| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately-to-Severely Active Ulcerative Colitis |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| 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 |
Phase 2b Dose-Finding Induction
• Assess the effect of TD-1473 taken daily for 8 weeks at daily doses of 20 mg, 80 mg, and 200 mg on the change in total Mayo score
• Assess the effect of TD-1473 on rates of clinical remission, endoscopic healing, clinical response, and mucosal (ie, histologic and endoscopic) healing
• Upon completion, select dose(s) of TD-1473, based on safety, tolerability, and efficacy data, including exposure-response data, for continued evaluation in the Phase 3 dose-confirming Induction Study and the Phase 3 Maintenance Study
Phase 3 Dose-Confirming Induction
• Assess the clinical remission rates associated with TD-1473 compared to placebo treatment at Week 8
• Assess the safety and tolerability of TD-1473 taken for up to 16 weeks
Phase 3 Maintenance
• Assess the clinical remission rates associated with TD-1473 compared to placebo treatment at mWeek 44
• Assess the safety and tolerability of TD-1473 with up to 44 additional weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
Phase 3 Dose-Confirming Induction
Assess the rates of the following associated with TD-1473 compared to placebo treatment:
• Endoscopic healing, symptomatic remission, clinical response, and mucosal healing (endoscopic and histologic) at Week 8
• Assess at Week 16 the clinical response rate following extended induction treatment with TD-1473 in subjects who did not demonstrate clinical response at Week 8
Phase 3 Maintenance
Assess the rates of the following associated with TD-1473 compared to placebo treatment:
• Clinical response, endoscopic healing, symptomatic remission, and mucosal healing at mWeek 44
• Corticosteroid-free remission at mWeek 44
• Maintenance of clinical remission at mWeek 44 in those who were in clinical remission at mWeek 0 |
|
| 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 |
Optional Genetic Test
An optional genetic testing will be performed in all subjects who agree to participate and provide their additional specific consent. The genetic blood sample should be collected at the Day 1 visit |
|
| E.3 | Principal inclusion criteria |
1. Are male or female 18 years of age or older at Screening
2. Has ≥ 3 months history of UC prior to screening (with involvement
beyond the rectum to at least 15 cm from the anal verge)
a. Diagnosed by sigmoidoscopy or colonoscopy AND
b. If possible, corroborated by histology report or documentation of
histological results in a physician note. However, if there was no biopsy
done previously or if no prior endoscopy or histology report is available
for review, the subject must have a colonoscopy instead of a
sigmoidoscopy at screening.
3. Must be willing to have a sigmoidoscopy or colonoscopy at screening.
Colonoscopy will be performed instead of a sigmoidoscopy at screening
in the following scenarios: a. If UC diagnosis precedes screening by ≥ 8
years for pan-colitis or ≥12 years for left-sided colitis and the subject
does not have documentation of a surveillance colonoscopy within 12
months prior to screening to rule out dysplasia (report must be reviewed
by the investigator and included in the source documents). During
colonoscopy, if chromoendoscopy or surveillance biopsies are indicated
as per locally adopted guidelines, these should be performed.
b. If UC diagnosis precedes screening by < 12 years and the subject does
not have documentation of a colonoscopy within 2 years prior to
screening (report must be reviewed by investigator and included in the
source documents).
c. If there is no documented histology report from prior endoscopy
showing chronic colitis or other signs of UC. In this case, consideration
should be made to do biopsies during the screening endoscopy with
histology sent locally to confirm diagnosis of UC, if there is doubt of
diagnosis.
d. If chromoendoscopy has to be performed or ≥ 10 biopsies are to be
collected for dysplasia surveillance, either should be done after
completion of a full colonoscopy to avoid chromoendoscopy dye or
biopsy-related bleeding artifact from interfering with endoscopic images
for central reading.
4. Has moderately-to-severely active UC, defined as having:
a. a centrally read Mayo endoscopic sub score of ≥ 2 points based on the
results of the Screening Stage 2 endoscopy and
b. an adapted Mayo score between 4 and 9 points, inclusive, on Day 1.
5. Is corticosteroid-dependent or had intolerance or inadequate
response to any of the following: aminosalicylates, corticosteroids,
immunomodulators (azathioprine or 6 mercaptopurine), or biologics
(anti-TNF, anti-integrin, or anti-IL-12/23)[Refer to Appendix 7 of the
protocol]
NOTE: for subjects in Portugal, subject must have had intolerance or
inadequate response to biologics
6. If currently receiving an oral corticosteroid, subject is eligible if:
a. the subject has been on corticosteroids 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
beclomethasone diproprionate (ie, Clipper) at 5 mg/day or budesonide 9
mg/day AND
c. the dose is stable for at least 2 weeks prior to Screening Stage 2 visit
7. If subject is currently receiving oral aminosalicylate (eg, mesalamine
products, balsalazide, or sulfasalazine): subject is eligible provided the
subject has been on it at a stable dose for ≥ 4 weeks prior to Day 1.
8. During the Study and for 7 days after receiving the last dose of the
Study drug, females of childbearing potential or men capable of
fathering children must agree to use highly effective birth control
measures (failure rate <1% when used consistently and correctly) or
agree to abstain from sexual intercourse. Females of childbearing
potential must test negative for pregnancy at screening and at Day 1
(Refer to Section 4.3 of the protocol).
9. All male subjects must agree to refrain from semen donation during
the Study and for 7 days after the last dose of Study drug.
10. Must be able and willing to adhere to the Study visit schedule and
comply with other protocol requirements.
11. Are capable of providing informed consent, which must be obtained
prior to any Study-related procedures.
Inclusion Criteria for Extended Induction (additional 8 weeks):
12. Did not meet criteria for clinical response by adapted Mayo score
using centrally read endoscopic subscore at Week 8a
Inclusion Criteria for Maintenance Study:
13. Must have met the criteria for a clinical response by adapted Mayo
score using centrally read endoscopic sub score during Induction at
Week 8a or during Extended Induction at Week 16.
|
|
| E.4 | Principal exclusion criteria |
Subjects may not be enrolled if they:
1. Has symptoms or signs suggestive of fulminant colitis, toxic megacolon, intestinal perforation
2. Has primary sclerosing cholangitis
3. Is likely to require surgery for UC or any other type of major surgery during the Study
4. Has had a clinically significant, as deemed by the investigator, prior
intestinal resection for UC or for other GI diseases
5. Has carried or carries a diagnosis of Crohn's disease, microscopic
colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or indeterminate colitis, or the subject has a current or past diagnosis of a fistula or abdominal abscess.
6. Has unresected colonic mucosal dysplasia
7. Taken or taking any prohibited medications as listed in the protocol
8. If subject has recently discontinued aminosalicylates or corticosteroids, these must have been stopped at minimum of 2 weeks before screening endoscopic procedure.
9. Has failed ≥3 biologics of ≥ 3 different mechanisms of action (i.e., anti TNF, anti-integrin, and anti-IL12/23
10. Currently taking or has taken within 14 days prior to Day 1 any concomitant medication, herbal supplement or dietary substance (eg, grapefruit) known to be a strong inhibitor or inducer of P-gp, BCRP, or CYP450 3A4 or is a substrate of P-gp or BCRP and has a narrow therapeutic index
11. Taking non-UC concomitant prescription medications that the
investigator deems may confound the safety assessment of the study drug and that have started or have had a dose adjustment within 28 days prior to Day 1 (with the exception of corticosteroids, antibiotics for infections, sedating agents for sigmoidoscopy or colonoscopy, hormonal contraceptives, hormone replacement therapy, iron, vitamin D, insulin therapy, and replacement thyroid hormone - Refer to Appendix 6 for
Prohibited medications). Anti diarrheal medications and probiotics are allowed only if dose has been stable for minimum of 14 days prior to Day 1.
12. Taking over-the-counter medications or dietary supplements that the
investigator deems may confound the safety assessment of the study drug and that have started or have had a dose adjustment within 14 days prior to Day 1 with the exception of up to 3 times per week use of non-steroid anti-inflammatory drugs or acetaminophen used on an as needed basis, aspirin ≤ 325 mg per day for cardiovascular prophylaxis,
and over the counter doses of vitamin D
13. Subject is positive for:
a. HBV surface antigen
b. HBV core antibody (unless subject has positive HB surface antibody and undetectable serum HB DNA).
c. HCV antibody unless: a) there is evidence of undetectable viral load
measured twice six months apart after successful completion of treatment regimen and b) viral load during Screening is undetectable
d. Hepatitis E IgM antibody
e. HIV antibody
14. Subject has had a live viral vaccine within 4 weeks prior to screening and/or is unwilling or unable to avoid live viral vaccines during the Study and for 8 weeks following completion of the Study. Subject must be willing to avoid contact with any household member who has been vaccinated with a live attenuated vaccine within 2 weeks after vaccination.
15. Has or may have untreated active or latent TB
16. Has any of the following:
a. An active, clinically significant,bacterial, parasitic, fungal,mycobacterial (including atypical infection), or viral infection, except for local skin or nail bed infection, within 2 weeks prior to Day 1.
b. Any infection requiring intravenous antibiotics within 30 days prior to screening.
c. Any infection requiring oral antimicrobial treatment within 2 weeks
prior to Day 1.
d. A history of more than two episodes of herpes zoster or one or more episodes of disseminated/complicated herpes zoster (complicated: multi-dermatomal, ophthalmic, or CNS involvement or post-herpetic neuralgia) or disseminated herpes simplex.
e. Has had a chest radiograph or equivalent chest imaging within 90 days prior to Screening or at Screening that shows an abnormality suggestive of a malignancy of current active infection, including TB, chronic lung disease or a potentially active fungal, viral, or bacterial
infection.
f. Has C. difficile or other GI infections (eg, Salmonella, Shigella, Yersinia, Campylobacter, E. coli 0157, etc.) on stool testing or CMV colitis suspected on endoscopy within 30 days of Day 1.
17. Has ever had a bone marrow transplant.
18. Are pregnant, lactating, breastfeeding or planning to become pregnant during the Study or within 7 days after the last dose of Study Drug
19. Has known moderate or severe hepatic impairment (eg, Child-Pugh
Class B or C)
20. Has clinically significant abnormalities in the results of laboratory
valuations at screening
21. Has a clinically significant abnormal ECG at screening
22. Has known hypersensitivity to excipients or contents of the Study drug
Please refer to the protocol for the complete list of exclusion criteria
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Ph2b Induction Efficacy Endpoints - Change in total Mayo score from baseline at Week 8
Ph3 Induction Efficacy Endpoints - Clinical remission by adapted Mayo score components at Week 8
Ph3 Maintenance Efficacy Endpoints - Clinical remission by adapted Mayo score components at mWeek 44 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Ph2b Induction Efficacy Endpoints - Week 8
Ph3 Induction Efficacy Endpoints - Week 8
Ph3 Maintenance Efficacy Endpoints - Maintenance Phase Week 44 |
|
| E.5.2 | Secondary end point(s) |
Ph2b Induction Efficacy Key Secondary Endpoints (with multiplicity control):
• Clinical remission by adapted Mayo score components at Week 8
Ph3 Induction Efficacy Key Secondary (with multiplicity control) Endpoints:
• Endoscopic healing at Week 8
• Symptomatic remission at Week 8
• Clinical response by adapted Mayo score definition at Week 8
• Mucosal healing at Week 8
Ph3 Maintenance Efficacy Key Secondary (with multiplicity control) Endpoints:
• Maintenance of clinical response by adapted Mayo score at mWeek 44
• Endoscopic healing at mWeek 44
• Symptomatic remission at mWeek 44
• Corticosteroid-free remission at mWeek 44
• Maintenance of clinical remission at mWeek 44 in those who were in clinical remission at mWeek 0
• Mucosal healing at mWeek 44 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Ph2b Induction Efficacy Endpoints - Week 8
Ph3 Induction Efficacy Endpoints - Week 8
Ph3 Maintenance Efficacy Endpoints - Maintenance Phase Week 44 |
|
| 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) | Yes |
| 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 | 4 |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
| Bulgaria |
| Canada |
| Croatia |
| France |
| Georgia |
| Germany |
| Greece |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Taiwan |
| 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
|
| last subject study visit (including the 4 week follow up visit) in the Phase 3 Maintenance study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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