| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ulcerative Proctitis (UP) or Ulcerative Procto-Sigmoiditis (UPS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| chronic, relapsing inflammatory disease of the large intestine |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036783 |
| E.1.2 | Term | Proctitis ulcerative |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036789 |
| E.1.2 | Term | Proctosigmoiditis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| 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 | 10045362 |
| E.1.2 | Term | Ulcerative (chronic) proctosigmoiditis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| 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 evaluate the safety and tolerability of Niclosamide enemas (150 mg/60 ml or 450 mg/60 ml, either open label or compared to placebo);
• To explore the efficacy of the DSMB selected dosage of Niclosamide enema compared to placebo |
|
| E.2.2 | Secondary objectives of the trial |
• To assess open-label clinical efficacy of Niclosamide enemas (150 mg/60 ml or 450 mg/60 ml).
Other Exploratory Objectives
• Stages 1 and 2 only: To determine if there is measurable Niclosamide in the blood after rectal administration of Niclosamide enemas 150 mg/60 ml and 450 mg/60 ml;
• To determine the Niclosamide concentration in colon tissue after rectal administration of Niclosamide enemas at a dose of 450 mg/60 ml ;
• To evaluate the effects of Niclosamide enemas 150 mg/60 ml and 450 mg/60 ml (open-label or compared to placebo) on markers of inflammation (hs-CRP, fecal calprotectin, intestinal mucosal cytokine expression and cell infiltrate);
• To evaluate the effects of Niclosamide enemas 150 mg/60 ml and 450 mg/60 ml (open-label or compared to placebo) on histology (Geboes Index);
• To assess the quality of life (SF 12-item Short-Form) during treatment with Niclosamide enemas 150 mg/60 ml and 450 mg/60 ml (open-label or compared to placebo). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects aged ≥ 18 years at the time of signing the informed consent;
2. Must understand and voluntarily sign an informed consent from (ICF) 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 (subcategories UP and /or UPS) with a duration of at least 3 months prior to the Screening Visit, extending at least 5 cm, but no further 40 cm from the anal verge. Patients who at the time of screening endoscopy have active disease identified in the sigmoid colon without active disease being apparent in the rectum as result of recent topical treatment within 2 weeks from screening are eligible.
5. MMS score ≥4 to < 8 (range: 0-9) prior to enrolment in the study, with verification of the following conditions:
• Stool frequency subscore (SFS) ≥ 1
• Rectal bleeding subscore (RBS) = 1 or 2;
• Endoscopic sub-score (mucosal appearance) = 1 or 2;
6. Availability to perform an endoscopy (colonoscopy or flexible rectosigmoidoscopy); colonoscopy is mandatory only if not been performed within 12 months prior to the Screening Visit; For the patient that will not go through the colonoscopy procedure, an abbreviated endoscopic procedure to collect the biopsy will be performed.
7. Patients who have relapsed on maintenance therapy with oral and/or rectal doses of 5-ASA;
8. Patients must meet the following laboratory criteria:
• White blood cells (WBC) count ≥3000/mm3 (≥3.0 × 10^9/L) and <14,000/mm3 (<14 × 10^9/L);
• Platelet count ≥100,000/mm3 (≥100 × 10^9/L);
• Serum creatinine ≤1.5 mg/dL (≤132.6 μmol/L);
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2 × upper limit of normal (ULN). If initial test shows ALT or AST >2 × ULN, one repeated test is allowed during the screening period;
• Total bilirubin ≤2 mg/dL (≤ 34 μmol/L) or albumin > LLN (lower limit of normal). If initial total bilirubin test result is >2 g/dL, one repeated test is allowed during the screening period;
• Hemoglobin ≥ 9 g/dL (≥5.6 mmol/L);
9. Females of childbearing potential (FCBP) must have a negative pregnancy test at screening and the Baseline Visit. While receiving the investigational medicinal product (IMP) and for at least 28 days after taking the last dose of IMP, FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options 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;
10.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 non-latex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while receiving the IMP and for at least 28 days after taking the last dose of IMP. |
|
| 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. UC extended more than 40 cm from the anal verge;
3. Patients 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. Evidence of pathogenic enteric infection;
5. History of colorectal cancer or colorectal dysplasia;
6. Use of any tumor necrosis factor (TNF) inhibitors (or any biologic agent) within 12 months prior to screening;
7. Prior use of mycophenolic acid, tacrolimus, sirolimus, cyclosporine, or thalidomide;
8. Patients who in the opinion of the Investigator may require treatment with chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) and / or aspirin during the entire study (may potentially require daily or more frequent dosing for continuous periods longer than 7 days);
9. Use of budesonide-multimatrix (MMx) within the last 8 weeks of day 1 (first study treatment);
10. Use of oral and/or IV corticosteroids within the last 2 weeks of day 1 (first study treatment);
11. Use of immunosuppressants (azathioprene [AZA], 6-mercaptopurine [6-MP] or methotrexate [MTX]) within the last 8 weeks of day 1 (first study treatment);
12. Current use of coumadin, unfractionated or low molecular weight heparins or anticoagulant medications other than aspirin due to bleeding risk;
13.History of any clinically significant neurological, renal, hepatic, gastrointestinal, pulmonary, metabolic, psychiatric, endocrine, hematological disorder or disease or any other medical condition that, in the Investigator's opinion, would preclude participation in the study;
14.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;
15.History of suicide attempt at any time in the subject’s lifetime prior to study start or major psychiatric illness requiring hospitalization within 3 years before study start;
16. 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;
17. Pregnant or breast feeding females;
18. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis, 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;
19. Patients with active hepatitis B, C and HIV infections;
20. Patients with active intestinal parasite infections;
21. History of congenital or acquired immunodeficiency (eg, Common Variable Immunodeficiency Disease);
22. History of malignancy, except for:
• Treated (ie, cured) basal cell or squamous cell in situ skin carcinomas;
• Treated (ie, cured) carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years;
23. Patients who have received any investigational drug or device in the last 3 months;
24. History of alcohol, drug, or chemical abuse within the last 6 months;
25. Known hypersensitivity to niclosamide or any excipients in the formulation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Serious adverse reactions (i.e. treatment-related) during 6 weeks of treatment with Niclosamide enemas;
• Grade ≥ 3 adverse reactions during 6 weeks of treatment with Niclosamide enemas;
• Grade ≥ 2 adverse reactions during 6 weeks of treatment with Niclosamide enemas. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Clinical remission defined as MMS ≤ 2 with no individual subscore >1 after 6 weeks of treatment for niclosamide compared to Placebo.
• Change in signs and symptoms (rectal bleeding and stool frequency) from baseline to 2, 4 and 6 weeks of treatment;
• Change in sigmoidoscopic score (mucosal appearance) from baseline to 6 weeks of treatment;
• Change in hs-CRP and fecal calprotectin from baseline to 2, 4 and 6 weeks of treatment;
• Change in intestinal mucosal cytokine expression and cell infiltrate from baseline to 6 weeks of treatment;
• Change in histology (Geboes index) from baseline to 6 weeks of treatment;
• Adverse events and toxicities with Niclosamide enemas at 150 mg/60 ml and 450 mg/60 ml;
• Change in safety laboratory tests (hematology, blood chemistry, urinalysis) from baseline to 6 weeks of treatment;
• Change in 12-lead ECG from baseline to 2, 4 and 6 weeks of treatment;
• Change in vital signs (heart rate, blood pressure, body temperature) from baseline to 2, 4 and 6 weeks of treatment;
• New abnormal findings or changes in previously identified abnormal findings in physical examination during 6 weeks of treatment;
• Change in quality of life (12-item Short-Form) from baseline to 6 weeks of treatment;
• In Stages 1 and 2 only plasma levels of Niclosamide measured before the first dose and after 4, 8 (pre-dose) and 24 hours (pre-dose) after the first dose; and before the last morning dose of last treatment day and after 4 and 8 (pre-dose) hours after the morning dose of last treatment day.
• Colon tissue concentration of Niclosamide measured within 12 hours of the morning dose administered on the last treatment day for niclosamide-treated subjects. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | Yes |
| 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 | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 Study 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 (SAP), 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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