Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02987257 |
| Other study ID # |
212370 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
March 21, 2023 |
| Est. completion date |
August 1, 2028 |
Study information
| Verified date |
April 2024 |
| Source |
Vanderbilt University Medical Center |
| Contact |
Elizabeth J Phillips, MD |
| Phone |
615-310-0339 |
| Email |
elizabeth.j.phillips[@]vumc.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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).
Description:
Background and Scientific Rationale Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN), are severe, life-threatening immunologically mediated adverse drug
reactions representing the same disease across a spectrum of severity that affects 60,000
patients per year globally at an incidence of 5 cases per 1,000,000 in the United States.
This study has been preceded by a planning phase to ensure the testing and development of
standardized infrastructure and operating procedures across sites. The scientific rationale
for this study is the lack of evidence-based treatment for SJS/TEN. The study will aim to
establish the most clinically effective therapy for SJS/TEN, as there is currently no level
1A evidence for any treatment above aggressive supportive care which still has equipoise as
to the standard of care. A multi-centered, three-arm, double-blind double-dummy randomized
controlled trial with a planned enrollment of 267 patients over 6 years will be undertaken to
evaluate which of supportive care, cyclosporine or etanercept leads to the shortest time to
complete re-epithelialization. The controlled setting of the clinical trial provides the
basis for which samples can be sequentially collected to answer important mechanistic
questions. Samples collected in the course of the study will include DNA, RNA, plasma, serum,
blister fluid cells and supernatant, sloughed epidermis, and punch biopsies of skin. Samples
will be biobanked to do immediate targeted high-resolution HLA sequencing, cytokine
profiling, and single-cell multidimensional analyses to identify biological markers that have
the potential to predict the risk and outcome of SJS/TEN. A pharmacokinetic study to assess
the disposition of cyclosporine and etanercept will be done on a subset of patients. Samples
will be biobank for later analysis for other transcriptomic, proteomic whole-genome studies.
These mechanistic studies will allow us to gain important insights into the
immunopathogenesis of SJS/TEN. Our study will be the first to examine in a blinded randomized
controlled design both management and mechanisms of SJS/TEN. We anticipate that this will
lead to new ways to prevent, diagnose and treat SJS/TEN, and will create a roadmap and
evidence-based for studies in serious immunologically mediated adverse drug reactions and
other immunologically mediated diseases.
Interventions Supportive care is the currently accepted standard of care of SJS/TEN. Systemic
treatment of SJS/TEN and the preferred agents remain a matter of debate and contention.
Observational studies performed over the last 15 years suggest that cyclosporine and
etanercept may be promising treatments.
1. Study Hypotheses/Objectives 1.1. Hypotheses Our primary hypothesis is that both
cyclosporine and etanercept will show benefit over supportive care alone and that
etanercept 50 mg subcutaneously given at study day 1 and repeated at day 4. We further
hypothesize that we will discover a number of genetic and biological predictors of both
occurrence and prognosis of SJS/TEN including genetic associations (HLA and others),
cytokine biomarkers that predict that course, and the likelihood of re-epithelialization
and single-cell multidimensional studies that will identify promising targets for
prognosis and treatment.
1.2. Primary Objective(s) Our primary objective is to conduct a 25-site three-arm
randomized double-blind controlled stratified multicenter phase III study to determine
whether two therapeutic interventions - cyclosporine and etanercept will improve
short-term outcomes associated with Stevens-Johnson Syndrome and toxic epidermal
necrolysis (SJS/TEN) over harmonized best supportive care alone. Our hypothesis is that
both etanercept and cyclosporine will show benefit over supportive care alone and that
etanercept 50 mg subcutaneously on study day 0 and repeated 72 hours later on study day
3 for all subjects will show significant benefit over both cyclosporine and supportive
care alone. The justification for a second dose is the short half-life of the drug and
the usual twice a week dosing in other skin conditions such as psoriasis and a recent
non-blinded randomized study of etanercept in SJS/TEN that used repeat dosing of
etanercept.
Secondary Objective(s) Secondary objectives of this study are to determine the acute
secondary outcomes and secondary clinical outcomes at 3 and 12 months (see secondary
outcomes) and to determine the molecular and cellular mechanisms of SJS/TEN through the
collection of timed DNA, PBMC, RNA, blister fluid and blister fluid cells and skin. We
hypothesize that patients will have significant sequelae identified at 3 and 12 months
that will differ between treatment arms. We hypothesis that treatment interventions will
significantly impact cytotoxic and cytokine signals and that these biomarkers will
correlate with primary and secondary outcomes. We further hypothesize that significant
genetic associations (in particular class I HLA) will be found in association with
drug-induced SJS/TEN.
2. Study Design 2.1. Description of Study Design This is a three-arm, randomized,
double-blind double-dummy phase III multicenter placebo-controlled trial comparing
cyclosporine, etanercept, and best supportive care for the treatment of SJS/TEN. A total
enrollment of 267 subjects (89 per arm) over 24 sites is planned. The sample size is
based on a 90% power to determine the primary outcome and a minimum clinically important
difference (MCID) of one day for full re-epithelialization of the skin. The study will
enroll from multiple sites due to the low SJS/TEN incidence at individual sites and the
need to identify patients with very specific inclusion criteria including those who have
had no more than a 5-day window from onset of symptoms to presentation. We aim to
complete enrollment over a period of 6 years.
Consenting adult subjects (≥18 years of age) who meet clinical criteria for diagnosis of
SJS/TEN will undergo randomization stratified by baseline SJS/TEN prognosis (SCORTEN)
and will be allocated 1:1:1 to cyclosporine plus best supportive care, etanercept plus
best supportive care or best supportive care alone. Randomization will occur by a secure
central online, computer-generated random randomization tool in REDCap using permuted
blocks of sizes 3 and 6.
The active treatment period is from randomization until re-epithelialization is
achieved. This is expected to be at most 21 days. The primary outcome is time (days) to
full re-epithelialization of the skin. Subjects will be followed in the hospital during
their admission; patients with SJS/TEN in this study will be on active drug or placebo
intravenously for at least 14 days. The plan will be the earliest discharge from the
hospital to occur at the completion of the full 14 days of placebo versus active
treatment if full re-epithelialization has occurred at that time but not until complete
re-epithelialization. Death is a competing risk for the primary outcome (see statistical
plan section 4.4). Subjects will be followed for 3 months and 12 months after complete
re-epithelialization. Under circumstances where patients are inadvertently discharged
prior to complete re-epithelialization appropriate and comparable follow-up to provide
documentation of appropriate wound, eye, and urogynecological care and of the timing of
complete re-epithelialization at a clinical research center at supportive sites and/or
the Hawthorne effect clinical trials services (see operations manual).
2.2. Stratification, Randomization, and Blinding/Masking
Randomization will occur by a secure central online, computer-generated random number
system in REDCap. Randomization will be stratified by baseline SJS/TEN prognosis
(SCORTEN) and will occur in randomly varying blocks of sizes 3 and 6. 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 physicians and
outcome assessors will be blinded to the allocated treatment. All patients will receive
supportive care, either with a double placebo or with their study drug (cyclosporine or
etanercept) plus placebo. The central randomization scheme will provide the site
pharmacist with a unique drug code corresponding to either study drugs and matching
placebos. These will be kept in identical, coded containers. Only the study central
pharmacy and the site pharmacy who will prepare the preparations for blinding will be
aware of the coding scheme. Masking will be carried out as follows:
- Cyclosporine: The study drug is given as per protocol for 2 weeks. A single SC
injection is given on study day 0 of admission and study day 3.
- Etanercept: Study drug given as per protocol on study days 0 and 3. Receive IV
normal saline for 2 weeks to mimic the cyclosporine schedule.
- Supportive therapy: A single saline SC injection on study day 0 and study day 3 of
admission and an additional 14 days of IV normal saline placebo to mimic the
cyclosporine schedule 2.2.1. Procedure for Unblinding/Unmasking Unblinding must be
approved by the study medical monitor unless an immediately life-threatening
condition has developed, and the medical monitor is not available. The site
investigator will notify the protocol chair(s) and the study statistical and
clinical coordinating center of the unblinding event by the next business day. The
emergency unblinding will also be reported to the Data and Safety Monitoring Board
(DSMB). A full account of the event will be recorded, including the date, time of
the unblinding, the reason or the decision to unblind and the name of the
individual who made the decision and the names of the Medical Monitor, and others
who were notified. The reasons for unblinding of a participant's treatment will be
included in the final study report. Unblinding the study due to an approved interim
analysis, final analysis, or study termination will require written approval from
the institute sponsor (NIAID).
3. Selection of Participants and Clinical Sites/Laboratories 3.1. Rationale for Study
Population Subject enrollment will reflect the population at large in our participating
centers. All subjects who meet inclusion criteria will be screened for enrollment into
the study. We will not discriminate based on sex, race, or ethnicity. Females, including
those of childbearing potential, will be included in the trial.
Supportive care High-quality supportive care is always used in the treatment of SJS/TEN.
We know it can decrease the chance of serious complications and death even in the
absence of adjuvant medications to treat the condition.
There are no significant side effects associated with supportive care aside from
possible discomfort with dressing changes.
3.5. Risks of Other Protocol Specified Medications Cyclosporine
The risks of the venipuncture (bruising at the site and very low risk of infection)
apply as cyclosporine is an intravenous medication. There is extensive experience with
this medication in SJS/TEN for the treatment of other conditions. In general, few side
effects have been seen when used for SJS/TEN. When they have occurred, they have had no
long-term impact on the person receiving the medication. Risks include:
Less likely (5% to 20%):
- Mild changes in kidney function: 1-6% had mild changes in their kidney function
that required a change of dose; Serious infections were not more common than those
treated with short-term use, as proposed in this study. Flu-like illness symptoms
and a predisposition for lung infections have been experienced in 8- 10% of
patients with long-term use (months to years).
Rare (1% to 4%):
• Hypertension: 1-3% needed to have their blood pressure lowered. Very rare but serious
(less than 1%): Severe liver or kidney problems may be permanent in those taking
cyclosporine for greater than one 1year. Patients receiving cyclosporine under the
NATIENS protocol will undergo treatment for a short amount of time; therefore, the
chance of this occurring in this study is extremely unlikely. Close monitoring for
hepatic or renal dysfunction is built into the NATIENS study protocol.
Discontinuing the study medication in the case of imminently organ-threatening effects,
type I allergy, or rare immune reactions (e.g., thrombotic thrombocytopenic purpura] in
the case of cyclosporine) will be documented. Cyclosporine would be the only arm where
this may occur as the protocol is for 2 weeks of therapy.
An investigator and research coordinator will be available 24 hours a day from both the
Vanderbilt Coordinating Center and Ottawa Coordinating Center. The consent form has
contact numbers for reaching study personnel. In the event an investigator or research
coordinator is on vacation or out-of-town, appropriate coverage will be provided.
The safety of the participant will remain of primary importance. All patients will
undergo intensive monitoring while in hospital in accordance with usual ICU and Burn
Unit practices.
3.6. Risks of Study Procedures Venipuncture and Blood Samples: The protocol requires
patients to have blood drawn for research purposes. The risks of drawing blood are
uncommon and may include bleeding, minor infection, and bruising. Blood draws may be
painful. Some people may feel faint or dizzy. The amount of blood drawn represents a
small percentage of the amount of the total blood volume and will not represent a
significant risk to the patient. Samples are planned to align with blood samples taken
in the course of usual clinical care to minimize the need for repeat venipuncture. Blood
sampling is performed by trained nurses or phlebotomists with experience performing
venipuncture. We have also aligned our study-related blood samples with those taken for
usual patient care. Multiple tests are also performed on blood from the same sample
tubes. This minimizes the volume of blood required to complete Aims 2 and 3 as well as
significantly reduces the number of needle sticks.
Tissue Samples: Tissue samples will be taken to understand the disease process of
SJS/TEN. A sample of healthy skin, where possible, will be taken for comparison. Where
samples of normal skin can be taken, this will be discussed with the patient. Some
patients have little healthy skin to sample. Risks primarily include minor bleeding, a
small chance of infection, and a small scar.
All tissue sampling will be done by an experienced physician to reduce the risk of
complications.
Salivary Swab: There are no significant risks associated with the saliva samples being
collected. In those with oral mucosal involvement due to SJS/TEN, there may be
irritation or a small degree of discomfort while producing a sample.
Blister Fluid Collection: This process involves aspirating fluid from an intact blister.
There is a very low risk of infection, but there is no discomfort with the procedure.
4. Investigational Agent /Device/Intervention (see investigators brochure, section 5) 4.1.
Drug Accountability Under Title 21 of the Code of Federal Regulations (21CFR §312.62),
the investigator will maintain adequate records of the disposition of the
investigational agent, including the date and quantity of the drug received, to whom the
drug was dispensed (participant-by-participant accounting), and a detailed accounting of
any drug accidentally or deliberately destroyed.
Records for receipt, storage, use, and disposition will be maintained by the study site.
A drug-dispensing log will be kept current for each participant. This log will contain
the identification of each participant and the date and quantity of drug dispensed. All
records regarding the disposition of the investigational product will be available for
inspection. Any remaining product will be destroyed in accordance with pharmacy
regulations.
4.2. Assessment of Participant Compliance with Investigational Agent All medications
will be administered by the investigator and/or study staff in the Burn Unit.
Administration of study medication(s) will be witnessed by the investigator and/or study
staff. The total volume of study medication-infused will be compared with the total
volume prepared to determine compliance with each dose administered.
4.3. Toxicity Prevention and Management Etanercept: No modifications are permitted.
Cyclosporine: The study is blinded and the adjustment and stopping rules that primarily
apply to cyclosporine will be carried out by an unblinded pharmacists according to
well-defined rules. A table will be provided for anticipated severe drug interactions
with cyclosporine and for patients where those drugs are necessary these patients may be
excluded from the study. Non-serious medication side-effects such as diastolic
hypertension or mild renal failure will be medically managed while still maintaining
blinding. For example, standard adjustments for cyclosporine will be made based on serum
creatinine and blood pressure monitoring. These orders will be written and carried out
by an unblinded pharmacist. The adjusted dose will appear on the IV bag
cyclosporine/placebo and the treating team will remain blinded as to the treatment arm
of the patient. Creatinine will be monitored daily by a non-blinded pharmacist at each
site for all patients. A standard dose-adjustment algorithm to maintain a target
creatinine of <130% above baseline will be used. Down-dosing of 25-30% will be used if
diastolic blood pressure >100 mm. If >3 dose adjustments, 48-hours apart fail to control
rises in creatinine beyond this threshold, cyclosporine is stopped. Any study treatment
will also be stopped in the presence of any grade 3-4 toxicity (e.g.
leukoencephalopathy) or creatinine >150% of initial value and diastolic blood pressure
>110 or systolic persistently > 160 mmHg which is a common indicator of cyclosporine
toxicity.
6.5 Premature Discontinuation of Investigational Agent Patients who discontinue any
study medication will be analyzed by intent-to-treat analysis and followed for
complications of SJS/TEN as per study protocol. Stopping for lack of efficacy will occur
according to pre-described stopping rules. Study therapy may be prematurely discontinued
for any participant for any of the following reasons:1. Grade 3 or 4 toxicity 2.
Toxicity that has not responded to clinical management (see cyclosporine above); 3.
Necessary medication that interacts with cyclosporine (as per protocol table) 4. Patient
request. All patients are administered the drug in the ICU and are monitored around the
clock for adverse signs and symptoms by the investigator and/or study staff. If adverse
signs are observed, patients will be evaluated by physicians from various specialties
including intensive care, and dermatology. Following evaluations, decisions will be
taken to decrease, adjust, or stop the dosage. Each site will be individually managed
for treating adverse reactions.
Study therapy may also be prematurely discontinued for any participant if the
investigator believes that the study treatment is no longer in the best interest of the
participant.
5. Other Medications 5.1. Concomitant Medications 5.1.1. Protocol-mandated 1% lidocaine
with epinephrine at a dilution of 1:100,000 as local anesthesia at the time of
obtainment of biopsy samples (for research biopsies) 5.1.2. Other permitted concomitant
medications All topical agents for wound and eye care are permitted as outlined in the
respective supportive care protocols.
5.2. Prophylactic Medications Any non-interacting medications (as per cyclosporine
protocol) may be administered at the discretion of the clinical team.
5.3. Prohibited Medications 1) Medications that interact with cyclosporine where there
are suitable alternatives20,21; 2) immunomodulatory agents other than those used in this
clinical trial
The following medications will be considered to be contraindicated during the course of
the study. If patients are on these medications and an alternative is available it
should be substituted:
Aliskiren, atorvastatin, bosentan, cholic acid, cladribine, conivaptan, crizotinib,
dronedarone, elagolix, enzalutamide, eplerenone, foscarnet, any new drug found to be a
significant CYP3A4 inhibitor or p-glycoprotein/ABCB1 inhibitor). A complete list of
interacting drugs, potentially interacting drugs is included in the operations manual.
5.4. Rescue Medications Cyclosporine increases blood pressure. Blood pressure will be
managed by administering non-interacting blood pressure-lowering drugs at the discretion
of the treating physician. Cyclosporine could also decrease renal function. Patients
will be managed as per standard of care protocols for patients with acute renal failure
(see operations manual for detailed procedures).
6. Study procedures (for laboratory procedures and sampling schedule, see section 5,
comprehensive laboratory plan) Enrollment The research study will be explained in lay
terms to each potential research participant. The potential participant will sign an
informed consent form before undergoing any study procedures. Once informed consent has
been signed and completed by both the participant and key study personnel, the
participant is considered enrolled in the study and will be assigned a unique
participant number. Consent will be obtained at the time of clinical encounter or
diagnosis. To initially identify patients for consent, medical records may be reviewed
for suitability or the admitting service (e.g., emergency, intensive care unit, burn
surgery) may identify suitable patients to the study team. Then, a health care
professional from the research team of key personnel will discuss the study with
prospective participants (or substitute decision-makers) or obtain permission for the
research personnel to discuss the study. In rare cases where emergency treatment is
required (e.g., altered level of consciousness, lack of capacity), enrollment may still
occur; however, confirmation of consent will be required by the research team at the
first opportunity after the patient is initially managed or restoration of capacity
occurs. Consent will be obtained from a substitute decision-maker or the patient at the
earliest possible moment and the subject will be reconsented when their capacity for
medical decision-making returns. A copy of the patient's consent will be kept in the
patient's chart. It is available in English and Spanish. If consent is withdrawn at any
time, it should be determined to what aspect of the study consent is being withdrawn
(e.g., consent to the use of genetic samples or the study itself). In case of full
withdrawal of consent, the treating team may modify any of the study procedures as per
their medical judgment.
8.1 Screening/Baseline Visit The purpose of the screening period is to confirm eligibility to
continue in the study.
The following procedures, assessments, and laboratory measures will be conducted to determine
participant eligibility:
1. Research staff will screen potential participants upon being notified of their admission
to the ICU or Burn ICU based on the study inclusion/exclusion criteria. (so as written
here - the subjects will be screened and consented here).
2. A diagnostic punch biopsy will be obtained from the patient on the day of admission by
the institution's appropriate staff. (is this a clinical biopsy or a research biopsy)
3. The results of the diagnostic biopsy will be reviewed by research staff to determine
eligibility to continue in the study within 2-3 days after admission.
Randomization: will occur by a secure central online, computer-generated random number
system. Randomization will be stratified by baseline SJS/TEN prognosis (SCORTEN) and will
occur in randomly varying blocks of sizes 3 and 6. Subjects will be allocated 1:1:1 to
cyclosporine plus best supportive care, etanercept plus best supportive care, or best
supportive care alone. Continuation of the patient in the study will be contingent on a
compatible clinical picture in combination with supportive pathology. Since pathology can
take 48 hours to come back however subject randomization will occur prior to the availability
of the biopsy results.
Patients, treating physicians, and outcome assessors will be blinded to the allocated
treatment. The central randomization scheme will provide the site pharmacists with a unique
drug code corresponding to either study drugs or matching placebo. These will be kept in
identical, coded containers. Only the study center and site pharmacy will be aware of the
coding scheme. Masking will be carried out as follows: 1) Cyclosporine: study drug given as
per protocol for 2 weeks. A single SC injection is given on Day 1 of admission. With a second
injection given on day 4 of admission.; 2) Etanercept: Study drug given as per protocol.
Receive IV normal saline for 2 weeks to mimic the cyclosporine schedule. Subcutaneous
injection of etanercept given on study day 1 and study day 4; 3) Supportive therapy: A single
saline SC injection on Day 1 and Day 4 to mimic etanercept and normal saline for 14 days to
mimic the cyclosporine schedule.
8.2 Study Visits or Study Assessments
Also as listed in the research plan, facilities, and resources, and detailed laboratory
plan).
8.3 Unscheduled Visits (following discharge between 3 and 12-month follow-ups) Following
discharge, the patient will be discharged to the care of their clinical team that will
generally include follow-up with dermatology and ophthalmology at a minimum and if disease
activity increase or other concerns arise they will be asked to liaise with the clinical team
however study personnel should also be contacted and the participant may be asked to return
for an "unscheduled" visit.
9. Biospecimen Storage (see comprehensive laboratory plan) 10. Criteria for Participant and
Study Completion and Premature Study Termination
a. Participant Stopping Rules and Withdrawal Criteria
Participants may be prematurely terminated from the study for the following reasons:
1. The participant elects to withdraw consent from all future study activities, including
follow-up.
2. The participant is "lost to follow-up" (i.e., no further follow-up is possible because
attempts to reestablish contact with the participant have failed). [use specific
criteria to define "lost to follow-up"]
3. The participant dies.
4. The participant is withdrawn from the study.
5. Individual safety stopping rules as defined under the study drugs section.
Study stopping rules:
We plan two interim analyses to allow early stopping for efficacy. These analyses will take
place when we have acquired outcome measures for one-third and for two-thirds of the total
target sample. We will use the Haybittle-Peto rule applied to each of the three pairwise
Mann-Whitney comparisons of time to re-epithelialization between arms. As with the primary
analysis, patients who die prior to achieving re-epithelialization will be allocated the
maximum observed time to re-epithelialization plus one, so as to ensure that death is treated
as worse than any time to successful treatment. One arm will be declared inferior to another
if the p-value for the difference is less than 0.001. No adjustment will be made to the final
analysis for interim testing. If one arm is found to be inferior to another arm, the Data
Safety Monitoring Board will be instructed to strongly consider stopping recruitment to that
arm. If one arm is found to be inferior to both other arms, the Data Safety Monitoring Board
will be instructed to immediately stop recruitment in the inferior arm. If the other two arms
also differ with a p-value less than 0.001, the recruitment will be stopped in all arms. We
will have no formal stopping rules for safety outcomes different from time to
re-epithelialization, but the Data Monitoring Committee will be explicitly mandated to
carefully consider any safety signals with a view towards stopping recruitment if any
expected or unexpected safety signal emerges.
b. Participant Replacement If a participant withdraws or is withdrawn from the study, no
further data or samples will be collected. The participant will not be replaced.
c. Follow-up after Early Study Withdrawal Participants who withdraw from the study will be
taken out of the study and no further data or samples will be collected. Study drugs and
interventions will no longer continue after the patient is withdrawn from the study. Data and
samples collected during the time of participation in the study will still be kept for study
analysis.
11. Safety Monitoring and Reporting (see data safety monitoring plan section 3.3)
