My introduction to the world of clinical trials in sepsis
occurred in the 1990’s while I was an Internal Medicine Resident in the MICU at
the Cleveland Clinic. My attending physician and ICU director, Charles J.
Fisher, Jr, was the lead investigator for the Phase III trial of Interleukin-1
receptor antagonist (IL-1 ra) in patients with sepsis. The basis of the strategy
related to the discovery by Charles Dinarello, M.D. of IL-1 and the role it
played in the pathophysiology of febrile vasodilatory shock. During this
rotation I had the opportunity to enroll a patient of mine into this trial. He
was a previously healthy 28 year old male who perforated his bowel as an initial
presentation of inflammatory bowel disease. At the time of enrollment the
patient was maxed out on vasopressors for septic shock, in ARDS, DIC and acute
renal failure. Within 24 hours of beginning the study drug infusion the patient
had a miraculous improvement and ultimately survived. When the study blind was
broken at the end of the trial my patient had in fact received IL-1ra and I
remain convinced that it was the reason for his survival. The results of the
trial indicated a non-statistically significant improvement in survival with
IL-1 ra and the drug was ultimately abandoned for the treatment of sepsis. The
drug, Kineret, has subsequently been approved for rheumatoid arthritis where it
works quite well, has a wide therapeutic index, and a good safety profile.
So what went wrong with IL-1ra with respect to sepsis? The
major flaw was the assumption that all patients with sepsis have “a cytokine
storm” as the main driver of organ failure with IL-1 as a main player. We now
know that a hyper-inflammatory response is just one of the many diverse gene
expression profiles that occur in patients with sepsis. The second major flaw
was the assumption that a clinical phenotype of patients with a systemic
inflammatory response due to infection with an organ failure would describe a
population with cytokine storm.
Two recent papers by Steve Opal and colleagues raise
interesting hypotheses of target subgroups within the sepsis population who may
indeed benefit from IL-1 ra. The first analysis was performed because of the
benefits that have been described with IL-1ra in patients with Macrophage
Activation Syndrome (MAS), previously known as secondary Hemophagocytic
Lymphohistiocytosis (HLH). Macrophage Activation Syndrome is essentially a
syndrome characterized by cytokine storm and is associated with rheumatologic
illnesses such as Still’s Disease, malignancies and infections.
Pro-inflammatory cytokines including IL-1 and IL-18 play a key role in this
illness which is characterized by bicytopenia, coagulopathy, liver dysfunction,
and hemphagocytosis. Opal and colleagues did a post-hoc subgroup analysis of
the Phase III IL-ra in patients with Macrophage Activation- like Syndrome
(MALS) as bone marrow aspirates looking for hemphagocytosis were not available.
The clinical phenotype for MALS was described as sepsis patients with both DIC
and hepatobiliary dysfunction. MALS was seen in 43/763 (5.6%) of the trial
population however the mortality seen in the IL-1ra population was 34.6%
compared with 64.7% in the placebo group; p=0.0071.
A number of caveats come with this data. First, and most
importantly, is that this is a post-hoc analysis with a result that did not
undergo a Bonferroni correction for the multiplicity of hypotheses being tested
raising the possibility that the observed treatment effect could be due to
chance alone. The best that can be said is that the result raises a hypothesis that
needs to be tested in a confirmatory trial. Secondly, the data are from a trial
completed in the 1990’s where the background care was likely different from
what occurs today. Thirdly, data from
Giamerellos-Bourboulis and the Hellenic Sepsis Society would suggest that a
ferritin level of > 4420 ng/ml may be a more specific marker to define
sepsis population with MALS. Finally, The MALS population constitutes ~ 5% of
patients with sepsis which raises its own issues. How can you present a
business case to the manufacturer on this population? That being said 5% of the
estimated 1.7 million hospitalizations with sepsis in the US each year would
translate into 85,000 cases with MALS. From clinical trial feasibility one
would have to expect a protracted trial and need many sites to complete
enrollment. However, if the subgroup data are to believed, you would need to
enroll only 40 patents per treatment arm to have 80% power at an alpha of 0.05.
A second post-hoc analysis on the Phase III IL- 1 ra sepsis was
performed to examine treatment effect by baseline IL-1ra levels. A total of 529
subjects had baseline plasma samples available. Data from these samples
indicated co-linearity between IL-I beta levels and IL-ra levels thus indicating
that IL-1 ra is a good surrogate for a population that has IL-1 activation. In
the 54% of patients with baseline IL-1 ra levels >2071pg/ml the 28-day
mortality was 45.4% in the placebo group and 34.3% in the IL- 1ra treatment
group. This constitutes an absolute risk reduction of 12% and a RRR of 74% at a
p value of 0.044.
Many of the same caveats regarding the MALS publication can
be stated about this data. Again, this is a post-hoc study that was not corrected
for the multiplicity of analyses being conducted. The standard of care was
different during this trial and the frozen plasma samples assayed were quite
old. That being said, this subgroup makes biologic sense as you are describing
a population where IL-1 activation is a key feature. A confirmatory trial in
this subgroup would be quite feasible and attractive from a business standpoint
as it constitutes 50% of the total sepsis population. Based on the observed
treatment effect observed in the subgroup, 302 patients per treatment arm would
need to be enrolled in a confirmatory, randomized, placebo-controlled study. One
would have to develop a “real-time” IL-1ra assay that could be deployed to
investigative sites for use as an inclusion criterion.
In summary, two recent post-hoc analyses raise hypotheses of
sepsis subgroups that may benefit from IL-1ra treatment. I would implore the manufacturer
of the drug to consider revisiting IL-1ra in sepsis given the devastating toll
of the disease and the lack of adjuvant treatments.
Disclaimer: I have no financial conflict of interest with
respect Swedish Orphan Biovitrum (the maker of Kineret (IL-1ra)
References:
Crit Care Med 2016; 44(2); 44 (2):275-281
Crit Care Med 2018; 46; 21-28
BMC Medicine 2017; 15:172
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