PrimaryTo evaluate the long-term safety and tolerability of baricitinib in patients with SLE.
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability assessments will include:
* Proportion of patients with treatment-emergent adverse events (TEAEs),
adverse events of special interest (AESIs), and serious adverse events (SAEs).
* Proportion of patients with temporary investigational product interruptions
and permanent discontinuations.ctivity (Section 9.1.1.4).
Secondary outcome
Proportion of patients achieving SRI-4 response through Week 156, defined as:
o Reduction of *4 points from baseline in SLEDAI-2K score; and
o No new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new
BILAG B disease activity score; and
o No worsening (defined as an increase of *0.3 points [10 mm] from baseline) in
the Physician*s Global Assessment of Disease Activity.
Background summary
3.2. Background
Systemic lupus erythematosus is a chronic, often debilitating, multisystem,
autoimmune disease that is characterized by the presence of autoreactive B
cells and elevated autoantibodies, which directly damage the body*s cells and
tissues. Systemic lupus erythematosus can affect multiple organ systems
simultaneously or sequentially, and follows a highly variable clinical course
where periods of relatively stable disease are followed by flares and/or
periods of persistently
active disease; all of which can ultimately lead to irreversible damage to
tissues and organ systems.
Systemic lupus erythematosus is predominately a disease affecting women
(approximately 9:1 female to male ratio), which can begin at any age but most
commonly begins in adolescence or early adulthood (Yu et al. 2017). It affects
20 to 150 people per 1,000,000 people in the US (UpToDate® 2018 [WWW]) and is
more common in African-Americans (Lim et al. 2014; Somers et al. 2014), with as
many as 1 in 537 African-American women afflicted with SLE (Somers et al.
2014). Additionally, SLE appears to be more severe in African-Americans,
Asian-Americans, and Latinos compared to Caucasians (Kaslow 1982; Alarcón et
al. 2001).
Clinically, SLE presents with varying signs and symptoms, including fever,
arthralgia/arthritis, skin rash, alopecia, pleuritis, pericarditis, nephritis,
vasculitis, stroke, seizure, leukopenia, thrombocytopenia, anemia,
photosensitivity, and the presence of autoantibodies reactive with nuclear
antigens. Fatigue is the most prevalent symptom reported among patients with
SLE (Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria for
Fatigue 2007). Pain that interferes with daily living activities is also
commonly reported (Özel and Argon 2015). Skin and joint disease are also among
the most prevalent features of the illness. Age, African-American
race/ethnicity, SLEDAI-2K score, steroid use, and hypertension were associated
with transition from no damage to damage, and increase(s) in preexisting damage
(Bruce et al. 2015). Over 60% of patients with SLE will develop clinically
detectable organ damage within 2 to 7 years of diagnosis, as measured by the
Systemic Lupus Erythematosus International Collaborating Clinics
(SLICC)/American College of Rheumatology (ACR) damage index (Cooper et al.
2007).
Improvements in earlier diagnosis, treatment regimens, and medical care over
the past several decades have reduced mortality in SLE. However, patients
continue to experience premature death, with cardiovascular disease being the
leading cause. A recent meta-analysis of published data involving over 27,000
patients with SLE observed a 3-fold increase in the risk of death in patients
with SLE compared with the general population (Yurkovich et al. 2014).
Morbidity remains substantial as measured by various tools for features, such
as health-related quality of life, loss of work productivity, pain, and fatigue
(Ad Hoc Committee on Systemic Lupus
Erythematosus Response Criteria for Fatigue 2007; Özel and Argon 2015). Thus,
there remains substantial unmet medical need for individuals who have SLE.
Standard of care for SLE includes antimalarial agents, corticosteroids,
nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressive agents, and
cytotoxic agents; however, there are relatively few drugs approved for the
treatment of SLE. For example, in the US, approved therapies for SLE include
aspirin, antimalarials, corticosteroids, and belimumab. In general, treatment
regimens are broadly similar around the world and are tailored to the severity
of disease and the specific organs involved. Mild disease is often treated with
low-dose corticosteroids, NSAIDs, and antimalarials; while serious,
organ-threatening or life-threatening disease is typically treated with
high-dose corticosteroids and immunosuppressive agents. In addition to their
direct impact on disease, immunosuppressive agents are also utilized as so
called *corticosteroid-sparing agents* to reduce chronic exposure to
corticosteroids.
The current SoC therapies have broad effects on immune and inflammatory
pathways, including host defense, and have been associated with short- and
long-term morbidity. For example, long-term use of corticosteroids is
associated with cataracts, osteoporosis, avascular necrosis, increased
infection, cardiovascular events, hyperglycemia, and weight gain, while
cyclophosphamide increases the risk of premature ovarian failure, serious
infection, and cancer.
Although recent improvements in treatment regimens and medical care have
reduced overall morbidity and mortality, many patients still have incompletely
controlled disease, which progresses to end-stage organ involvement. In
addition, the disease increases mortality and negatively impacts health-related
quality of life. New treatment options with an acceptable safety profile that
reduce disease activity and flares, delay organ damage, and reduce the
requirement for corticosteroids and cytotoxic agents are urgently needed for
patients with SLE.
Accordingly, pharmacologic interventions that target specific pathways
associated with the pathology of SLE may provide novel therapeutic approaches
to disease management. One of the signaling pathways implicated in SLE disease
activity is the type I IFN signaling pathway. Upregulation of genes associated
with the activation of type I IFN signaling, referred to as a type I IFN
signature, is observed in approximately 75% of patients with SLE (Hoffman et
al. 2017).
In SLE, a high type I IFN signature was associated with increased disease
severity, as measured by SLEDAI score, increased anti-double-stranded
deoxyribonucleic acid (anti-dsDNA), decreased complement, and increased risk of
severe flares (Hoffman et al. 2017). Another cytokine implicated in the
pathogenesis of SLE is IL-6. Increased expression of IL-6 has been found in
murine models of SLE and in patients with SLE, and inhibition of IL-6 signaling
was associated with a decrease in disease activity (Linker-Israeli et al. 1999,
Illei et al. 2010). Both type I IFNs and IL-6 signal through the JAK/STAT
pathway; therefore, treatment of SLE with
baricitinib or other JAK inhibitors is an area of intense interest.
Study objective
Primary
To evaluate the long-term safety and tolerability of baricitinib in patients
with SLE.
Study design
Study I4V-MC-JAIM [JAIM] is a Phase 3, multicenter, randomized, outpatient,
long term extension trial to evaluate the long-term safety and efficacy of
baricitinib in eligible patients with SLE who have completed the treatment
period in an originating study (such as, Study I4V-MC-JAHZ [JAHZ] or Study
I4V-MC-JAIA [JAIA]).
Intervention
Patients randomized to active treatment, baricitinib 4-mg daily or baricitinib
2-mg daily, during Study JAHZ or Study JAIA will continue on the same, blinded,
dose of baricitinib in Study JAIM. Patients randomized to placebo during Study
JAHZ or Study JAIA will be randomized 1:1 to receive baricitinib 4-mg or
baricitinib 2-mg daily during Study JAIM. The treatment period will last up to
156 weeks (3 years) from enrollment into Study JAIM.
Study burden and risks
Risks associated with baricitinib
Eli Lilly and Company (Lilly) regularly reviews all important safety
information for their study drugs. As of 13 August 2019, a total of 8267
people have taken 1 or more doses of baricitinib in studies. This number
includes healthy people and people with arthritis, lupus (autoimmune disease),
dermatitis, diabetic kidney disease, psoriasis, alopecia areata (spot
baldness), and primary biliary cholangitis (autoimmune disease of the liver).
Baricitinib is also being provided to children and young adult people with very
rare diseases. Baricitinib is being sold in many countries around the world.
It is estimated that 95100 people have taken baricitinib worldwide as of 31
July 2019. Lilly looked at the most recent data from all of these people. The
risks and discomforts found are described below.
Baricitinib blocks the effects of proteins in the body called Janus kinases.
Blocking these proteins can affect the immune system. Drugs that affect the
immune system can increase the risk of infection and cancer. Baricitinib may
also increase these risks and other risks as described below.
Infections
Upper respiratory tract infections include symptoms similar to the common cold
(cough, stuffy or runny nose, scratchy or sore throat, sneezing). These have
been very common during studies in people taking baricitinib. Infections that
were common include shingles and cold sores. Some people with atopic dermatitis
had other rashes caused by the cold sore virus.
Serious infections requiring hospitalization have also occurred in people
taking baricitinib. These were common during studies.
Unusual infections can occur in people with weakened immune systems. These
infections include tuberculosis, invasive fungal infections, and some viruses.
These have been uncommonly reported in people taking baricitinib.
Your doctor will decide what treatment, if any, you may need for an infection.
Cancers
Drugs that affect the immune system may increase the risk for cancer.
Individual events of cancer have been reported in people taking baricitinib.
The types of cancer that were most frequently reported were skin cancer,
including melanoma and non-melanoma cancer types, lung cancer, and breast
cancer.
Blood Clots in the Blood Vessels
Some people who received baricitinib developed blood clots in the blood vessels
of their legs. These clots may then dislodge and travel to the lungs.
Baricitinib should be used with caution in people who are at high risk for
blood clots in their blood vessels.
Tell your doctor if you have had blood clots in the veins of your legs or lungs
in the past. The study drug will be stopped if signs or symptoms of blood clots
develop.
Digestive System
Small increases in blood tests related to the liver were common in people
taking baricitinib during trials. These increases were also seen when
baricitinib was given along with another medicine (methotrexate) used to treat
arthritis. This medicine (methotrexate) is known to be associated with effects
on the liver.
Upset stomach has been commonly reported with baricitinib. This has usually
been seen when first starting baricitinib. In most people, the upset stomach
got better with continued baricitinib use.
Blood Tests
Higher amounts of cholesterol in the blood (good and bad cholesterol) were very
common in people who took baricitinib. Higher amounts of fat in the blood were
uncommon. Taking baricitinib did not increase the chance of having heart
related problems such as heart disease, heart attack, heart failure, or stroke.
A higher number of parts of the blood that aid in clotting (blood platelets)
were commonly reported in people taking baricitinib. These increases have not
been associated with an increased risk of stroke, heart attack, or blood clots.
Small changes in blood tests related to muscle have been seen uncommonly in
people treated with baricitinib. In most people with these changes, the changes
were temporary. Although there was no clear link with any muscle problems,
symptoms such as muscle aches and pain were reported by some people. In people
with atopic dermatitis, small changes in blood tests related to muscle were
seen commonly.
Baricitinib affects your immune system. It may decrease the number of parts of
the blood that aid in fighting infections (white blood cells). This decrease
may increase your risk for infections. Decreases in white blood cells have been
uncommon with baricitinib.
Weight Gain
People taking baricitinib gained on average 1 kg of weight over 16 weeks. Some
people had weight gain greater than 1 kg.
Skin
Skin rash was commonly reported, while hives and swelling of the face or lips
were uncommonly reported. Some of these reactions occurring in the first days
after starting baricitinib could be due to an allergic reaction to baricitinib.
Acne has been seen uncommonly in people taking baricitinib. In people with
atopic dermatitis, acne was seen commonly.
Headache
Headache was commonly reported during the first months of treatment.
Additional Information
Your doctor will frequently check your general health. Your doctor will also
check your white blood cell count, platelet count, kidney function, liver
function, blood tests related to muscles, and levels of blood cholesterol and
fat during the study.
You should report any changes in your medical condition to your doctor. Make
sure you tell your doctor about any medicine that you take, including
prescription medicine, over-the-counter medicine, and herbal products.
Baricitinib is removed from the body by the kidneys. People with reduced kidney
function do not remove baricitinib as quickly as those with normal kidney
function. People with reduced kidney function may require a lower dose of
baricitinib.
Elderly
Only a small number of people who are 75 years old or older have taken
baricitinib. Based on the data in people 65 years old or older, unwanted
effects appear to be the same as those seen in younger people.
Risks associated with study
procedures
Risks of Blood Tests:
You may feel an uncomfortable needle prick when your blood is drawn.
For most people, needle punctures for blood draws do not cause any bad
problems. However, sometimes they may cause bleeding, bruising, discomfort,
infections, and/or pain where you had the blood drawn. You may also feel dizzy
or faint. If you feel faint or dizzy, tell the study doctor or staff right
away.
Questions on Your Well-Being:
You will be asked questions on how you feel during your treatment. You will
also be asked about what you think the treatment is doing to your symptoms.
Your answers, along with the answers of others in the study, will be collected
to see if a new treatment will help patients in the future. The answers that
you give are confidential, but there is always a risk that your answers will be
read by people who should not read your personal information. You may also feel
uncomfortable answering some of the questions. If you do not want to
participate in answering these questions, this will not cause you to be taken
off the trial.
Risks of a urine test:
You will be asked to urinate or *pee* into a small cup. The test involves only
normal urination. There is usually no discomfort.
In addition to the risks named above, baricitinib and the study procedures may
have other unknown risks.
Bornweg 12C
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Bornweg 12C
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Listed location countries
Age
Inclusion criteria
6.1. Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the
following criteria at
screening:
Type of Patient and Disease Characteristics
[1] Have completed the final treatment study visit of an originating study,
such as Study JAHZ or Study JAIA.
Patient Characteristics
[2] Male or nonpregnant, nonbreastfeeding female patient
a. Patients of child-bearing potential who are abstinent (if this is complete
abstinence, as their preferred and usual lifestyle) or in a same-sex
relationship
(as part of their preferred and usual lifestyle) must agree to either remain
abstinent or stay in a same-sex relationship without sexual relationships with
the opposite sex.
b. Total abstinence is defined as refraining from intercourse during the
entirety of the study and for at least 1 week following the last dose of
investigational
product. Periodic abstinence, such as calendar, ovulation, symptothermal,
post-ovulation methods, and withdrawal, are not acceptable methods of
contraception.
c. Otherwise, patients of childbearing potential together with their partners
must agree to use 2 effective methods of contraception, where at least 1 form is
highly effective, for the entirety of the study and for at least 1 week
following the last dose of investigational product.
d. The following contraception methods are considered acceptable (the patient
should choose 2, and 1 must be highly effective [defined as less than 1%
failure rate per year when used consistently and correctly]):
* Highly effective birth control methods:
* Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation: oral,intravaginal, or transdermal
* Progestogen-only containing hormonal contraception associated with inhibition
of ovulation: oral, injectable, or implantable
* Intrauterine device (IUD)/intrauterine hormone-releasing system (IUS)
* Vasectomized male (with appropriate post-vasectomy documentation of the
absence of sperm in the ejaculate).
* Effective birth control methods:
* Male or female condom with spermicide. It should be noted that the use of
male and female condoms as a double barrier method is not considered acceptable
due to the high failure rate when these methods are combined.
* Diaphragm with spermicide
* Cervical sponge
* Cervical cap with spermicide
Note: When local guidelines concerning highly effective or effective methods of
birth control differ from the above, the local guidelines must
be followed. Patients of non*child-bearing potential are not required to use
birth control andthey are defined as:
* Women who are infertile due to surgical sterilization (hysterectomy,
bilateral oophorectomy, or tubal ligation)
* Post-menopausal * defined either as
* A woman at least 50 years of age with an intact uterus, not on hormone
therapy, who has had either
* Cessation of menses for at least 1 year
* At least 6 months of spontaneous amenorrhea with folliclestimulating hormone
>40 mIU/mL
* Women aged 55 years or older who are not on hormone therapy, and who have had
at least 6 months of spontaneous amenorrhea
* Women aged 55 years or older who have a diagnosis of menopause
Informed Consent
[3] Must read and understand the informed consent approved by Eli Lilly and
Company (Lilly), or its designee, and the institutional review board
(IRB)/ethics review board (ERB) governing the site, and provide written
informed consent.
Exclusion criteria
6.2. Exclusion Criteria
Medical Conditions
[4] Have significant uncontrolled cerebro-cardiovascular (for example,
myocardial infarction, unstable angina, unstable arterial hypertension, severe
heart failure, or cerebrovascular accident), respiratory, hepatic, renal,
gastrointestinal, endocrine, hematologic, neuropsychiatric disorders, or
abnormal laboratory values that, in the opinion of the investigator, pose an
unacceptable risk to the patient if investigational product continues to be
administered.
[5] Have a known hypersensitivity to baricitinib or any component of this
investigational product.
[6] Had investigational product permanently discontinued at any time during a
previous baricitinib study.
[7] Had temporary investigational product interruption at the final study visit
of a previous baricitinib study and, in the opinion of the investigator, this
poses an unacceptable risk for the patient*s participation in the study.
[8] Have any other condition that, in the opinion of the investigator, renders
the patient unable to understand the nature, scope, and possible consequences
of the study or precludes the patient from following and completing the
protocol.
[9] Are currently enrolled in any other clinical study involving an
investigational product or any other type of medical research, judged not to be
scientifically or medically compatible with this study.
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 | EUCTR2017-005028-11-NL |
| ClinicalTrials.gov | NCT03843125 |
| CCMO | NL71584.029.20 |