Moderately-to-Severely Active Ulcerative Colitis MedDRA version: 20.1 Level: LLT Classification code 10066678 Term: Acute ulcerative colitis System Organ Class: 100000004856
Conditions
Sponsors
Theravance Biopharma Ireland Limited
Eligibility
Sex/Gender
All
Inclusion criteria
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 a
Exclusion criteria
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 w
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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;Secondary Objective: 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;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 Eff | — |
Secondary
| Measure | Time frame |
|---|---|
| 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;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 | — |
Countries
Australia, Bulgaria, Canada, Croatia, France, Georgia, Germany, Greece, Hungary, India, Israel, Italy, Poland, Portugal, Russian Federation, Serbia, Slovakia, South Africa, Spain, Taiwan, Ukraine, United Kingdom, United States
Contacts
Public ContactClinical Operations - CC
Theravance Biopharma Ireland Limited
Outcome results
None listed