COVID-19 Study of Safety and Tolerability of Alvelestat

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Phase Ib/II, Single Center, Placebo-Controlled, Randomized, Blinded Study in Adult Patients (> 18 Years) With COVID-19 Respiratory Disease, to Evaluate, Safety, Tolerability and Mechanistic Effect of Alvelestat on Top of Standard of Care (COSTA)

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Drug: Alvelestat
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo oral tablet<br>placebo | Drug: Placebo<br>* oral tablet<br>|
| Active Comparator: Alvelestat oral tablet - dose 1<br>MPH966 | Drug: Alvelestat<br>* oral tablet<br>* Other names: MPH966;|
| Active Comparator: Alvelestat oral tablet - dose 2<br>MPH966 | Drug: Alvelestat<br>* oral tablet<br>* Other names: MPH966;|
| Active Comparator: Alvelestat oral tablet - dose 3<br>MPH966 | Drug: Alvelestat<br>* oral tablet<br>* Other names: MPH966;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numbers and % of Subjects Who Experience at Least 1 Treatment-emergent Adverse Event | Safety Outcome Assessment | to day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Alvelestat on Blood Pharmacodynamic Biomarkers of NETosis | Change in blood markers of NETosis | Randomization through Day 10 or hospital discharge, whichever was shorter. | 
| Effect of Alvelestat on Blood Pharmacodynamic Biomarkers of Inflammation | Change in blood markers of inflammation | Randomization through Day 10 or hospital discharge, whichever was shorter. | 
| Effect of Alvelestat on Blood Pharmacodynamic Biomarkers of D-dimer | Change in blood markers of d-dimer | Randomization through Day 10 or hospital discharge, whichever was shorter. | 
| Effect of Alvelestat on Blood Pharmacodynamic Biomarkers of Desmosine | Change in blood markers of desmosine | Randomization through Day 10 or hospital discharge, whichever was shorter. | 
| Mortality Rate |  | to Day 90 |