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Safety and Antiviral Activity of BLD-2660 in COVID-19 Hospitalized Subjects

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: NCT04334460
Recruitment Status : Recruiting
First Posted : April 6, 2020
Last Update Posted : May 21, 2020
Sponsor:
Collaborator:
Clinipace Worldwide
Information provided by (Responsible Party):
Blade Therapeutics

Brief Summary:
BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9 that is selective over the cathepsins as well as other protease families, displays good metabolic stability and permeability, oral bioavailability and low cytochrome P450 (CYP) inhibition. It is under development for the treatment of coronavirus disease-19 (COVID-19) resulting from infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2), where there is significant unmet medical need.

Condition or disease Intervention/treatment Phase
Sars-CoV2 Drug: BLD-2660 Phase 2

Detailed Description:

Interleukin 6 (IL-6), a proinflammatory cytokine, is a key driver of a cytokine storm that plays a significant role in clinical complications and acute lung injury. Emerging data indicate that serum levels of IL-6 are elevated in COVID-19 patients and are predictive of respiratory failure and mortality. IL-6 has been shown to contribute to lung damage during SARS-CoV infection and the virus itself is capable of directly inducing its expression. Suppression of pro-inflammatory IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections.

In a mouse model of lung injury employing bleomycin, BLD-2660, at therapeutic doses of 30 and 100 mg/kg twice per day (BID), reduced IL-6 levels in bronchoalveolar lavage (BAL) fluid. BLD-2660 also attenuated fibrosis damage as measured by significant reductions in the alpha smooth muscle actin and collagen 1 in lung tissue. BLD-2660 also demonstrated target engagement by inhibiting cleavage of one of its substrates, spectrin, in bronchoalveolar cells.

BLD-2660 was also evaluated in a mouse model of NASH fibrosis, demonstrating an anti-fibrotic effect. A significant decrease in IL-6 transcription was also observed. This suggests that the effect of BLD-2660 on IL-6 is independent of the injury, or the affected organ.

It has been shown that the receptor for SARS-CoV-1 and -2 entry into the cell is angiotensin-converting enzyme 2 (ACE-2). ACE-2 and the dimeric calpains (data on file) are co-expressed in respiratory epithelial cells, the site of both viral entry and predominant early lung injury in COVID-19. Inhibition of dimeric calpain activity has not been associated with impairment of normal immune function. The safety and tolerability of BLD-2660 has been demonstrated in the recently completed Phase 1 single ascending dose (SAD)/multiple ascending dose (MAD) B-2660-101 study.

As BLD-2660 has been demonstrated to (1) reduce tissue IL-6 levels and (2) attenuate lung fibrosis damage, it could therefore, potentially reduce the nonproductive IL-6 mediated host-response to infection, which contribute to morbidity and mortality in COVID-19. In addition, data suggest that survivors of SARS-CoV-2 infection are at risk for chronic impairment of pulmonary function, likely attributable to pulmonary fibrosis secondary to lung injury and inflammation. Although there is not yet available data documenting numbers of patients infected with SARS CoV2 pneumonia who progress to pulmonary fibrosis, epidemiology, viral immunology, and current clinical evidence support that pulmonary fibrosis may become one of the serious long-term complications of survivors of COVID-19 related pneumonia.

Thus, BLD-2660 could not only potentially downregulate the nonproductive host-response to infection, which contributes to morbidity and mortality in COVID-19 but also could reduce potential long-term fibrosis and loss of pulmonary function resulting from SARS-CoV pneumonia. This study will evaluate BLD-2660 as an add-on therapy to standard of care (SOC) in hospitalized subjects with recent diagnosis of COVID-19.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Antiviral Activity of BLD-2660 in Hospitalized Subjects With Recently Diagnosed COVID-19 Compared to Standard of Care Treatment
Actual Study Start Date : May 4, 2020
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : September 2020

Arm Intervention/treatment
Active Comparator: Active Group Drug: BLD-2660
BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9.

Placebo Comparator: Placebo Group Drug: BLD-2660
BLD-2660 is a novel, synthetic, orally active, small molecule inhibitor of calpain (CAPN) 1, 2, and 9.




Primary Outcome Measures :
  1. Time to recovery [ Time Frame: Course of study; 28 days ]
    To evaluate time to recovery as defined by no longer requiring oxygen support or hospital discharge, whichever occurs first.

  2. Change in oxygenation [ Time Frame: 10 days ]
    To evaluate change in oxygenation in hospitalized adults with COVID-19 treated with BLD-2660. Measured by change from baseline to Day 10 or hospital discharge, if sooner, in the ratio of peripheral hemoglobin oxygen saturation to fraction of inspired oxygen (SpO2/FiO2)


Secondary Outcome Measures :
  1. Safety & Tolerability: incidence of TEAEs and serious adverse events (SAEs) [ Time Frame: Course of study; 28 days ]
    To evaluate the safety and tolerability of BLD-2660 in the same population. Measured by incidence of TEAEs and serious adverse events (SAEs)

  2. Change in oxygenation [ Time Frame: Course of study; 28 days ]

    To evaluate change in oxygenation while hospitalized & during follow-up visits. Measured by:

    Improvement from baseline to Days 10, 14, 21 and 28 as measured by the ratio of hemoglobin oxygen saturation to inspired oxygen fraction (SpO2/FiO2), categorized on the 4-point ordinal scale Time to discontinuation of oxygen supplementation requirement Mean SpO2 for subjects not requiring oxygen supplementation at Days 5, 10, 21 and 28 Number of O2 supplementation free days during hospitalization Proportion of subjects who do not require oxygen supplementation (sustained for at least 24 hours) during hospitalization



Other Outcome Measures:
  1. Rate of mortality [ Time Frame: Course of study; 28 days ]
    Measured by mortality rate during the 28-day study period following enrollment.

  2. Time to discharge readiness [ Time Frame: Course of study; 28 days ]
    Measured by time to discharge readiness

  3. Proportion of subjects discharged during study [ Time Frame: Course of study; 28 days ]
    Measured by proportion of subjects ready to be discharged from the hospital during the 28-day study period following enrollment.

  4. Proportion of subjects with resolved fever [ Time Frame: 10 days ]
    Measured by proportion of subjects with resolution of fever below entry criteria for 24 hours by Day 10 in subjects with fever at baseline

  5. Time to resolution of fever [ Time Frame: Course of study; 28 days ]
    Measured by time to resolution of fever below entry criteria for 24 hours in subjects with fever at baseline

  6. Duration of Remdesivir use [ Time Frame: Course of study; 28 days ]
    Measured by duration (in days) of remdesivir use in subjects starting remdesivir within 24 hours of first dose of BLD-2660

  7. Change in clinical status [ Time Frame: Course of study; 28 days ]
    Measured by change from baseline to Days 10, 14, 21 and 28 in clinical status outcome using a 6-point ordinal scale

  8. Proportion of subjects in each category of the 6-point ordinal scale [ Time Frame: Course of study; 28 days ]
    Measured by proportion of subjects reporting each 6-point ordinal scale of the clinical status outcome assessment.

  9. Change from in NEWS score [ Time Frame: Course of study; 28 days ]
    Measured by change from baseline to Days 5, 10, 14, 21 and 28 in NEWS score

  10. Change in IL-6 [ Time Frame: Course of study; 28 days ]
    Measured by change from baseline to Days 10, 14, 21 and 28 in IL-6 in ng/mL measured by analytical assay

  11. Change in D-dimer [ Time Frame: Course of study; 28 days ]
    Measured by change from baseline to Days 10, 14, 21 and 28 in D-dimer in ng/mL measured by analytical assay



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:

At least 18 years of age at the time of signing the ICF.

Hospitalized for COVID-19.

Diagnosed with COVID-19 as defined by having at least 2 of the following signs or symptoms within the past 2 days:

  • Fever defined as a body temperature of ≥ 38.0 °C oral, or ≥ 38.3 °C rectal, ≥37.7 °C forehead or ≥38.7°C aural (axillary temperatures are not allowable);
  • Cough;
  • Fatigue;
  • Shortness of breath.

Radiographic evidence (chest x-ray or CT scan) of one the following:

  • Ground-glass opacities, or
  • Local or bilateral patchy infiltrates, or
  • Interstitial pulmonary infiltrates.

Oxygen requirements:

  • SpO2 ≤ 94% on ambient air OR
  • Requires supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device.

Male and/or female subjects.

- Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

All subjects (male or female) who are of childbearing potential must agree to use highly effective contraception during the study. Female subjects and male partners of female subjects must continue to use highly effective contraception for 30 days after the last dose of study drug. Female subjects should not donate oocytes during this time. Male subjects and female partners of male subjects must continue to use highly effective contraception for 90 days. Male subjects must agree not to donate sperm during this time.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Note: Ethinyl estradiol is the primary estrogen used in hormonal contraceptives. The progestin component consists of norethindrone, levonorgestrel, norgestrel, norethindrone acetate, ethynodiol diacetate, norgestimate, desogestrel, and drospirenone. As BLD-2660 is a weak CYP3A4 inducer, exposure to both the estrogen and progestin components in hormonal contraceptives may be decreased, resulting in an increased risk of pregnancy. As such, it is recommended that subjects who are on hormonal contraceptives for birth control should use an alternate means of contraception (condoms, diaphragms, intrauterine device (IUD), other barrier methods, sexual abstinence, etc.) during participation in the study.

Women of childbearing potential must have a negative serum pregnancy test at Screening within 72 hours prior to first administration of study drug.

Women not of childbearing potential must be postmenopausal (defined as cessation of regular menstrual periods for at least 1 year

Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

Exclusion Criteria:

Active bacterial pneumonia infection

Known active tuberculosis (TB).

History of Child-Pugh B or C cirrhosis.

History of ischemic heart disease or myocardial infarction or acute coronary syndrome.

Subjects requiring supplemental oxygen ≥0.75 FiO2.

It is not in the best interest of the subjects to participate, in the opinion of the treating Investigator.

Female subjects who are pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the screening visit through 90 days after the last dose of study drug.

The following laboratory parameters are excluded:

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper limit of normal (ULN);
  • Creatinine clearance < 50 mL/min.

Requiring, or expected to require mechanical ventilation at screening.

Treatment with chloroquine or hydroxychloroquine at study entry.

Treatment with anti-IL 6, anti-IL-6 receptor antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period.

Participation in any other clinical study of an experimental drug treatment for COVID-19 within 6 half-lives of the experimental treatment.

Note: Subjects participating in an observational study are an exception to this criterion and may qualify for the study with Sponsor approval.

Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

  • Unable to swallow solid oral medication or known malabsorption disorder.
  • Subjects who have allergy to BLD-2660 or inactive components of BLD-2660.

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): NCT04334460


Contacts
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Contact: Maria Walters, M.P.H. (650) 443-7366 mwalters@blademed.com
Contact: Joanne Imperial, MD

Locations
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United States, California
Blade Research Site Not yet recruiting
Irvine, California, United States, 92697
Blade Research Site Not yet recruiting
Los Angeles, California, United States, 90048
Blade Reseach Site Not yet recruiting
San Jose, California, United States, 95128
United States, District of Columbia
Blade Research Site Recruiting
Washington, District of Columbia, United States, 20010
United States, Florida
Blade Research Site Not yet recruiting
Tampa, Florida, United States, 33620
United States, Illinois
Blade Research Site Not yet recruiting
Peoria, Illinois, United States, 61603
United States, Louisiana
Blade Research Site Not yet recruiting
Metairie, Louisiana, United States, 70006
United States, Maryland
Blade Research Site Recruiting
Baltimore, Maryland, United States, 21201
United States, Michigan
Blade Research Site Not yet recruiting
Detroit, Michigan, United States, 48202
United States, Missouri
Blade Research Site Not yet recruiting
Saint Louis, Missouri, United States, 63110
United States, Nevada
Blade Research Site Not yet recruiting
North Las Vegas, Nevada, United States, 89030
United States, North Carolina
Blade Research Site Not yet recruiting
Durham, North Carolina, United States, 27708
Blade Research Site Not yet recruiting
Fayetteville, North Carolina, United States, 28304
United States, Pennsylvania
Blade Research Site Recruiting
Philadelphia, Pennsylvania, United States, 19140
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37203
Contact: Jennifer Scott, RN         
Principal Investigator: Todd Rice, MD         
Sponsors and Collaborators
Blade Therapeutics
Clinipace Worldwide
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Responsible Party: Blade Therapeutics
ClinicalTrials.gov Identifier: NCT04334460    
Other Study ID Numbers: B-2660-204
First Posted: April 6, 2020    Key Record Dates
Last Update Posted: May 21, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No