To evaluate the long-term safety and efficacy of RPC1063 for the treatment of all patients with moderate to severe UCTo evaluate the long-term efficacy of RPC1063 for the treatment of adult patients with moderate to severe UC.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy Endpoints:
- Proportion of patients in clinical remission
- Proportion of patients with a clinical response
- Proportion of patients with endoscopic improvement
- Proportion of patients with mucosal healing
- Proportion of patients with corticosteroid-free remission
- Change from Baseline in complete Mayo score, Partial Mayo score, and 9-point
Mayo score
- Proportion of patients with histologic remission
- Proportion of patients with clinical response, clinical remission, or
endoscopic improvement in patients who had previously received anti-TNF therapy
Safety Endpoints:
- The incidence, severity, and relationship of treatment-emergent adverse
events (TEAEs), serious AEs (SAEs), TEAEs leading to discontinuation of
investigational drug, AEs of special interest (AESIs), and TEAEs of special
interest will be summarized.
- Exploratory safety endpoints include changes from baseline for clinical
laboratory measures, vital signs, ECGs, and pulmonary function tests.
Other Exploratory Endpoints:
- Absolute lymphocyte count (ALC) derived from hematology laboratory results
- Blood biomarkers (cytokines, chemokines, other markers of inflammation)
- Stool biomarkers (eg FCP)
- Mucosal tissue blood biomarkers (eg, lymphocyte subsets)
- Exploratory measurements of immune response (e.g. SARS-CoV-2 serology), from
blood samples (processed for serum only) collected after the amendment, every
48 weeks thereafter and end of treatment, and
the potential association between these measurements and selected endpoints
related to safety, efficacy, and/or biomarkers.
Secondary outcome
As this is an open-label extension trial for patients who previously
participated in a trial of RPC1063 for UC, there is no statistical basis for
the sample size. All endpoints are therefore described under primary endpoints.
Background summary
RPC1063 is a small molecule compound that potently activates the sphingosine-1-
phosphate 1 receptor (S1P1R) and the S1P 5 receptor (S1P5R) receptor, although
it is more selective towards S1P1R over S1P5R. In vitro, RPC1063 has little
activity on the other sphingosine-1-phosphate (S1P) receptors, showing greater
than 20,000-fold selectivity over S1P 2R, 3R, or 4R. The RPC1063 metabolites,
RP101075 and RP101442, show a similar potency and selectivity profile to
RPC1063. RPC1063 and metabolites were also shown to be selective for binding to
the S1P1R and S1P5R relative to a G protein-coupled receptors enriched panel of
55 non-target receptors in vitro.
RPC1063 has been studied in two Phase 1 studies completed (RPCS-001 and
RPC01-102) in healthy volunteers, the latter was a thorough QT study that
showed RPC1063 at therapeutic (1 mg) and supratherapeutic (2 mg) doses did not
prolong the QTc interval. A Phase 2/3 randomized, double-blind, controlled
trial (RPC01-201, RADIANCE) in patients with relapsing multiple sclerosis (RMS)
is ongoing, with positive efficacy and safety results reported from the
24-week, Phase 2 portion of the trial in June 2014. The Phase 3 portion of the
trial is still enrolling and expected to complete in 2017. The induction phase
of a Phase 2 trial in adult patients with moderate to severe UC (RPC01-202) was
completed in October 2014. At the conclusion of the induction phase, the
proportion of patients achieving clinical response and clinical remission with
RPC1063 1 mg was greater than placebo and the difference was both clinically
meaningful and statistically significant. In addition, all secondary endpoints
at the conclusion of the induction phase, including clinical response, change
in the Mayo score, and mucosal improvement on endoscopy, were also positive and
statistically significant for the RPC1063 1 mg dose. The maintenance phase of
this trial is expected to be completed in 2015.
Study objective
To evaluate the long-term safety and efficacy of RPC1063 for the treatment of
all patients with moderate to severe UC
To evaluate the long-term efficacy of RPC1063 for the treatment of adult
patients with moderate to severe UC.
Study design
This is an open-label, multicenter, maintenance trial to evaluate the long term
safety and efficacy of RPC1063 in patients with moderately to severely active
ulcerative colitis (UC). Patients who have previously participated in a trial
of RPC1063 for UC will be eligible for entry in this trial if they meet the
eligibility criterion for participation as outlined in the prior trial.
Intervention
Patients will receive treatment until the patient completes 5 years (Week 238)
and the Safety Follow-up Visit, unless the Sponsor discontinues the development
program. Patients who are not in clinical response or remission at trial entry
should be discontinued from investigational medication if they do not show
clinical improvement by Week 10.
Study burden and risks
During the study subjects will have to come to the hospital for the following
visits: a baseline visit (day 1), treatment visits (weeks 5, 10, 16, 22, 34 and
46) followed by additional treatment visits (every 24 weeks), an end of
trial/early termination visit and a safety follow-up visit. Procedures that
will be performed during these visits include: blood draw (all visits),
physical exam (all visits), ECG (3x), pulmonary function test (4x + every other
visit during the additional treatment visits), optical coherence tomography
(3x), and endoscopy with colonic biopsy (3x + every 4th visit during the
additional treatment visits). Subjects will need to come to the first visit in
a fasted state. A urine pregnancy test will be performed at each visit for all
female subjects. Subjects will furthermore be asked to complete a daily
electronic diary. During the study and until at least 30 days after their final
dose of study drug, subjects will have to use effective contraception. The
study will last until March 2023, or until the Sponsor discontinues the
development program.
The most common side effects of the study drug in patients with UC and MS are
elevations in liver enzymes or abnormal liver function tests; pain in the back,
arms, legs, joints or headache; swelling of the legs or hands; low blood
pressure; infections to the urinary tract or respiratory tract; retinal
disorder; worsening of ulcerative colitis; rash; fever; and anemia. As RPC1063
works in a similar way to the approved drug fingolimod, the risks associated
with fingolimod may additionally be potential risks for subjects receiving the
study drug. As for all new drugs, there may also be side effects and
discomforts that are not yet known.
It is expected that patients will benefit from the treatment. Positive Phase 2
results on remission rates during the Induction Period of protocol RPC01-202
suggest that RPC1063 potentially is a clinically meaningful addition to the
treatment of moderate to severe UC.
Route de Perreux 1 ---
Boudry 2017
CH
Route de Perreux 1 ---
Boudry 2017
CH
Listed location countries
Age
Inclusion criteria
1. Previously participated in a trial of RPC1063 (eg, RPC01-3101 or completed
at least 1 year of the open-label period for RPC01-202) and meet the criteria
for participation in the open label extension as outlined in the prior trial.
2. Female patients of childbearing potential (FCBP)*:
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
-complete sexual abstinence
For the purposes of this study, a female patient is considered to be of
childbearing potential if she has reached menarche, and 1) has not undergone a
hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy
(the surgical removal of both ovaries) or 2) has not been postmenopausal for at
least 24 consecutive months (that is, has had menses at any time during the
preceding 24 consecutive months)
**Contraception Education: Counselling about pregnancy precautions and the
potential risks of fetal exposure must be conducted for FCBP.
The Investigator will educate all FCBP about the different options of
contraceptive methods or abstinence, as appropriate, at the Screening and
Baseline Visits. The patient will be re-educated every time her contraceptive
measures/methods or ability to become pregnant
changes. The female patient's chosen form of contraception must be effective by
the time the female patient is randomized into the study (for example, hormonal
contraception should be initiated at least 28 days before baseline).
Periodic abstinence (calendar, symptothermal, post-ovulation methods),
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea
method are not acceptable methods of contraception.
3. Must provide written informed consent/assent and have the ability to be
compliant with the schedule of protocol assessments, which must be obtained
prior to any trial-related procedures.
Exclusion criteria
Exclusions Related to Medications:, 1. Have received any of the following
therapies since the first dose of investigational drug in the prior RPC1063
trial:, • Treatment with a biologic agent
• Treatment with an investigational agent other than RPC1063
• Treatment with D-penicillamine, leflunomide, thalidomide, natalizumab or
fingolimod, etrasimod, or tofacitinib
• Treatment with lymphocyte-depleting therapies (e.g., Campath, anti-CD4,
cladribine, rituximab, ocrelizumab, cyclophosphamide, alemtuzumab, daclizumab)
• Treatment with a live vaccine or live attenuated vaccine within 4 weeks
prior to Visit 1 of this trial., 2. Are currently receiving or require
initiation of any of the following therapies:, • Treatment with corticosteroids
at a dose that exceeds the prednisone equivalent of 40 mg
• Treatment with immunosuppressive agents immunosupressive agents (e.g.,
azathioprine, 6-MP, or methotrexate)
• Chronic non-steroidal anti-inflammatory drug (NSAID) use (Note: occasional
use of NSAIDs and acetaminophen [eg, headache, arthritis, myalgias, or
menstrual cramps] and aspirin up to 325 mg/day is permitted)
• Treatment with Class Ia or Class III anti-arrhythmic drugs or treatment with
two or more agents in combination known to prolong PR interval
3. Are receiving treatment with any of the following drugs or interventions
within the corresponding timeframe:
At Day 1
- CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) or indcers (eg, rifampicin)
Two weeks prior to Day 1
- Monamine oxidase inhibitors (eg, selegiline, phenelzine)
4. Are receiving treatment with breast cancer resistance protein (BCRP)
inhibitors (eg, cyclosporine, eltrombopag), Exclusions Related to General
Health:, 5. Pregnancy, lactation, or a positive serum beta human chorionic
gonadotropin (hCG)
6. Clinically relevant hepatic, neurological, pulmonary, ophthalmological,
endocrine, psychiatric or other major systemic disease making implementation of
the protocol or interpretation of the trial difficult or that would put the
patient at risk by participating in the trial or that would have required a
patient to discontinue treatment in previous RPC1063 trial
7. Clinically relevant cardiovascular conditions, including history or presence
of recent myocardial infarction, unstable angina, stroke, transient ischemic
attack, decompensated heart failure requiring hospitalization, Class III/IV
heart failure, sick sinus syndrome, or severe untreated sleep apnea, Exclusions
Related to Laboratory Results:, 8. Liver function impairment or persisting
elevations of aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) > 5 times the upper limit of normal (ULN), or direct bilirubin > 3 times
the ULN
9. FEV1 or FVC <50% of predicted values
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 | EUCTR2015-001600-64-NL |
| ClinicalTrials.gov | NCT02531126 |
| CCMO | NL54683.029.15 |