E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately-to-Severely Active Ulcerative Colitis |
Colite ulcéreuse modérément à sévèrement active |
|
E.1.1.1 | Medical condition in easily understood language |
Ulcerative Colitis (UC) |
Colite ulcéreuse (CU) |
|
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 | 10066678 |
E.1.2 | Term | Acute 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 |
Test génétique optionnel
Un test génétique facultatif sera effectué chez tous les patients qui acceptent de participer et fournissent leur consentement spécifique supplémentaire. L’échantillon de sang génétique doit être prélevé lors de la visite du jour 1 |
|
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. Corroborated by histology report or documentation of histological results in a physician note. If neither is available, 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 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 centrally read Mayo endoscopic sub score of ≥ 2 points based on the results of the Screening Stage 2 endoscopy and 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 or anti-integrin) [Refer to Appendix 7 of the protocol]
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. |
1. Être de sexe masculin ou féminin et âgé de 18 ans ou plus à la sélection
2. Avoir des antécédents de RH ≥ 3 mois avant la sélection (avec une atteinte s’étendant au-delà du rectum jusqu’à au moins 15 cm de la marge de l’anus)
a. Diagnostic fait par sigmoïdoscopie ou coloscopie ET
b. Confirmé par un rapport d’histologie ou une documentation des résultats histologiques dans une note du médecin. Si ni l’un ni l’autre ne sont disponibles, le patient doit subir une coloscopie plutôt qu’une sigmoïdoscopie à la sélection.
3. Doit être disposé à subir une sigmoïdoscopie ou coloscopie à la sélection. Une coloscopie plutôt qu’une sigmoïdoscopie sera réalisée à la sélection dans les cas suivants (exposés dans la Section 6.4.1.20) :
a. Si le diagnostic de RH précède la sélection de ≥ 8 ans pour une pancolite ou de ≥ 12 ans pour une colite limitée au côlon gauche et que le patient ne dispose d’aucun document pour une coloscopie de surveillance réalisée dans les 12 mois précédant la sélection pour écarter une dysplasie (le rapport doit être examiné par l’investigateur et ajouté dans les documents sources). Pendant la coloscopie, si une chromoendoscopie ou des biopsies de surveillance sont indiquées selon les directives adoptées localement, celles-ci doivent être réalisées.
b. Si le diagnostic de RH précède la sélection de < 12 ans et que le patient ne possède aucun document concernant la réalisation d’une coloscopie dans les 2 ans précédant la sélection (le rapport doit être examiné par l’investigateur et ajouté dans les documents sources).
c. Si une chromoendoscopie doit être réalisée ou ≥ 10 biopsies doivent être prélevées pour la surveillance d’une dysplasie, elles doivent être effectuées à l’issue d’une coloscopie complète afin d’éviter que les artefacts associés au colorant utilisé pour la chromoendoscopie ou aux saignements liés aux biopsies n’interfèrent avec les images endoscopiques pour la lecture centralisée.
4. Avoir une RH modérément à sévèrement active définie comme ayant un sous-score endoscopique Mayo lu de façon centralisée ≥ 2 points selon les résultats de l’endoscopie de l’étape 2 de la sélection et un score Mayo adapté entre 4 et 9 points, inclus, le Jour 1.
5. Être dépendant des corticostéroïdes ou être intolérant ou présenter une réponse insuffisante à l’un des traitements suivants : aminosalicylates, corticostéroïdes, immunomodulateurs (azathioprine ou 6-mercaptopurine) ou traitements biologiques (anti-TNF ou anti-intégrine) [consulter l’Annexe 7]
6. S’il est actuellement sous traitement par un corticostéroïde oral, le patient est eligible
si :
a. le patient prend des corticostéroïdes depuis au moins 4 semaines avant le Jour 1 ET
b. la dose est équivalente ou inférieure à 25 mg/jour de prednisone ou à 5 mg/jour de dipropionate de béclométhasone (c.-à-d. Clipper) ou à 9 mg/jour de budésonide ET
c. la dose est stable depuis au moins 2 semaines avant la visite de l’étape 2 de la selection
7. S’il est actuellement sous traitement par un aminosalicylate oral (par ex., produits à base de mésalamine, balsalazide, ou sulfasalazine), le patient est éligible si la dose du traitement est stable depuis ≥ 4 semaines avant le Jour 1.
8. Au cours de l’étude et pendant 7 jours après avoir reçu la dernière dose du médicament de l’étude, les femmes susceptibles d’être enceintes ou les hommes capables d’engendrer des enfants doivent accepter d’utiliser des mesures de contraception hautement efficaces (taux d’échec < 1 % lors d’une utilisation régulière et correcte) ou accepter de s’abstenir de relations sexuelles. Les femmes susceptibles d’être enceintes doivent avoir un résultat négatif au test de grossesse réalisé à la sélection et le Jour 1 (consulter la Section 4.3).
9. Tous les patients de sexe masculin doivent accepter de ne pas effectuer de don de sperme pendant l’étude et pendant 7 jours après la dernière dose du médicament de l’étude.
10. Être capable et disposé à respecter le calendrier des visites de l’étude et les autres exigences du protocole.
10. Être capable et disposé à respecter le calendrier des visites de l’étude et les autres exigences du protocole.
11. Être capable de fournir un consentement éclairé, qui doit être obtenu avant la réalisation de toute procédure liée à l’étude.
Critères d’inclusion pour l’induction prolongée (8 semaines supplémentaires) :
12. Ne pas avoir satisfait aux critères de réponse clinique selon le score Mayo adapté utilisant un sous-score endoscopique lu de façon centralisée en Semaine 8a
Critères d’inclusion pour l’étude d’entretien :
13. Avoir satisfait aux critères d’une réponse clinique selon le score Mayo adapté utilisant un sous-score endoscopique lu de façon centralisée pendant l’étude d’induction en Semaine 8a ou pendant l’étude d’induction prolongée en Semaine 16 |
|
E.4 | Principal exclusion criteria |
Induction Studies and Maintenance Study Exclusion Criteria (Please refer to the protocol for the complete list of 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 (PSC)
3. Is likely to require surgery for UC or any other type of major surgery (ie, surgical procedure requiring general anesthesia) during the Study
4. Has had a clinically significant, as deemed by the investigator, prior intestinal resection for UC or other gastrointestinal 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 a history of 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 been refractory to 3 biologics of ≥ 2 mechanisms of action
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-glycoprotein (P-gp), breast cancer resistance protein (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 have started or have had a dose adjustment within 28 days prior to Day 1. 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 started or with 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. Hepatitis B virus (HBV) surface antigen
b. Hepatitis B virus core antibody (unless subject has positive hepatitis B surface antibody and undetectable serum hepatitis B DNA).
c. Hepatitis C virus (HCV) antibody unless: a) there is evidence of undetectable viral load measured twice six months apart after successful completion of treatment regimen (reviewed by Study Medical Monitor) and b) viral load during Screening is undetectable
d. Hepatitis E
e. Human immunodeficiency virus (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 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 screening.
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 3 months 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 gastrointestinal infections (eg, Salmonella, Shigella, Yersinia, Campylobacter, E. coli 0157, etc.) on stool testing or cytomegalovirus (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 evaluations at screening
21. Has a clinically significant abnormal electrocardiogram (ECG) at screening
22. Has known hypersensitivity to excipients or contents of the Study drug
Exclusion Criteria for Phase 3 Maintenance Study
Subjects who required change of UC medications or any prohibited medication to control UC symptoms during Induction Study |
|
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 78 |
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 |
Poland |
Portugal |
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 | 5 |
E.8.9.1 | In the Member State concerned months | 7 |
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 |