The purpose of this study is to determine the safety, tolerability and pharmacokinetics (PK), and explore the mechanistic and clinical effect of alvelestat (an oral neutrophil elastase inhibitor) orally twice per day for 10 days added to standard of care in adult patients (≥18 years) with COVID-19 respiratory disease.
Drug: Alvelestat
oral tablet
Other Name: MPH966
Drug: Placebo
oral tablet
Inclusion Criteria:
- Male or Female
- Age ≥18 years
- Proven SARS-Cov-2 infection (confirmed by PCR from a nasopharyngeal or lower
respiratory tract sample)
- A score of Grade 3 to 5 on the WHO 9-point Ordinal Scale
- Male participants must agree to use a highly effective contraception during the
treatment period and for at least 4 days after the last dose of study treatment and
refrain from donating sperm during this period.
- Female participants are eligible to participate if not pregnant; not breastfeeding;
and at least one of the following conditions is met:
Not a woman of childbearing potential OR A woman of childbearing potential who agrees to
follow the contraceptive guidance during the treatment phase and for at least 4 days after
the last dose of study medication - Capable of giving signed informed consent which
includes a commitment to comply with the requirements and restrictions listed in the
informed consent form (ICF) and within this protocol.
Exclusion Criteria:
- Patients who have previously had a score of 6 or 7 on the WHO 9-point Ordinal Scale
- Patients who require support with invasive mechanical ventilation at the time of
inclusion, or expected to be required within 24 hours of randomization
- Alanine aminotransferase (ALT) OR aspartate aminotransferase (AST) >2 × the upper
limit of normal (ULN) OR Total Bilirubin > ULN. In patients with a documented history
of Gilbert's Syndrome AND baseline total bilirubin elevation consistent with an
exacerbation of Gilbert's Syndrome (i.e. no other cause of total bilirubin elevation),
subjects may enroll if total bilirubin is < 5x ULN.
- Diagnosis of liver cirrhosis, esophageal varices, ascites or hepatic encephalopathy
- Chronic liver diseases such as autoimmune hepatitis, primary biliary cholangitis,
primary sclerosing cholangitis, Wilson's disease, haemochromatosis
- Significant renal disease or infection (as determined by the Investigator) including
stage 4 chronic kidney disease or estimated glomerular filtration rate <60mL/min
- Absolute neutrophil count ≤ 1000/µL at screening
- Myocardial infarction, transient ischemic attack or stroke within 3 months prior to
the first dose
- Current unstable angina or congestive heart failure (New York Heart Association
III/IV)
- Screening 12-lead EKG with a measurable QTc interval according to Fridericia
correction (QTcF) >450 ms
- Anticipated transfer to another hospital that is not the study center within 24 hours
- Allergy to study medication or excipients
- Inability to swallow tablets
- Other documented comorbidities or laboratory abnormalities that in the opinion of the
Investigator could affect the outcome of the study assessments, participant safety, or
ability of the participant to comply with the requirements of the protocol
- Any patient whose interests are not best served by study participation, as determined
by the Investigator
Excluded Prior/Concomitant Therapy
- Requirement for medications mainly metabolized by CYP2C9 and with narrow therapeutic
index (eg, warfarin, phenytoin) is prohibited unless therapeutic monitoring available
for duration of alvelestat dosing
- Medicines that are potent CYP3A4 inhibitors including (but are not limited to)
clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir,
verapamil and potent inducers including but not limited to phenobarbital, phenytoin
and rifampicin, will be exclusionary
- Requirement for medications substantially reliant on OATP1B1 for metabolism where
discontinuation during study drug administration is not possible or where fluctuations
in levels are considered clinically important (as per investigator judgement) and
cannot be clinically monitored (e.g., statins, valsartan, olmesartan, enalapril,
repaglinide)
Excluded Prior/Concurrent Clinical Study Experience
- Participation in any clinical investigation using investigational treatments within 4
weeks or 5 half-lives of the drug (whichever is longer) prior to the initial dosing (or
longer if required by local regulations) is prohibited. Use of remdesivir (Veklury) under
the conditions of the authorization for emergency use in the US, and per manufacturer's
instructions, is permitted.
UAB Lung Health Center
Birmingham, Alabama, United States
James M Wells, MD, Principal Investigator
The University of Alabama at Birmingham