A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Evaluate the Testicular Safety of Filgotinib in Adult Males with Moderately to Severely Active Inflammatory Bowel Disease

IBD is a chronic inflammatory condition affecting the gastrointestinal tract.
In UC, this inflammation is limited to the mucosal layer and involves the
rectum, with or without direct extension to the colon. The inflammation of CD
can involve any segment of the gastrointestinal tract (from oral cavity to
perianal area) and, in addition to affecting the mucosal surface, can extend
through the full thickness of the gastrointestinal wall.
.Over the last decade, changes in IBD treatment strategies, accompanied by
advances in drug development and the addition of targeted biological therapies,
have greatly improved patient outcomes. Despite these developments, therapeutic
challenges remain. Only a subset of patients respond to currently available
biologic therapy, with some losing response and others becoming intolerant over
time. There is an unmet medical need for safe, well tolerated, orally
administered therapies with novel and targeted mechanisms of action that can
effectively improve the disease course. While providing a treatment option for
male subjects with moderately to severely active IBD, the present study seeks
to evaluate the impact, if any, of filgotinib on spermatogenesis in humans.

The purpose of this study is to see how filgotinib, the experimental drug,
affects male sperm and to see if it is a safe and effective treatment for men
with moderately to severely active inlammatory bowel disease.

This is a randomized, double-blind, placebo-controlled Phase 2 study in adult
males with moderately to severely active inflammatory bowel disease (IBD) who
may be on protocol-specified therapy.

Up to 250 males between the age of 21 and 65 years (inclusive) at the time of
consent will be randomized to receive 26 weeks of filgotinib 200 mg or placebo
once daily.

Randomization will be stratified according to the type of IBD (ie, ulcerative
colitis [UC] versus Crohn*s disease [CD]), by concurrent use of methotrexate
(MTX; yes or no), and by sperm concentration measured at Screening
(*Baseline*) according to the following strata:
* 15 to 25 million/mL
* > 25 to 50 million/mL
* > 50 million/mL

There are 5 distinct parts to the study which subjects may enter depending upon
the individual subject*s response of the underlying IBD to assigned treatment
and/or observed changes in semen parameters. The 5 parts which are described in
the following sections comprise of the following:
1) Part A (Day 1 through Week 13 Study Visit)
2) Part B (After Week 13 through Week 26 Study Visit)
3) Open-Label Filgotinib Phase
4) Monitoring Phase
5) Long Term Extension

The study parts are described in the following sections.

Part A (Day 1 through Week 13 Study Visit)
In Part A, all subjects will receive blinded study drug for the first 13 weeks,
starting from the Day 1/Randomization Study Visit. At the Week 13 Study Visit,
IBD response status (ie, Non responder vs Responder, see Definition of Terms)
will be determined based on the partial Mayo Clinic Score (partial MCS) for
subjects with UC, or the Crohn*s Disease Activity Index (CDAI) for subjects
with CD. In addition, sperm parameters (see Section 6.13 Semen Collection
Procedure) will be evaluated to determine whether any of the pre-specified
decrease thresholds (see Definition of Terms) have been met.
* Subjects who are Responders and whose sperm parameters do not meet a
pre-specified decrease threshold will continue blinded study drug in Part B.
* Subjects who are Non-responders and whose sperm parameters do not meet a
pre-specified decrease threshold will discontinue blinded study drug and
commence open-label filgotinib.
* Subjects whose sperm parameters meet a pre-specified decrease threshold,
regardless of IBD response status, will discontinue blinded study drug and
enter the Monitoring Phase.

Part B (After Week 13 through Week 26 Study Visit)
In Part B, all subjects will continue on blinded study drug for up to an
additional 13 weeks. Subjects may experience Disease Worsening (see Definition
of Terms) of their underlying IBD at any time during blinded study drug
treatment (after Week 13 through Week 26). If Disease Worsening is confirmed,
sperm parameters will be evaluated to determine whether a pre-specified
decrease threshold has been met prior to a study drug change (changing from
blinded study drug to open-label filgotinib). Based upon the sperm parameters
at this time point, subjects may follow one of the following pathways:
* All subjects whose sperm parameters meet a pre-specified decrease threshold,
regardless of IBD response status, will discontinue blinded study drug and
enter the Monitoring Phase.
* Subjects who experience Disease Worsening after Week 13 and prior to Week 26,
and whose sperm parameters do not meet a pre-specified decrease threshold will
discontinue blinded study drug and commence open label filgotinib.
* Subjects who do not experience Disease Worsening, and are Responders at Week
26, and whose sperm parameters do not meet a pre-specified decrease threshold,
will continue blinded study drug as part of the Long Term Extension (LTE).
* Subjects who do not experience Disease Worsening, but are Non responders at
Week 26, and whose sperm parameters do not meet a pre-specified decrease
threshold, will discontinue blinded study drug and complete a safety follow-up
visit 30 days after last study drug dose.

Open-Label Filgotinib Phase (Open-Label Day 1 through Open Label Week 13 Study
Visit)
After exposure to 13 weeks of open-label filgotinib, the subject*s IBD response
status will be determined and sperm parameters will be evaluated to determine
whether a pre-specified decrease threshold has been met. Subjects will be
evaluated during this phase as follows:
* All subjects whose sperm parameters meet a pre-specified decrease threshold,
regardless of Responder status, will discontinue open label filgotinib,
complete a safety follow-up visit 30 days after last study drug dose, and enter
the Monitoring Phase.
* Subjects who experience Disease Worsening and whose sperm parameters do not
meet a pre-specified decrease threshold will discontinue open-label filgotinib,
complete ET and a safety follow up visit 30 days after last study drug dose.

Subjects who do not experience Disease Worsening, and are Responders at OL Week
13 after exposure to 13 weeks of open label filgotinib, and whose sperm
parameters do not meet a pre-specified decrease threshold, may continue
receiving open-label filgotinib as part of the LTE.
* Subjects who do not experience Disease Worsening, but are Non responders
after exposure to 13 weeks of open-label filgotinib, and whose sperm parameters
do not meet a pre-specified decrease threshold, will discontinue open-label
filgotinib and complete a safety follow-up visit 30 days after last study drug
dose.

Monitoring Phase (up to 52 weeks)
All subjects who enter the Monitoring Phase will undergo semen evaluations
every 13 weeks from the day of study drug discontinuation, for up to 52 weeks
or until Reversibility (see Definition of Terms) is met, whichever is achieved
first. Subjects will be offered locally approved standard of care (SOC) therapy
during the Monitoring Phase.

Long Term Extension (up to 195 weeks)
All subjects who enter the LTE will undergo scheduled visits for safety
assessments every 13 weeks from the start of LTE, for up to 195 weeks, and
semen monitoring (every 13 weeks) until the Week 13 primary study results are
analyzed. Subjects will receive either open label filgotinib or blinded study
drug based on the individual*s response criteria described above. If a subject
experiences Disease Worsening during the LTE, the treatment (either open-label
filgotinib or blinded study drug) will be discontinued and the subject will
complete an ET visit, followed by a safety follow-up visit 30 days after last
study drug dose.

Data Monitoring Committee (DMC)
An external, multidisciplinary DMC, including an expert in male fertility, will
review the progress of the study and perform interim unblinded reviews of
safety data (details in Section 8.8).

Internal Independent Safety Review
A Gilead internal unblinded team, independent of the blinded study team, will
be assembled. The Gilead internal unblinded team will be granted the access to
blinded and unblinded clinical data including treatment assignment to closely
monitor semen parameters in real time. This internal team will be supported by
an external expert in male fertility. To mitigate the risk of inadvertently
releasing treatment assignment to sites and subjects, the internal team will
keep the unblinded information confidential and will not communicate any
information to the blinded study team, site staff or subjects. Data unblinding
due to medical emergency will follow standard Gilead procedures. The Internal
Independent Safety Review committee*s specific activities will be defined by a
mutually agreed upon charter, which will define the committee membership,
conduct, and meeting schedule.

Key Concomitant Medication Considerations
Subjects may be treated with 5-aminosalicylic acid (5 ASA), conventional
immunomodulators, and/or corticosteroid therapy, as defined by the inclusion
criteria. Subjects are prohibited from receiving sulfasalazine, beginning 26
weeks prior to Screening until the end of study, as defined by Exclusion
Criteria.
A list of permitted and prohibited medications is provided in the exclusion
criteria and Section 5.3.

200 mg filgotinib tablet orally once daily or placebo

FILGOTINIB COMMON ADVERSE EVENTS

Some adverse effects (unwanted side effects) have been reported in studies of
filgotinib given to people or to animals. This information is summarized below.

Across three completed rheumatoid arthritis (RA) and CD phase 2 studies lasting
20 weeks or longer, the most common adverse events were infections and the next
most common adverse event were issues related to the stomach and intestines
(gastrointestinal tract). In a Phase 2 study among subjects with CD receiving
filgotinib for 10 weeks, 24.6% of study participants had infections and 24.6%
had adverse events of the gastrointestinal tract. The most common adverse
events were headache (13.8%), Crohn*s disease (9.2%), asthenia (weakness or
lack of energy, 6.9%), and nausea (6.9%).

INFECTIONS
Drugs that affect the immune system can lower the body*s ability to fight
infection. There is a possibility that the ability to fight infection will be
weakened while taking filgotinib. In RA and CD studies, there have been more
infections in study participants who took filgotinib compared to those who took
placebo (pill without filgotinib). Pneumonia (a lung infection that can be
potentially serious) has been identified as an adverse effect of filgotinib
based on RA and CD studies. Serious infections leading to hospitalization have
been reported and in some cases study participants with an infection have died.
Based on the information that is available so far, it is estimated that if 100
subjects take filgotinib for one year, 2 people would develop a serious
infection, on average.

Neutrophils are a type of white blood cell that helps to fight infection. The
number of neutrophils was lower in the blood of study participants with RA who
were given filgotinib, but only approximately 1.5% of these study participants
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 producing blood
levels of filgotinib slightly higher than blood levels produced by the planned
doses in study participants 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 adverse effects did not go away. These adverse effects were not
seen in the testes of rats and dogs when these animals were given a dose that
produces blood levels of filgotinib similar to blood levels produced by 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). This study is being
done to help understand the effect of filgotinib on sperm production.
Currently, the long term effect of filgotinib on sperm production in humans is
unknown. Patients should not enroll in this study unless they understand and
accept the risk that they 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 they leave the study; it could be
permanent. If reduced fertility or infertility is a concern for the patient it
is possible to store a sample of the patients semen (sperm banking) for future
use before starting this study. While sperm banking may be an option for the
patient, it is not considered to be a highly reliable way to preserve future
fertility in all cases. If patients are interested in sperm banking, they
should talk to their study doctor or regular health care provider. Sperm
banking is not part of this study.

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 producing blood levels of filgotinib
comparable to blood levels produced by the planned doses in study participants
in this study. Other effects were also seen, including increased pregnancy loss
and decreased fetal body weights.

Based on these animal data, filgotinib may cause birth defects in humans.
Patients should not enroll in this study unless they understand and accept this
risk and are willing to take appropriate measures to avoid pregnancy in a
female partner. Birth control should be considered for female partners of male
participants; the study doctor can provide details on recommended types of
birth control.

CANCER
Lymphoma (a type of cancer of the immune system) and other types of cancers
have been seen in study participants with RA taking filgotinib. Some of these
cancers have resulted in death. Based on the information that is available so
far, it is estimated that if 100 subjects with RA take filgotinib for one year,
1 person would develop cancer, on average. Some types of cancer, such as
lymphoma, are known to happen more often in people with RA, but it is not yet
known if filgotinib increases this risk.It is not known if filgotinib increases
the risk of cancer in people with UC and CD.

OTHER EFFECTS
Increases in cholesterol, including certain types of both *good* and *bad*
cholesterols, have been seen in study participants 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 adverse effects or risks of taking
this drug are known. In the future, more serious and/or long-term adverse
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. The patients health will be checked at each study visit
by the study doctor, and the patients will be asked to report any changes or
problems they may have noticed. If the patients partner becomes pregnant during
the study, they should let their study doctor know right away. If the patient
has any changes in their health or if the patient has any health problems, they
should let their study doctor know right away.

The patient should talk to their study doctor if they have any questions about
the possible side effects of filgotinib.

RISKS TO STUDY PROCEDURES

BLOOD DRAWS
Collecting a blood sample from a vein may cause pain, bruising,
lightheadedness, fainting, and very rarely, infection at the site of the needle.

HOME STOOL COLLECTION
You may be required to provide a stool sample at home if you are not able to
provide one during your clinic visit. You will be sent home with Para-Pak®
containers which contain potentially harmful liquids (such as formalin,
polyvinyl alcohol, and mercuric chloride). These substances can irritate your
skin and eyes, and they are dangerous to inhale or ingest. It is important that
you follow the instructions on handling the stool containers correctly
(including wearing gloves).

ILEOCOLONOSCOPY/FLEXIBLE SIGMOIDOSCOPY
Ileocolonoscopies and flexible sigmoidoscopies are generally safe procedures,
but with any procedure there are risks. These risks will be discussed with you
by your medical doctor. You will sign a separate consent form for the
procedure. Preparation for this test may require use of an enema or laxative,
or both, which may cause abdominal discomfort and increased loose stools during
the preparation period. Preparation may also include a special diet where you
clean your intestines. You may experience cramping from the air used to inflate
your colon during the procedure, which will pass.

ECG
After the patient has an ECG, they may have mild irritation, slight redness,
and itching on their skin where the recording patches were attached. The
patients may need to have their chest hair shaved for this procedure.

FASTING
Fasting could cause dizziness, headache, stomach discomfort, or fainting.

CHEST X-RAY
The patients may receive some radiation exposure from a chest x-ray. Generally,
the amount of radiation received during this procedure is the same as a person
gets from exposure to natural sources of radiation in the environment in a 10
day period.

ALLERGIC REACTION
Allergic reaction is always possible with any drug. Serious allergic reactions
that can be life-threatening may happen. Some things that may happen during an
allergic reaction to any type of medication are:

* skin rash
* having a hard time breathing
* wheezing when you breathe
* a sudden drop in blood pressure
* swelling around the mouth, throat, or eyes
* fast pulse
* sweating

UNKNOWN/UNEXPECTED RISKS AND DISCOMFORTS
There may be unwanted side events that are not yet known or may happen rarely
when people take these study drugs. The patient will be told of any new
information that might cause them to change their mind about continuing to take
part in this study.

As with any new drug, extra care has to be taken to watch for the side effects
that are not always obvious. If the patients feel any side effects or unusual
symptoms, they should notify their study doctor as soon as possible at the
phone number listed in the informed consent form.

PREGNANCY
It is very important that the patients do NOT cause a woman to become pregnant
while they are in this study from the time of screening and for at least 90
days after the last dose of study drug. Not having sex is the only certain way
to prevent pregnancy.

To be in this study, the patients must agree to protect their partner from
becoming pregnant before, during, and after the study. Men with female
partners, who may become pregnant, must use effective methods of birth control.
The study doctor will need to discuss what type(s) of birth control the patient
is using.

Other not yet identified side effects could happen to the patient, and/or to
the embryo or fetus (unborn child) if the patients partner becomes pregnant
during the time they are in the study and for 90 days after your last dose of
study drug.

These potential side effects may harm an unborn baby. If the patient has a
female partner who is pregnant or suspects that she has become pregnant while
the patient was in the study or within 90 days after their last dose of study
drugs, they must stop taking the study drug immediately and tell their study
doctor. As the risk to the partner and unborn baby are not known, it is
recommended for the partner to receive appropriate prenatal care from her own
doctor. The partner will be asked to sign a consent form to allow her to give
the study doctor information about the pregnancy and its outcome.

The study doctor may need to tell the patients partner details about this study
and about him taking part in it. The Study Sponsor and the study doctor will
not be responsible for the costs related to the pregnancy, delivery, or care of
the child.

The patient must also agree not to donate sperm during the study (except for
required study sperm collection) and until 90 days after the last dose of study
drugs. The patients sexual activity and sexual behaviors are not restricted
except for the periods around the time they are donating sperm for the study.