NATIENS: Optimal Management and Mechanisms of SJS/TEN
Status:
Not yet recruiting
Trial end date:
2027-08-01
Target enrollment:
Participant gender:
Summary
The NATIENS study is a phase III randomized study to examine the optimal treatment and
mechanisms of each of two treatments (cyclosporine 5 mg/kg bid for 14 days versus etanercept
50 mg subcutaneously at day 0 and day 3) versus the current standard of care which is
harmonized supportive care for the treatment of Stevens-Johnson Syndrome and toxic epidermal
necrolysis (SJS/TEN). SJS/TEN is typically a drug-induced disease in adults with a mortality
of up to 50% or higher in elderly adults. Although progress has been made in elucidating
strong genetic risk factors that have led to pre-prescription screening and prevention the
risk factors for most drugs and ethnicities represented in the United States are currently
unknown. Currently there are a number of small observational studies and a non-blinded small
randomized study however there is no strong or definitive evidence base to support any one
treatment intervention over supportive care alone and this remains considered a standard of
care for SJS/TEN. The primary objective of the study is to conduct a randomized double-blind
double dummy stratified multicenter phase III study across 24 sites across the Unites States
to determine whether two therapeutic interventions (etanercept versus cyclosporine) will
improve short-term outcomes associated with SJS/TEN. The primary hypothesis of this study is
that both etanercept and cyclosporine will show benefit over supportive care alone and that
single dose etanercept 50 mg sc at days 0 and repeated 72 hours following initial dosing will
show significant benefit over cyclosporine 5 mg/kg bid and supportive care alone. Our
secondary outcomes are to determine the clinical outcomes at 3 and 12 months following
initial presentation and to determine the molecular and cellular mechanisms of SJS/TEN
through collection of timed samples to include DNA, RNA, PBMCs, blister cells and supernatant
and skin. We hypothesize that patients will have significant sequelae identified at 3 and 12
months that will differ between treatment arms and that treatment interventions will
significantly impact cytotoxic and cytokine signals with these biomarkers correlating with
primary and secondary outcome. We also hypothesize that significant genetic associations will
be found in association with drug-induced SJS/TEN. Eligible patients are >/= 18 who meet
evidence for SJS/TEN clinical criteria as evidence by erythematous/dusky macules coalescing
or denuded skin and blistering with positive Nikolsky sign which is mandatory criteria
associated with mucous membrane involvement, prodromal symptoms including fever, myalgia and
headache, increasing number of lesions and history of a medication. To continue with the
study patients must meet pathological criteria. Randomization will occur by a secure central
online computer-generated random number system through REDCap. Subjects will be allocated
1:1:1 to cyclosporine plus best supportive care, etanercept plus best supportive care or best
supportive care alone. Patients, treating physician and outcome assessors will be blinded to
the allocated treatment. The primary outcome of the study is time to complete
re-epithelialization as defined by complete absence of erosion and compromised skin. Time to
expected re-epithelialization of 21 days is the maximum healing time with supportive care in
SJS/TEN patients which reflects the healing time of adult skin. The primary outcome will be
independently assessed by the treating team to include any of a burn surgeon, dermatologist
or wound specialist. Disagreement will be solved by independent adjudication by a minimum of
two reviewers. Patients who have to discontinue a study medication will be analyzed by
intent-to-treat analysis and followed for complications of SJS/TEN as per study protocol.
Secondary outcomes of the study include: 1)time to halting of progression of SJS/TEN skin
disease. Progression will be considered significant if there are any new blisters or erosions
and halting of progression is defined as absence of these criteria with any new lesions; 2)
all-cause mortality at 30 days, 3 months and 1 year following symptoms onset; 3) composite
cause-specific mortality - outcome including death from sepsis, multi-organ failure and acute
respiratory distress syndrome; 4) actual mortality versus expected mortality (as calculated
by SCORTEN); 5) Time to cessation of acute ocular involvement (this will be tracked by the
same serial photography evaluated by two independent Ophthalmology experts in SJS/TEN eye
disease; 6) incidence of infections; 7) hospital length of stay; 8) adverse events due to
therapy; 9) serial plasma granulysin, IL-15 concentrations (and other relevant
biomarkers);10) Follow-up 3 months and 1 year from initial presentation for physical and
mental health complications. For aims 2 and 3 a number of mechanistic studies will be
performed on paired samples (DNA, RNA, PBMCs, plasma, blister fluid and skin).
Phase:
Phase 3
Details
Lead Sponsor:
Ottawa Hospital Research Institute Vanderbilt University Medical Center
Collaborators:
Brooke Army Medical Center Canadian Dermatology Foundation University of Ottawa University of Toronto Vanderbilt University