The primary objective of this study is:* To evaluate the long-term safety and tolerability of filgotinib in subjects who have completed one of the parent studies of filgotinib in RA.The secondary objectives of this study are:* To evaluate the long-…
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Brief title
Condition
- Autoimmune disorders
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety will be assessed by the reporting of AEs, clinical laboratory tests,
physical examination, vital signs, and 12-lead ECGs.
Efficacy will be evaluated by ACR-N responses in each arm.
Secondary outcome
Exploratory Endpoints will include subject achievement of ACR20/50/70 and EULAR
responses.
Background summary
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that
affects approximately 1.3 million adults in the United States (US) {Helmick et
al 2008}. Rheumatoid arthritis manifests principally as an attack on peripheral
joints and may lead to marked destruction and deformity of joints, with
considerable disability and impact on quality of life. It is characterized by
the production of autoantibodies, synovial inflammation with formation of
pannus tissue, and erosion of underlying cartilage and bone. Although people of
any age can be affected, the onset of RA is most frequent between the ages of
40 and 50 years, and women are affected 3 times more often than men. While the
cause of RA is still not completely understood, aberrant Bcell activation,
Tcell costimulation, osteoclast differentiation, and cytokine release all have
been implicated in its pathogenesis.
Treatment of RA is dependent on severity, the patient*s co*morbidities and
initial response to therapy. Methotrexate (MTX) is a conventional disease
modifying antirheumatic drug (DMARD) and continues to be the cornerstone of RA
therapy {Singh et al 2012}. Patients with an inadequate response to
conventional DMARD(s) are often treated with biologic therapies such as tumor
necrosis factor inhibitors (TNFi) as an initial second line therapy. However,
approximately 28% to 58% of RA patients with inadequate response to MTX fail
TNFi as reviewed in {Redlich et al 2003}. In this setting, treatment guidelines
recommend either switching to another TNFi, alternate biologic, or to a small
molecule drug {Singh et al 2012}. Despite significant advances in disease
management in recent years, there remains a need for new treatments, since not
all patients respond adequately to current therapies, have comorbidities and
some patients experience toxicities and/or intolerance that limit the use of
approved therapies.
In November 2012, tofacitinib (Xeljanz®) became the first Janus kinase (JAK)
inhibitor to receive Food and Drug Administration (FDA) approval for the
treatment of adult patients with RA. Tofacitinib is a small molecule, has
strong binding affinity for JAK1 and JAK3, and weaker affinity for JAK2. The
extensive preclinical and clinical development programs demonstrated its
mechanisms of action via antiinflammatory and immunosuppressive effects. The
drug proved to be efficacious in treating the signs and symptoms of RA.
However, the observed side effects and risk profile of tofacitinib are similar
to those of several existing antirheumatic agents with cytopenias, elevated
levels of liver function enzymes, increased total cholesterol levels, with
increase in LDL typically exceeding those for HDL, and increased risk for
infections including serious and opportunistic infections. At higher doses,
tofacitinib treatment was associated with anemia, which is thought to be linked
to inhibition of JAK2.
While the pan JAK inhibitor tofacitinib has shown an early onset of action and
longterm efficacy in RA as mono therapy and in combination with background
conventional synthetic disease modifying antirheumatic drugs (csDMARDs)
therapy, dose levels were limited by side effects potentially mediated by its
effect on JAK 2 and JAK 3. This highlights the need for more selective and
targeted therapies with improved immunomodulatory and hematologic effects.
JAK1 is thought to be an integral part of RA pathogenesis due its role in
transmitting inflammatory cytokine signaling. Hence, targeted inhibition of
JAK1 has great potential for the treatment of RA with an improved safety and
side effect profile.
Study objective
The primary objective of this study is:
* To evaluate the long-term safety and tolerability of filgotinib in subjects
who have completed one of the parent studies of filgotinib in RA.
The secondary objectives of this study are:
* To evaluate the long-term efficacy of filgotinib in subjects with RA
* To evaluate the long-term effects of filgotinib on subject-reported outcomes,
such as disability, fatigue, and quality of life.
The exploratory objective of this study is:
* To characterize the association of host genetics and other markers with
disease severity, disease progression and treatment response to filgotinib in
subjects with RA
Study design
This will be a dose-blinded, long term extension (LTE) study of safety and
efficacy of filgotinib in subjects with RA. Subjects may be enrolled in the
study after they have completed one of the 2 parent RA studies (GS US 417 0301
and GS-US-417-0302).
The Day -1 visit for this study will be performed at either the last visit for
the parent protocol (week 52 visit for GS-US-417-0301, week 24 visit for
GS-US-417-0302) or within 4 weeks after the final study visit for the parent
protocol.
The subject*s first dose of LTE study drug defines the first day of
participation on the LTE, and should not occur sooner than the day after the
final visit for the parent protocol. However, the subject may be consented and
eligibility confirmed on Day -1 (the same day as the last visit for the parent
protocol), with study drug dispensed to start on Day 1 of the LTE study.
Subjects will review and sign the consent for the LTE study prior to any
procedures or tests being performed. After eligibility for the study has been
confirmed, the subject will be assigned to one of the two filgotinib dosing
arms in a blinded fashion.
Subjects who were on blinded filgotinib at the final visit of the parent study
will continue on their same dose of filgotinib in a blinded fashion (100 mg or
200 mg QD). Subjects who were receiving adalimumab (GS-US-417-0301) or placebo
(GS-US-417-0302) at their final visit of the parent study, will be
re-randomized on Day -1 of the LTE in a 1:1 ratio to either 100 mg or 200 mg
filgotinib QD in a blinded fashion.
Subjects from study GS-US-417-0301, who completed the study after being
transitioned to standard of care therapy, are not eligible for the LTE study.
Subjects from study GS-US-417-0302, who discontinued blinded study drug due to
inadequate response of their RA, but completed all study visits are eligible
for the LTE, and will be re-randomized on Day 1 of the LTE in a 1:1 ratio to
either 100 mg or 200 mg filgotinib QD in a blinded fashion.
* Subjects will be provided filgotinib for up to 3 years, or until filgotinib
becomes commercially available, or until Gilead Sciences terminates clinical
development of filgotinib; whichever comes first.
* All subjects may continue their stable dose of permitted csDMARD(s) as
indicated in the parent protocol.
All subjects who are re-randomized on Day -1 of the LTE will be stratified by
geographic region and parent study.
Intervention
200 mg filgotinib orally once daily (QD)
100 mg filgotinib orally once daily (QD)
Study burden and risks
FILGOTINIB COMMON ADVERSE EVENTS
INFECTIONS
Drugs that affect your immune system can lower your body*s ability to fight off
infections. There is a possibility that your ability to fight off infections
will be weakened while taking filgotinib. In studies of patients with RA and
CD, there have been more infections in people who took filgotinib compared to
those who took a placebo. Pneumonia (lung infection) has been identified as a
side effect of filgotinib based on studies in people with RA and CD. Serious
infections leading to hospitalization and, in 3 cases, death have been
reported. Overall, less than 3% of patients taking filgotinib developed a
serious infection of any type.
Neutrophils are a type of blood cell that helps to fight infections. The number
of neutrophils was lower in the blood of patients with RA who were given
filgotinib, but only approximately 1.5% of these patients had a severe decrease
in neutrophils. Other types of infection fighting cells in the blood were not
affected.
MALE INFERTILITY
Filgotinib caused damage to the testes (testicles) of male rats and dogs. In
these animals, filgotinib caused deterioration and loss of cells that make
sperm, resulting in less sperm, or no sperm being produced. As a result,
filgotinib caused male rats to be infertile (unable to get a female rat
pregnant).
Damage to the testes in rats and dogs was observed at doses slightly higher
than the doses that are planned to be given to people in this study. At these
doses, while sperm counts in rats and dogs increased after filgotinib was
stopped, they stayed low overall and did not return to normal. At the highest
doses tested in male rats and dogs, these side effects did not go away. These
side effects were not seen in the testes of rats and dogs when a dose was given
that was similar to the 200 mg daily dose in humans.
Based on the results in male rats and dogs, there is a risk that men treated
with filgotinib may have reduced sperm production, and may become temporarily
or permanently infertile (unable to get a woman pregnant). An additional study
will be done in men with RA to measure the effect of filgotinib on sperm
production. Until results from that study are available, the long term effect
of filgotinib on sperm production in humans is unknown. Do not enroll in this
study unless you understand and accept the risk that you may have reduced
fertility (a lower chance of getting a woman pregnant) or infertility (unable
to get a woman pregnant), and that this side effect may not go away after you
leave the study; it could be permanent.
BIRTH DEFECTS
Filgotinib treatment caused malformations (birth defects) of the bone and
internal organs in the fetuses (unborn babies) of pregnant rats and rabbits.
These birth defects happened at doses of filgotinib similar to those planned to
be given to humans. Other effects were also seen, including increased pregnancy
loss and decreased fetal body weights.
Based on this animal data, filgotinib may cause birth defects in humans. Do not
enroll in this study unless you understand and accept this risk and are willing
to take appropriate measures to avoid pregnancy. To be in this study, highly
effective birth control is required for both men and women. Birth control
should also be considered for female partners of male participants; your study
doctor can provide details on recommended types of birth control. If you are
planning to become pregnant in the future, you should discuss this with your
study doctor before entering the study.
OTHER EFFECTS Increases in cholesterol, including certain types of both good
and bad cholesterols, have been seen in people taking filgotinib, but the
importance of these findings is not yet known. A small increase in creatinine
(which is a measure of how well the kidney is working) was seen in studies with
RA patients. The creatinine levels overall, however, stayed within normal
limits.
As with any drug, there are unknown risks involved, since only a limited number
of people have taken this drug and not all side effects and risks of taking
this drug are known. In the future, more serious and/or long term side effects
could happen, including allergic reactions. Also, the risks or discomforts
described here could happen more often or be more severe than what has been
seen before. Your health will be checked at each visit during the study by your
Study Doctor, and you will be asked to report any changes or problems you may
have noticed.
Flowers building, Granta Park -
Foster City CB21 6GT
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Flowers building, Granta Park -
Foster City CB21 6GT
GB
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Age
Inclusion criteria
1) Male or female subjects who may benefit from filgotinib as judged by the investigator AND who completed a Gilead sponsored filgotinib parent study for RA as outlined below:
a) Subjects who completed GS-US-417-0301 or GS-US-417-0302 on study drug OR
b) Subjects who completed GS-US-417-0302 on standard of care therapy due to RA non-responder status
2) Females of childbearing potential must have a negative pregnancy test prior to first dose of study drug in the LTE;
3) Lactating female subjects must agree to discontinue nursing at Day -1 for the duration of the study
4) Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception, during the study and through 35 days (female) or 90 days (male) after their last dose of study drug or longer as indicated by the product label of the subject*s concurrent csDMARD therapy.
5) Subjects receiving protocol permitted RA medications should be on a stable dose (defined as no change in prescription) within 7 days or 5 half lives (whichever is longer) prior to the first administration of LTE study drug on Day 1, as much as possible.
6) Subjects, who meet study drug interruption criteria at Day 1, are eligible to enter into the LTE, but should not start study drug until deemed medically appropriate.
Exclusion criteria
1) Diagnosis of an autoimmune or inflammatory joint disease other than RA, which would put the subject at risk by participating in the study or would interfere with study assessments/data interpretation, per judgment of the investigator
2) Known hypersensitivity to the study drug or its excipients.
3) Any medical condition (including, but not limited to, cardiac or pulmonary disease, alcohol or drug abuse) which would put the subject at risk by participating in the study or would interfere with study assessments/data interpretation, per judgment of the investigator.
4) History of an infected joint prosthesis or other implanted device with retention of the prosthesis or device in situ.
5) Administration of a live/ attenuated vaccine within 30 days prior to Day 1
6) Currently on any therapy for chronic infection (such as pneumocystis, cytomegalovirus, herpes zoster, and atypical mycobacteria)
7) History of disseminated/complicated herpes zoster infection (multi dermatomal involvement, ophthalmic zoster, central nervous system involvement or postherpetic neuralgia)
8) Any condition or circumstances which in the opinion of the investigator or Sponsor may make a subject unlikely or unable to complete the study or comply with study procedures and requirements
9) Use of prohibited medication as outlined in the protocol
10) Subjects who meet discontinuation criteria as outlined in the protocol
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 | EUCTR2016-003630-25-NL |
| ClinicalTrials.gov | NCT03025308 |
| CCMO | NL61321.044.17 |