A study to examine the safety and effect of the study drug PTG-100 in patients with inflammation of the colon

• Register: EUCTR
• Last refreshed on: 10 September 2018
• Main ID: EUCTR2016-003452-75-PL
• Date of registration: 04/01/2017
• Prospective Registration: Yes
• Primary sponsor: Protagonist Therapeutics, Inc
• Public title: A study to examine the safety and effect of the study drug PTG-100 in patients with inflammation of the colon
• Scientific title: A PHASE 2B RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL ADAPTIVE 2-STAGE, MULTI-CENTRE STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ORAL PTG-100 INDUCTION IN SUBJECTS WITH MODERATE TO SEVERE ACTIVE ULCERATIVE COLITIS
• Date of first enrolment: 09/02/2017
• Target sample size: 240
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003452-75
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Adaptive design If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Bosnia and Herzegovina, Croatia, Czech Republic, Germany, Greece, Hungary, Latvia, Netherlands, Poland, Russian Federation, Serbia, Slovenia, Ukraine, United Kingdom, United States

Contacts

• Name: Clinical trials information
• Affiliation: Protagonist Therapeutics, Inc

• Name: Clinical trials information
• Affiliation: Protagonist Therapeutics, Inc

Key inclusion & exclusion criteria

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 total 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-a 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-a antagonists. For subjects in the Netherlands, only subjects who have had prior exposure to anti TNF agents will be allowed to enrol in the study (as confirmed by medical record documentation or by 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 mont
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 cluded from the study because of a pathology finding of indefinite dysplasia with reactive atypia. Subjects with resected adenomatous polyps may be enrolled. 4. Current bacterial or parasitic pathogenic enteric infection, including Clostridium difficile, (confirmed by toxin result), current infection with hepatitis B or C virus, (subjects treated for HCV infection must have
evidence of sustained virologic response 12 weeks after the end of
treatment [SVR12], 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 reated 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. 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 ad

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Moderate to Severe Active Ulcerative Colitis
MedDRA version: 20.1 Level: LLT Classification code 10045365 Term: Ulcerative colitis System Organ Class: 100000004856

Intervention(s)

Product Name: PTG-100
Product Code: PTG-100
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: -
Current Sponsor code: PTG-100
Other descriptive name: PN-10884A
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: PTG-100
Product Code: PTG-100
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: -
Current Sponsor code: PTG-100
Other descriptive name: PN-10884A
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: 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 a4ß7 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

Main Objective: 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.

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

Timepoint(s) of evaluation of this end point: Efficacy:
1) Week 12

Safety:
1) Refer to schedule of study procedures

Secondary Outcome(s)

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)

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

Secondary ID(s)

PTG-100-02

2016-003452-75-LV

Source(s) of Monetary Support

Protagonist Therapeutics, Inc