, CRP, D-dimer, Ferritin, G-CSF, IL-1*, IL-6,
IL-18, IP-10, LDH, Platelets, White blood cell (WBC) count.
Safety variables collected in the study will be:
* AEs during the clinical trial;
* Safety laboratory measures (chemistry, hematology, and urinalysis);
* Vital signs (pulse, respiratory rate, resting blood pressure, temperature,
and oxygen saturation/SpO2).
The safety endpoints in the study will evaluate the safety of dapansutrile
relative to placebo by assessing:
* Cumulative incidence of SAEs;
* Cumulative incidence of Grade 3 and Grade 4 AEs;
* Discontinuation or temporary suspension of participation (for any reason);
* Changes in white cell count, hemoglobin, platelets, creatinine, glucose,
total bilirubin, ALT, and AST over time;
* Incidence of new infection that occurs during the study, regardless of
organism (i.e., viral or non-viral), and including site of infection and source
of culture (BALF, tracheal aspirate, sputum, blood, urine, etc.) should be
recorded;
* Incidence of opportunistic infections.
Exploratory endpoints in the study will evaluate:
* Association of biomarkers with disease progression, treatment efficacy,
and/or adverse events associated with treatment;
* Increased knowledge and understanding of the pathogenesis of COVID-19.
Background summary
The Coronavirus disease 2019 (COVID-19) is primarily a respiratory disease
characterized by fever, cough, and shortness of breath, caused by a new strain
of coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2 [SARS-CoV-2]);
in some infected subjects, COVID-19 has manifestations of systemic organ
involvement. While the majority of individual diagnosed with COVID-19
experience mild symptoms, others may progress quickly to acute respiratory
stress and multi-organ failure. The relentless progression of COVID-19 is due
in part to the absence of proven therapeutic interventions beyond supportive
care and respiratory support both of which have demonstrated limited benefit or
availability.
Activation of the NLRP3 inflammasome leads to production and secretion of
active IL-1*, which plays an important role in antiviral host defenses. NLRP3
inflammasome activation represents an early immune response following
SARS-CoV-2 infection in COVID-19. In some individuals, SARS-CoV-2 infection
results in maladaptive hyper-activation of the NLRP3 inflammasome and in
aberrant production of IL 1*, leading to an excessive and detrimental
inflammatory response. This culminates in a cytokine release syndrome (CRS)
that includes other downstream pro-inflammatory cytokines such as IL-6, and
tumor necrosis factor (TNF) and neutrophil influx in the target organs. CRS
plays an important role in the progression of tissue inflammation causing acute
respiratory distress syndrome (ARDS).
Dapansutrile is a small molecule novel chemical entity that specifically binds
to and inhibits NLRP3. In this study, dapansutrile is expected to inhibit
NLRP3, and thereby the subsequent inflammatory cascade leading to CRS, in
subjects with moderate, COVID-19 and evidence of early CRS to prevent their
disease progression.
Study objective
The primary objective is to assess the clinical efficacy of dapansutrile versus
placebo in subjects presenting with moderate COVID-19 respiratory symptoms and
evidence of early cytokine release syndrome.
Secondary objectives are to assess:
* Complete resolution of fever symptoms (feeling feverish, chills, shivering
and/or sweating) and shortness of breath by the Day 8, Day 15, Day 29, and Day
45 visits; note: complete resolution is defined as having a symptom described
as *absent* on the subject diary with no return of the symptom before Day 45;
* Clinical safety and tolerability of dapansutrile including frequency, type,
and severity of adverse events (AEs) and serious adverse events (SAEs), changes
in vital signs, as well as safety laboratory data leading to early
discontinuation of treatment, study drug related discontinuation of treatment,
or treatment emergent Grade 3 adverse events whether or not related to study
drug;
* Time to complete resolution in fever symptoms and shortness of breath;
* Clinical improvement in individual symptoms relevant to COVID 19 (e.g.,
cough, diarrhea, vomiting);
* Time to recovery of each symptom relevant to COVID-19 (e.g., cough, diarrhea,
vomiting)
* Incidence and duration of hospitalization, supplemental oxygen, or mechanical
ventilation or death before Day 15. Hospitalization is defined as * 24 hours of
acute care due to COVID-19 (note: if the PI has chosen to treat the subject for
COVID-19 on an in-patient basis [e.g., the subject is elderly or frail], this
is not applicable);
* Improvement from Baseline in their score by Day 15 on the WHO Ordinal Scale
for Clinical Improvement;
* Improvement in oxygenation over the course of the study and maintenance of
this effect;
* Immunological and inflammatory biomarkers; C-reactive protein (CRP);
hematological parameters, as listed below:
* To assess and compare changes in:
Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Blood
glucose, Erythrocyte Sedimentation Rate (ESR), Hemoglobin A1c (HbA1C), Lactate
dehydrogenase (LDH), Lymphocyte absolute count, Monocyte absolute count,
Neutrophils absolute count, Eosinophil absolute count;
* To assess and compare changes in COVID-19-related biomarkers:
CRP, D-dimer, Ferritin, Fibrinogen, Partial Thromboplastin Time (PTT)
and International Normalized Ratio (INR);
* To assess and compare changes in cytokine levels:
Interleukin (IL)-1*, IL-6, IL-18, granulocyte colony-stimulating factor
(G CSF), interferon-*-induced protein 10 (IP-10), C3a;
* To assess and compare changes in:
* Heart rate
* Oxygen saturation/SpO2
* Respiratory rate.
Exploratory objectives are as follows:
* Association of biomarkers with disease progression, treatment efficacy,
and/or adverse events associated with treatment;
* Increased knowledge and understanding of the pathogenesis of COVID-19.
Study design
This is a Phase 2, randomized, double-blind, placebo-controlled, study to
evaluate the safety and efficacy of use of dapansutrile to mitigate the
pulmonary and systemic sequelae associated with early cytokine release syndrome
in ambulatory COVID-19 patients with confirmed SARS-CoV-2 infection and
moderate symptoms.
Approximately 80 subjects randomized 1:1 (40 dapansutrile, 40 placebo) are
planned to be enrolled.
At the screening/baseline/day1 visit subjects will provide informed consent and
be screened for eligbility and randomized to one of the treatment groups.
The first dose of 8 capsules (2000 mg) will be taken at the study site. The
second dose of 4 capsules (1000 mg) will be taken approximately 12 hours after
the first dose.
Study drug will be continued twice daily (morning and evening dose of 4
capsules (1000 mg)) through day 14.
After screening the subjects visit the study site on day 4, day 8 and day 15
for study assessments. Due to the ongoing COVID-19 health emergency, a subject
may be seen at a different location than the study site (e.g., at home, in a
clinic, or as an in-patient in the hospital) for each of the designated study
site visits.
Safety and tolerability will be evaluated by monitoring the occurrence of AEs,
vital signs and safety lab tests at all site visits.
In addition subjects will be asked to maintain two paper diaries at home daily
for the first 14 days:
- a dosing diary to record the number of capsules taken each morning and
evening;
- a subject diary to record temperature, oxygen levels, COVID-19 symptoms and
overall health.
At day 29 and day 45 additional assessments of safety and clinical activity
will occur by telephone or other means of communications.
Intervention
2 treatment arms will be used in this study. Subjects will be randomly to a
treatment arm with a 1:1 ratio.
The study medication and placebo are delivered as capsules and have the same
appearance.
The dose per capsule is 250 mg dapansutrile or placebo.
The capsules are taken orally with water.
The initial dose taken at the study site on day1 is 2000 mg (8 capsules). If
the initial dose is taken in the morning, a second dose of 1000 mg (4 capsules)
is taken in the evening. If the initial dose is taken in the late afternoon,
the second 1000 mg dose is taken the following morning.
After that the dose taken is 1000 mg (4 capsules) twice daily through day 14.
Study burden and risks
COVID-19 is primarily a respiratory disease characterized by fever, cough, and
shortness of breath. While the majority of individuals diagnosed with COVID-19
experience mild symptoms, other may progress quickly to acute respiratory
stress and multi-organ failure. There are no proven therapeutic interventions
beyond supportive care and respiratory support both of which have demonstrated
limited benefit or availability.
The progression to severe COVID-19 is caused by an excessive inflammatory
reaction of the immune system. A protein responsible for this is called NLRP3.
NLRP3 activation represents an early immune response following COVID-19.
The study medication dapansutrile is expected to inhibit NLRP3 in subjects with
moderate COVID-19 and evidence of early cytokine release syndrome to prevent
disease progression.
Dapansutrile will be delivered as capsules for oral intake.
Side effects of dapansutrile may be: diarrhea, joint pain, headache.
There is a risk of an allergic reaction with the following symptoms: rash,
difficulty breathing, wheezing, sudden drop in blood pressure, swelling around
the mouth, throat or eyes, high pulse, sweating.
Risk associated to study assessments:
- Blood draws: pain, bruising, minor infection or bleeding, risk of anaemia,
lightheaded feeling/fainting.
The following procedures are performded at all visits:
- Measurement of vital signs;
- Blood draws, 45 mL per draw:
- Standard urine analysis, including pregnancy test, if necessary, on day 1 and
15;
- Maintaining diaries by the subject through day 14.
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Age
Inclusion criteria
1) Male and female subjects * 18 years of age;
2) SARS-CoV-2-positive, confirmed by Food and Drug Administration (FDA)- or
European Medicines Agency (EMA)-authorized COVID-19 test * 7 days prior to
randomization;
3) Less than or equal to 7 days from first symptom onset to randomization;
4) Subjects with moderate COVID-19 consistent with the definition of *moderate*
as set forth by the February 2021 FDA Guidance for Industry: COVID-19:
Developing Drugs and Biological Products for Treatment or Prevention (FDA,
2021) who at the
Screening/Baseline/Day 1 Visit:
a. have felt feverish within the past 24 hours,
b. have an SpO2 > 93% on room air at sea level6 when sitting, and
c. meet at least one of the following criteria:
i. Respiratory rate: * 20 breaths/minute, when the subject is sitting,
ii. SpO2: * 96% on room air at sea level6, when the subject is sitting,
iii. Shortness of breath: with exertion, not requiring oxygen, or
iv. Heart rate: * 90 beats/minute, when the subject is sitting;
5) If all of the criteria in Inclusion 4c are met, subject must possess at
least one of the following high-risk conditions known to have an underlying
increased level of cytokine production; otherwise, at least two of these
high-risk conditions must be met:
a. 70 years or more of age,
b. Obesity (body mass index [BMI] * 30 kg/m2),
c. Diabetes (type 1 or 2),
d. Uncontrolled hypertension, defined as diastolic > 100 mm Hg and/or
systolic > 150 mm Hg without any current anti-hypertensive medications. At the
time of screening if the subject is on anti-hypertensive medication(s) and
diastolic or systolic rates are elevated, subject
may be enrolled after consultation with the Medical Monitor,
e. Known respiratory disease (including asthma or chronic obstructive
pulmonary disease [COPD]),
f. Known heart failure (note: subjects with New York Heart Association Class
IV congestive heart failure cannot be enrolled per Exclusion Criterion 4), or
g. Known coronary disease;
6) Plasma CRP level must be collected at Screening/Baseline/Day 1 Visit;
7) Acceptable overall medical condition to be safely enrolled in and complete
the study in the opinion of the Investigator;
8) Ability to provide written, informed consent prior to initiation of any
study-related procedures, and ability in the opinion of the Investigator to
understand and comply with all the requirements of the study, which includes
abstaining from the use of prohibited medications.
9) Subject must present with at least moderate symptomatology, based on having
symptoms in the prior 24 hours that were uncomfortable and interfered with
daily activities or required treatment other than study drug and having at
least one of the following symptoms: cough; fatigue; myalgia; diarrhea;
vomiting; nausea; headache; sore throat; nasal congestion; rhinorrhea; loss of
taste; loss of smell; fainting; or chills, shivering, and/or sweating.
Exclusion criteria
Main Criteria for Exclusion:
1) Women of childbearing potential, or men whose sexual partner(s) is a woman
of childbearing potential, who:
a. Are or intend to become pregnant (including use of fertility drugs)
during the study;
b. Are nursing (female subjects only);
c. Are not using an acceptable, highly effective method of contraception
until all follow-up procedures are complete.
2) Evidence of pre-existing or new-onset organ failure (with the exception of
those conditions required for enrollment per Inclusion Criterion 5);
3) Evidence of moderate concurrent nervous system, renal, endocrine, or
gastrointestinal disease, unrelated to COVID-19 as determined by the
Investigator (with the exception of those conditions required for enrollment
per Inclusion Criterion 5);
4) Evidence of cardiovascular disease with significant arrhythmia, congestive
heart failure (New York Heart Association Class IV), unstable angina, cor
pulmonale, or symptomatic pericardial effusion, not related to COVID-19 as
determined by the Investigator (with the exception of those conditions required
for enrollment per Inclusion Criterion 5);
5) Required use of vasoactive drug support;
6) History of myocardial infarction in the 6 months prior to the
Screening/Baseline/Day 1 Visit;
7) Evidence of current liver disease, not related to COVID-19 as determined by
the investigator;
8) History or evidence of active tuberculosis (TB) infection at
Screening/Baseline/Day 1 Visit or one of the risk factors for tuberculosis such
as but not limited or exclusive to:
a. History of any of the following: residence in a congregate setting (e.g.,
jail or prison, homeless shelter, or chronic care facility), substance abuse
(e.g., injection or non-injection), health-care workers with unprotected
exposure to subjects who are at high risk of TB or subjects with TB disease
before the identification and correct airborne precautions of the subject
or
b. Close contact (i.e., share the same air space in a household or other
enclosed environment for a prolonged period [days or weeks, not minutes or
hours]) with a person with active pulmonary TB disease within the last 12
months.
9) History of or currently active primary or secondary immunodeficiency;
10) Past or present requirement for oxygen (e.g., nasal cannula, proning,
mechanical ventilation and/or supplemental oxygen);
11) Use of any prohibited concomitant medications/therapies or planned use of
any concomitant medications/therapies during the Treatment Period, including
specifically:
a. use of ibuprofen or diclofenac
b. use of colchicine
c. use of systemic steroids within 30 days of randomization
d. use of janus kinase (JAK) inhibitors
e. use of off-label agents (e.g., hydroxychloroquine, remdesivir,
dexamethasone) and biologic and oral anti-cytokine agents (e.g., current
treatment with adalimumab, infliximab, etanercept, golimumab, certolizumab
pegol, tocilizumab, sarilumab, anakinra, canakinumab, rilonacept, baricitinib,
tofacitinib, or upadacitinib);
12) Known history of renal impairment (e.g., calculated glomerular filtration
rate [GFR] < 45 mL/min);
13) Evidence of malignant disease, or malignancies diagnosed within the
previous 5 years (except for local basal or squamous cell carcinoma of the skin
or carcinoma in situ of the cervix uteri that has been excised and cured);
14) History of infection or known active infection with human immunodeficiency
virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV);
15) Any other concomitant medical or psychiatric conditions, diseases, or prior
surgeries that, in the opinion of the Investigator, would impair the subject
from safely participating in the trial and/or completing protocol requirements;
16) Individuals who have been in a chronic care facility in the past 30 days;
17) Individuals who are incarcerated;
18) Participation in any clinical trial and/or use of any investigational
product within the immediate 30-day period prior to the Screening/Baseline/Day
1 Visit; or receipt prior to Screening/Baseline/Day 1 Visit or intending to
receive during the trial a COVID-19 vaccination.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005227-37-NL |
| ClinicalTrials.gov | NCT04540120 |
| CCMO | NL76051.056.20 |