| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately-to-Severely Active Crohn's Disease (CD) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10013099 |
| E.1.2 | Term | Disease Crohns |
| 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 |
The primary objectives of this study are to:
1. Assess the effect of TD-1473 when compared to placebo by using the Crohn’s disease Activity Index (CDAI) score, after 12 weeks treatment, in patients with moderately-to-severely active Crohn’s disease.
The CDAI quantifies the symptoms of Crohn’s disease by using several parameters.
2. Assess the safety and tolerability of TD-1473. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to assess the effects of TD-1473 compared to placebo after 12 weeks treatment by: clinical improvement, clinical effect, response confirmed by endoscopic assessment and improvement confirmed by the Simplified Endoscopic Score for Crohn’s disease (SES-CD).
The SES-CD quantifies the endoscopic appearance of the small and large bowel.
Exploratory objectives of the study are to assess the effects of TD-1473 given for 12 weeks compared to placebo as follows:
• To improve abdominal pain score by numerical rating scale (NRS) at Week 12 and active treatment extension (ATE) Week 24
• To induce clinical response with alternative definitions at Week 12 and active treatment extension (ATE) Week 24
• To assess the pharmacokinetics using a population PK-based approach
• To assess the relationship between inflammation-associated blood and tissue biomarkers and clinical endpoints
• To assess clinical endpoints and change in biomarkers during ATE |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| The sponsor considers the optional genetic testing to be a sub-study. |
|
| E.3 | Principal inclusion criteria |
1.Subject is willing and able to provide written, signed informed consent at Screening Part 1 prior to start of any study-related procedures
2.Subject is a male or female at least 18 years of age at the time of Screening
3.Subject has a diagnosis of CD with involvement of at least the ileum or any portion of the colon at a minimum, diagnosed by radiology, endoscopy, and/or histology at least 3 months prior to Screening. The
report of a previous diagnostic exam (endoscopy, radiology, and/or pathology) must be reviewed by the investigator and included in the source documents.
4.Subjects must have up-to-date colorectal cancer screening as per locally adopted guidelines (e.g., if subject has had ≥ 8 years of disease involving >30% of the colon, surveillance biopsies or chromoendoscopy
should be performed if either is indicated as per locally adopted guidelines but has not been performed within the 12 months prior to Screening). If indicated, the surveillance biopsies (if ≥ 10) and chromoendoscopy need to be performed during Screening Stage 2 ileocolonoscopy after recording of a full ileocolonoscopy has been completed to avoid dye or biopsy related bleeding artifact on the recorded images.
5.Subject has CDAI score ≥ 220 and ≤ 450
6.Subject has a SES-CD score of ≥ 3 with ulceration (corresponding to a score of ≥1) in at least 1 of the 5 ileocolonic segments on the Ulcerated Surface subscore of the SES CD, as assessed by central reading, during
Screening
a.Up to approximately 10% of the study population will have SES-CD score of between 3 and 5, inclusive, with the presence of ulceration in any 1 of the 5 ileocolonic segments, all other subjects (approximately
90% of the study population) will require an SES-CD score of ≥ 6 (≥ 4 if isolated ileal disease) with ulceration (corresponding to a score of ≥ 1) in at least 1 of the 5 ileocolonic segments on the Ulcerated Surface
subscore of the SES-CD
7.Subject is corticosteroid-dependent or had intolerance or inadequate response to any of the following: aminosalicylates, corticosteroids, immunomodulators (azathioprine, 6 mercaptopurine, or methotrexate),
or biologics (anti-TNF anti-IL-12/IL-23 therapy, or anti-integrin)
NOTE: For subjects in Portugal, subject must have had intolerance or inadequate response to biologics
8.If subject is currently receiving an oral corticosteroid, subject is eligible if:
a.the subject has been on corticosteroid for a minimum of 4 weeks prior to Day 1 AND
b.the dose is equivalent to or less than prednisone 25 mg/day or budesonide 9 mg/day or beclomethasone at 5 mg/day AND
c.the dose is stable for at least 2 weeks prior to Screening Stage 2 AND
d.the subject is willing to continue on the same dose as warranted until Week 8
9.if subject is currently receiving oral aminosalicylate (including, but not limited to sulfasalazine or mesalamine), the subject is eligible provided the subject has been on a stable dose for ≥ 4 weeks prior to Day 1 and is willing to stay on the same dose as warranted until Week 12. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria Pertinent to GI:
1.Subject with a confirmed or suspected diagnosis or history of primary sclerosing cholangitis (PSC)
2.Subject has had extensive colonic resection (i.e. more than half of colon), subtotal or total colectomy, intestinal resection within 6 months of Screening, > 2 small bowel resections or carries a diagnosis of short
bowel syndrome or currently has an ostomy
3.Subject has a history of unresected colonic mucosal dysplasia or history of resected high-grade colonic dysplasia within 3 years prior to Screening. Subjects will not be excluded from the study because of a pathology finding of indefinite dysplasia with reactive atypia or because of adenomas that have been completely resected
Exclusion Criteria Pertinent to Medications:
1.Medications of exclusion (Refer to Section 6.4.29 and Appendix 11 for prohibited medications) below must be discontinued within the timeframe specified (if applicable)
•azathioprine, 6-mercaptopurine, or methotrexate taken within the 14 days prior to Day 1
•anti-TNFs (e.g., adalimumab, infliximab, golimumab, etanercept, certolizumab, or biosimilars) taken within the 60 days or 5 half-lives, whichever is longer, prior to Day 1
•intravenous corticosteroids within the 14 days prior to Day 1
•rectal mesalamine or corticosteroid (i.e. enemas or suppositories) taken within the 14 days prior to Day 1
•prior exposure to vedolizumab, ustekinumab, mycophenolic acid, tacrolimus, sirolimus, or cyclosporine taken within 60 days or 5 half-lives, whichever is longer prior to Day 1
•any prior exposure to natalizumab, rituximab, efalizumab, fingolimod, cyclophosphamide, or thalidomide
•NSAIDs taken on a regular (more than 3 times per week, on average) basis (regular use of aspirin ≤ 325 mg per day for cardiovascular protection is allowed).
•anakinra or any other immune-modifying biologic agent taken within 90 days prior to Day 1
•A JAK inhibitor (e.g. tofacitinib) within 60 days prior to Day 1
2.Prior exposure or potential exposure to a JAK inhibitor that was stopped due to intolerance or lack of efficacy. This does not include subjects with prior exposure to another JAK inhibitor that was stopped
for any other reason (e.g. loss/lack of insurance coverage or end of study)
3.Subject has participated in another clinical trial of an investigational drug (or medical device) within 30 days prior to Screening or 5x the half-life of the investigational drug, whichever is longer, or is currently
participating in another trial of an investigational drug (or medical device)
4.Subject has had inadequate response (i.e. either primary or secondary non-response) to ≥ 3 biologic agents of 3 different mechanisms of action (i.e. anti TNF, anti-integrin, and anti-IL12/23)
Exclusion Criteria Pertinent to Infections:
1.Subject is positive for:
a.HBV surface antigen
b.HBV core antibody (unless subject has positive hepatitis B surface antibody and undetectable serum hepatitis B DNA)
c.HCV antibody unless: a) there is evidence of undetectable viral load measured twice 6 months apart after completion of treatment regimen and b) viral load during Screening is undetectable
d.hepatitis E IgM antibody
e.HIV antibody
2.The subject has or may have untreated active or latent TB as evidenced by any of the following:
a.Two indeterminate or two positive QuantiFERON®TB Gold result within 90 days prior to screening or during the Screening Period, without having completed an adequate treatment for latent or active TB before Screening OR
b.Chest X-ray or equivalent chest imaging within 90 days prior to Screening in which active or latent pulmonary TB cannot be excluded.
A subject who has a history of latent or active TB may be eligible for the study if criteria outlined in Section 6.4.15 are met.
3.Subject has:
a.an active, clinically significant bacterial, parasitic, fungal, mycobacterial (including atypical infection), or viral infection, except for local skin or nail bed infection, within 30 days prior to Day 1
b.any infection requiring hospitalization or intravenous antibiotics within 30 days prior to Screening
c.any infection requiring oral antimicrobial treatment within 2 weeks prior to Screening
d.a history of more than one episode of herpes zoster or one or more episodes of disseminated or complicated herpes zoster (complicated: multi-dermatomal, ophthalmic, or CNS involvement or post-herpetic neuralgia) or disseminated herpes simplex
4.Subject has C. difficile or other gastrointestinal infections (e.g. Salmonella, Shigella, Yersinia, Campylobacter, E. coli O157, etc.) on stool testing or cytomegalovirus [CMV] colitis suspected on endoscopic
appearance during Screening. Subject may be treated, re-tested, and rescreened.
5.Within 4 weeks of Screening or during Screening, subject has: Confirmed OR Suspected SARS-CoV-2 infection (coronavirus disease 2019 [COVID-19]) (test positive), OR close contact with a person with known or suspected SARS-CoV-2 infection |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • CDAI score change from baseline at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
• CDAI clinical response (defined as reduction from baseline of ≥ 100
points or CDAI < 150) at Week 12
• CDAI clinical remission (defined as CDAI < 150) at Week 12
• SES-CD change from baseline at Week 12
• Endoscopic response (SES-CD reduction of ≥ 50% from baseline or
endoscopic remission) at Week 12
• SFAP clinical remission defined as abdominal pain score ≤ 1 (on a scale
of 0-3), stool frequency ≤ 2.8, and both not worse than baseline at Week
12
Study Safety Endpoints:
• Changes from baseline in vital signs, ECGs, and clinical laboratory
results
• Incidence and severity of AEs |
|
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Combined Induction and Active Treatment Extension (ATE) phase |
|
| 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 | 80 |
| 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 |
| Austria |
| Bulgaria |
| Croatia |
| France |
| Georgia |
| Germany |
| Greece |
| Hungary |
| Israel |
| Korea, Republic of |
| New Zealand |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| South Africa |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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