The primary objectives of this study are:1. To evaluate the safety and tolerability of PTG-1002. To evaluate the efficacy of PTG-100 in the induction treatment of subjects with moderate to severe active UC compared to placebo.The secondary…
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Source
Brief title
Condition
- Gastrointestinal ulceration and perforation
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the:
1. Proportion of subjects receiving PTG-100 with clinical remission at Week 12
compared with placebo
Clinical remission is defined as follows, using the Mayo subscores of stool
frequency, rectal bleeding, and endoscopy:
• Stool frequency subscore of 0 or 1 with a pre-specified change of 1 or more
from baseline
• Rectal bleeding subscore of 0
• Endoscopy subscore of 0 or 1 (modified so that a score of 1 does not include
friability)
The primary safety endpoint is:
1. Proportion of subjects with at least 1 AE comparing individual PTG-100
dosing groups with placebo
Secondary outcome
The secondary efficacy endpoints (all based on comparison of individual PTG-100
dose levels to placebo) are:
1. Proportion of subjects with endoscopic response at Week 12 (Day 84) (defined
as an endoscopic subscore of 0 or 1)
2. Proportion of subjects with clinical response at Week 12 (Day 84) (defined
as at least 1 point and 30% reduction from baseline in rectal bleeding and
stool frequency subscores)
3. Mean change in endoscopy subscore from baseline to Week 12
4. Mean change in rectal bleeding and stool frequency subscores from baseline
to Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112)
5. Proportion of subjects with endoscopic remission at Week 12 (Day 84)
(defined as an endoscopic subscore of 0)
6. Mean change in complete Mayo Score (including all 4 subscores) from baseline
to Week 12 (Day 84)
7. Mean change in partial Mayo Score (excluding endoscopy subscore) from
baseline to Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and
112)
8. Mean change in faecal calprotectin levels from baseline to Weeks 6 (Day 42),
12 (Day 84), and 16 (Day 112)
9. Mean change in IBDQ score from baseline to Week 12 (Day 84)
10. Proportion of subjects developing ADA by Weeks 12 (Day 84) and 16 (Day 112)
The exploratory efficacy endpoints (all based on comparison of individual
PTG-100 dose levels to placebo) are:
1. Mean change in histological score from baseline to Week 12 (Day 84)
2. Effects of ADA on PK, safety, and efficacy in subjects with positive ADA
The secondary safety endpoints (all based on comparison of individual PTG-100
dose levels to placebo) are:
1. Frequency and type of AEs (affecting >= 5% of subjects)
2. Proportion of subjects with at least 1 serious AE (SAE)
3. Number and type of SAEs
4. Frequency of AEs of special interest including serious or opportunistic
infection (viral, bacterial, fungal including systemic/gut localization),
allergic/drug reactions, immune system disorders, and suspected PML.
5. Clinically significant changes in safety labs, ECGs, or physical examination
findings (including vital signs)
Background summary
Protagonist Therapeutics, Inc. is developing PTG-100 as a potential oral
therapy for patients with moderate to severe active ulcerative colitis (UC).
PTG-100, a peptide dimer comprised of natural and unnatural amino acids and a
homologated amide bond, is an orally-stable peptide that binds specifically to
α4β7 integrin on leukocytes.
PTG-100 is designed to be stable against various forms of gastrointestinal (GI)
degradation and to target α4β7 integrin within the GI tissue compartment.
Animal pharmacokinetic (PK) studies have shown these peptides are orally stable
because they can be detected as full-length intact peptides in gut tissues and
faeces after oral dosing. The PK studies have also shown the oral peptides have
high exposure in the colon, small intestine, and to a lesser extent in the
mesenteric lymph nodes with less than 0.5% systemic bioavailability; therefore,
its presence is largely restricted to the GI tract.
PTG-100 binds specifically to α4β7 integrin on leukocytes, the same target as
the approved antibody therapeutic vedolizumab (Entyvio®). PTG-100 is a potent
and selective inhibitor of α4β7 integrin with binding selectivity identical to
the antibody product vedolizumab. PTG-100 does not bind to α4β1 integrin. The
α4β7 integrin, which is primarily involved in the recruitment of leukocytes to
the GI tract, is present on the cell surface of a small population of
circulating T- and B-lymphocytes. The major ligand for α4β7, mucosal addressin
cell adhesion molecule 1 (MAdCAM-1), is selectively expressed on the
endothelium of the intestinal vasculature and is present in increased
concentrations in inflamed tissue. Through blockade of leukocyte trafficking in
the gut, PTG-100 may inhibit inflammation in the GI tract, potentially reducing
the signs and symptoms of active UC.
Vedolizumab (Entyvio®), an intravenously administered monoclonal antibody that
similarly targets α4β7 integrin, has been approved for the treatment of adult
patients with moderate to severe active UC who have had an inadequate response
with, lost response to, or were intolerant to a tumour necrosis factor-alpha
(TNF-α) blocker or immunomodulator; or had an inadequate response with, were
intolerant to, or demonstrated dependence on corticosteroids.1 Vedolizumab has
also been approved for treatment of patients with Crohn*s disease (CD).2
Therefore, it is considered that blockade of this interaction is a safe and
effective therapy for inflammatory bowel disease.
Ulcerative colitis is a chronic inflammatory bowel disease characterised by
bloody diarrhoea, abdominal cramps, and fatigue.3 Current medical therapy has
important limitations. Aminosalicylates are only modestly effective;
glucocorticoids can cause unacceptable adverse events (AEs) and do not provide
a benefit as maintenance therapy.4 6 Tumour necrosis factor-alpha antagonist
antibody drugs, although efficacious, may predispose patients to serious
infection, a risk of malignancy, and development of anti-drug antibodies
(ADA).7-9 Vedolizumab (Entyvio®) is administered as an intravenous (IV)
infusion with potential for systemic infection and risk of
immunogenicity.1,2,10 Therefore, new treatment strategies are needed for
patients with UC.
Due to the inconvenience of injectable therapies, associated safety risks of
systemic treatment, and risk of development of ADA, PTG-100, an orally-stable,
GI-restricted peptide therapeutic candidate that targets α4β7, may provide a
significant benefit to patients with moderate to severe UC.
Both in vitro and in vivo pharmacology studies have been conducted to assess
the activity, mechanism of action, and toxicity of PTG-100. PTG-100 is a potent
and selective inhibitor of α4β7 with binding properties highly similar to the
antibody product vedolizumab. Similar to vedolizumab, PTG-100 does not bind
α4β1 integrin. A dextran sulphate sodium-induced colitis mouse model
demonstrated that PTG-100 administration induced a dose-dependent reduction in
α4β7+ memory T cell homing to inflamed gut tissue and a significant improvement
in mucosal damage as assessed by blinded endoscopy. Pharmacokinetic studies
show that drug levels are much higher in GI tissues compared to blood, which
suggests that drug exposure in the GI tissues is the principal driver for the
in vivo pharmacology. Fluorescence-activated cell sorter (FACS) analysis of
whole blood from healthy cynomolgus monkeys demonstrated that a peripheral
blood receptor occupancy (RO) of less than 50% is correlated with in vivo
efficacy in the mouse studies. Levels of circulating α4β7+ memory T cells were
increased when normalised to total CD4 cells following PTG-100 dosing,
confirming that blocking homing of α4β7+ memory T cells redistributes these
cells to the blood.
In 42- and 90-day (Good Laboratory Practice [GLP]) toxicology studies, no
adverse toxicological findings were observed at once daily (QD) doses up to 90
mg/kg/day and 75 mg/kg/day in rats and monkeys, respectively. The no observed
effect level (NOEL) in rats was 90 mg/kg/day, the highest level evaluated. In
the monkey study, the no observed adverse effect level (NOAEL) was considered
to be 75 mg/kg/day, the highest dose tested. Also, histology from the 90-day
toxicology studies demonstrated no adverse testicular findings.
Reproductive and developmental toxicity studies of limited scope (6 dams/group)
in rats and rabbits have been completed. There were no maternal or
developmental effects noted in either study. The maternal and developmental
NOEL for PTG-100 was 90 mg/kg/day in pregnant rats and 75 mg/kg/day in pregnant
rabbits, the highest dose levels tested in these studies. Definitive
reproductive and developmental toxicity studies to evaluate embryo-foetal
development will be completed prior to the Phase 3 clinical program.
PTG-100 did not inhibit the human Ether-à-go-go Related Gene potassium channel
current. No effects of PTG-100 were observed on the cardiovascular or
respiratory systems in conscious monkeys, or in central nervous system
functional assessment (Irwin) or GI motility studies in rats. In vitro GLP
genotoxicity tests were negative, indicating a low genotoxic potential.
Protagonist has completed a Phase 1 randomised, double-blind,
placebo-controlled, 3-part study (Study PTG-100-01) of PTG-100 in 78 normal
healthy male volunteers in Australia. Sixty-four of the 78 subjects were
treated with PTG-100. Parts 1 and 2 evaluated single and multiple ascending
doses of PTG-100, respectively, up to a maximum daily dose of 1000 mg using a
liquid phosphate buffer (PB) formulation of PTG-100. Doses up to 1000 mg/day
were tested as a single dose and as QD dosing for 14 days. Part 3 was a single
dose cross-over study of PTG-100 capsule formulation compared to solution-based
PB formulation. These data informed the selection of doses in Phase 2 (Section
2.2).
In this Phase 1 study, PTG-100 was well tolerated; there were no serious AEs
(SAEs) or dose-limiting toxicities observed. All AEs were mild to moderate in
severity. No dose-dependent increase in AEs was noted. There were no clinically
significant abnormalities or trends in clinical labs, electrocardiograms
(ECGs), or vital signs. The maximum dose tested for both single and multiple
dosing was 1000 mg; no dose-limiting toxicities were observed at this or any
doses.
Consistent with the preclinical data in mice, rats, and cynomolgus monkeys, in
Study PTG-100-01, the plasma exposure to PTG-100 was extremely low (< 1%) as
determined by the area under the concentration-time curve (AUC) and maximum
observed concentration (Cmax), thus reflecting the GI-restricted nature of the
drug. In a small cohort of subjects administered a single dose of PTG-100 (300
mg), the systemic exposure (as measured by Cmax and AUC from time 0 to the time
of the last sample collection [AUC0 t]) of PTG-100 when given to participants
after a high-fat meal was approximately 30% of that for PTG-100 administered
under fasted conditions. All subjects in the multiple ascending dose (MAD)
cohorts in the trial were fed a standard diet. There was minimal drug
accumulation at Day 14 in the MAD cohorts, related to the relatively short
half-life in the blood.
Dose-dependent increases in blood RO and reduction in receptor expression (RE;
eg, receptor down-regulation), as reflecting target engagement in the GI tissue
compartment, were observed, thus supporting evidence of sustained target
engagement and pharmacologic activity of PTG-100 in healthy volunteers
comparable to the data in mouse and cynomolgus monkey studies. Saturating
levels of receptor down-regulation were observed at the 300-mg dose level
following multiple dose exposure. Blood RO and RE levels in the healthy
volunteers (at the 300-mg dose level) exceeded threshold levels in the healthy
mice at comparable dose levels (based on allometric scaling; eg, approximately
50 mg/kg/day); this dose threshold also correlated with inhibition of
lymphocyte trafficking and improvements in disease activity in the colitis
mouse studies. Therefore, the data suggest a potentially efficacious dose of
300 mg in patients with UC.
To support the use of the capsule formulation in Study PTG-100-02, in vivo PK
bridging studies in cynomolgus monkey and normal healthy volunteers have
demonstrated that the relative bioavailability of the capsule formulation
compared to the liquid PB formulation (used in the GLP toxicology studies and
Phase 1 single ascending dose and MAD cohorts) was approximately 60% based on
AUC0-t and AUC from time 0 to infinity. Despite the lower plasma exposure of
the capsule formulation compared to the liquid formulation, the pharmacodynamic
(PD) effects (eg, blood RO and RE) were highly similar between the capsule and
liquid formulations. These data support the use of the capsule formulation in
the Phase 2b clinical trial at doses established by single and multiple dose
cohorts using the liquid PB formulation.
Further information about the preclinical and Phase 1 studies are provided in
the Investigator*s Brochure (IB).
Study objective
The primary objectives of this study are:
1. To evaluate the safety and tolerability of PTG-100
2. To evaluate the efficacy of PTG-100 in the induction treatment of subjects
with moderate to severe active UC compared to placebo.
The secondary objectives are:
1. To evaluate the dose-response relationship and select PTG-100 induction
regimens for continued development
2. To evaluate the pharmacokinetics (PK) of PTG-100 in subjects with active UC
3. To evaluate the pharmacodynamic (PD) effects of PTG-100 including the
assessment of receptor occupancy (RO) and α4β7 receptor expression (RE) in
peripheral blood lymphocytes
4. To evaluate changes in faecal calprotectin levels for subjects receiving
PTG-100 compared to placebo
5. To evaluate the incidence of positive anti-drug antibodies (ADAs) in
subjects receiving PTG-100.
The exploratory objectives are:
1. To evaluate the ability of subjects receiving PTG-100 to achieve
histological improvement in colonic tissue biopsies compared to placebo
2. To characterise immunologic biomarkers in the target population and to
evaluate changes in immunological/PD biomarkers in subjects receiving PTG-100
compared to placebo.
Study design
This will be a randomised, double-blind, placebo-controlled, multi-centre,
parallel adaptive 2-stage design study.
Subjects will be screened for eligibility within 42 days of dosing. Eligible
subjects will return for sigmoidoscopy/ biopsy and baseline Mayo Score within
14 days of randomisation (with all attempts made for this visit to occur as
close to randomisation as possible)however, subjects may have a combined
Screening visit that includes endoscopy. Randomisation must occur within 7 days
of dosing. On Day 0, assessments including physical examination, safety labs,
electrocardiogram (ECG), progressive multifocal encephalopathy (PML)
assessment, PK, PD, ADA, faecal calprotectin, and Inflammatory Bowel Disease
Questionnaire (IBDQ) will be performed predose followed by dosing and physical
examination, adverse event (AE) assessment, and blood sampling for PK and PD
analysis.
Treatment duration will be 12 weeks in order to optimise duration of induction
dosing for continued development. There will be a total of 9 visits to the
clinical site, including: 2 Screening visits (one for general
inclusion/exclusion criteria assessment and a second including recording
baseline Mayo scoring and sigmoidoscopy/ biopsy, with the latter occurring
within 14 days of randomisation;Day 42 to Day -7; however, subjects may have a
combined Screening visit that includes endoscopy);); dose initiation (Day 0);
and assessment visits on Days 14, 28, 42, 56, and 84. Post-treatment
sigmoidoscopy/biopsy will be performed on Day 84 (Week 12). Day 70 will be a
phone visit in which subjects will be instructed to record the stool frequency
and rectal bleeding data preceding Day 70. A final Follow-up visit will occur
on Day 112 and a phone call for assessing PML signs and symptoms will occur
approximately 6 months after the completion of treatment.(or 6 months after
discontinuation of treatment if the subject terminates early).
Subjects are to be randomised 1:1:1:1 by interactive web/voice response system
(IXRS) in Stage 1. Subjects will be stratified by prior treatment with tumour
necrosis factor-alpha (TNF-α) antagonist use. Subject enrolment will occur in 2
stages relative to an interim analysis (IA), the purpose of which will be to
conduct a futility analysis and to identify which study arms provide optimal
data in order to select one (or 2) PTG-100 dose levels and placebo to continue
enrolling subjects to the most informative and effective dose arms. After the
unblinded IA (Stage 1, see below) by the Adaptive Design Review Committee,
additional subjects will be randomised equally (1:1 or 1:1:1, as appropriate)
to the selected doses of PTG-100 and placebo with stratification maintained
(Stage 2).
The IA will be performed after approximately 60 to 80 subjects have been dosed
and completed 12 weeks of dosing or terminated early(Stage 1). The IA
guidelines for dose selection will be defined in the Data Monitoring Committee
charter and will be made in consideration of safety data and sound clinical
judgment. Subjects will continue to be randomised across the 4 arms during the
IA until dose(s) are selected for Stage 2 of the trial, at which time the
randomisation of remaining subjects to be enrolled will be modified to the
remaining trial arms. Final analyses will combine all observed data from both
stages of the trial.
It should be noted that for subjects in the Netherlands, only subjects who have
had prior exposure to anti-TNF agents will be allowed to enrol in the study.
Intervention
Subjects will receive the following treatments according to a randomisation
schedule generated by IXRS:
• PTG-100 (150 mg) once daily (QD) by oral administration
• PTG-100 (300 mg) QD by oral administration
• PTG-100 (900 mg) QD by oral administration
• Placebo QD by oral administration
Matching PTG-100 (150 mg or 300 mg unit dose) and placebo capsules will be
provided to subjects in prepackaged individual study drug kits, identical in
appearance, according to the randomisation schedule. During the double-blind
treatment period, subjects will take a total of 3 capsules QD, as indicated
below, without regard to meals.
• 150 mg PTG-100: 1 × 150-mg capsule, 2 × placebo capsules
• 300 mg PTG-100: 2 × 150-mg capsules, 1 × placebo capsule
• 900 mg PTG-100: 3 × 300-mg capsules
• Placebo: 3 x placebo capsules
Study burden and risks
PTG-100 has been tested in animals at much higher doses than patient will
receive. No specific side effects were observed in these animals for up to 3
months of treatment.
PTG-100 has previously been tested in a study of normal healthy male
volunteers. A total of 64 participants were given different doses of PTG-100 up
to a maximum dose of 1000 mg for 14 days. The highest dose you would be
assigned to in this study is 900 mg. In the completed study, PTG-100 was
generally well tolerated by the volunteers. The most frequent side-effects of
PTG-100 in this study were:
• headaches
• upper respiratory infections (colds, flu)
• back pain and fatigue (tiredness)
Upper respiratory tract infection and headache events also occurred in some
subjects taking placebo. All of the side effects that were observed resolved
without complications. There were no abnormalities in blood counts, blood
chemistry tests, urine tests or electrocardiograms observed in the participants
in the study.
PTG-100 is similar to an approved treatment for ulcerative colitis called
vedolizumab (marketed as Entyvio®). Both PTG-100 and vedolizumab block the same
*alpha-4*beta-7 integrin target; however, vedolizumab is given through the
vein. Vedolizumab has been generally safe and well-tolerated when tested in
over 3000 patients who participated in carefully monitored studies. The most
common side effects reported with vedolizumab include nasopharyngitis (nasal
congestion, throat irritation), headache, arthralgia (joint aches), nausea,
pyrexia (fever), upper respiratory tract infection (colds), fatigue, cough,
bronchitis (an inflammation of airways in the lungs), influenza (flu), back
pain, rash, pruritus (itchiness), sinusitis (sinus infection), oropharyngeal
(mouth) pain, and pain in arms and legs. Vedolizumab may increase the risk of
serious infection in some patients. Some patients have had increases in liver
function tests while receiving vedolizumab. Vedolizumab must be discontinued in
patients who develop jaundice (yellowing skin) or other evidence of significant
liver injury. Vedolizumab is also associated with the development of anti-drug
antibodies (formation of proteins in the body that may reduce the effectiveness
of vedolizumab). It is not known if the risks of these side effects with
vedolizumab will be similar while receiving PTG-100. Patient will be carefully
monitored for any side effects including infections and liver tests.
Although nothing in pre-clinical (in animals) testing of PTG-100 and the human
experience to date indicates that an allergic reaction is likely, a reaction to
any drug is possible. Some symptoms of allergic reactions are:
• Rash
• Wheezing, or difficulty breathing
• Dizziness or fainting (also a possible outcome of a drop in blood pressure)
• Swelling around the mouth, throat or eyes
• A fast heart rate
• Sweating
Progressive multifocal leukoencephalopathy (PML)
Another drug which blocks a different integrin receptor has been associated
with a rare and often fatal infection of the central nervous system (CNS)
called PML. PML is caused by the John Cunningham (JC) virus and typically only
occurs in patients who are immunocompromised (have severe suppression of the
immune system). Typical signs and symptoms associated with PML may be variable,
may progress over days to weeks, and include increasing weakness on one side of
the body or clumsiness of limbs, changes in vision, and changes in thinking,
memory, and orientation (awareness of surroundings) leading to confusion and
personality changes. The progression of changes in PML usually leads to death
or severe disability over weeks or months.
In clinical trials of vedolizumab, patients were actively monitored for PML
with frequent and regular screenings, and evaluations of any new, unexplained
neurological symptoms, as necessary. While zero cases of PML were identified
among patients with at least 24 months of exposure (and in patients taking
vedolizumab since its approval in 2014), it is not possible to definitely
exclude a risk of PML in patients taking drugs which block the alpha-4 beta-7
integrin. Therefore, patients taking vedolizumab must be carefully monitored
for any new or worsening neurological signs and symptoms.
Cottonwood Drive 521, Suite 100
California Milpitas
US
Cottonwood Drive 521, Suite 100
California Milpitas
US
Listed location countries
Age
Inclusion criteria
The following are the inclusion criteria. Subjects must meet ALL of the following inclusion criteria to be enrolled. Subjects may be screened up to 3 different times separated by at least 14 days.
1. Male and female subjects aged 18 to 80 years, inclusive.
2. Diagnosis of UC for >= 2 months prior to screening, with a history of disease activity extending beyond the rectum; if the UC has been present for > 10 years, a colonoscopy with biopsy must have been performed within 2 years of screening to rule out dysplasia. Subjects with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age > 50 years, or other known risk factor must be up-to-date on colorectal cancer surveillance per local standards and guidelines (may be performed during screening). Subjects with extensive colitis or pancolitis of > 8 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial Screening visit (may be performed during screening).
3. Moderate to severe active UC as defined by complete Mayo Score of 6 to 12, inclusive (range 0 to 12), at baseline (pre-randomisation) with endoscopy score of at least 2 (range 0 to 3), extending 15 cm or more from the anal verge, as determined by blinded central read, within 14 days of randomisation.
4. Demonstrated, over the previous 5-year period, an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents as defined below:
a. Immunomodulators
i. Signs and symptoms of persistently active disease despite a history of at least one >= 8-week regimen of oral azathioprine (>= 1.5 mg/kg) or 6-mercaptopurine (6-MP) (>= 0.75 mg/kg), OR
ii. History of intolerance of at least 1 immunomodulator (including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, lymphopaenia, thiopurine S-methyltransferase genetic mutation, and/or infection)
b. TNF-α antagonists
i. Signs and symptoms of persistently active disease despite a history of at least 1 induction regimen of at least 6 weeks duration, OR
ii. Recurrence of symptoms during maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify), OR
iii. History of intolerance (including, but not limited to, infusion- or injection-related reaction, demyelination, congestive heart failure, and infection)
Note: A maximum of 50% of randomised subjects may have had prior treatment with TNF-α antagonists.For subjects in the Netherlands, only subjects who have had prior exposure to anti-TNF agents will be allowed to enrol in the study (as confirmed by medical record documentation or by self-reporting).
c. Corticosteroids
i. Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone 30 mg daily orally for 2 weeks or intravenous (IV) for 1 week, OR
ii. Two failed attempts to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally on 2 separate occasions, OR
iii. History of intolerance of corticosteroids (including, but not limited to, Cushing*s syndrome, osteopaenia/ osteoporosis, hyperglycaemia, insomnia, and infection).
5. Subject is unlikely to conceive, as indicated by at least one *yes* answer to the following criteria:
a. Subject is a male
b. Subject is a surgically sterilised female (at least 90 days prior to Screening)
c. Subject is a post-menopausal female >= 45 years of age with > 1 year since last menses; if a female subject is < 45 years of age, or cessation of menses is < 1 year and > 6 months, follicle-stimulating hormone must be documented as elevated into the post-menopausal range at Screening
d. Subject is a non-sterilised, premenopausal female with a non-sterile male partner and agrees to abstain from heterosexual activity, use adequate hormonal contraception, OR use double barrier contraception (ie, a combination of male condom with either cervical cap, diaphragm, or sponge with spermicide) as per local regulations and guidelines during the study and for 28 days after the last dose of study drug.
e. If subject is a non-sterilised, premenopausal female with a sterile male partner, the above requirements for contraception do not apply.
6. For women of childbearing potential, a negative serum pregnancy test at Screening and a negative urine pregnancy test within 24 hours prior to the first dose of study medication.
7. Subject is eligible according to tuberculosis screening criteria.
8. Subject understands the study procedures and agrees to participate in the study by giving written informed consent.
Note: Subjects may be permitted to enrol in the study on stable doses of oral 5-aminosalicylic acid (5-ASA) agents, oral corticosteroids, antidiarrhoeals, azathioprine/ 6-MP, or probiotics according to specifications noted in the protocol.
Exclusion criteria
The following are the exclusion criteria; subjects must meet NONE of the following exclusion criteria to be enrolled.
Gastrointestinal exclusion criteria
1. Subject with Crohn*s disease (CD), indeterminate colitis, or presence or history of fistula consistent with CD.
2. History of toxic megacolon, abdominal abscess, symptomatic colonic stricture, or stoma; history of extensive colonic resection, or subtotal or total colectomy; or is at imminent risk of colectomy.
3. History or current evidence of colonic dysplasia or adenomatous colonic polyps. Note: Subjects will not be excluded from the study because of a pathology finding of indefinite dysplasia with reactive atypia. Subjects with resected adenomatous polyps may be enrolled.
Infectious disease exclusion criteria
4. Current bacterial or parasitic pathogenic enteric infection, including Clostridium difficile,(confirmed by toxin result), current infection with hepatitis B or C virus (subjects treated for HCV infection must have evidence of sustained virologic response 12 weeks after the end of treatment [SVR12],, infection requiring hospitalisation or IV antimicrobial therapy, opportunistic infection within 6 months of dosing, any infection requiring antimicrobial therapy within 2 weeks of dosing, history of more than one episode of herpes zoster, history of infection with human immunodeficiency virus, or any episode of disseminated zoster. Note: Subjects with a history of C. difficile infection treated with antibiotics with or without faecal microbial transplant may be rescreened after 2 weeks following completion of treatment.
5. Live virus vaccination within 1 month prior to screening.
General exclusion criteria
6. Subject has a concurrent clinically significant, unstable, or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, haematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the subject by their participation in the study.
Note: Subjects with a history of uncomplicated kidney stones, childhood asthma, or concurrent stable and well-controlled asthma may be enrolled in the study at the discretion of the Investigator.
7. Known primary or secondary immunodeficiency.
8. History of myocardial infarction, unstable angina, transient ischaemic attack, decompensated heart failure requiring hospitalisation, congestive heart failure (New York Heart Association Class 3 or 4), uncontrolled arrhythmias, cardiac revascularisation, stroke, uncontrolled hypertension (systolic blood pressure [BP] > 160 mmHg or diastolic BP > 100 mmHg at Screening), or uncontrolled diabetes (haemoglobin A1c > 9% or > 1 episode of severe hypoglycaemia) within 6 months of screening.
9. Clinically meaningful laboratory abnormalities at Screening including, but not limited to, the ranges below:
a. Absolute neutrophil count < 1000/µL
b. Platelet count < 100,000/µL
c. Haemoglobin < 9 g/dL
d. Creatinine >= 1.5 mg/dL
e. alanine aminotransferase or aspartate aminotransferase >= 2.5 x upper limit of normal (ULN) or bilirubin > 1.5 x ULN
10. Pregnant or lactating females.
11. Any surgical procedure requiring general anaesthesia within 1 month prior to screening, or planned elective surgery during the study.
12. History of malignant neoplasms or carcinoma in situ within 5 years prior to screening. (Subjects who are cancer-free for the previous 5 years may be enrolled. Subjects with adequately treated non-metastatic basal cell skin cancer, squamous cell skin cancer that has not recurred for at least 1 year prior to screening, or history of adequately treated cervical dysplasia/cervical intraepithelial neoplasia or cervical carcinoma in situ that has not recurred at least 3 years prior to screening may be enrolled.)
13. History of any major neurological disorders, as judged by the Investigator, or positive PML subjective symptom checklist.
14. Current or recent history of alcohol dependence or illicit drug use within 1 year prior to screening.
15. Subject is mentally or legally incapacitated at the time of Screening visit or has a history of clinically significant psychiatric disorders that would impact the subject*s ability to participate in the trial according to the Investigator. Note: Subjects who have had situational depression or adjustment disorder or treated depression may be enrolled at the discretion of the Investigator.
16. Unable to attend study visits or comply with procedures.
17. Concurrent participation in any other interventional study.
Medication exclusion criteria
18. Use of topical 5-ASA or corticosteroid enemas/suppositories within 2 weeks of administration of the screening endoscopy.
19. Use of TNF-α antagonists within 60 days prior to screening.
20. Use of ustekinumab within 3 months prior to screening.
21. Use of cyclosporine, thalidomide, tacrolimus, sirolimus, or mycophenolate mofetil within 1 month prior to screening.
22. Have received any investigational or biologic agent within 1 month (or 5 half-lives of the agent, whichever is longer) prior to screening.
23. Prior treatment with vedolizumab or natalizumab.
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 | EUCTR2016-003452-75-NL |
| CCMO | NL59662.018.16 |