VERDICT: In actiVE ulcerative colitis, a RanDomIzed Controlled Trial for determination of the optimal treatment target

Disease activity and response to therapy in ulcerative colitis (UC) can be
assessed by a range of endpoints including symptoms, endoscopic mucosal
activity, histological disease activity, and biomarkers. Within the same
subject, however, considerable discordance exists between these endpoints.
Symptoms inherently have a degree of subjectivity and, if used alone for
therapeutic decision making, are likely to lead to under or overtreatment of
disease. Accordingly, consensus recommendations that define treatment targets
in UC acknowledge that resolution of symptoms is not a sufficient treatment
target and that objective evaluation of inflammation of the mucosa by endoscopy
is necessary. It should be recognized that this recommendation is based on
expert opinion in the absence of any controlled data to confirm that a
treatment target of endoscopy is superior to one based on resolution of
symptoms. Nevertheless, achievement of endoscopic mucosal healing is associated
with lower rates of relapse, hospitalization, colectomy, and cancer.2-4
Furthermore, the combination of achieving clinical
(symptomatic) and endoscopic remission in newly diagnosed subjects with UC has
been shown to reduce rates of relapse, hospitalization, and colectomy compared
to subjects achieving resolution of symptoms alone in up to 5 years of
follow-up. While endoscopic mucosal healing is accepted as the treatment goal
in UC, this treatment target is not *curative* and relapses are still observed
in subjects who reach this objective, despite continuation of therapy.
Importantly, histological disease activity persists in approximately
one-quarter of subjects with normal appearing mucosa. Several studies now
indicate strong associations between the achievement of histological disease
remission and lower risk of
corticosteroid use, hospitalization, and development of colorectal cancer,
compared with endoscopic remission alone, suggesting that the concept of
histological remission may be a distinct treatment target in UC. These
observations have led clinicians to challenge existing concepts of deep
remission and explore whether histological healing can confer additional
prognostic benefit.
Attainment of histological improvement and/or remission in UC has been reported
with several therapeutic classes of drugs including aminosalicylates,
corticosteroids, biologics, and small molecules. In a small, open-label study
of subjects with moderately to severely active UC, 35% of subjects achieved
histological remission, defined as a Geboes score of <= 3.0, after 52 weeks of
treatment with infliximab. Given the gut-selective mechanism of action,
efficacy, and highly attractive safety profile, there is considerable interest
in whether vedolizumab can improve these rates. In a post hoc analysis of 41
subjects from the GEMINI 1 and GEMINI long-term safety (LTS) studies, 55% of
subjects who achieved endoscopic mucosal healing were also in histological
remission at Week 52, notwithstanding that remission was defined more
stringently as a Geboes score of <= 1.

This study has been transitioned to CTIS with ID 2024-514183-21-00 check the CTIS register for the current data.

The primary objective of this trial is to determine whether, in subjects with
moderately to severely active UC, treating to achieve a target of
corticosteroid-free symptomatic + endoscopic + histological remission is
superior to a treatment target of corticosteroid-free symptomatic remission,
with regards to a primary endpoint of time to UC-related complication within up
to 80 weeks of follow-up after achieving target.

In this multicenter, controlled trial, subjects with active UC will be
randomized to 1 of 3 groups, each with a different treatment target.
Group 1 will be treated to a target of corticosteroid-free symptomatic remission
Group 2 will be treated to a target of corticosteroid-free endoscopic +
symptomatic remission
Group 3 will be treated to a target of corticosteroid-free histological +
endoscopic + symptomatic remission.
Randomization will be stratified by the following factors: current
corticosteroid use (yes; no), current immunosuppressive use (yes; no), and
tumor necrosis factor (TNF) antagonist use (current; past; never).
Subjects will be followed up every 16 weeks of treatment to determine whether
their assigned remission target has been achieved.
At Week 16, Week 32, and Week 48, there will be an assessment of symptoms,
endoscopic disease, histological disease,
corticosteroid use and collection of urine, stool, mucosa, and blood samples
for biomarkers and drug concentrations.
Treatment Algorithm
Treatment algorithms will feature the use of vedolizumab. A key premise is that
vedolizumab has a favorable safety profile and can be safely and effectively
used to treat subjects who are in symptomatic remission but who have not
attained endoscopic or histopathologic remission.
Investigators will be trained on the algorithms and the 3 target groups. Study
subjects will be blinded to target group assignment, whereas investigators will
be unblinded. Investigators and site personnel must not share subject target
group assignments or influence subject-reported symptom scores. Endoscopic and
histopathologic assessments will be completed by central readers who are
blinded to target group assignment. All endoscopy and histopathology images
will be provided to an unblinded offsite assessor, along with details of
corticosteroid use and visit; these will be used to inform the site
investigator regarding the need to escalate the algorithm. For the treat to
symptom group, decisions will be based upon the subject*s self-reported
symptoms of bleeding, as well as corticosteroid use.
If the subject has reached their remission target corticosteroid-free, no
further treatment escalation will be required. If the remission target is
reached but the subject is taking corticosteroids, the subject must taper
steroids and continue therapy (if Week 16). If the remission target is not
achieved, the subject will escalate therapy (if Week 32). If the remission
target has not been reached, treatment will be escalated as per the algorithm
and another assessment will take place 16 weeks later. There will be 3
opportunities, approximately 16 weeks apart, to escalate treatment according to
the study algorithms. Once the remission target has been reached
(corticosteroid-free) for a subject at a scheduled visit, he/she will continue
therapy for the remainder of the follow-up visits. After Week 48, if the
subject has not reached their remission target, subsequent therapies will be
prescribed according to investigator judgement. Otherwise, subjects are
expected to continue the same therapy from the time of achieving corticosteroid
free remission target.

Group 1 will be treated to a target of corticosteroid-free symptomatic remission
Group 2 will be treated to a target of corticosteroid-free endoscopic +
symptomatic remission
Group 3 will be treated to a target of corticosteroid-free histological +
endoscopic + symptomatic remission.

Participation in a trial involves some risk.
During the trial, depending on what (if any) UC treatments de patient is
currently receiving and on how he responds to treatment he might receive
vedolizumab. During the trial de patient should not take any other medications
without talking to the investigator or trial staff. This includes over the
counter medications, herbal preparations (tablets, capsules, etc.,) or
vitamins. As of 19 May 2019 approximately 6376 subjects have received at least
1 dose of vedolizumab in clinical trials and approximately 2553 subjects have
received 12 months of vedolizumab. In IV studies to date, vedolizumab has been
well tolerated. No side effects have been seen in more than 20% of subjects who
received at least 1 dose of vedolizumab.
Even if previous studies have shown that vedolizumab was normally well
tolerated, patients might still experience the following side
effects:
Very Common (10-20% of patients)
• worsening of ulcerative colitis in patients with UC • common cold • headache
• joint pains Common (2-9% of patients)
• nausea • fever • stomach pain • upper respiratory tract infection • tiredness
• vomiting • low levels of red blood cells (anemia)
• cough • back pain • bronchitis • flu • urinary tract infection • dizziness •
diarrhea • sinus infection • flu-like illness
• rash • sore throat • itching • swollen ankles • pains in arms or legs •
stomach flu
• an infected cavity filled with pus near the anus or rectum (anal abscess)
• small tunnel which connects an infected gland inside the anus to an opening
on the skin around the anus (anal fistula)
Since many of these symptoms are commonly reported in patients with UC, it is
unclear which may be related to vedolizumab, which may be related to the
underlying illness, and which may have occurred by chance.
In addition to the risks listed above, vedolizumab and study procedures may
have unknown risks. There is always the possibility that a patient will have a
side effect that is currently unknown or not expected. It is important that
patients report any and all symptoms/health problems to the study doctor/staff,
whether or not they think these problems are related to the study drug.
Patients will be monitored for side effects and the study doctor may decide
that the patient should be withdrawn from the study for their safety. If any
new information becomes available during the course of the study that may
affect the patients willingness to participate, they will be informed.

As with any drug, allergic reactions may occur. If patients have a very bad
allergic reaction, they could die. Some things that happen during an allergic
reaction are:
• a rash (reddening or blistering of the skin)• difficulty breathing• wheezing
when you breathe• sudden drop in blood pressure
• swelling around the mouth, throat, or eyes • fast pulse • sweating

The patient should notify the study doctor/staff immediately if they have these
or any other side effects during the study. The study doctor and team will be
prepared to treat the patient if he has an allergic reaction.
There is possibility of a greater chance of getting an infection, difficulty
fighting off an infection, or reactivation of an old infection. Serious
infections have occurred. The patient will be monitored for infections and
treated as needed. The patient should notify their study doctor if they
currently have, or have recently had, any infections or symptoms of an
infection.
There is a possibility that treatment with vedolizumab could cause reactivation
of an old infection such as tuberculosis (TB). Patients will be tested to see
if they have ever been exposed to TB.
Patients with inflammatory bowel disease have an increased risk for colon
cancer, and some of the drugs that are currently being used for treating UC can
increase the risk of certain cancers.
Less than 1 % of patients who received vedolizumab as part of the UC studies
were diagnosed with cancer, including colon cancer. It is also not known
whether the events of cancer happened by chance or whether vedolizumab was a
contributing factor. Progressive Multifocal Leukoencephalopathy (PML) is a
serious and sometimes fatal brain infection. There is currently not enough
information to know if vedolizumab will increase the risk of PML and a risk of
PML cannot be ruled out. PML is caused by a virus called JCV (John Cunningham
virus) that can infect the brain. Many people carry the virus but do not get
sick from PML. When PML does occur, it is usually in people who have a weakened
immune system and a decreased ability to fight off infection. PML usually
causes death or severe disability. There is no proven treatment, prevention or
cure for PML. During this study the patient will be monitored to see if they
have any symptoms of PML. The patient will be instructed about the symptoms of
PML. If they have any one of these symptoms, they must report them to the study
doctor immediately. The study doctor will be prepared to test the patient and
send him to a specialist for further tests if needed.
Deaths have occurred in patients participating in vedolizumab clinical trials.
The details of these cases were reviewed by an Independent Safety Monitoring
Board that oversaw the safety of these patient studies. No changes in
monitoring of the trials were recommended by the Board.
The possible risks or discomforts of the examinations during the trial:
Below is described the study tests/procedures and their possible risks and/or
discomforts: The patient is asked to ask the doctor if there is something they
do not understand.
Blood samples: Pain. bruising and/or bleeding where the needle enters your
vein. Some people feel light-headed or faint. Rarely blood taking can lead to
swelling and/or infection of the vein.

Flexible Sigmoidoscopy: Cramping, pain, abdominal bloating (common).Peritonitis
Onflammation of the lining of the abdominal cavity) (rare).
Perforation (a hole) of the intestinal wall (rare). Surgery may be needed if a
perforation occurs (rare).
Intestinal biopsy: Persistent bleeding after biopsy or polyp removal (if taken)
can occur. Biopsy results can identify a cancer of the intestine (bowel) you
did not know about.

Stool sample: No discomfort/risk expected. Some may find stool collection
unpleasant.
Video capture sigmoidoscopy: No discomfort/risk is expected from the video
capture. Video images are identified by study identification number. There is
the chance that the video images may accidentally identify you however that is
not planned or expected.

Risks associated with infusion site reactions OV administration):
An infusion site reaction is a localized reaction that may occur along the vein
or surrounding area where the medication is injected. Symptoms associated with
an infusion site reaction may include redness, tenderness, warmth, itching, or
discomfort. An additional risk could occur as a result of the medication
leaking out from the blood vessel where it was infused which would cause pain,
blistering, and severe skin damage. The patient need to tell the study
doctor/staff right away if he experiences any problems at the infusion site.

Risks associated with injection site reactions (Subcutaneous administration):
An injection site reaction is a localized reaction that may occur at the site
where the medication is injected. Symptoms associated with an injection site
reaction may include redness, tenderness, warmth, itching, discomfort,
bleeding, or a nodule or hardening of the skin in the area surrounding where
the medication was administered or severe skin or tissue damage. The patient
needs to tell the study doctor/staff rig