A Phase 2b Study to Evaluate the Efficacy and Safety of Oral TAK-279 in Subjects with Moderately to Severely Active Crohn’s Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

4 Sep 2024 → ongoing

Decision date (initial)

2024-07-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2023-506704-14-00

ClinicalTrials.gov

NCT06233461

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacogenomic, Pharmacodynamic, Therapy, Safety, Efficacy, Pharmacokinetic, Pharmacogenetic

To evaluate the efficacy of TAK-279 orally administered, compared to placebo, in achieving endoscopic response at Week 12 in subjects with moderately to severely active CD.

Secondary objectives 3

1. 1. To evaluate efficacy of TAK-279 orally administered compared to placebo in achieving clinical remission, clinical response, and endoscopic remission at Week 12 in subjects with moderately to severely active CD.
2. 2. To evaluate the effect of TAK-279 on patient-reported symptoms over time in subjects with moderately to severely active CD.
3. 3. To evaluate the effect of TAK-279 on disease-specific health-related quality of life in subjects with moderately to severely active CD.

Conditions and MedDRA coding

Moderately to Severely Active Crohn's Disease

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, Pharmaceuticals And Medical Devices Agency

Plan to share IPD

Yes

IPD plan description

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. The subject is willing and able to understand and fully comply with study procedures and requirements (including digital tools and applications), in the opinion of the investigator. The subject has provided informed consent (that is, in writing, documented via a signed and dated ICF) and any required privacy authorization prior to the initiation of any study procedures.
2. Subjects must be ≥18 and ≤75 years of age at the time of the signing of the ICF. In South Korea, the age requirement for adult subjects is ≥19 years of age.
3. Disease-Specific Inclusion Criteria: Subjects must have active moderate to severe ileal (terminal ileum), ileocolonic, or colonic CD at baseline during screening period as defined by: a) CDAI score between 220 and 450 (inclusive) and b) Presence of ulcerations that are characteristic to CD, as determined by ileocolonoscopy performed during screening, and as defined by the SES-CD ≥6 (SES-CD ≥4 for isolated ileitis)
4. Disease-Specific Inclusion Criteria: Subjects must have a documented diagnosis (endoscopic with histology) of CD for at least 30 days before screening. Documented diagnosis is defined as: a) A biopsy report to confirm the histological diagnosis AND b) A report documenting disease duration based upon prior ileocolonoscopy. Note: If a biopsy report is not available in the source document at the time of screening, a local histology report of a biopsy performed during the screening ileocolonoscopy should be consistent with a CD diagnosis. If the histology diagnosis is not clear and the endoscopy is inconsistent with CD at this time point, the subject will not be randomized.
5. Disease-Specific Inclusion Criteria: Subjects with a family history of colorectal cancer, personal history of increased colorectal cancer risk, aged >50 years, or other known risk factors must be up to date on colorectal cancer surveillance (may be performed during screening).
6. Disease-Specific Inclusion Criteria: Subjects must be willing and able to undergo ileocolonoscopy with biopsies during screening after all other inclusion criteria have been met.
7. Prior Treatment Failure Criteria: 7. Subjects with a history of inadequate response to, loss of response to, or intolerance to one or more of these therapies for CD based on Physician assessment: (according to either (a) or (b) below or a combination of both) (Details provided in Appendix 2).: a) 6-mercaptopurine or azathioprine, oral or IV corticosteroids or history of corticosteroid dependence (an inability to successfully taper corticosteroids without return of CD symptoms), oral 5-ASAs AND/OR b) Biologic agents (such as TNF antagonists, antibodies to IL-23p19, IL-12/23p40, vedolizumab) or any advanced therapy (such as JAKi or S1P receptor modulators).
8. Other General Inclusion Criteria: 8. Subjects are (CCI). For individuals of reproductive potential, if sexually active, agree to comply with the contraceptive requirements for the duration of the study and 10 days after the last dose of the study drug. The following birth control requirements must be met: b) Female (sex-assigned at birth) subjects must be surgically sterile or be of nonchildbearing potential with confirmation of postmenopausal status (ie, follicle-stimulating hormone level >40 mIU/mL); or, if sexually active with a nonsterilized individual who produces sperm agrees to use a highly effective method of contraception from the signing of informed consent throughout the duration of the study

Exclusion criteria 28

1. Exclusion Criteria Related to GI Tract: Subjects with IBD indeterminate or unclassified, microscopic colitis, ischemic colitis, infectious colitis, or radiation colitis, and diverticular disease associated with colitis, and/or clinical/histologic findings suggestive of ulcerative colitis.
2. Exclusion Criteria Related to GI Tract: Have complications of CD such as strictures, stenoses, short gut syndrome, or any other manifestation that might require surgery during the study, could preclude the use of the CDAI/PRO2 to assess response to therapy, or would possibly confound the evaluation of benefit from treatment with TAK-279.
3. Exclusion Criteria Related to GI Tract: Have any current or prior abscesses unless they have been drained and treated at least 6 weeks prior to randomization and are not anticipated to require surgery during the treatment period. Subjects with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses present.
4. Exclusion Criteria Related to GI Tract: Subjects with presence of enterovesical (ie, between the bowel and urinary bladder) or enterovaginal fistulae.
5. Exclusion Criteria Related to GI Tract: Have had any kind of bowel resection or diversion within 6 months or any other intraabdominal surgery within 3 months prior to screening. Subjects with >2 bowel resections, subtotal colectomy, or proctocolectomy are excluded. Subjects who have had limited surgery for CD may be allowed in the study, provided that this does not affect efficacy assessment. Discussion with the sponsor medical team should occur prior to screening.
6. Exclusion Criteria Related to GI Tract: Subjects with a current ileostomy or colostomy. Subjects who had a j-pouch are excluded as a j-pouch could result in a stoma.
7. Exclusion Criteria Related to GI Tract: Subjects with obstructive/ symptomatic colonic stricture may require surgery for CD during treatment period.
8. Exclusion Criteria Related to GI Tract: Subjects with past medical history or presence of toxic megacolon.
9. Exclusion Criteria Related to GI Tract: Subjects with gastrointestinal dysplasia or neoplasia except history of adenomatous polyps that have been completely removed.
10. Exclusion Criteria Related to GI Tract: Subjects with evidence or suspicion of liver disease or primary sclerosing cholangitis.
11. Exclusion Criteria related to Medication:
12. Exclusion Criteria Related to Other Prohibited Concomitant Medications: Subjects on CD-related antibiotics who have not been on stable doses for greater than or discontinued within 14 days prior to the first administration of study drug.
13. Exclusion Criteria Related to Other Prohibited Concomitant Medications: Subjects on oral 5-ASAs who have not been on stable doses for greater than, or discontinued within, at least 14 days prior to the first administration of study drug or receiving mesalamine >4.8g/day (or equivalent).
14. Subjects on high dose corticosteriods
15. Subjects on prohibited medications as listed in the protocol
16. Exclusion Criteria related to Infectious Diseases: Tuberculosis (TB): a) Subject has current active TB infection, regardless of treatment status. b) Subject who has positive QuantiFERON will require to start treatment for latent TB at least 2 weeks prior to randomization. c) Subject has a positive QuantiFERON-TB Gold (QFT) or T-Spot, TB skin test (TST) result or 2 indeterminate QFT or TST results. TST is considered positive if reaction ≥10 mm, unless there are no signs/symptoms of active TB and documentation of prior and complete treatment for latent TB (appropriate in duration and type according to current local country guidelines) has been completed or subject has initiated prophylaxis based on local guidelines a minimum of 2 weeks prior to the first administration of study drug and documentation of no history of active TB can be provided. Note: TB prophylaxis regimens should be administered according to local guidelines. However, because of potential interactions with TAK-279, rifampin should not be used. Note: QFT or TST may be used based on country and site-specific guidelines. d) Subject has had any imaging study during or 6 months prior to screening, including x-ray, chest computed tomography, magnetic resonance imaging, or other chest imaging suggesting evidence of current active of TB.
17. Exclusion Criteria related to Infectious Diseases: Herpes infections: a) Subject has active herpes virus infection, including herpes zoster or herpes simplex 1 and 2 (demonstrated on physical examination and/or medical history) at screening or prior to the first administration of study drug, b) Subject has a history of herpetic infection within 8 weeks prior to screening. c) Subject has history of serious herpetic infection that includes any episode of disseminated disease, multidermatomal herpes simplex virus, herpes encephalitis, ophthalmic herpes, or recurrent herpes zoster (defined as 2 episodes within 2 years).
18. Non-herpetic viral diseases: a) Subject has presence of hepatitis C virus (HCV) antibody and a positive confirmatory test result for HCV RNA (nucleic acid test or polymerase chain reaction). b) Subject has presence of positive hepatitis B surface antigen (HBsAg+), presence of hepatitis B virus DNA, or positive anti-hepatitis B core antibody without concurrent positive hepatitis B surface antibody (HBcAb+ and HBsAb-). c) Subject has positive results for HIV by serology, regardless of viral load.
19. Other infectious diseases: a) Subject has history of symptoms suggestive of systemic or invasive infection within 30 days prior to the first administration of study drug. b) Subject has history of bacterial, viral, or fungal infection that required hospitalization or treatment with intravenous antimicrobial therapy within 8 weeks prior to the first administration of study drug, or oral antimicrobial therapy within 30 days prior to the first administration of study drug. c)Subject has a history of chronic or recurrent bacterial disease, including but not limited to chronic pyelonephritis or cystitis, chronic bronchitis/pneumonitis, osteomyelitis, or chronic skin ulcerations/infections or fungal infections (except superficial onychomycosis). d) Subject has a history of an infected joint prosthesis unless that prosthesis has been removed or replaced within 60 days prior to the first administration of study drug. e) Subject has a history of opportunistic infections (eg, Pneumocystis jirovecii pneumonia, histoplasmosis, coccidiomycosis). f) Subjects with active enteric infections (positive stool culture and sensitivity), intestinal pathogens, Clostridioides difficile infection or pseudomembranous colitis (subjects with infection at screening may be allowed retest after treatment) within 4 weeks prior to the first administration of study drug. g) Subject has active CMV colitis requiring treatment in last 2 weeks prior to the first administration of study drug.
20. Exclusion Criteria related to Health: Noninfectious Disorders Exclusions: Subject has any clinically significant medical condition, evidence of an unstable clinical condition (eg, cardiovascular, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, or immunologic), or vital signs/physical/laboratory/ ECG abnormality that would, in the opinion of the investigator, put the subject at undue risk or interfere with interpretation of study results. These include but are not limited to: a) Subject has a history of known or suspected condition/illness that is consistent with compromised immunity, including but not limited to any identified congenital or acquired immunodeficiency, splenectomy. b) Subject had a major surgery within 60 days prior to the first administration of study drug or has a major surgery planned during the study. c) Subject has uncontrolled hypertension characterized by systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg at screening, confirmed by 2 separate visits. d) Subject has a history of Class III or IV congestive heart failure as defined by New York Heart Association criteria. e) Subject has a history of cancer or lymphoproliferative disease within 5 years prior to the first administration of study drug. Note: Subjects with successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix are not to be excluded based on this exclusion criterion. f) For subjects with asthma, chronic obstructive pulmonary disease, or other pulmonary illnesses, subject has been hospitalized in the past 3 months, has ever required intubation for treatment, currently requires oral corticosteroids treatment, or has required more than one course of oral corticosteroids within 6 months prior to the first administration of study drug. g) Subject has any of the following cardiovascular history or unstable cardiovascular disease: •A new diagnosis of atrial fibrillation or an episode of atrial fibrillation with rapid ventricular response or other dysrhythmia, non-acute cardiac hospitalization (eg, pacemaker implantation), pulmonary embolism, or deep venous thrombosis within the past 6 months prior to screening. •Any history of cerebrovascular event, myocardial infarction, coronary stenting, or aorto-coronary bypass surgery within the past 6 months prior to screening. h) Subject has ECG abnormalities that are considered clinically significant and would pose an unacceptable risk to the subject if they participate in the study, in the opinion of the investigator. i) Subject has history of any significant/uncontrolled psychiatric illness (including but not limited to active suicidal ideation at screening or prior to the first administration of study drug) for which participation in the trial would, in the opinion of the investigator, put the subject at undue risk, or would interfere with interpretation of study results. j) Subject has a known history of clinically significant drug or alcohol abuse within 12 months prior to the first administration of study drug as determined by the investigator.
21. Exclusion Criteria related to Laboratory Investigations: Subject has inadequate renal or hepatic function before randomization based on the following parameters: a) Total bilirubin (unconjugated and/or conjugated) ≥1.5 × ULN unless the subject has known Gilbert’s syndrome that can explain the elevation of bilirubin, or b) Serum ALT or AST ≥3 × ULN, or c)Creatinine >1.5 × ULN. –Note: The subjects may be retested (1 time) to meet eligibility criteria at the discretion of the investigator. d) Estimated creatinine clearance <45 mL/min based on the Cockcroft-Gault calculation.
22. Exclusion Criteria related to Laboratory Investigations: Subject with any of the following laboratory values at the screening visit: a) Hemoglobin <9.0 g/dL (<90.0 g/L) b) Absolute white blood cell count <3.0 × 109/L (<3000/mm3) c) Absolute neutrophil count of <1.2 × 109/L (<1200/mm3) d) Absolute lymphocyte count of <0.75 × 109/L (<750/mm3) e) Platelet count <100 × 109/L g) Thyroid-stimulating hormone (TSH), free T4 (thyroxine) or T3 (triiodothyronine) outside the normal reference range. h) Subject has any other significant laboratory abnormalities that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study. i)CPK > ULN. CPK may be repeated once; if repeat value is CTCAE Grade 1 or lower (or ≤2.5 × ULN) and no higher than the initial value, subject remains eligible. Investigators should assess the subject for modulating factors including concomitant medications or vigorous exercise that may affect CPK levels.
23. Other General Exclusion Criteria: Subject does not tolerate venipuncture or inability to be venipunctured.
24. Allergies and Adverse Drug Reactions Exclusions: a) Subject has history of significant drug allergy (such as anaphylaxis). b) Subject has a known or suspected intolerance, hypersensitivity, or allergy to TAK-279 or any of its components, as follows:
25. Subject has a positive pregnancy test result or plans to become pregnant or donate sperm during the study period, or subject is pregnant or lactating/nursing.
26. Subjects who have given greater than 500 mL of blood or plasma within 30 days of screening (during a clinical trial or at a blood bank donation) or plans to donate blood during the study.
27. Subject is compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
28. Subject is a study site employee, an immediate family member (eg, spouse, parent, child, sibling), or is in a dependent relationship with a study site employee who is involved in conduct of this study or may consent under duress.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Endoscopic response at Week 12, assessed as proportion of subjects achieving decrease in Simple Endoscopic Score for Crohn’s Disease (SES‑CD) >50% from baseline (or for subjects with isolated ileal disease, SES-CD ≤4 or at least a 2‑point reduction from baseline) read centrally.

Secondary endpoints 9

1. 01. Clinical remission at Week 12, assessed as proportion of subjects achieving CD Activity Index (CDAI)<150.
2. 02. Clinical response at Week 12, assessed as proportion of subjects achieving reduction of CDAI from baseline of >100.
3. 03. Endoscopic remission at Week 12, assessed as proportion of subjects achieving SES-CD ≤4 or ≤2 for ileal disease, no subscore >1.
4. 04. Clinical remission in two patient-reported outcome items (PRO2) of the CDAI at Week 12, assessed as proportion of subjects with average daily liquid or very soft stool frequency (SF) score ≤2.8 and not worse than baseline and average daily abdominal pain (AP) score ≤1 and not worse than baseline.
5. 05. Clinical response in PRO2 at Week 12, assessed as proportion of subjects with ≥30% decrease in average daily very soft or liquid stools and/ or ≥30% decrease in average AP from baseline.
6. 06. Proportion of subjects with no bowel urgency as measured by the bowel urgency eDiary item at Week 12.
7. 07. Disease-specific health-related quality of life (HRQoL) as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 12, assessed as proportion of subjects with total score ≥170.
8. 08. Change from baseline in disease-specific HRQoL as measured by the IBDQ total score at Week 12.
9. 09. Change from baseline in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score at Week 12.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

500 Kendall Street

City

Cambridge

Postcode

02142-1108

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Namita Singh

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 15

Locations

14 EU/EEA countries · 96 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 482 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

24 submissions — initial application plus substantial / non-substantial modifications