| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A form of inflammatory bowel disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| 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 |
| To determine the effect of treatment with APD334 in inducing clinical remission at 12 weeks |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the effect of treatment with APD334 in inducing clinical response at 12 weeks
• To determine the effect of treatment with APD334 on endoscopic improvement at 12 weeks |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men or women of age 18 to 80 years, inclusive
2. Able to give signed informed consent
3. Willing and able to comply with the study requirements
4. Considered to be in stable health in the opinion of the investigator, as determined by:
• A pre-study physical examination with no clinically significant abnormalities unrelated to ulcerative colitis
• Vital signs (VS) at screening: pulse rate ≥ 55 bpm, systolic blood pressure (SBP) ≥ 90, and diastolic blood pressure (DBP) ≥ 55
• Liver function tests (ALT/AST, bilirubin and alkaline phosphatase) <2X the upper limit of normal [ULN]
• All other pre-study clinical laboratory findings within normal range, or if outside of the normal range are not deemed clinically significant in the opinion of the investigator
• 12-lead electrocardiogram (ECG) showing no clinically significant abnormalities (for confirmation please refer to exclusion criteria # 24)
• A chest x-ray showing no evidence of active pulmonary disease (a chest x-ray taken within the previous 12 months from the screening visit may also be used)
• Ophthalmology evaluation (by an ophthalmologist) without evidence of macular edema, supported with OCT where available (dependent on site capability)
5. Diagnosis of ulcerative colitis established at least 6 months prior to screening by clinical and endoscopic evidence and corroborated by histopathology report.
6. Moderately to severely active ulcerative colitis defined as a 3-component Mayo Clinic score of 4 to 9 that includes an endoscopic subscore of ≥ 2 and a rectal bleeding score of≥ 1 (using 3 of the 4 components of the complete Mayo Clinic score [endoscopic findings, rectal bleeding, and stool frequency]). These values will be obtained from patient diary entries of rectal bleeding and stool frequency within the 10 days prior to randomization and flexible proctosigmoidoscopy results as determined by a blinded central reader within 7 days prior to randomization
7. Evidence of colonic ulcerative colitis activity on endoscopy (i.e., UC extending ≥ 15 cm proximal to the rectum)
8. Patients with history of extensive colitis or pancolitis of > 8 years duration or left-sided colitis of > 12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit (if not, the patient should undergo a colonoscopy in lieu of a flexible proctosigmoidoscopy during screening).
9. Demonstrated, over the previous 5 year period, an inadequate response to, loss of response to, or intolerance of at least one of the following agents below as defined in Section 4.2 of the protocol:
• Oral 5-aminosalicylates (5-ASAs)
• Corticosteroids
• Immunosuppressives
• TNFα antagonists
• Integrin antagonists
10. May be receiving a therapeutic dose of the following drugs:
a. Oral 5-ASA compounds provided that the dose has been stable for the 2 weeks immediately prior to randomization
b. Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day, budesonide at a stable dose ≤ 9 mg/day, or equivalent steroid) provided that the dose has been stable for the 4 weeks immediately prior to screening if corticosteroids have just been initiated
c. Azathioprine or 6-mercaptopurine provided that the dose has been stable for the 8 weeks immediately prior to screening. (These immunosuppressive agents must be discontinued at the time of randomization.)
d. Probiotics (e.g., Culturelle, Saccharomyces boulardii) provided that the dose has been stable for the 2 weeks immediately prior to randomization
e. Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea
11. Eligible female patients must be:
a. non-pregnant, evidenced by a negative serum human chorionic gonadotropin (hCG) pregnancy test at screening and a urine dipstick pregnancy test at Day 1
b. non-lactating
c. sexually abstinent (if this is the preferred and usual lifestyle of the individual). Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), and lactational amenorrhoea method, are not acceptable methods of contraception
d. surgically sterile, postmenopausal, or agree to continue to use an accepted method of birth control during and for at least 30 days after last study medication administration.
12. Eligible male patients must:
- Agree to use the double barrier method (condom and occlusive cap [diaphragm or cervical cap] with spermicide) when sexually active with a female partner who is pregnant, breastfeeding, or not using an acceptable method of birth control, during the study and for 30 days after last study medication administration.
13. Eligible male and female patients must agree not to participate in a conception process (i.e. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) for 30 days after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. Evidence of abdominal abscess or toxic megacolon at the initial screening visit
2. Previous extensive colonic resection (subtotal or total colectomy)
3. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
4. Within 30 days prior to randomization, receipt of any of the following for the treatment of underlying disease:
a. Non-biologic therapies (eg, cyclosporine, tacrolimus, tofacitinib, thalidomide) other than those specifically listed in Section 6.12.1 of the protocol.
b. A non-biologic investigational therapy
c. An approved non-biologic therapy in an investigational protocol
5. Within 60 days prior to randomization, receipt of any of the following:
a. Infliximab, adalimumab, golimumab, certolizumab, vedolizumab
b. Any other investigational or approved biologic agent
6. Any prior exposure to natalizumab, efalizumab, or rituximab
7. Previous treatment with more than 2 biologic agents
8. Use of topical (rectal) treatment with 5-ASA or corticosteroid enemas/suppositories within 2 weeks of the administration of the first dose of study drug
9. Evidence of or treatment for C. difficile infection within 60 days or other intestinal pathogen within 30 days prior to randomization
10. Currently require or are anticipated to require surgical intervention for UC during the study
11. Current evidence of adenomatous colonic polyps that have not been removed
12. Current evidence of colonic mucosal dysplasia
13. Diagnosis of Crohn’s colitis or indeterminate colitis
14. Infection with the Hepatitis B or C virus
15. Active or latent tuberculosis, regardless of treatment history, as evidenced by any of the following:
a. History of tuberculosis (that has not been acceptably treated)
b. A positive diagnostic tuberculosis (TB) test within one month of randomization defined as:
i. a positive QuantiFERON® test or 2 successive indeterminate QuantiFERON tests OR
ii. a tuberculin skin test reaction ≥10 mm ( ≥5 mm in patients receiving the equivalent of > 15 mg/day prednisone).
c. Chest X-ray within 12 months of randomization in which active or latent pulmonary tuberculosis cannot be excluded
16. Any known history of congenital or acquired immunodeficiency (e.g., common variable immunodeficiency, human immunodeficiency virus [HIV] infection [ELISA and Western blot] test result, organ transplantation)
17. Clinically significant extra-intestinal infection (e.g., pneumonia, pyelonephritis) within 30 days prior to randomization
18. Prior participation in any study of APD334
19. History of any clinically significant medical condition that, in the investigator's opinion, would preclude participation in the study
20. Recent history (within 6 months of screening visit) of cardio or cerebrovascular disease, ACS, MI, unstable angina, CVA, TIA at screening
21. Any surgical procedure requiring general anesthesia within 30 days prior to randomization or plans to undergo major surgery during the study period
22. History of retinal macular edema
23. History of or signs and symptoms of progressive multifocal leukoencephalopathy (PML) as assessed by the PML Checklist
24. History of cardiac arrhythmia, conduction system disease (including AV node dysfunction, 2nd or 3rd degree heart block, and sick sinus syndrome), or use of Class 1a and Class III anti-arrhythmic agents, or baseline QTc ≥ 500 msec.
25. FEV1 or FVC < 80% of predicted values (i.e., abnormal)
26. Infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic infection within 4 weeks of screening
27. History of more than one episode of herpes zoster or any episode of disseminated zoster
28. Without documented positive varicella zoster virus (VZV) IgG antibody status or who have completed VZV vaccination within 30 days prior to randomization
29. Receipt of live vaccine within 4 weeks prior to screening
30. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma
31. History of malignancy except for adequately treated basal cell skin cancer
32. Receipt of any investigational therapy, excluded medications as defined in the protocol, or any approved therapy in an investigational protocol within 30 days prior to screening.
33. History of severe allergic or anaphylactic reactions requiring medical attention
34. Current or recent history (within one year prior to randomization) of alcohol dependence or illicit drug use
35. History of clinically significant leukopenia or lymphopenia at screening.
36. Active psychiatric problems that, in the investigator’s opinion, may interfere with compliance with the study procedures
37. Use of moderate to strong inhibitors of CYP2C9
38. History of severe renal impairment
39. History of severe hepatic impairment
40. Inability to attend all the study visits or comply with study procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • The proportion of patients achieving clinical remission [defined as individual subscores of the 3-component Mayo Clinic score as follows: an endoscopy score (using flexible proctosigmoidoscopy) of 0 or 1, a rectal bleeding score of 0, and a stool frequency score of 0 or 1 with a decrease of ≥ 1 point from baseline subscore] at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• The proportion of patients who achieve clinical response [defined as a decrease in 3-component Mayo Clinic score of ≥ 2 points and a decrease of ≥ 30% with either a decrease of rectal bleeding of ≥ 1 or rectal bleeding score of 0 or 1] at Week 12
• The proportion of patients who achieve endoscopic improvement [defined as Mayo endoscopic subscore (using findings of flexible proctosigmoidoscopy) of ≤ 1 point] at Week 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| 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 |
| Belgium |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Israel |
| Latvia |
| Lithuania |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Ukraine |
| United Kingdom |
| 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
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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