A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Ravulizumab in Adult Participants Who Have Thrombotic Microangiopathy Associated With a Trigger

Thrombotic microangiopathy is a rare, life-threatening disease often caused by
complement activation that results in endothelial damage. In some patients,
complement-mediated TMA may result from a trigger that injures the endothelium,
such as post-partum, malignant hypertension
(sometimes termed hypertensive emergency), infection, transplant (solid organ
or bone marrow), autoimmune disease, and certain drugs. Many patients present
in critical condition, require management in an intensive care unit, and often
need dialysis. Once multiorgan dysfunction develops, patients have a poor
prognosis. Two complement C5 inhibitors, ravulizumab and eculizumab, are
approved for the treatment of patients with aHUS, a type of complement-mediated
TMA. There are currently no approved therapies for the broader
complement-mediated TMA population. Treatment typically consists of
corticosteroids and/or therapeutic plasma exchange (TPE) or plasma infusion.
The underlying trigger may also be treated, along with other supportive
measures (eg, transfusion, dialysis), as appropriate. While TPE/plasma infusion
will improve hematologic parameters in
complement-mediated TMA, neither corticosteroids nor TPE/plasma infusion will
address the underlying complement dysregulation and the TMA process is likely
to persist. Removal of the trigger and supportive care are sometimes sufficient
to reverse TMA symptoms; however, in patients with severe renal manifestations,
outcomes are not greatly improved after removing/treating the trigger and
providing supportive care.

In patients with aHUS, ravulizumab achieved immediate, complete, and sustained
inhibition of terminal complement and improved renal function. It is
hypothesized that ravulizumab will be similarly effective in the treatment of
complement-mediated TMA at the approved aHUS dosing regimen.

Primary
To assess the efficacy of ravulizumab in the treatment of participants with TMA

Secondary
To characterize TMA response
To assess impact on hemoglobin levels
To evaluate change in kidney function
To assess duration of Complete TMA Response and TMA Relapse
To assess improvement in patient-reported QoL outcomes


PK/PD/Immunogenicity
To assess PK/PD of ravulizumab in participants with TMA
To characterize the potential for immunogenicity of ravulizumab in participants
with TMA

Safety
To characterize the safety profile of ravulizumab in participants with TMA

This is a Phase 3, randomized, double-blind, placebo-controlled study of
ravulizumab in addition to standard of care in adult participants (>= 18 years
of age) with TMA following a defined trigger. All participants must have severe
acute kidney injury and a diagnosis of TMA based on protocol-defined criteria
(ie, thrombocytopenia, microangiopathic hemolytic anemia, elevated lactate
dehydrogenase, which is associated with at least 1*trigger, such as autoimmune,
infection, solid organ transplant, drugs, or malignant hypertension, occurring
<=*14*days prior to randomization.

The study consists of an up to 2-week Screening Period, a 26-week randomized
Treatment Period, and a 26-week Post-treatment Follow-up Period. Thus, the
total treatment duration is 26*weeks and the total study duration is up to
54*weeks.

Participants will be screened for eligibility for up to 2 weeks during the
Screening Period. Approximately 100 adult participants will be randomized in a
1:1 ratio to receive either ravulizumab or placebo. Randomization will be
stratified by baseline dialysis status and by primary trigger type.

During the 26-week Treatment Period, all participants will receive a
weight-based loading dose of ravulizumab or placebo on Day*1, followed by
weight-based maintenance doses of ravulizumab or placebo on Day*15 and then
once every 8*weeks (q8w) thereafter. All participants will receive standard of
care throughout the study.

During the 26-week Post-Treatment Follow-up Period, participants will continue
to receive standard of care, at the discretion of the Investigator and will be
monitored for safety, TMA response, and clinical events of interest.

The end of the study is defined as the last participant*s last visit in the
Post-treatment Follow-up Period.

Eligible participants will be enrolled into the study and will be randomized in
a 1:1 ratio to receive either ravulizumab IV infusion or placebo IV infusion in
combination with standard of care.

Ravulizumab will be supplied as a sterile, preservativefree 10*mg/mL solution
in singleuse vials, designed for administration via IV infusion by diluting
into commercially available saline (0.9% sodium chloride injection).

Ravulizumab may cause side effects.

The following side effects are common:
- Diarrhea
- Nausea
- Fever
- Tiredness
- Nasopharyngitis (swelling of the nasal passages and throat)
- Upper respiratory tract infection (common cold)
- Headache

The following side effects can be serious:
Meningococcal infection/ meningococcal sepsis is an uncommon side effect seen
in less than 1% of the patients. The infection can affect the tissues that
surround the brain and spinal cord (meningococcal meningitis) or can develop in
blood (meningococcal sepsis). Meningococcal infections can rapidly become
life-threatening or fatal.

The study drug can also have side effects that we do not know about at the
moment.

The study procedures may also cause side effects.

There is still a need for an effective treatment. The sponsor believes that the
side effects and burden of participating are proportional, given the positive
effects that participation in the trial may have on the progression of the
patient's disease.