| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Active Ulcerative Colitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| A long-term condition that results in inflammation and ulcers of the colon and rectum. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000016670 |
|
| 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 |
1. To evaluate the safety and tolerability of PTG-100
2. To evaluate the efficacy of PTG-100 in the induction treatment of subjects with moderate to severe active UC compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the dose-response relationship and select PTG-100 induction regimens for continued development
2. To evaluate the pharmacokinetics (PK) of PTG-100 in subjects with active UC
3. To evaluate the pharmacodynamic (PD) effects of PTG-100 including the assessment of receptor occupancy (RO) and α4β7 receptor expression (RE) in peripheral blood lymphocytes
4. To evaluate changes in faecal calprotectin levels for subjects receiving PTG-100 compared to placebo
5. To evaluate the incidence of positive anti-drug antibodies (ADAs) in subjects receiving PTG-100 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects aged 18 to 80 years, inclusive.
2. Diagnosis of UC for ≥ 2 months prior to screening, with a history of disease activity extending beyond the rectum; if the UC has been present for > 10 years, a colonoscopy with biopsy must have been performed within 2 years of screening to rule out dysplasia. Subjects with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age > 50 years, or other known risk factor must be up-to-date on colorectal cancer surveillance per local standards and guidelines (may be performed during screening). Subjects with extensive colitis or pancolitis of > 8 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial Screening visit (may be performed during screening).
3. Moderate to severe active UC as defined by complete Mayo Score of 6 to 12, inclusive (range 0 to 12), at baseline (pre-randomisation) with endoscopy score of at least 2 (range 0 to 3), extending 15 cm or more from the anal verge, as determined by blinded central read, within 14 days of randomisation.
4. Demonstrated, over the previous 5-year period, an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents as defined below:
a. Immunomodulators
i. Signs and symptoms of persistently active disease despite a history of at least one ≥ 8-week regimen of oral azathioprine (≥ 1.5 mg/kg) or 6-mercaptopurine (6-MP) (≥ 0.75 mg/kg), OR
ii. History of intolerance of at least 1 immunomodulator (including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, lymphopaenia, thiopurine S-methyltransferase genetic mutation, and/or infection)
b. TNF-α antagonists
i. Signs and symptoms of persistently active disease despite a history of at least 1 induction regimen of at least 6 weeks duration, OR
ii. Recurrence of symptoms during maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify), OR
iii. History of intolerance (including, but not limited to, infusion- or injection-related reaction, demyelination, congestive heart failure, and infection)
Note: A maximum of 50% of randomised subjects may have had prior treatment with TNF-α antagonists. Only subjects who have had prior exposure to anti-TNF agents will be allowed to enrol into this study in The Netherlands (as confirmed by medical record documentation or by patient self-reporting).
c. Corticosteroids
i. Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone 30 mg daily orally for 2 weeks or intravenous (IV) for 1 week, OR
ii. Two failed attempts to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally on 2 separate occasions, OR
iii. History of intolerance of corticosteroids (including, but not limited to, Cushing’s syndrome, osteopaenia/osteoporosis, hyperglycaemia, insomnia, and infection).
5. Subject is unlikely to conceive, as indicated by at least one “yes” answer to the following criteria:
a. Subject is a male
b. Subject is a surgically sterilised female (at least 90 days prior to Screening)
c. Subject is a post-menopausal female ≥ 45 years of age with > 1 year since last menses; if a female subject is < 45 years of age, or cessation of menses is < 1 year and > 6 months, follicle-stimulating hormone must be documented as elevated
into the post-menopausal range at Screening
d. Subject is a non-sterilised, premenopausal female and agrees to abstain from heterosexual activity, use adequate hormonal contraception, OR use double barrier contraception (ie, a combination of male condom with either cervical cap, diaphragm, or sponge with spermicide) as per local regulations and guidelines during the study and for 28 days after the last dose of study drug.
6. For women of childbearing potential, a negative serum pregnancy test at Screening and a negative urine pregnancy test within 24 hours prior to the first dose of study medication.
7. Subject is eligible according to tuberculosis screening criteria.
8. Subject understands the study procedures and agrees to participate in the study by giving written informed consent. |
|
| E.4 | Principal exclusion criteria |
Gastrointestinal exclusion criteria
1. Subject with Crohn’s disease (CD), indeterminate colitis, or presence or history of fistula consistent with CD.
2. History of toxic megacolon, abdominal abscess, symptomatic colonic stricture, or stoma; history of extensive colonic resection, or subtotal or total colectomy; or is at imminent risk of colectomy.
3. History or current evidence of colonic dysplasia or adenomatous colonic polyps. Note: Subjects will not be excluded from the study because of a pathology finding of indefinite dysplasia with reactive atypia. Subjects with resected adenomatous polyps may be enrolled.
Infectious disease exclusion criteria
4. Current bacterial or parasitic pathogenic enteric infection, including Clostridium difficile, infection with hepatitis B or C virus, infection requiring hospitalisation or IV antimicrobial therapy, opportunistic infection within 6 months of dosing, any infection requiring antimicrobial therapy within 2 weeks of dosing, history of more than one episode of herpes zoster, history of infection with human immunodeficiency virus (HIV), or any episode of disseminated zoster. Note: Subjects with a history of C. difficile infection treated with antibiotics with or without faecal microbial transplant may be rescreened after 2 weeks following completion of treatment.
5. Live virus vaccination within 1 month prior to screening.
General exclusion criteria
6. Subject has a concurrent clinically significant, unstable, or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, haematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the subject by their participation in the study.
Note: Subjects with a history of uncomplicated kidney stones, childhood asthma, or concurrent stable and well-controlled asthma may be enrolled in the study at the discretion of the Investigator.
7. Known primary or secondary immunodeficiency.
8. History of myocardial infarction, unstable angina, transient ischaemic attack, decompensated heart failure requiring hospitalisation, congestive heart failure (New York Heart Association Class 3 or 4), uncontrolled arrhythmias, cardiac revascularisation, stroke, uncontrolled hypertension (systolic blood pressure [BP] > 160 mmHg or diastolic BP > 100 mmHg at Screening), or uncontrolled diabetes (haemoglobin A1c > 9% or > 1 episode of severe hypoglycaemia) within 6 months of screening.
9. Clinically meaningful laboratory abnormalities at Screening including, but not limited to, the ranges below:
a. Absolute neutrophil count < 1000/μL
b. Platelet count < 100,000/μL
c. Haemoglobin < 9 g/dL
d. Creatinine ≥ 1.5 mg/dL
e. alanine aminotransferase or aspartate aminotransferase ≥ 2.5 x upper limit of normal (ULN) or bilirubin > 1.5 x ULN
10. Pregnant or lactating females.
11. Any surgical procedure requiring general anaesthesia within 1 month prior to screening, or planned elective surgery during the study.
12. History of malignant neoplasms or carcinoma in situ within 5 years prior to screening. (Subjects who are cancer-free for the previous 5 years may be enrolled. Subjects with adequately treated non-metastatic basal cell skin cancer, squamous cell skin cancer that has not recurred for at least 1 year prior to screening, or history of adequately treated cervical dysplasia/cervical intraepithelial neoplasia or cervical carcinoma in situ that has not recurred at least 3 years prior to screening may be enrolled.)
13. History of any major neurological disorders, as judged by the Investigator, or positive PML subjective symptom checklist.
14. Current or recent history of alcohol dependence or illicit drug use within 1 year prior to screening.
15. Subject is mentally or legally incapacitated at the time of Screening visit or has a history of clinically significant psychiatric disorders that would impact the subject’s ability to participate in the trial according to the Investigator. Note: Subjects who have had situational depression or adjustment disorder or treated depression may be enrolled at the discretion of the Investigator.
16. Unable to attend study visits or comply with procedures.
17. Concurrent participation in any other interventional study.
Medication exclusion criteria
18. Use of topical 5-ASA or corticosteroid enemas/suppositories within 2 weeks of administration of the screening endoscopy.
19. Use of TNF-α antagonists within 60 days prior to screening.
20. Use of ustekinumab within 3 months prior to screening.
21. Use of cyclosporine, thalidomide, tacrolimus, sirolimus, or mycophenolate mofetil within 1 month prior to screening.
22. Have received any investigational or biologic agent within 1 month (or 5 half-lives of the agent, whichever is longer) prior to screening.
23. Prior treatment with vedolizumab or natalizumab. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
1. Proportion of subjects receiving PTG-100 with clinical remission at Week 12 compared with placebo. Clinical remission is defined in the protocol.
Safety:
1. Proportion of subjects with at least 1 AE comparing individual PTG-100 dosing groups with placebo |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
1) Week 12
Safety:
1) Refer to schedule of study procedures |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
1. Proportion of subjects with endoscopic response at Week 12 (Day 84) (defined as an endoscopic subscore of 0 or 1)
2. Proportion of subjects with clinical response at Week 12 (Day 84) (defined as at least 1 point and 30% reduction from baseline in rectal bleeding and stool frequency subscores)
3. Mean change in endoscopy subscore from baseline to Week 12
4. Mean change in rectal bleeding and stool frequency subscores from baseline to Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112)
5. Proportion of subjects with endoscopic remission at Week 12 (Day 84) (defined as an endoscopic subscore of 0)
6. Mean change in complete Mayo Score (including all 4 subscores) from baseline to Week 12 (Day 84)
7. Mean change in partial Mayo Score (excluding endoscopy subscore) from baseline to Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112)
8. Mean change in faecal calprotectin levels from baseline to Weeks 6 (Day 42), 12 (Day 84), and 16 (Day 112)
9. Mean change in IBDQ score from baseline to Week 12 (Day 84)
Safety:
1. Frequency and type of AEs (affecting ≥ 5% of subjects)
2. Proportion of subjects with at least 1 serious AE (SAE)
3. Number and type of SAEs
4. Frequency of AEs of special interest including serious or opportunistic infection (viral, bacterial, fungal including systemic/gut localization), allergic/drug reactions, immune system disorders, and suspected PML
5. Clinically significant changes in safety labs, ECGs, or physical examination findings (including vital signs) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
1. Week 12 (Day 84)
2. Week 12 (Day 84)
3. Week 12
4. Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112)
5. Week 12 (Day 84)
6. Week 12 (Day 84)
7. Weeks 2, 4, 6, 8, 10, 12, and 16 (Days 14, 28, 42, 56, 70, 84, and 112)
8. Weeks 6 (Day 42), 12 (Day 84), and 16 (Day 112)
9. Week 12 (Day 84)
Safety:
1-5) Refer to schedule of study procedures |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 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 | 38 |
| 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 |
| Belgium |
| Bosnia and Herzegovina |
| Croatia |
| Czech Republic |
| Germany |
| Greece |
| Hungary |
| Latvia |
| Netherlands |
| Poland |
| Russian Federation |
| Serbia |
| Slovenia |
| 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
|
|
| 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 | 2 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
