The primary objective is to test the hypothesis that baricitinib high dose level in combination with topical corticosteroids (TCS) or baricitinib medium dose level in combination with TCS is superior to placebo in combination with TCS in the…
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Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
The primary research variable is the proportion of patients achieving
Investigator*s Global Assessment (IGA) of 0 or 1 with a >=2-point improvement at
Week 16.
Secondary outcome
There are multiple secondary variables, of which the key variables are the
following:
- Proportion of patients achieving IGA of 0 or 1 with a >=2-point improvement at
Week 16
- Proportion of patients achieving EASI75 at 16 weeks
- Proportion of patients achieving EASI90 at 16 weeks
- Percentage change from baseline in EASI score at 16 weeks
- Proportion of patients achieving SCORAD75 at 16 weeks
- Proportion of patients achieving a 4-point improvement in Itch NRS at 16, 4,
2, and 1 weeks
- Mean change from baseline in the score of Item 2 of the ADSS at 16 weeks and
1 week.
- Mean change from baseline in Skin Pain NRS at 16 weeks
- Proportion of patients achieving IGA of 0 or 1 with a >=2-point improvement
from baseline at Week 24
- Proportion of patients achieving EASI75 at 24 weeks
Please refer to section 4 of the Protocol for all other secondary variables and
those of the substudy.
Background summary
Atopic dermatitis (AD), or atopic eczema, is a common, chronic, relapsing,
highly symptomatic inflammatory skin disease. Patients with AD may present with
skin lesions that can be acute with oozing, crusted, eroded vesicles or papules
on erythematous plaques. Patients may also present with lesions that have a
subacute appearance, with thick and excoriated plaques, or chronic appearance,
with lichenified, slightly pigmented, excoriated plaques. Atopic dermatitis
causes pruritus throughout the day, which is the primary source of morbidity in
this disorder. Pruritus often leads to an *itch-scratch* cycle, further
compromising the epidermal barrier and resulting in dry skin, microbial
colonization, and secondary infections, with 36% of patients reporting that
they often or always scratch until their skin bleeds. Pruritus from AD can
worsen at night, resulting in sleep disturbances, with approximately 27% of
adult patients with AD experiencing sleep disturbance as a result of itching.
In adult patients with moderate-to-severe AD, sleep quality and latency were
significantly associated with poor quality of life (QoL).
In clinical practice, AD is classified as mild, moderate, or severe based on a
variety of clinical features, including severity of skin lesions and pruritus,
and extent of disease (body surface area [BSA] involved).
Whereas mild AD can be controlled by appropriate skin care and topical
anti-inflammatory treatments (topical corticosteroids [TCS] and topical
calcineurin inhibitors [TCIs]), moderate and severe AD usually require
additional treatments such as phototherapy or systemic immunosuppressants.
Cyclosporine A (CyA) has been approved for the treatment of patients with
severe AD in most European countries and for AD not controlled with existing
therapies in Japan and is used off-label in the US and other geographies.
Cyclosporine A is usually considered a first-line option for patients requiring
immunosuppressive treatment. However, the safety profile of CyA limits its use
to the short-term treatment of acute flares; for chronic severe AD, treatment
duration should not exceed 1 year. Hence, there is a need for alternative
therapy for patients with moderate-to-severe AD requiring systemic therapies,
particularly those who have experienced failure to cyclosporine or are
intolerant to, or have contraindication to, cyclosporine.
Until recently, there were no Food and Drug Administration (FDA)-approved
systemic treatments for patients with moderate-to-severe AD, with the exception
of systemic corticosteroids. In March 2017, Dupixent (dupilumab) injection, an
IgG4 monoclonal antibody that inhibits interleukin (IL)-4 and IL-13, was
approved by the FDA for this patient population (Dupixent package insert,
2017). In the European Union, only cyclosporine has been approved for the
treatment of patients with severe AD. A recently completed Phase 2 study
(I4V-MC-JAHG [JAHG]) evaluated the safety and efficacy of baricitinib (a Janus
kinase [JAK] inhibitor) in AD and results showed significant improvement in
disease severity compared to placebo and no new safety concerns were
identified.
In addition to AD, baricitinib has also been studied in Phase 3 in patients
with rheumatoid arthritis (RA) and in Phase 2 in patients with diabetic
nephropathy, moderate-to-severe psoriasis, and systemic lupus erythematosus.
Baricitinib has been administered as single doses ranging from 1- to 40-mg and
as repeat oral doses ranging from 2- to 20-mg to healthy subjects. Baricitinib
has also been administered to patients with RA at doses up to 15-mg daily for 4
weeks, 10-mg daily for 24 weeks, 8-mg daily for 76 weeks, and lower doses up to
4-mg daily for up to approximately 7 years. Through 13 February 2019, nearly
3861 patients have been treated with baricitinib within the RA program at doses
of 2-mg once daily (QD) or 4-mg QD. Of these, more than 2700 patients have been
treated with baricitinib for more than a year and more than 2100 patients have
been treated with baricitinib for more than 2 years.
Study objective
The primary objective is to test the hypothesis that baricitinib high dose
level in combination with topical corticosteroids (TCS) or baricitinib medium
dose level in combination with TCS is superior to placebo in combination with
TCS in the treatment of moderate to severe atopic dermatitis.
The secondary objectives are:
- To test the hypothesis that baricitinib low dose level+ topical
corticosteroids (TCS) is superior to placebo + TCS in the treatment of patients
with moderate to severe atopic dermatitis.
- To compare the efficacy of baricitinib high dose level+ TCS, baricitinib
medium dose level + TCS, or baricitinib low dose level + TCS to placebo + TCS
in atopic dermatitis during the double blind placebo controlled treatment
period as measured by improvement of signs and symptoms of atopic dermatitis.
- To compare the efficacy of baricitinib high dose level + TCS, baricitinib
medium dose level + TCS, or baricitinib low dose level + TCS to placebo + TCS
in atopic dermatitis during the double blind placebo controlled treatment
period as assessed by patient reported outcome measures.
During the long term extension (Period 3), eligible patients will participate
in a downtitration substudy.
Study JAIN will include the possibility to downtitrate baricitinib in patients
who are responders (IGA 0 or 1) or partial responders (IGA 2) in the context
of a randomized downtitration substudy starting at Week 52. Study JAIN will
also evaluate the possibility to uptitrate nonresponders (IGA >=3) during Period
3.
Study design
Study I4V-MC-JAIN (JAIN) is a Phase 3, multicenter, double-blind, randomized,
placebo-controlled study evaluating the safety and efficacy of baricitinib low
dose level QD, medium dose level QD, and high dose level QD in combination with
TCS in patients with moderate-to-severe atopic dermatitis (AD) who have
experienced failure of cyclosporine, or are intolerant to, or have a
contraindication to, cyclosporine.
The study is divided into 5 periods: a 5-week Screening period, a 1-year
Double-Blind Treatment period (Week 0 through Week 52), a 1-year doubleblind,
long-term extension (Week 52 through Week 104) that includes a randomized
downtitration substudy, a bridging extension that may last up to 96 weeks (Week
104 to up to Week 200), and a 4-week Post-Treatment Follow-Up period.
Approximately 500 patients >=18 years of age will be randomized at a 1:1:2:1
ratio to receive placebo QD, baricitinib low dose level QD, baricitinib medium
dose level QD, or baricitinib high dose level QD (100 patients in the placebo
group; 100 patients each in the baricitinib low dose level and high dose level
groups; and 200 patients in the baricitinib medium dose level treatment group).
Patients will be stratified at randomization according to disease severity
(Investigator*s Global Assessment [IGA] 3 versus 4) and geographic region if
the planned country allocation justifies.
Intervention
This study involves a comparison of placebo, baricitinib low dose level,
baricitinib medium dose level, and baricitinib
high dose level administered orally once a day. Table 3 in the Protocol shows
the treatment regimens.
Study burden and risks
In the baricitinib Phase 2 study in moderate-to-severe AD, Study I4V-MC-JAHG
(JAHG), baricitinib doses of medium- and high dose level showed early
improvement in both physician- and patient-reported signs and symptoms of AD,
including improvement in skin inflammation, itch, sleep disruption, and quality
of life.
There are several risks involved with the study drug. Serious infections,
venous thromboembolic events, hepatotoxicity, and fetal malformations were
identified as important potential risks with baricitinib in RA studies. More
information can be found in the Protocol, section 3.2 and in the Investigator*s
brochure.
Furthermore, the subjects undergo a number of study procedures, such as filling
out questionnaires, blood draws and X-rays. These procedures may also be
accompanied by certain (unknown) risks.
Benefits: In the baricitinib Phase 2 study in moderate-to-severe AD, Study
I4V-MC-JAHG (JAHG), baricitinib doses of medium- and high dose level showed
early improvement in both physician- and patient-reported signs and symptoms of
AD, including improvement in skin inflammation, itch, sleep disruption, and
quality of life.
In the context of the cumulative knowledge, the benefit/risk balance for
baricitinib for the treatment of adult patients with moderate-to-severe AD is
assessed to be favorable.
More information about the known and expected benefits, risks, serious adverse
events (SAEs), and reasonably anticipated adverse events (AEs) of baricitinib
are to be found in the investigator*s brochure (IB).
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Age
Inclusion criteria
• Have been diagnosed with moderate to severe Atopic Eczema (Atopic Dermatitis)
for at least 12 months.
• Have had inadequate response or intolerance to existing topical (applied to
the skin) medications within 6 months preceding screening.
• Are willing to discontinue certain treatments for eczema (such as systemic
and topical treatments during a washout period and throughout the study).
• Agree to use emollients daily.
• Have a medical contraindication to cyclosporine A, or had intolerance and/or
unacceptable toxicity or inadequate response to cyclosporine A in the past.
Exclusion criteria
• Are currently experiencing or have a history of other concomitant skin
conditions (e.g., psoriasis or lupus erythematosus), or a history of
erythrodermic, refractory, or unstable skin disease that requires frequent
hospitalizations and/or intravenous treatment for skin infections.
• A history of eczema herpeticum within 12 months, and/or a history of 2 or
more episodes of eczema herpeticum in the past.
• Participants who are currently experiencing a skin infection that requires
treatment, or are currently being treated, with topical or systemic antibiotics.
• Have any serious illness that is anticipated to require the use of systemic
corticosteroids or otherwise interfere with study participation or require
active frequent monitoring (e.g., unstable chronic asthma).
• Have been treated with the following therapies:
- Monoclonal antibody for less than 5 half-lives prior to randomization.
- Received prior treatment with any oral Janus kinase (JAK) inhibitor.
- Received any parenteral corticosteroids administered by intramuscular or
intravenous (IV) injection within 2 weeks prior to study entry or within 6
weeks prior to planned randomization or are anticipated to require parenteral
injection of corticosteroids during the study.
- Have had an intra-articular corticosteroid injection within 2 weeks prior to
study entry or within 6 weeks prior to planned randomization.
• Have high blood pressure characterized by a repeated systolic blood pressure
>160 millimeters of mercury (mm Hg) or diastolic blood pressure >100 mm Hg.
• Have had major surgery within the past eight weeks or are planning major
surgery during the study.
• Have experienced any of the following within 12 weeks of screening:
venous thromboembolic event (VTE), myocardial infarction (MI), unstable
ischemic heart disease, stroke, or New York Heart Association Stage III/IV
heart failure.
• Have a history of recurrent (>= 2) VTE or are considered at high risk of VTE
as deemed by the investigator.
• Have a history or presence of cardiovascular, respiratory, hepatic, chronic
liver disease gastrointestinal, endocrine, hematological,
neurological, lymphoproliferative disease or neuropsychiatric disorders or any
other serious and/or unstable illness.
• Have a current or recent clinically serious viral, bacterial, fungal, or
parasitic infection including herpes zoster, tuberculosis.
• Have specific laboratory abnormalities.
• Have received certain treatments that are contraindicated.
• Pregnant or breastfeeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2017-004574-34-NL |
CCMO | NL63684.056.18 |