Primary ObjectiveTo evaluate the clinical efficacy of apremilast (30 mg twice daily [BID] and 40 mg BID), compared with placebo, in subjects with active UC.Secondary Objective To evaluate the safety and tolerability of apremilast (30 mg BID and 40…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Details of the statistical analysis are outlined in Section 10 of the Protocol.
Key elements of the analysis are described below.
The ITT population will be the primary population for efficacy analyses. A
supportive analysis using the PP population will also be performed for the
primary efficacy endpoint.
The comparisons for the primary efficacy endpoint will be based on two-sided
statistical tests at a significance level of 0.1. A hierarchical approach will
be used to adjust for multiplicity. For the primary endpoint, the first test in
the hierarchy will be the apremilast 40 mg BID treatment group compared to
placebo, followed by the apremilast 30 mg BID treatment group compared to
placebo. If any of the active treatment groups (apremilast 30 mg or 40 mg BID)
is discontinued prior to the end of the study, the treatment comparison will be
conducted for the retained treatment group vs. placebo based on a two-sided
statistical test at the 0.1 level. Additional endpoints subsequent to the
primary endpoint comparisons may be added to the hierarchy and specified in the
SAP.
Summary of all efficacy endpoints over time will be provided using frequency
and percent for categorical endpoints and descriptive statistics for continuous
endpoints.
The primary efficacy endpoint is clinical remission, as defined as a TMS of * 2
with no individual subscore > 1 at Week 12. The proportion of subjects who
achieve a clinical remission at Week 12 between any apremilast (30 mg BID or 40
mg BID) group and the placebo group will be compared using the
Cochran-Mantel-Haenszel (CMH) test controlling for the randomization
stratification factors specified. Subjects who prematurely discontinue the
study before Week 12 will be considered.
Secondary outcome
The secondary efficacy endpoints defined in Section 3.2.1 will be analyzed
using the CMH test
controlling for the randomization stratification factors as will be done for
the primary efficacy
endpoint.
Background summary
The main objectives of treatment in patients with UC are to induce and maintain
the remission of symptoms and mucosal inflammation in order to improve
patients* quality of life. Treatment of UC currently involves pharmacological
treatment and surgery, which is indicated when pharmacological treatment fails
or when a surgical emergency (eg, perforation of the colon) occurs. Treatment
takes into consideration the level of clinical activity combined with the
extent of disease (proctitis, left-sided disease, extensive disease, or
pancolitis). Pharmacological treatment usually involves aminosalicylates and
glucocorticoids as an initial approach. Various immunosuppressants, as well as
biologic tumor necrosis factor (TNF) blockers, are used in refractory or severe
disease. Although these drugs can provide clinical benefit, they have important
limitations. Aminosalicylates are only modestly effective. Glucocorticoids can
cause unacceptable adverse events (AEs) and do not provide a benefit as
maintenance therapy.
Additionally, immunosuppressant use has been restricted to maintenance therapy
and is also
associated with significant potential toxicities. The TNF blockers, although
efficacious,
predispose patients to serious infections (including opportunistic infections)
and possibly
malignancies. Because apremilast specifically inhibits PDE4,
which increases intracellular cyclic adenosine monophosphate (cAMP) and this
modulates
multiple pro-inflammatory and anti-inflammatory mediators, such as TNF-*,
IL-12, and IL-23, it is believed there may be a role for this drug in the
treatment of UC.
The additional burden caused by comorbidities induced by adverse effects of
some of these drugs indicates that an unmet medical need exists for effective
and well-tolerated orally active agents for inducing and maintaining remission
in patients with active UC.
Study objective
Primary Objective
To evaluate the clinical efficacy of apremilast (30 mg twice daily [BID] and 40
mg BID), compared with placebo, in subjects with active UC.
Secondary Objective To evaluate the safety and tolerability of apremilast (30
mg BID and 40 mg BID), compared with placebo, in subjects with active UC.
Exploratory Objectives
**To evaluate the onset of clinical effect of apremilast (30 mg BID and 40 mg
BID),
compared with placebo, in subjects with active UC
**To evaluate the benefit of apremilast (30 mg BID and 40 mg BID) on
health-related
quality of life (HRQoL) outcome measures, compared with placebo, in subjects
with
active UC
** To evaluate the long-term safety in subjects with active UC, receiving
apremilast (20 mg BID or 40 mg BID)
**To evaluate the durability of response in subjects with active UC, receiving
apremilast (30 mg BID or 40 mg BID) Pharmacokinetic (PK) Objectives,
Pharmacodynamic (PD) Objectives, and Pharmacogenetic (PG) Objective
**To characterize the PK of apremilast (30 mg BID and 40 mg BID) in subjects
with
active UC
**To explore the relationship between apremilast exposure and the efficacy of
apremilast (30 mg BID and 40 mg BID) in subjects with active UC
**To evaluate the change in biomarkers such as high sensitivity C-reactive
protein
(hsCRP) and fecal calprotectin (FCP) in response to apremilast (30 mg BID and 40
mg BID) compared with placebo in subjects with active UC
**To explore the PD effects of apremilast (30 mg BID and 40 mg BID) such as
inflammatory cell infiltration, tissue destruction and gene expression in
colonic
mucosal biopsies from subjects with active UC
**To explore the association of the PD parameters with the efficacy of
apremilast (30
mg BID and 40 mg BID) in subjects with active UC
**To explore the association of PG markers with the efficacy of apremilast (30
mg BID and 40 mg BID) in subjects with active UC
Study design
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled,
parallel-group, study to evaluate the efficacy and safety of 2 doses of
apremilast in subjects with active UC (defined as a total Mayo score [TMS] of *
6 to * 11, with an endoscopic subscore * 2). Approximately 165 subjects (55
subjects per arm) will be randomized in a 1:1:1 ratio to receive oral
apremilast (30 mg BID or 40 mg BID), or identically appearing placebo BID for
up to 20 weeks. Treatment assignment will be stratified via an Interactive
Voice Response System (IVRS)/or an Interactive Web Response System (IWRS) based
on (1) concomitant use of oral aminosalicylates and (2) previous exposure to
immunosuppressants (eg, 6-mercaptopurine [6-MP], azathioprine [AZA], or
methotrexate [MTX]).The number of subjects with previous
exposure to immunosuppressants is targeted to comprise no more than 50% of the
subjects enrolled, and no less than 30%.
The study will consist of 3 phases:
**Screening Phase * up to 4 weeks
**Double-blind Placebo-controlled Phase * Weeks 0 to 12
** Blinded Active-treatment Phase * Weeks 12 to 52
**Extension Phase * Weeks 52 to 104
**Post-treatment Observational Follow-up Phase * Weeks 52 to 56 or weeks 104 to
108, or for subjects who are discontinued early, the 4-week period after the
last dose of investigational product (IP).
Double-blind Placebo-controlled Phase
Eligible subjects will enter the Double-blind, Placebo-controlled Phase at the
Baseline Visit (Week 0/Visit 2). Subjects will be randomly assigned to study
treatment as described above. With the aim to mitigate potential dose-related
side effects associated with apremilast, such as headache and gastrointestinal
(GI) disturbances, apremilast-treated subjects will be dose titrated in
10-mg/day increments over the first 8 days of treatment. All subjects will
receive blister cards of identical appearance to maintain blinding. Subjects
will continue to receive the treatment assigned at baseline for 12 weeks.
Blinded Active-treatment Phase
Following 12 weeks of treatment, subjects will enter the Blinded
Active-treatment Phase. At the Week 12 visit, subjects will be evaluated for
clinical improvement based on the TMS. The endoscopy subscore assessed by the
investigator will be used for the calculation of the Week 12 TMS.
Subjects who achieve at least a 20% decrease from baseline in the TMS at Week
12 will receive
the following IP between the Week 12 Visit and the Week 52 Visit:
* Subjects who were randomized to apremilast (30 mg BID or 40 mg BID) at
baseline will continue to receive the treatment assigned at baseline.
* Subjects who were randomized to placebo at baseline will be re-randomized to
receive apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in
10-mg/day increments
over the first 8 days of treatment (Table 5).
Subjects who do not achieve at least a 20% decrease from baseline in the TMS at
Week 12 will receive the following IP until the Week 52 Visit:
* Subjects who were randomized to apremilast 30 mg BID at baseline will be
re-assigned apremilast 40 mg BID, with no dose titration.
* Subjects who were randomized to apremilast 40 mg BID at baseline will
continue to receive apremilast 40 mg BID.
* Subjects who were randomized to placebo at baseline will be re-randomized to
receive apremilast (30 mg BID or 40 mg BID) and will be dose-titrated in
10-mg/day increments over the first 8 days of treatment (Table 5). In order to
maintain the blind for the treatment assigned at baseline, all subjects will
receive blister cards of identical appearance during the titration period
beginning at Week 12. However, for subjects continuing on the dosage of
apremilast assigned at baseline, and for subjects who are not undergoing dose
titration (as noted above), the IP included in the *titration* portion of the
blister card will include the total daily dose of apremilast (30 or 40 mg BID)
and will not include the dose titration.
Extension Phase
At the end of the Blinded Active-treatment Phase (Week 52), subjects who have a
Mayo endoscopy score * 1 will have the opportunity to participate in the
Extension Phase. Subjects participating in the Extension Phase will continue to
receive the same treatment assigned during the Blinded Active-treatment Phase
for an additional 52 weeks (Weeks 52 to 104).
Post-treatment Observational Follow-up Phase
Subjects who complete the Double-blind Placebo-controlled Phase, as well as
subjects who prematurely discontinue from study, for any reason, will enter the
Post-treatment Observational Follow-up Phase, the 4-week period after the last
dose of IP.
Intervention
Subjects will receive one of two dose regimens of apremilast in the
Double-blind Placebocontrolled Phase (30 mg BID or 40 mg BID), or placebo BID.
Apremilast will be provided in blister cards as 10-mg, 20-mg, or 30-mg tablets
in the clinical image. Matched placebo tablets will also be provided. Tablets
will be taken by mouth twice daily, morning and evening, approximately 12 hours
apart, with no food restrictions.
Study burden and risks
RISKS DUE TO THE STUDY PROCEDURES
Blood sampling. Blood sampling and the use of needles are associated with a
certain risk. Possible side effects may be: fainting, bleeding, bruising,
discomfort, dizziness, infection and/or pain at the site of the injection.
Electrocardiogram (ECG) * Sometimes, an ECG may cause irritation where the
adhesive pads have been applied or if the study staff has to shave the area
where the pads are applied.
Blood Pressure * Although it is very rare, blood pressure measurements might
bruise. Also, the blood pressure cuff will be very tight and might pinch a
little for a short time.
X-ray examinations. Exposure to radiation.
Rectosigmoidoscopy or colonoscopy: This procedure may involve some discomfort.
Rare complications include tearing of the colon, intestinal perforation (poking
a hole in the gut), and/or bleeding that may require surgical repair. When a
biopsy (removal of a small piece of tissue) is performed during the procedure,
bleeding from the biopsy site may occur. Other complications that may occur
include infection at the biopsy site and bacteria in the blood.
RISKS DUE TO THE STUDY MEDICINE
The following list of side effects is the ones that may be associated with the
use of apremilast:
* Very common: Diarrhea, Nausea (stomach upset), Vomiting
* Common: Upper abdominal (stomach) pain, Indigestion, Frequent bowel movement,
Heartburn, Fatigue, Bronchitis (infection of the tubes to the lungs),
Redness/swelling/pain in the sinuses, Inflammation or infections of the nose
and throat Weight loss, Decreased appetite, Back pain, Headache (including
tension and migraine), Difficulty sleeping, Cough, Rash, Dizziness, Weakness,
Flu, Muscle pain, Numbness, Itchiness
* Uncommon: Allergic reaction.
Reports of various types of cancers, heart problems, and serious infections
have been found from apremilast studies. However, these events in patients
being treated with apremilast happened as often as those being treated with
placebo (sugar pill).
Severe diarrhea, nausea, and vomiting has been reported with the use of
apremilast. Some patients were hospitalized. If you are 65 years of age or
older, and/or become dehydrated or experience low blood pressure, you may be at
a higher risk of complications. If you experience severe diarrhea, nausea, or
vomiting please notify your study doctor immediately.
Morris Avenue 86
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Morris Avenue 86
New Jersey 07901
US
Listed location countries
Age
Inclusion criteria
1. Male or female aged 18 and over at the time of signing the informed
consent.
2. Must understand and voluntarily sign an informed consent document
prior to any study related assessments/procedures being conducted.
3. Must be able to adhere to the study visit schedule and other protocol
requirements.
4. Diagnosis of UC with duration of at least 3 months prior to the
Screening Visit
5. TMS * 6 to * 11 (range: 0-12) prior to randomization in the study.
6. Endoscopic subscore * 2 (range: 0-3) on the Mayo score prior to
randomization in the study.
7. Subjects are required to have a colonoscopy if not performed within
12 months of the Screening Visit
8. Subjects must have had a therapeutic failure, been intolerant to, or
have a contraindication to, at least one of the following: oral
aminosalicylates (ie, 5-aminosalicylic acid [5-ASA] compounds or
sulfasalazine [SSZ]), budesonide, systemic corticosteroids, or
immunosuppressants (eg, 6-mercaptopurine [6-MP], azathioprine [AZA],
or methotrexate [MTX]).
9. Subjects receiving oral corticosteroids may continue their use during
the study, provided that the dose (prednisone * 20 mg/day or
equivalent, budesonide * 9 mg/day) has been stable for 3 weeks prior
to the Screening Visit. If oral corticosteroids were recently discontinued,
discontinuation must have been completed at least 3 weeks prior to the
Screening Visit. Corticosteroid doses should remain stable until the
subject is eligible to start corticosteroids tapering, beginning at the
Week 12 Visit.
10. Oral aminosalicylates are permitted during the study, provided that
treatment started at least 6 weeks prior to randomization with a stable
dose of at least 14 days prior to the Screening Visit. The dose of oral
aminosalicylates must remain stable through Week 52 or until Week 104 for subjects who participate in the Extension Phase.
11. Must meet the following laboratory criteria:
- White blood cell count * 3000/mm3 (* 3.0 X 10E9/L) and <
14,000/mm3 (< 14 X 10E9/L)
- Platelet count * 100,000/mm3 (* 100 X 10E9/L)
- Serum creatinine * 1.5 mg/dL (* 132.6 *mol/L)
- AST (SGOT) and ALT (SGPT) *2 X upper limit of normal (ULN). If initial
test shows ALT or AST > 2 times the ULN, one repeat test is allowed
during the screening period
- Total bilirubin * 2 mg/dL (* 34 *mol/L) or albumin > lower limit of
normal (LLN). If initial test result is > 2 g/dL, one repeat test is allowed
during the screening period
- Hemoglobin * 9 g/dL (* 5.6 mmol/L)
12. Females of childbearing potential (FCBP) must have a negative
pregnancy test at Screening and the Baseline Visit. While on IP and for
at least 28 days after taking the last dose of IP, FCBP who engage in
activity in which conception is possible must use one of the approved
contraceptive options2 described below:
Option 1: Any one of the following highly effective methods: hormonal
contraception (oral, injection, implant, transdermal patch, vaginal ring);
intrauterine device (IUD); tubal ligation; or partner's vasectomy
OR
Option 2: Male or female condom (latex condom or nonlatex condom
NOT made out of natural [animal] membrane [for example,
polyurethane]; PLUS one additional barrier method: (a) diaphragm with
spermicide; (b) cervical cap with spermicide; or (c) contraceptive
sponge with spermicide
13. Male subjects (including those who have had a vasectomy) who
engage in activity in which conception is possible must use barrier
contraception (male latex condom or nonlatex condom NOT made out of
natural [animal] membrane [for example, polyurethane]) while on
investigational product and for at least 28 days after the last dose of
investigational product.
Exclusion criteria
1. Diagnosis of Crohn's disease, indeterminate colitis, ischemic colitis,
microscopic colitis, radiation colitis or diverticular disease-associated
colitis.
2. Ulcerative colitis restricted to the distal 15 cm or less (eg, ulcerative
proctitis).
3. Subjects who have had surgery as a treatment for UC or who, in the
opinion of the Investigator, are likely to require surgery for UC during
the study.
4. Clinical signs suggestive of fulminant colitis or toxic megacolon.
5. Evidence of pathogenic enteric infection.
6. History of colorectal cancer or colorectal dysplasia (with the exception of adenomatous colonic polyps that have been completely resected).
7. Prior use of any TNF inhibitor (or any biologic agent).
8. Prior use of mycophenolic acid, tacrolimus, sirolimus, cyclosporine or
thalidomide.
9. Use of IV corticosteroids within 2 weeks of the Screening Visit
10. Use of immunosuppressants (AZA, 6-MP or MTX) within 8 weeks of
the Screening Visit.
11. Use of topical treatment with 5-ASA or corticosteroid enemas or
suppositories within 2
weeks of the Screening Visit
12. History of any clinically significant neurological, renal, hepatic,
gastrointestinal,
pulmonary, metabolic, cardiovascular, psychiatric, endocrine,
hematological disorder or
disease, or any other medical condition that, in the investigator's
opinion, would preclude
participation in the study.
13. Prior history of suicide attempt at any time in the subject's lifetime
prior to
randomization in the study or major psychiatric illness requiring
hospitalization within 3
years of study randomization.
14. Any condition, including the presence of laboratory abnormalities,
which places the
subject at unacceptable risk if he/she was to participate in the study or
confounds the
ability to interpret data from the study.
15. Pregnant or breast feeding.
16. History of any of the following cardiac conditions within 6 months of
screening:
myocardial infarction, acute coronary syndrome, unstable angina, new
onset atrial
fibrillation, new onset atrial flutter, second- or third-degree
atrioventricular block,
ventricular fibrillation, ventricular tachycardia, heart failure, cardiac
surgery,
interventional cardiac catheterization (with or without a stent
placement), interventional
electrophysiology procedure, or presence of implanted defibrillator.
17. Known active current or history of recurrent bacterial, viral, fungal,
mycobacterial or
other infections (including but not limited to tuberculosis and atypical
mycobacterial
disease and herpes zoster), human immunodeficiency virus (HIV), or any
major episode
of infection requiring hospitalization or treatment with intravenous (IV)
or oral
antibiotics within 4 weeks of screening.
18. Subjects with active hepatitis B infection as described in Appendix E
are ineligible for
the study. Subjects without current hepatitis B infection, as described in
Appendix F, may
participate in the study.
19. Subjects who are confirmed positive for hepatitis C antibody not eligible
for the study.
20. History of congenital or acquired immunodeficiency (eg, Common
Variable Immunodeficiency Disease).
21. History of malignancy, except for:
a. Treated (ie, cured) basal cell or squamous cell in situ skin carcinomas
b. Treated (ie, cured) cervical intraepithelial neoplasia (CIN) or
carcinoma in situ of the cervix with no evidence of recurrence within the
previous 5 years
22. Any condition that could affect oral drug absorption, including gastric
resections,
gastroparesis or bariatric surgery, such as gastric bypass.
23. Subjects has received any investigational drug or device within
1 months or 5 elimination half-lives, whichever is longer, prior to the Screening Visit.
24. History of alcohol, drug, or chemical abuse within the 6 months prior
to screening.
25. Known hypersensitivity to apremilast or any excipients in the
formulation.
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 | EUCTR2014-002981-64-NL |
| ClinicalTrials.gov | NCT02289417 |
| CCMO | NL51337.028.15 |