| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with active ulcerative colitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ulcerative colitis is a chronic inflammatory condition of the colon of unknown origin, that is characterized by bloody diarrhea and pain in the lower abdomen. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to evaluate the clinical efficacy of apremilast (30 mg BID and 40 mg BID), compared with placebo, in subjects with active ulcerative colitis (UC). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
- To evaluate the safety and tolerability of apremilast (30 mg BID and 40 mg BID), compared with placebo, in subjects with active UC.
- To evaluate the long-term safety in subjects with active UC, receiving apremilast (30 mg BID or 40 mg BID). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 form 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 μmol/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 μmol/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. |
|
| E.4 | Principal 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 are 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. Subject has received any investigational drug or device within 1 month 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the proportion of subjects achieving a clinical remission in the TMS at Week 12, defined as a TMS of ≤ 2, with no individual subscore > 1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are:
-The proportion of subjects achieving clinical response at Week 12, defined as a decrease from baseline in the TMS of at least 3 points and at least 30%, along with a reduction in the rectal bleeding subscore (RBS) of at least 1 point or an absolute RBS of ≤ 1
- The proportion of subjects achieving endoscopic remission at Week 12, defined as a Mayo endoscopic subscore of 0
- The proportion of subjects achieving endoscopic response at Week 12, defined as a decrease from baseline of at least 1 point in the Mayo endoscopic subscore
- The proportion of subjects achieving a RBS ≤ 1 at Week 12
- The proportion of subjects achieving clinical remission in the modified Mayo Score (range: 0 to 9, based on stool frequency (SFS), RBS and endoscopy) at Week 12, defined as a score of 2 points or lower, with no individual subscore exceeding 1 point
- The proportion of subjects achieving clinical response in the modified Mayo Score at Week 12, defined as a decrease from baseline at least 2 points and at least 25%, along with a reduction in the RBS of at least 1 point or an absolute RBS of ≤ 1 point
- The proportion of subjects achieving clinical remission at Week 8 defined as a PMS of ≤ 2, with no individual subscore > 1
- The proportion of subjects achieving clinical response at Week 8 defined as a decrease from baseline in the PMS of at least 2 points and at least 25%, along with a reduction in the RBS of at least 1 point or an absolute RBS of ≤ 1 point
The following safety parameters will be evaluated for the duration of the study:
- Type, frequency, severity, and relationship of AEs to IP
- Number of subjects who discontinue IP due to any AE
- Frequency of clinically significant changes in physical examination, vital signs, and/or laboratory findings
Exploratory efficacy endpoints
- The proportion of subjects who are in clinical remission per the TMS, PMS, or modified Mayo score, as applicable, over time
- The proportion of subjects who are in clinical response per the TMS, PMS, or modified Mayo score, as applicable, over time
- The proportion of subjects achieving a RBS ≤ 1 over time, except at Week 12
- The proportion of subjects achieving SFS ≤ 1 over time
- The proportion of subjects achieving a physician’s global assessment (PGA) ≤ 1 Week 2 through Week 52
- The proportion of subjects who achieve corticosteroid-free clinical remission at Week 52 among subjects receiving oral corticosteroids at baseline
- The change from baseline in the PMS at Week 2 through Week 52
- The proportion of subjects with endoscopic remission, defined as a Mayo endoscopic subscore ≤ 1 and histological remission at Week 12
- The proportion of subjects achieving a clinical remission in the TMS at Week 12, defined as a TMS ≤ 2 with no individual subscore >1 and no evidence of friability on the Mayo endoscopic subscore
- The change from baseline in the TMS at Week 12 and Week 52
- The change from baseline in the SF-12v2 score over time
- The exposure-adjusted incidence of UC-related health outcomes (for example UC -related hospitalizations, emergency room visits, and surgeries)
- Exploratory Endpoints (Other)
PK Endpoint:
- The population-based PK estimates of apremilast
- The estimates to reflect the relationship of apremilast exposure and key efficacy
endpoints
PD/Biomarker Endpoints:
- The change from baseline in hsCRP concentration over time
- The change from baseline in FCP concentration over time
- The correlation between FCP/hsCRP and clinical outcomes over time
- The change from baseline in PD markers from intestinal mucosa at Week 12 and 52, such as, but not limited to, hematoxylin and eosin (H&E) staining to measure the degree of cellular inflammatory infiltrate and of tissue destruction, and gene expression (messenger ribonucleic acid [mRNA] for the inflammatory mediators TNF-α, IL-12, IL-23, IFN-γ, IL-5, IL-13, IL-17, and matrix metalloproteinase-3 [MMP-3])
PG Endpoint:
- The association of PG markers with the efficacy of apremilast in subjects with active
UC |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The Secondary end points will be evaluated for the duration of the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| New Zealand |
| Poland |
| Russian Federation |
| Slovakia |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the study, or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical Analysis Plan, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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