| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Mild to Moderate Ulcerative Colitis
Inflammatory bowel disease (IBD) is an autoimmune disease of the gastrointestinal (GI) tract with unknown etiology that encompasses 2 primary clinical manifestations: ulcerative colitis (UC) and Crohn’s disease (CD).
UC manifests through complex interactions between the gut microbiome, dysregulated immune responses, genetic mutations, diet, and other environmental factors.
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| E.1.1.1 | Medical condition in easily understood language |
| Ulcerative colitis is an Inflammatory Bowel Disease (IBD) that effects the colon and causes the digestive tract to become inflamed and develop sores that produce pus and mucous. |
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| 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 | 10009900 |
| E.1.2 | Term | Colitis ulcerative |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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| 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 | 10017947 - Gastrointestinal disorders |
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| 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 |
Objectives
induction and maintenance period
The primary objective of this study is to assess the efficacy and safety of oral BT-11 in inducing clinical remission at Week 12 in subjects with mild to moderate ulcerative colitis (UC).
Open Label extension period
To assess the safety of the extended use of oral BT-11 in subjects with mild to moderate ulcerative colitis |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate the following at Week 12:
1. The effects of BT-11 on disease activity measured by symptoms, endoscopy, histology, and biomarkers
2. Health-related quality of life
3. The pharmacokinetic (PK) parameters of BT-11
4. Safety
The exploratory objectives of this study are to evaluate the following through Week 30:
1. The effects of BT-11 on disease activity measured by symptoms, endoscopy, histology, and biomarkers
2. Health-related quality of life
3. The PK parameters of BT-11
4. Safety
5. Target engagement and mechanism of action
6. The association of drug exposure in colonic mucosal tissue biopsies with clinical, endoscopic, histopathologic, cellular, and molecular outcomes
Open Label Extension period
To assess the safety of the extended use of oral BT-11
To evaluate the effects of BT 11 on measures of efficacy (based on subgroups defined in the statistical analysis plan)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male and female subjects aged 18 to 75 years, inclusive.
2) Diagnosis of UC for at least 3 months prior to screening.
3) Mild to moderate UC, as defined by a total Mayo Score of 4 to 10 inclusive at baseline with a MES ≥ 2 (confirmed by central reader).
4) If subjects have previously received biologic therapy for UC (i.e., TNF antagonists, vedolizumab or ustekinumab), they must have a washout period of 8 weeks prior to randomization, and any previous failure of biologic treatment is limited to only 1 class of biologic. (Note: this inclusion criterion is only applicable until 58 subjects with prior exposure to biologic therapy have been randomized).
5) If subjects are receiving the following UC treatments, they must be on a stable dose for at least 1 month prior to randomization: 5-aminosalicylates (5-ASAs) (not exceeding 4.8 g per day), oral corticosteroids (not exceeding prednisone 20 mg, budesonide 9 mg, or equivalent).
6) If subjects are receiving bile-salt sequestrant, they must be on a stable dose for at least 3 months prior to randomization.
7) If subjects are receiving any nonprohibited medications, they must agree to maintain stable doses of concomitant medications for UC for the duration of the trial.
8) Unlikely to conceive, as defined by 1 of the following: a) subject is surgically sterilized female, b) subject is postmenopausal female ≥ 45 years of age with clinical documentation of menopause (i.e., 12 months without menses), or c) subject is male or subject is woman of child bearing potential (WOCBP), and agrees to abstain from heterosexual activity, use adequate hormonal contraception, or use double barrier contraception.
9) For WOCBP, the subject must have a negative pregnancy test at screening and within 24 hours prior to the first dose of study drug.
10) Able to participate fully in all aspects of this clinical trial.
11) Written informed consent must be obtained and documented.
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| E.4 | Principal exclusion criteria |
1) A diagnosis of CD, indeterminate colitis, or presence or history of fistula with CD.
2) Severe UC as per modified Truelove and Witts criteria (≥ 6 bloody stools per day and one or more of the following: pulse > 90 bpm, temperature > 37.8°C, hemoglobin < 10.5 g/dl, or high sensitivity C- reactive protein (hs-CRP) > 30 mg/l.
3) Disease activity limited to distal 15 cm (proctitis).
4) Treatment with immunosuppressant (azathioprine, 6-mercaptopurine [6-MP]) within 25 days prior to randomization.
5) History of toxic megacolon, abdominal abscess, symptomatic colonic stricture, or stoma; history or is at imminent risk of colectomy.
6) History or current evidence of colonic dysplasia or adenomatous colonic polyps.
7) Current bacterial or parasitic pathogenic enteric infection, including Clostridium difficile, known infection with hepatitis B or C virus, known infection with human immunodeficiency virus, infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic infection within 6 months prior to screening, any infection requiring antimicrobial therapy within 2 weeks prior to screening, history of more than 1 episode of herpes zoster or any episode of disseminated zoster.
8) Live virus vaccination within 1 month prior to screening.
9) Treatment with cyclosporine, mycophenolate, tacrolimus, or tofacitinib within 4 weeks prior to randomization.
10) Treatment with intravenous corticosteroids, rectal corticosteroids, or rectal 5-ASA within 2 weeks prior to randomization.
11) Fecal microbiota transplantation within 1 month prior to screening.
12) A concurrent clinically significant, unstable, or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, might confound the study results or poses additional risk to the subject.
13) Known primary or secondary immunodeficiency.
14) History of myocardial infarction, unstable angina, transient ischemic attack, decompensated heart failure requiring hospitalization, congestive heart failure (New York Health Association Class 3 or 4), uncontrolled arrhythmias, cardiac revascularization, stroke, uncontrolled hypertension, or uncontrolled diabetes within 6 months of screening.
15) Clinically meaningful laboratory abnormalities at screening, as determined and documented by the investigator.
16) Pregnant or lactating females.
17) Any surgical procedure requiring general anesthesia within 1 month prior to screening, or planned elective surgery during the study.
18) History of malignant neoplasms or carcinoma in situ within 5 years prior to screening.
19) Current or recent history of alcohol dependence or illicit drug use that in the opinion of the investigator may interfere with the subject’s ability to comply with the study procedures.
20) Mental or legal incapacitation at the time of screening visit or a history of clinically significant psychiatric disorders that would impact the ability to participate in the trial according to the investigator.
21) Unable to attend study visits or comply with procedures.
22) Concurrent participation in any other interventional study.
23) Received any investigational therapy within 30 days of initiation of study drug.
24) Serious underlying disease other than UC that in the opinion of the investigator may interfere with the subject’s ability to participate fully in the study.
25) Previous exposure to BT-11.
26) Prior enrollment in the current study and had received study treatment.
27) Current treatment with antimotility medications.
28) Treatment with sirolimus within 4 weeks prior to randomization.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
induction and maintenance period
To assess the efficacy of BT-11 in inducing clinical remission in subjects with UC, this study will evaluate the primary efficacy endpoint of clinical remission rate at Week 12 as defined by total Mayo Score ≤ 2 with all subscores ≤ 1.
Open Label Extension period
• Percentage of subjects with treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and TEAEs that lead to discontinuation of study drug at each study visit
• Results of vital signs and physical examination
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
induction and maintenance period
week 12 or visit 6
open label extension period
each study visit |
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| E.5.2 | Secondary end point(s) |
induction and maintenance period
• Endoscopic remission rate at Week 12 defined as a Mayo endoscopic subscore (MES) of 0 or 1
• Endoscopic response rate at Week 12 defined as a decrease from baseline in MES of ≥ 1 point)
• Mucosal healing rate at Week 12 defined by a MES of 0 or 1 and a Geboes score of < 3.1
• Histologic remission rate at Week 12 defined by a Geboes score of < 3.1
• Clinical response rate at Week 12 defined as decrease from baseline in Mayo Score of ≥ 3 points and ≥ 30 percent, with an accompanying decrease in the subscore for rectal bleeding of ≥ 1 point or an absolute subscore for rectal bleeding of 0 or 1.
OTHER SECONDARY EFFICACY EVALUATIONS
• Mean change in partial Mayo Score from baseline to Weeks 2, 6, and 12
• Mean change in Mayo rectal bleeding subscore from baseline to Weeks 2, 6, and 12
• Mean change in Mayo stool frequency subscore from baseline to Weeks 2, 6, and 12
• Mean change in MES from baseline to Week 12
• Mean change in Robarts Histopathology Index (RHI) scores from baseline to Week 12
• Mean change in fecal calprotectin from baseline to Weeks 2, 6, and 12
• Normalization of fecal calprotectin at Weeks 2, 6, and 12 in subjects with abnormal fecal calprotectin at baseline (abnormal defined as fecal calprotectin > 250 mg/kg)
• Mean change in high-sensitivity C-reactive protein (hs-CRP) from baseline to Weeks 2, 6, and 12
• Normalization of hs-CRP at Weeks 2, 6, and 12 in subjects with abnormal hs-CRP at baseline (abnormal defined as hs-CRP > 3.0 mg/L)
• Mean change in UC-100 score from baseline to Week 12
• Change in Robarts Symptom and Impacts Questionnaire for Ulcerative Colitis (SIQ UC) items - from baseline to Week 12
• Mean change in Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline to Week 12
• BT-11 concentration in serum, feces, and tissue for the active BT-11 treatment group
• Frequency and severity of adverse events (AEs)
• Changes in clinical chemistry and hematology from baseline
• Results of vital signs and physical examination
• ECG findings
Exploratory Week 30 endpoints:
• Durable clinical remission defined as clinical remission at both Week 12 and Week 30
• Durable clinical response defined as clinical response at both Week 12 and Week 30
• Endoscopic remission rate at Week 30 defined by a MES of 0 or 1
• Endoscopic response rate at Week 30 defined as a decrease from baseline in MES of ≥ 1 point)
• Corticosteroid-free clinical remission at Week 30
• Corticosteroid-free endoscopic remission at Week 30
• Mucosal healing rate at Week 30 defined by a MES of 0 or 1 and a Geboes score of < 3.1
• Histologic remission rate at Week 30 defined by a Geboes score of < 3.1
• Clinical response rate at Week 30 defined as decrease from baseline in Mayo Score of ≥ 3 points and ≥ 30 percent, with an accompanying decrease in the subscore for rectal bleeding of ≥ 1 point or an absolute subscore for rectal bleeding of 0 or 1
• Mean change in partial Mayo Score from baseline to Weeks 18, 24, and 30
• Mean change in Mayo rectal bleeding subscore from baseline to Weeks 18, 24, and 30
• Mean change in Mayo stool frequency subscore from baseline to Weeks 18, 24, and 30
• Mean change in MES from baseline to Week 30
• Mean change in RHI scores from baseline to Week 30
• Mean change in fecal calprotectin from baseline to Weeks 18, 24, and 30
• Normalization of fecal calprotectin at Weeks 18, 24, and 30 in subjects with abnormal fecal calprotectin at baseline (abnormal defined as fecal calprotectin > 250 mg/kg)
• Mean change in hs-CRP from baseline to Weeks 18, 24, and 30
• Normalization of hs-CRP at Weeks 18, 24, and 30 in subjects with abnormal hs-CRP at baseline (abnormal defined as hs-CRP > 3.0 mg/L)
• Mean change in UC-100 score from baseline to Week 30
• Change in Robarts Symptom and Impacts Questionnaire for Ulcerative Colitis (SIQ-UC) items baseline to Week 30
• Mean change in IBDQ score from baseline to Week 30
• BT-11 concentration in serum, feces, and tissue at Week 30 in the active BT-11 treatment group
• Frequency and severity of adverse events (AEs)
• Changes in clinical chemistry and hematology from baseline
• Results of vital signs and physical examination
• ECG findings
Open Label Extension period
• Partial Mayo Score clinical remission, defined as partial Mayo Score < 2, at each study visit
• Partial Mayo Score clinical response, defined as partial Mayo Score decrease of ≥ 2 points from Day 1, at each study visit
• Mean change in partial Mayo Score from Day 1 to each study visit
• Mean change in Mayo rectal bleeding subscore from Day 1 to each study visit
• Mean change in Mayo stool frequency subscore from Day 1 to each study visit
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
induction and maintenance period
at various timepoints during the study at baseline and week 2, 6 , 12,18,24 and 30.
open label extension period
each study visit |
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| 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 | 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Belarus |
| Bosnia and Herzegovina |
| Croatia |
| Georgia |
| Hungary |
| Moldova, Republic of |
| Poland |
| Russian Federation |
| Serbia |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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