The primary objective of the study is to compare the efficacy of RPC1063 vs placebo for induction of clinical remission at Week 8 in patients with moderately to severely active ulcerative colitis (UC)The secondary objectives are to:• Compare the…
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Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the proportion of patients in clinical remission at
Week 8, defined as a Mayo score of <= 2 points and with no individual subscore
of > 1 point.
Secondary outcome
Secondary Efficacy Endpoints:
• Proportion of patients with a clinical response at Week 8, defined as a
reduction from baseline in Mayo score of >= 3 points and >= 30%, and a decrease
from baseline in the rectal bleeding subscore of >= 1 point or an absolute
rectal bleeding subscore of <= 1 point
• Change from baseline in Mayo score at Week 8
• Proportion of patients with mucosal healing at Week 8, defined by an
endoscopy subscore of <= 1 point
• Proportion of patients in clinical remission at Week 32 defined as Mayo score
of <= 2 points with no individual subscore of > 1 point
• Proportion of patients with a clinical response at Week 32, defined as a
reduction from baseline in Mayo score of >= 3 points and >= 30%, and a decrease
from baseline in the rectal bleeding subscore of >= 1 point or an absolute
rectal bleeding subscore of <= 1 point
• Proportion of patients with mucosal healing at Week 32, defined as an
endoscopy subscore of <= 1 point
Exploratory Efficacy Endpoints:
• Proportion of patients with clinical response, remission, or mucosal healing
at Week 8 in the patients who had previously received anti-TNF therapy; who
were refractory to anti-TNF therapy during initial anti-TNF therapy, or who
lost response to anti-TNF therapy and were intolerant of anti-TNF therapy
• Proportion of patients with histologic remission at Week 8 as determined by a
Geboes index score < 2.0
Safety Endpoints:
• The incidence and type of AEs, SAEs, AEs leading to discontinuation of study
treatment, target AEs of special interest, laboratory abnormalities, vital
signs, ECG, and physical exam abnormalities
Pharmacokinetic (PK) and Pharmacodynamic (PD) Endpoints:
• PK assessments will include PK sampling to determine plasma concentration of
RPC1063 and active metabolites at scheduled assessments during the treatment
period.
• Absolute lymphocyte count (ALC) derived from blinded hematology laboratory
results
• Plasma protein biomarkers (cytokines, chemokines, other inflammatory proteins)
• Stool culture for fecal biomarkers - fecal lactoferrin and calprotectin
• Total immunoglobulins (Igs) - IgA, IgG, IgM
Background summary
Ulcerative colitis (UC) is a chronic gastrointestinal inflammatory disorder
which involves the colon. UC is characterized by a life-long chronic course of
remissions and exacerbations. Besides, patients with UC have an increased risk
of carcinoma when compared with the general population. The overall goal of
treatment for patients with active UC is to induce and maintain remission and
to induce and maintain mucosal healing. For patients who do not respond to
standard care treatment with 5-ASA or those with more severe disease,
corticosteroids is generally the first-line treatment for inducing disease
remission. However, treatment with corticosteroids is associated with multiple
adverse effects. Therefore, there is an unmet need for a UC treatment that is
highly effective, well-tolerated, and orally active.
RPC1063 is an orally available, potent, and selective S1P1R agonist that
induces rapid, reversible lymphopenia in rodents, dogs, and nonhuman primates.
A clinical development program for RPC1063 is being pursued in UC. The
objective of the RPC1063 clinical development program in UC is to demonstrate
that RPC1063 administered orally is safe and effective in inducing and
maintaining remission in patients with moderately to severely active UC.
Study objective
The primary objective of the study is to compare the efficacy of RPC1063 vs
placebo for induction of clinical remission at Week 8 in patients with
moderately to severely active ulcerative colitis (UC)
The secondary objectives are to:
• Compare the efficacy of RPC1063 vs placebo at weeks 8 and 32 as measured by
clinical response, clinical remission, and mucosal healing
• Compare the overall safety and tolerability of RPC1063 vs placebo for the
duration of the study
The exploratory objectives are to:
• Examine the efficacy of RPC1063 vs placebo for induction of clinical
response, remission, and mucosal healing in patients who had previously
received anti-TNF therapy.
• Compare the efficacy of RPC1063 vs placebo for induction of histologic
remission at Week 8
• Assess the pharmacokinetics (PK) and pharmacodynamics (PD) of RPC1063 in
patients with UC
Study design
Phase 2, multi-center, randomized, double-blind, placebo-controlled,
parallel-group
Intervention
Induction Period
On Day 1, patients will be randomly assigned 1:1:1 to 1 of 3 treatment regimens
through Week 8:
• 0.5 mg RPC1063 oral capsule daily
• 1.0 mg RPC1063 oral capsule daily
• Matching placebo oral capsule daily
For patients randomized to one of the active treatment groups, there will be a
8-15 day dose titration regimen in the IP consisting of 4-7 days of treatment
with 0.25 mg RPC1063, followed by 3-7 days treatment with 0.5 mg RPC1063,
followed by the assigned treatment level.
Maintenance Period
Patients will continue to receive the same study treatment in the MP as
received during the IP, and individual patient treatment will remain blinded
until all patients have reached Week 32. Patient who complete the MP will be
given the option to participate in the OLP.
Open label treatment Period
All patients in the OLP will receive daily oral study treatment with 1.0 mg
RPC1063. There will be a 8-
15 day dose titration regimen consisting of 4-7 days of treatment with 0.25 mg
RPC1063, followed by 3-7 days treatment with 0.5 mg RPC1063, followed by 1.0 mg
RPC1063. The OLP will continue for up to 6 years or until marketing approval of
RPC1063 for UC in the country of the clinical site (estimated to be in 2019),
or until the Sponsor discontinues the development program.
Study burden and risks
Treatment with RPC1063 may lead to:
- a slowing of heart rate, and/or a blockage of electrical impulses that
normally travel through the heart.
- a decline in lung function tests or respiratory symptoms (trouble breathing,
cough, wheezing).
RPC1063 works in a similar way to the approved drug, fingolimod (GilenyaTM).
Therefore, risks associated with fingolimod could also be seen in patients who
use RPC1063.
- Fingolimod is known to cause increases in liver enzymes in some patients,
requiring them to stop taking the medication.
- Fingolimod has been known to cause a serious condition called macular oedema
(swelling or thickening of the part of your eye responsible for detailed,
central vision), which left untreated, can cause vision loss or blindness.
- Because fingolimod and RPC1063 work by changing your body*s immune system,
RPC1063 could reduce the response to infections and should not be given to
patients with infections or who are at risk for infections.
- Suppression of the immune system (reducing how well it works) may also
increase the risk of skin cancer.
During the Phase 1 study in healthy volunteers, most side effects and
discomforts were considered unrelated to the study drug by the doctor. The
most common events considered probably or possibly related to RPC1063 were
headache (6/68 subjects); sleepiness and nausea (5/68 subjects); dizziness,
nausea and fatigue (3/68 subjects); decreased appetite, decline in lung
function tests (tests that measure how well your lungs work) without symptoms,
and dry mouth (2/68 subjects each). Most side effects (132) were considered
mild in severity, with some (38) considered moderate. None were thought to be
severe.
During the second Phase 1 study, the most common events considered probably or
possibly related to RPC1063 were orthostatic hypotension (drop in blood
pressure on standing, 5/62 subjects), headache (3/62 subjects), and dizziness
(2/62 subjects).
Side effects due the study procedures
Blood sampling
During this study your blood will be taken to perform a variety of tests. The
standard risks of drawing blood include temporary discomfort, bruising,
swelling, in rare circumstances, infection.
Endoscopy
You might experience some discomfort from the Endoscopy examinations, but this
is only during a short time during the examination and it is not harmful.
For a complete overview please refer to the schedule of events in the protocol.
Patients must take one tablet of study medication one time a day. Patients are
asked to complete a diary. There is a patient diary for holter monitoring, a
diary to monitor the Mayo score, a diary for induction/ maintenance phase and a
diary for the open label phase.
Rue du Pre-Jorat 14
Couvet 2108
CH
Rue du Pre-Jorat 14
Couvet 2108
CH
Listed location countries
Age
Inclusion criteria
1. Males or female patients aged 18 to 75 years, inclusive
2. Have had UC diagnosed at least 2 months prior to screening. The diagnosis of
UC must be confirmed by endoscopic and histologic evidence
3. Have active UC confirmed on endoscopy with >= 15 cm involvement
4. Have active UC defined as Mayo score of 6-12 inclusive with endoscopic
subscore of >= 2
5. Have undergone colonoscopy or sigmoidoscopy within the past 2 years for
extent of disease, and if the UC has been present for > 10 years, have had a
colonoscopy with biopsy to rule out dysplasia
6. Female patients of childbearing potential:
Must agree to practice a highly effective method of contraception throughout
the trial until completion of the 90-day safety follow-up visit. Highly
effective methods of contraception are those that alone or in combination
result in a failure rate of a Pearl index of less than 1% per year when used
consistently and correctly. Acceptable methods of birth control in the trial
are the following:
- Combined hormonal (oestrogen and progestogen containing) contraception, which
may be oral, intravaginal, or transdermal
- Progestogen-only hormonal contraception associated with inhibition of
ovulation, which may be oral, injectable, or implantable
- Placement of an intrauterine device (IUD)
- Placement of an intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion
- Vasectomised partner
- Sexual abstinence
- Periodic abstinence (calendar, symptothermal, post-ovulation methods),
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea
method are not acceptable methods of contraception.
7. Must be currently receiving treatment with at least 1 of the following
therapies:
a. Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine,
balsalazide) for at least 6 weeks with the dose stable for at least 3 weeks
prior to screening endoscopy
b. Prednisone (doses <= 30 mg) or equivalent for at least 4 weeks and receiving
a stable dose for at least 2 weeks
8. If oral aminosalicylates or corticosteroids have been recently discontinued,
they must have been stopped for at least 2 weeks prior to the endoscopy used
for baseline Mayo Score
9. All patients aged 45 years or over must have had a colonoscopy to screen for
adenomatous polyps within 5 years of their first dose of investigational drug
or must have had a colonoscopy at screening to assess for polyps. The
adenomatous polyps must be removed prior to their first dose of investigational
drug.
10. Ability to provide written informed consent and to be compliant with the
schedule of protocol assessments
11. patients must have documentation of positive varicella zoster virus (VZV)
IgG antibody status or complete vaccination at least 30 days prior to
randomization.
12. Documentation of no evidence of chronic lung disease or tuberculosis (TB)
on a chest X-ray completed within the 6 months prior to screening. If a chest
x-ray was not done in the 6 months precreding the screening visit, it may be
performed during the screening visit.
Exclusion criteria
1. Have severe extensive colitis evidenced by:
- Physician judgment that patient is likely to require colectomy or ileostomy
within 12 weeks of baseline
- Current evidence of fulminant colitis, toxic megacolon or bowel perforation
- Previous total colectomy
- Have 4 or more of the following:
Temp > 38°C, Heart rate (HR) > 110 (bpm); Focal severe or rebound abdominal
tenderness; Anemia (hemoglobin < 8.5 g/dL); Transverse colon diameter > 5cm on
plain X-ray
2. Diagnosis of Crohn*s disease or indeterminate colitis or the presence or
history of a fistula consistent with Crohn*s disease
3. Have positive stool culture for pathogens (O+P, bacteria) or positive test
for C. difficile at screening. If C. difficile is positive, the patient may be
treated and retested
4. Have had treatment with cyclosporine, tacrolimus, sirolimus, or
mycophenolate mofetil (MMF) within 16 weeks of screening
5. Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin
(hCG) measured during screening
6. Clinically relevant hepatic, neurological, pulmonary, ophthalmological,
endocrine, psychiatric or other major systemic disease making implementation or
interpretation of the study difficult or that would put the patient at risk
7. Clinically relevant cardiovascular conditions, including history or presence
of
i. Recent (within the last 6 months) occurrence of myocardial infarction,
unstable angina, stroke, transient ischemic attack, sick sinus syndrome,
decompensated heart failure requiring hospitalization, , Class III/IV heart
failure or severe untreated sleep apnea
ii. Prolonged a QTcF interval (QTcF > 450 msec males, > 470 msec females), or
at additional risk for QT prolongation (e.g. hypokalemia, hypomagnesemia,
congenital long-QT syndrome)
iii. Patients with other pre-existing stable cardiac conditions who have not
been cleared for the study by an appropriate cardiac evaluation by a
cardiologist.
8. Resting HR less than 55 beats per minute (bpm) when taking vitals as part of
a physical exam at screening.
9. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type
2 with hemoglobin A1c > 7%, or diabetic patients with significant co-morbid
conditions such as retinopathy or nephropathy.
10. History of uveitis
11. Known active bacterial, viral, fungal, mycobacterial infection or other
infection (including TB or atypical mycobacterial disease [excluding fungal
infection of nail beds]) or any major episode of infection that required
hospitalization/treatment with intravenous (IV) antibiotics within 30 days or
oral antibiotics within 14 days prior to screening
12. History or known presence of recurrent or chronic infection (e.g.,
hepatitis A, B, C or E, human immunodeficiency virus, syphilis, TB); recurring
urinary tract infections are allowed
13. History of cancer, including solid tumors and hematological malignancies
(except basal cell and in situ squamous cell carcinomas of the skin that have
been excised and resolved)
14. History of alcohol or drug abuse within 1 year prior to randomization
15. History of or currently active primary or secondary immunodeficiency
16. History of treatment with a biologic agent within 5 half-lives of that
agent prior to randomization
17. History of treatment with an investigational agent within 5 half-lives of
that agent prior to randomization
18. History of treatment with topical rectal steroids within 2 weeks of
screening
19. Receipt of a live vaccine or attenuated live vaccine within 4 weeks prior
to screening
20. Previous treatment with lymphocyte-depleting therapies (e.g., Campath,
anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone,
total body irradiation, bone marrow transplantation, alemtuzumab, daclizumab)
21. Previous treatment with D-penicillamine, leflunomide or thalidomide
22. Previous treatment with natalizumab or fingolimod
23. History of treatment with IVIg, plasmapheresis, within 3 months prior to
randomization
24. Planned concurrent treatment with immunosuppressive agents (e.g.,
azathioprine, 6-MP, or methotrexate) after randomization. Subjects receiving
azathioprine, 6-MP or methotrexate at screening must discontinue treatment with
these agents prior to dosing with investigational drug.
25. Treatment with Class Ia or Class III anti-arrhythmic drugs or treatment
with two or more agents in combination known to prolong PR interval.
26. Treatment with any of the following drugs or interventions within the
corresponding
timeframe:
* At randomization: CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) or
inducers (eg, rifampicin)
* Two weeks prior to randomization: Monoamine oxidase inhibitors (eg,
selegiline, phenelzine)
27. Serum creatinine > 1.4 mg/dL for women or > 1.6 mg/dL for men
28 Liver function impairment or persisting elevations of aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) >2 times the upper
limit of normal (ULN), or direct bilirubin > 1.5 times the ULN
29. Platelet count < 100,000 mircrolitres
30. Hgb <8.5 g/dL
31. Neutrophils <1500 microlitres
(Please refer to the protocol for the remaining criteria)
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 | EUCTR2012-003123-38-NL |
| ClinicalTrials.gov | NCT01647516 |
| CCMO | NL44266.018.13 |