A randomized, double-blind, placebo-controlled, study evaluating the efficacy and safety of otilimab IV in patients with severe pulmonary COVID-19 related disease (study 214094)

Severe pulmonary COVID-19 related disease, which is a life-threatening
condition affects your lungs, resulting in a dangerously low level of oxygen in
your blood. Currently there are no treatments available for this condition
apart from oxygen. Although many patients with COVID-19 related severe lung
disease get better with oxygen alone, between 20-30% get worse. Studies
conducted recently suggest that critically-ill patients who get worse also have
high levels of inflammation.
GM-CSF is involved in inflammation and is found in higher levels in the blood
and lungs of patients with severe pulmonary COVID-19 related illness. Otilimab
is an antibody drug specifically made to block GM-CSF. By blocking GM-CSF it's
expected to improve the working of your lungs, reduce your need for oxygen
support, and improve your chances of survival.

Supplement:
About 400 subjects received otilimab in this study (Part 1). The initial
results from Part 1 indicate that otilimab may be beneficial in people between
the ages of 70 and 79. That is why we are starting a second part (Part 2) of
the study in which an additional group of approximately 350 subjects aged 70
and older will participate. This potentially beneficial effect is further
explored in Part 2 of the study.

Primary:
Compare the efficacy of single IV injection with otilimab 90 mg in adults with
severe pulmonary COVID-19 related disease.

Secondary:
Other aspects of efficacy. Safety and tolerability.

Part 1
Phase II randomized double-blind placebo-controlled study of 9 weeks.
Randomisation (1:1)
Single IV injection with otilimab 90 mg or placebo
28 days observation period at the hospital (or till discharge of the patient)
Follow up of two telephone contacts 42 and 60 days IV injection.
An Independent Data Monitoring Committee (IDMC) will regularly review the
safety data.
800 subjects

Part 2
Phase III randomized double-blind placebo-controlled study of 9 weeks.
Randomisation (1:1)
Single IV injection with otilimab 90 mg or placebo
28 days observation period at the hospital (or till discharge of the patient)
Follow up of two telephone contacts 42 and 60 days IV injection.
An Independent Data Monitoring Committee (IDMC) will regularly review the
safety data.
350 subjects

In total 1150 subjects

Half of the group wil receive a single IV injection with otilimab 90 mg, the
other half will receive a single IV injection with placebo.

Burden:
Part 1
Single IV injection with otilimab 90 mg or placebo
28 days observation period at the hospital (or till discharge of the patient)
Follow up of two telephone contacts 42 and 60 days IV injection.
Physical examination: 2x
Blood draws: 5-15 ml, 200 ml blood in total
Pregnancy test: 2x
ECG: 3x
X-ray or CT-scan: 1x

Part 2
Single IV injection with otilimab 90 mg or placebo
28 days observation period at the hospital (or till discharge of the patient)
Follow up of two telephone contacts 42 and 60 days IV injection.
Physical examination: 2x
Blood draws: 5-15 ml, 200 ml blood in total
ECG: 2x
X-ray or CT-scan: 1x

Part 1 and 2
Risks study procedures:
Injection site reaction: As the study drug will be given through an IV cannula,
there is a risk of you developing local inflammation around the injection
site. This could include redness, swelling and infection.
Blood samples can be painfull or bruise, some people have a tendency to faint.

Risks:
Cytokine release syndrome: Antibody drugs like otilimab can, in rare instances,
trigger a widespread abnormal inflammation response within the body. This can
potentially be life-threatening, and might cause additional symptoms on top of
your existing ones, such as: rash, headache, nausea, tiredness, vomiting,
confusion, rigors (cold feeling with shivers), low blood pressure, breathing
difficulties, increased need for oxygen, muscle aches, worsening kidney
function, worsening liver function, other laboratory test abnormal values, and
multi-organ system failure that can be fatal.

Allergic reaction: Antibody drugs like otilimab may cause allergic reactions,
although in general, severe reactions happen very rarely.

Increased risk of infection: Otilimab acts on the immune system and may reduce
the resistance to infection and it is possible that there may be at increased
risk of getting an infection.

Blood cell counts: Otilimab may reduce the number of blood cells, in particular
white blood cells, called neutrophils), and may make you more prone to
infections.

Lung disease: pulmonary alveolar proteinosis (or PAP) is a very rare lung
disease known to be caused by reduced levels of GM-CSF in the lungs. It is
characterised by the build-up of grainy material in the alveoli (air sacs) of
the lungs which makes it difficult for the lungs to absorb oxygen and over time
leads to breathing difficulties. So far PAP has not been seen in any clinical
studies with otilimab.

Delayed recovery to infection: GM-CSF has been noted to play a role in helping
the lung fight infection and recover from any injury. Therefore, it is
possible that otilimab, by blocking GM-CSF, may affect the ability of the lungs
to fight lung infection or properly recover from infection.

Risk of cancer: otilimab may reduce the activity of your immune system.
Medicines that affect the immune system may increase your risk of certain
cancers. So far, an increased risk of cancer has not been seen in any of the
previous clinical or animal studies with otilimab.