Mavrilimumab to Reduce Progression of Acute Respiratory Failure in COVID-19 Pneumonia and Systemic Hyper-inflammation

• ClinicalTrials.gov Identifier: NCT04399980
• Recruitment Status: Completed
• First Posted: May 22, 2020
• Results First Posted: May 13, 2021
• Last Update Posted: May 13, 2021
• Sponsor: The Cleveland Clinic
• Collaborator: Kiniksa Pharmaceuticals, Ltd.
• Information provided by (Responsible Party): The Cleveland Clinic

Tracking Information

• First Submitted Date: May 21, 2020
• First Posted Date: May 22, 2020
• Results First Submitted Date: May 6, 2021
• Results First Posted Date: May 13, 2021
• Last Update Posted Date: May 13, 2021
• Actual Study Start Date: May 20, 2020
• Actual Primary Completion Date: April 23, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 11, 2021)

Subjects Alive and Off of Oxygen at Day 14 [ Time Frame: Day 14 ]

Number and percentage of subjects alive and off of oxygen at day 14

Original Primary Outcome Measures (submitted: May 21, 2020)

Proportion of subjects alive and off of oxygen at day 14 [ Time Frame: Day 14 ]

Number of subjects alive and off of oxygen

Current Secondary Outcome Measures (submitted: May 11, 2021)

• Number of Subjects Alive and Without Respiratory Failure at Day 28 [ Time Frame: Day 28 ]
  Number and percentage of subjects that are alive and without respiratory failure at Day 28
• Mortality at Day 28 [ Time Frame: Day 28 ]
  Number and percentage of patients that expired by Day 28

Original Secondary Outcome Measures (submitted: May 21, 2020)

Proportion of subjects alive and without respiratory failure at 28 days [ Time Frame: Day 28 ]

Number of subjects alive and without respiratory failure

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Mavrilimumab to Reduce Progression of Acute Respiratory Failure in COVID-19 Pneumonia and Systemic Hyper-inflammation
• Official Title: Mavrilimumab to Reduce Progression of Acute Respiratory Failure in Patients With Severe COVID-19 Pneumonia and Systemic Hyper-inflammation
• Brief Summary: The purpose of this prospective, Phase 2, multicenter, blinded, randomized placebo controlled study is to demonstrate that early treatment with mavrilimumab prevents progression of respiratory failure in patients with severe COVID-19 pneumonia and clinical and biological features of hyper-inflammation.

Detailed Description

This prospective, Phase 2, multi-center, blinded randomized placebo-controlled study is designed to demonstrate that early treatment with mavrilimumab prevents progression of respiratory failure in patients with severe Covid-19 pneumonia and clinical and biological features of hyper-inflammation.

The study population includes patients who have severe pneumonia, defined as hospitalization due to Covid-19 with abnormal chest imaging and SpO2 <92% on room air or requirement for supplemental oxygen.

Enrollment: The study will be performed in approximately 4 months total, starting from the first patient enrolled with enrollment expected to complete within 2 months.

Follow-up period: The follow-up period is 60 days for each patient enrolled.

A total of 60 patients will be randomized using a 1:1 allocation ratio: 30 subjects will receive mavrilimumab, and 30 subjects will receive placebo infusion. The investigator, clinical team, and subject will be blinded to treatment assignment.

Participants will be identified by regular review of hospitalized COVID19 patients to evaluate for inclusion and exclusion criteria. Participants will then be approached in the standard manner by study investigator and coordinator/research nurse.

Research interventions will take place in the hospital in accordance with privacy standards.

The study team is informed on all study procedures and requirements with daily meetings and the opportunity to continuously update through secure channels.

In this multicenter consortium, each participating site will have their own IND for patients enrolled at their site. Data collection will occur at each of the 4 academic centers, and data analysis and randomization scheme will be performed by one site, Cleveland Clinic C5 Research.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• COVID 19
• SARS-CoV 2
• Pneumonia

Intervention

• Drug: Mavrilimumab
  Treatment infusion
  Other Name: KPL-301
• Drug: Placebos
  Placebo infusion
  Other Name: Control

Study Arms

• Active Comparator: Intervention
  Treatment infusion
  Intervention: Drug: Mavrilimumab
• Placebo Comparator: Control
  Placebo infusion
  Intervention: Drug: Placebos

• Publications *: Cremer PC, Abbate A, Hudock K, McWilliams C, Mehta J, Chang SY, Sheng CC, Van Tassell B, Bonaventura A, Vecchie A, Carey B, Wang Q, Wolski KE, Rajendram P, Duggal A, Wang TS, Paolini JF, Trapnell BC; MASH-COVID study group. Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Rheumatol. 2021 Jun;3(6):e410-e418. doi: 10.1016/S2665-9913(21)00070-9. Epub 2021 Mar 17.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 6, 2021): 40
• Original Estimated Enrollment (submitted: May 21, 2020): 60
• Actual Study Completion Date: April 23, 2021
• Actual Primary Completion Date: April 23, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria (must meet all):

1. Written informed consent must be obtained before any assessment is performed
2. Documented COVID19 pneumonia defined as positive SARS-CoV2 test AND abnormalities/ infiltrates on chest x-ray or computed tomography AND active fever or documented fever within 24-48 hours or ongoing anti-pyretic use to suppress fever
3. Hypoxia (Room air SpO2 <92% or requirement for supplemental oxygen)
4. Increased serum inflammatory marker (CRP > 5 mg/dL)
5. Severity of disease warrants inpatient hospitalization

Exclusion Criteria:

1. Onset of COVID-19 symptoms >14 days
2. Age < 18 years-old
3. Hospitalized >7 days
4. Mechanically ventilated

5. Serious concomitant illness which in the opinion of the investigator precludes the patient from enrolling in the trial, including (but not limited to):

   • History of immunodeficiency (congenital or acquired)
   • Neutropenia (absolute neutrophil count <1,500/mm3)
   • History of solid-organ or bone marrow transplant
   • History of current systemic autoimmune or autoinflammatory disease(s) requiring systemic immune-modulating drugs
   • History of myeloproliferative disorder or active malignancy receiving cytotoxic chemotherapy
   • Pre-existing severe pulmonary disease (i.e. steroid dependent asthma, COPD on home oxygen, or other restrictive/obstructive lung disease requiring home oxygen)
   • Pre-existing severe left ventricular systolic dysfunction (i.e. LVEF <35%)
   • Known or suspected active tuberculosis (TB), latent TB, or history of incompletely treated TB or at high risk for latent TB (from exposure or prior incarceration)
   • History of active or latent viral hepatitis (i.e. Hepatitis B or C)
   • Concomitant uncontrolled systemic bacterial or fungal infection
   • Concomitant viral infection other than COVID-19 (e.g. Influenza, other respiratory viruses)
   • History of chronic liver disease with portal hypertension
   • History of end-stage renal disease on chronic renal replacement therapy
6. Recent treatment with cell-depleting biological therapies (e.g., anti-CD20) within 12 months, cell-depleting biological therapies (such as anti-tumor necrosis factor [TNF], anakinra, anti-Interleukin [IL]-6 receptor [e.g. tocilizumab], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer), treatment with alkylating agents within 12 weeks, treatment with cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks
7. Recent treatment with intramuscular live (attenuated) vaccine within 4 weeks
8. Chronic or recent corticosteroid use > 10 mg/day
9. Pregnant. Breast-feeding women are eligible with the decision to continue or discontinue breast-feeding during therapy taking into account the risk of infant exposure, the benefits of breast-feeding to the infant, and benefits of treatment to the mother
10. Enrolled in another investigational study using immunosuppressive therapy
11. Known hypersensitivity to mavrilimumab or any of its excipients
12. In the opinion of the investigator, unable to comply with the requirements to participate in the study

13. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug. Such methods include:

    • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
    • Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04399980
• Other Study ID Numbers: IND 149324; IRB 20-523 ( Other Identifier: Cleveland Clinic IRB )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: The Cleveland Clinic
• Original Responsible Party: Paul Cremer, M. D., The Cleveland Clinic, Principal Investigator
• Current Study Sponsor: The Cleveland Clinic
• Original Study Sponsor: Same as current
• Collaborators: Kiniksa Pharmaceuticals, Ltd.

Investigators

• Principal Investigator: Paul C Cremer, M. D.; The Cleveland Clinic

• PRS Account: The Cleveland Clinic
• Verification Date: May 2021