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Trial record 2 of 7 for:    dapansutrile

Safety and Efficacy of Dapansutrile for Treatment of Moderate COVID-19 Symptoms and Evidence of Early Cytokine Release Syndrome

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ClinicalTrials.gov Identifier: NCT04540120
Recruitment Status : Recruiting
First Posted : September 7, 2020
Last Update Posted : October 22, 2020
Sponsor:
Collaborator:
CTI Clinical Trial and Consulting Services
Information provided by (Responsible Party):
Olatec Therapeutics LLC

Brief Summary:

The purpose of this study is to assess the safety and efficacy of orally administered NLRP3 inhibitor, dapansutrile, for the treatment of moderate COVID-19 symptoms and early cytokine release syndrome (CRS) in an ambulatory, at-home setting.

Coronavirus disease 2019 (COVID-19) is caused by infection from a new strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is characterized by fever, cough and shortness of breath, which in certain patients can lead to systemic organ failure and mortality.

The data show that SARS-CoV-2 activates the innate immune signaling sensor NLRP3. Activation of NLRP3 initiates the cytokine release syndrome (CRS), which includes the production of primary cytokine, IL-1, triggering an intense inflammatory response that is prevalent in symptomatic COVID-19 patients. When CRS advances further to a fulminant 'cytokine storm', the data show that respiratory distress syndrome and multiple-organ failure take place.

As a specific inhibitor of NLRP3, dapansutrile may reduce or prevent the hyperinflammation associated with CRS by inhibiting the production of IL-1β early to arrest the progression to a severe 'cytokine storm.' The end result would be a reduction in the need for COVID-19 patients to receive intensive medical treatment, allowing for fewer hospitalizations, administration of mechanical ventilation and deaths.


Condition or disease Intervention/treatment Phase
Covid19 Cytokine Release Syndrome Drug: dapansutrile capsules Drug: placebo capsules Phase 2

Detailed Description:

This is a Phase 2, randomized, double-blind, placebo-controlled study evaluating dapansutrile versus placebo. Approximately 80 subjects randomized 1:1 (40 dapansutrile, 40 placebo) are planned to be enrolled.

At the Screening/Baseline/Day 1 Visit, subjects will provide informed consent, be screened for eligibility, and be randomized/enrolled into the study. Subjects will also receive the first dose of study drug at this visit once study eligibility has been confirmed, and the second dose of study drug will be taken approximately 12 hours after the first dose. Study drug will be continued twice daily (morning and evening doses) through Day 14.

The trial duration will be approximately 45 days for all subjects enrolled, with assessments as follows: Screening/Baseline/Day 1, Day 4, Day 8, Day 15 (±1 day), Day 29 (±3 days), and Day 45 (± 3 days). The Day 29 and Day 45 follow-up visits may be conducted virtually via the institution's telehealth process.

Each subject will be asked to maintain two paper diaries at home daily for the first 14 days: a dosing diary and a subject diary. The dosing diary will be used to record the number of capsules taken each morning and evening. The subject diary will be used to record temperature, oxygen levels, COVID-19 symptoms, and overall health (using the prior 24-hour period for parameters requiring subject recall). The set of questions used in the subject diary will also be administered to the subjects at the Screening/Baseline/Day 1Visit (pre-dose), Day 15, Day 29, and Day 45 visits. Each subject will be provided a no-contact thermometer and a hand-held pulse oximeter at the Screening/Baseline/Day 1 Visit for home use.

At Day 29 and Day 45, additional assessments of safety and clinical activity will occur. The Day 29 and Day 45 follow-up visits will be conducted virtually via the sites' telehealth process.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Subjects will be assigned to receive either dapansutrile capsules or placebo capsules in a 1:1 ratio.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: This is a randomized, blinded, placebo-controlled study. Treatment allocation (to active or placebo treatment groups) will be blinded to all study participants, personnel, and investigators. Only the drug labeling personnel, unblinded pharmacist and DMC members may be unblinded to the treatment assignment. Also, in the event of an emergency, an unblinding envelope can be opened unmasking the treatment assignment to the PI.
Primary Purpose: Treatment
Official Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of the Safety and Efficacy of Orally Administered Dapansutrile Capsules for the Treatment of Moderate COVID-19 Symptoms and Evidence of Early Cytokine Release Syndrome
Actual Study Start Date : September 25, 2020
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : February 2021

Arm Intervention/treatment
Experimental: dapansutrile capsules
A total of 40 subjects will receive 4x 250mg dapansutrile capsules BID for 14 days
Drug: dapansutrile capsules
Hard opaque capsules containing 250 mg of API.
Other Name: OLT1177 capsules

Placebo Comparator: placebo capsules
A total of 40 subjects will receive 4x 250mg placebo capsules BID for 14 days
Drug: placebo capsules
Hard opaque capsules containing 0 mg of API.




Primary Outcome Measures :
  1. Proportion of subjects with complete resolution of fever symptoms and shortness of breath [ Time Frame: Day 15 ]
    Proportion of subjects with complete resolution of fever symptoms (feeling feverish, chills, shivering and/or sweating) and shortness of breath by Day 15


Secondary Outcome Measures :
  1. Cumulative incidence of SAEs [ Time Frame: Day 45 ]
    Evaluate the cumulative incidence of SAEs of dapansutrile relative to placebo

  2. Cumulative incidence of Grade 3 and Grade 4 Adverse Events [ Time Frame: Day 45 ]
    Evaluate the cumulative incidence of Grade 3 and Grade 4 Adverse Events of dapansutrile relative to placebo

  3. Discontinuation or temporary suspension of participation [ Time Frame: Day 45 ]
    Evaluate the cumulative incidence of discontinuation or temporary suspension (for any reason) of dapansutrile relative to placebo

  4. Changes in white cell count [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in white cell count of dapansutrile relative to placebo over time

  5. Changes in hemoglobin [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in hemoglobin of dapansutrile relative to placebo over time

  6. Changes in platelets [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in platelets of dapansutrile relative to placebo over time

  7. Changes in creatinine [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in creatinine of dapansutrile relative to placebo over time

  8. Changes in glucose [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in glucose of dapansutrile relative to placebo over time

  9. Changes in total bilirubin [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in total bilirubin of dapansutrile relative to placebo over time

  10. Changes in ALT [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in ALT of dapansutrile relative to placebo over time

  11. Changes in AST [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in AST of dapansutrile relative to placebo over time

  12. Incidence of new infection that occurs during the study [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in incidence of new infection that occurs during the study of dapansutrile relative to placebo

  13. Incidence of opportunistic infections [ Time Frame: Day 8, Day 15 ]
    Evaluate changes in incidence of opportunistic infections of dapansutrile relative to placebo

  14. Complete resolution of fever symptoms and shortness of breath [ Time Frame: Day 8, Day 29 and Day 45 ]
    Proportion of subjects who experience clinical resolution of fever symptoms and shortness of breath

  15. Time to clinical improvement [ Time Frame: Baseline/Day 1 to Day 15 ]
    Time to clinical improvement in fever symptoms and shortness of breath

  16. Time to sustained absence of fever [ Time Frame: Baseline/Day 1 to Day 15 ]
    Time to sustained absence of fever, defined as at least 2 days since last temperature measurement of ≥ 38˚C (100.4°F)

  17. Clinical improvement in symptoms relevant to COVID 19 [ Time Frame: Day 15 ]
    Proportion of subjects who experience clinical improvement in symptoms relevant to COVID 19 (e.g., cough, diarrhea, vomiting)

  18. Incidence of composite endpoint of hospitalization, supplemental oxygen, mechanical ventilation, or death [ Time Frame: Day 45 ]
    Incidence of subjects meeting the composite endpoint of subjects requiring hospitalization (hospitalization is defined as ≥ 24 hours of acute care), supplemental oxygen, mechanical ventilation, or who die

  19. Clinical improvement in symptoms [ Time Frame: Baseline/Day 1 to Day 15 ]
    Proportion of subjects who experience clinical improvement in symptoms by Day 15, defined as a reduction of two or more points on the WHO Ordinal Scale for Clinical Improvement (lowest score between Baseline Visit/Day 1 and Day 15)

  20. Improvement in oxygenation [ Time Frame: Baseline/Day 1 to Day 15 ]
    Improvement in oxygenation over the course of the study and maintenance of this effect

  21. Change in ALT [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in AST

  22. Change in AST [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in AST

  23. Change in blood glucose [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in blood glucose

  24. Change in Erythrocyte Sedimentation Rate (ESR) [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Erythrocyte Sedimentation Rate (ESR)

  25. Change in Hemoglobin A1c (HbA1C) [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Hemoglobin A1c (HbA1C)

  26. Change in Lactate dehydrogenase (LDH) [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Lactate dehydrogenase (LDH)

  27. Change in Lymphocyte, Absolute count [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Lymphocyte, Absolute count

  28. Change in Monocyte, Absolute count [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Monocyte, Absolute count

  29. Change in Neutrophils, Absolute count [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Neutrophils, Absolute count

  30. Change in Eosinophil, Absolute count [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Eosinophil, Absolute count

  31. Change in CRP [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in CRP

  32. Change in D-Dimer [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in D-Dimer

  33. Change in Ferritin [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Ferritin

  34. Change in Fibrinogen [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Fibrinogen

  35. Change in Partial Thromboplastin Time (PTT) and International Normalized Ratio (INR) [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in Partial Thromboplastin Time (PTT) and International Normalized Ratio (INR)

  36. Change in IL-1β [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in IL-1β

  37. Change in IL-6 [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in IL-6

  38. Change in IL-18 [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in IL-18

  39. Change in granulocyte colony-stimulating factor (G-CSF) [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in granulocyte colony-stimulating factor (G-CSF)

  40. Change in interferon-γ-induced protein 10 (IP-10) [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in interferon-γ-induced protein 10 (IP-10)

  41. Change in C3a [ Time Frame: Baseline/Day 1 to Day 15 ]
    Assess and compare change from Baseline in C3a



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 ≥ 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 ≤ 5 days prior to randomization;
  3. Less than or equal to 120 hours from first symptom onset to randomization;
  4. Subjects with moderate COVID-19 who have fever (temperature ≥ 38 ̊C / 100.4 ̊F) and shortness of breath (with exertion), not requiring oxygen, and meeting the definition of "moderate" as set forth by the May 2020 FDA Guidance for Industry: COVID-19: Developing Drugs and Biological Products for Treatment or Prevention (FDA, 2020), which includes all of the following criteria:

    1. Respiratory rate: ≥ 20 breaths/minute,
    2. SpO2: > 93% on room air at sea level, and
    3. Heart rate: ≥ 90 beats/minute;
  5. Subject must possess at least one of the following high-risk conditions known to have an underlying increased level of cytokine production:

    1. 70 years or more of age,
    2. Obesity (BMI ≥ 30 kg/m2),
    3. Diabetes (type 1 or 2),
    4. 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 patient is on anti- hypertensive medication(s) and diastolic or systolic rates are elevated, patient may be enrolled after consultation with the Medical Monitor,
    5. Known respiratory disease (including asthma or chronic obstructive pulmonary disease [COPD]),
    6. Known heart failure (note: subjects with New York Heart Association Class IV congestive heart failure cannot be enrolled per Exclusion Criterion 4), or
    7. Known coronary disease;
  6. Plasma CRP level ≤ 20 mg/L at Screening/Baseline/Day 1 Visit;
  7. Acceptable overall medical condition to be safely enrolled in and complete the study (with specific regard to cardiovascular, renal, and hepatic conditions) 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.

Exclusion Criteria:

  1. Women of childbearing potential, or men whose sexual partner(s) is a woman of childbearing potential, who:

    1. Are or intend to become pregnant (including use of fertility drugs) during the study;
    2. Are nursing (female subjects only);
    3. 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;
  3. Evidence of moderate concurrent nervous system, renal, endocrine, or gastrointestinal disease, unrelated to COVID-19 as determined by the Investigator;
  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;
  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:

    1. 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
    2. 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 over the defined or planned use of any concomitant medications/therapies during the

    Treatment Period, including specifically:

    1. use of ibuprofen or diclofenac
    2. use of colchicine
    3. use of systemic steroids within 30 days of randomization
    4. use of janus kinase (JAK) inhibitors
    5. 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);

    Note: During the treatment period a patient may meet the criteria for a treatment approved by the FDA specifically for COVID-19 (e.g. remdesivir). In this situation the investigator and medical monitor should confer and take the most appropriate decision for the patient. If possible, the preference would be for the patient to complete the 14 days of dosing before adding on the 2nd treatment. If that is not possible the preference would be for the patient to continue their 14 days on dapansutrile and complete all study related visits.

  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.

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): NCT04540120


Contacts
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Contact: Clinical Trial Operations +1 833-652-8321 inquiries@olatec.com

Locations
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United States, Texas
PanAmerican Clinical Research LLC Recruiting
Brownsville, Texas, United States, 78520
J & S Studies, Inc. Recruiting
College Station, Texas, United States, 77645
Sponsors and Collaborators
Olatec Therapeutics LLC
CTI Clinical Trial and Consulting Services
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Responsible Party: Olatec Therapeutics LLC
ClinicalTrials.gov Identifier: NCT04540120    
Other Study ID Numbers: OLT1177-10
First Posted: September 7, 2020    Key Record Dates
Last Update Posted: October 22, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Olatec Therapeutics LLC:
NLRP3
Covid19
Cytokine Release Syndrome
Dapansutrile
Additional relevant MeSH terms:
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Syndrome
Disease
Pathologic Processes
Dapansutrile
Anti-Inflammatory Agents