A Phase 3 Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-279 With a Randomized Withdrawal and Retreatment Period in Subjects With Moderate-to-Severe Plaque Psoriasis

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] - Skin and Connective Tissue Diseases [C17]

Trial duration

7 May 2024 → 7 Nov 2025

Decision date (initial)

2024-03-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Safety, Pharmacodynamic, Pharmacokinetic, Pharmacogenetic, Efficacy

To evaluate the efficacy of TAK-279 orally administered once daily (QD) for 16 weeks, compared to placebo, in subjects with moderate-to-severe plaque psoriasis

Secondary objectives 3

1. 1. To further evaluate whether TAK-279 orally administered QD for 16 weeks is superior to placebo in subjects with moderate-to-severe plaque psoriasis.
2. 2. To evaluate whether TAK-279 orally administered QD is superior to apremilast in subjects with moderate-to-severe plaque psoriasis after 16 and 24 weeks of continuous treatment with TAK-279 or apremilast.
3. 3. To evaluate the maintenance and durability of efficacy of TAK-279 during the randomized withdrawal and retreatment period from Week 40 through Week 60 for subjects continuing on TAK-279 compared to those re-randomized to placebo.

Conditions and MedDRA coding

Moderate to Severe Plaque Psoriasis

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

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 2

1. 1.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 2. Subject has provided written informed consent and any required privacy authorization before the initiation of any study procedures 3. Subject has a diagnosis of chronic plaque psoriasis for ≥6 months prior to the screening visit 4. Subject has stable plaque psoriasis defined as no significant flare or change in morphology (as assessed by the investigator) in psoriasis for ≥6 months before screening. 5. Subject has moderate-to-severe plaque psoriasis as defined by a PASI score ≥12 and a sPGA score ≥3 at screening and Day 1. 6. Subject has plaque psoriasis covering ≥10% of his or her total BSA at screening and Day 1. 7. Subject must be a candidate for phototherapy or systemic therapy. 8. Subject is aged 18 years or older at the time of consent. In the European Union (EU)/ European Economic Area (EEA) and the United Kingdom (UK), for subjects aged 65 years or older, the investigator must document a favorable benefit-risk assessment to justify the subject’s inclusion in the study. 9. In the EU/EEA and the UK, for subjects currently smoking or using chewing tobacco or with a history of long-term smoking (≥20 pack years) or chewing tobacco use, the investigator must document a favorable benefit-risk assessment to justify the subject’s inclusion in the study. 10. Subject meets the following birth control requirement: An individual with potential for pregrancy who is now of nonchildbearing potential with laboratory confirmation of postmenopausal status see Section 10.4.1 for definitions); or, if sexually active with a nonsterilized individual who produces sperm, an individual with potential for pregnancy who agrees to use a highly effective method of contraception from the signing of informed consent throughout the duration of the study and for 10 days after the last dose. The use of effective contraception is not required for assigned male sex at birth subjects during the duration of the study. In the EU/EEA and the UK, for subjects who elect to use hormonal contraception as a form of highly effective contraception, the investigator must document a favorable benefit-risk assessment to justify the subject’s inclusion in the study at screening and every 3 months during the study. Note: Oral hormonal contraception may be susceptible to interaction with TAK-279 which may reduce the efficacy of the contraceptive method. Therefore, if the subject is on a form of oral contraception, a second highly effective or effective method of contraception should be used during the treatment period and for at least 10 days after the last dose of study treatment if the subject is sexually active with a partner with whom the subject could become pregnant. A barrier method is recommended, preferably a male condom.
2. 11. For subjects in the EU/EEA or UK, the investigator must have no reason to believe that the participant would be placed at risk by participating in the trial with regard to the European Commission Decision as of 10 March 2023 on measures to minimise risk of serious side effects with Janus kinase inhibitors (EMA/142279/2023). and the UK Medicines and Healthcare products Regulatory Agency (MHRA) guideline on JAK inhibitors: new measures to reduce risks of major cardiovascular events, malignancy, venous thromboembolism, serious infections and increased mortality as of 26 April 2023 (Drug Safety Update volume 16, issue 9).

Exclusion criteria 7

1. 1. Subject has evidence of non-plaque psoriasis (erythrodermic, pustular, predominantly guttate psoriasis, predominantly inverse, or drug-induced psoriasis). If a subject meets criteria for inclusion based on typical plaque psoriasis presentation, a limited amount of inverse psoriasis is not exclusionary. 2. Subject requires systemic treatment, other than nonsteroidal anti-inflammatory drugs, during the trial period for an immune-related disease (eg, inflammatory bowel disease). 3. Subject has a history of excessive sun exposure, has used tanning booths within 4 weeks prior to Day 1, or is not willing to minimize natural and artificial sunlight exposure during the study period. Use of sunscreen products and protective apparel is recommended when sun exposure cannot be avoided. 4. Subject has concomitant comorbid skin condition that, in the opinion of the investigator, would interfere with the study assessments. 5. "Tuberculosis (TB): a. Subject has history of active TB infection, regardless of treatment status. b. Subject has signs or symptoms of active TB (including but not limited to chronic fever, chronic productive cough, night sweats, or weight loss) as judged by the investigator. c. Subject has evidence of latent TB infection (LTBI) as evidenced by a positive QuantiFERON-TB Gold (QFT) result OR 2 indeterminat QFT results and subject does not have documentation of appropriate LTBI prophylaxis or is not able or not willing to initiate appropriate LTBI prophylaxis. Subject remains eligible if there are no signs/symptoms of active TB AND documentation of no history of active TB can be provided AND (1) subject can provide documentation of prior and complete treatment for LTBI (appropriate in duration and type per current local country guidelines) or (2) subject has a positive QFT result or 2 indeterminate QFT results but has initiated prophylaxis (appropriate in duration and type per current local guidelines) a minimum of 2 weeks prior to Day 1. In the EU/EEA and the UK, subjects with evidence of LTBI, regardless of prophylaxis treatment status, must receive approval to participate in the study from an infectious disease or other TB specialist (eg, pulmonologist). Note: TB prophylaxis regimens should be administered according to local guidelines; however, because of potential interactions with TAK-279 and apremilast, rifampin should not be used. TB testing should be conducted using QuantiFERON-TB Gold submitted to central laboratory unless alternate or additional tests are required per local 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 or a history of active TB. X-ray is required for all subjects regardless of QuantiFERON-TB Gold results unless the subject has had normal chest imaging in the 6 months prior to screening.
2. 6. 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 Day 1. b. Subject has history of serious herpetic infection that includes any episode of disseminated disease, multidermatomal herpes zoster, herpes encephalitis, ophthalmic herpes, or recurrent herpes zoster (defined as 2 episodes within 2 years). 7. "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). In the EU/EEA and the UK, if the subject has total anti-HCV Ab positivity at screening but is confirmed to have no detectable HCV RNA by PCR testing, HCV RNA PCR testing will be assessed every 3 months until end of trial. b. Subject has presence of positive hepatitis B surface antigen (HBsAg+) or indeterminate hepatitis B surface antigen, presence of hepatitis B virus DNA (regardless of serology), or positive anti-hepatitis B core antibody without concurrent positive hepatitis B surface antibody (HBcAb+ and HBsAb-). In the EU/EEA and the UK, if the subject has total anti-HBc Ab positivity at screening but is confirmed to have no detectable HBV DNA by PCR testing, the subject will repeat HBV DNA PCR testing every 3 months until the end of trial; if a subject has anti-HBs Ab positivity at screening but is confirmed to have no detectable HBV DNA by PCR testing, unless the subject has documented completion of the HBV vaccination series by medical records, the subject will repeat HBV DNA PCR testing every 3 months until the end of trial. c. Subject has positive results for HIV by serology, regardless of viral load. 8. "Other infectious diseases: a. Subject has a history of active infection or febrile illness within 7 days prior to Day 1, as assessed by the investigator. b. Subject has history of symptoms suggestive of systemic or invasive infection within 30 days prior to Day 1. c. Subject has history of bacterial, viral, or fungal infection that required hospitalization or treatment with intravenous antimicrobial therapy within 8 weeks prior to Day 1, or oral antimicrobial therapy within 30 days prior to Day 1. d. 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). e. Subject has a history of an infected joint prosthesis unless that prosthesis has been removed or replaced at least 60 days prior to Day 1. f. Subject has a history of opportunistic infections (eg, Pneumocystis jirovecii pneumonia, histoplasmosis, coccidiomycosis). g. Subject had a bacterial infection within 60 days prior to Day 1 for which he or she did not receive treatment.
3. 9. 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 Day 1 or has a major surgery planned during the study. c. Subject has unstable, poorly controlled, or severe hypertension at screening, confirmed by 2 repeat assessments. 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 , with the exception of successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix; in the EU/EEA and the UK, investigators must document a favorable benefit-risk assessment. 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, or has required more than 1 course of oral corticosteroids within 6 months prior to Day 1. g. Subject has any of the following cardiovascular disease history: • 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. If, however, the investigator determines there are no suitable treatment alternatives available for the subject and it has been at least 6 months since the occurrence of any such event, the subject may enroll; in the EU/EEA and the UK, investigators must document a favorable benefit-risk assessment. h. Subject has ECG abnormalities that are considered clinically significant and would pose an unacceptable risk to the subject if he or she participated in the study, in the opinion of the investigator. i. Subject has significant/uncontrolled psychiatric illness, in the opinion of the investigator. j. Subject has any lifetime history of suicidal ideation, suicidal behavior, or suicidal attempts by 1) medical history; or 2) by C-SSRS documentation at screening or by answering “yes” to Question 5 for suicidal ideation on the C-SSRS at screening; or 3) is clinically deemed to have a suicide risk by the investigator. k. Subject has a PHQ-8 score of 15 or above at screening. l. Subject has a history of clinically significant drug or alcohol abuse within 12 months prior to Day 1.
4. 10. "Subject has received any of the following biologics or biosimilar versions within the time frame indicated: a) Antibodies to IL-12/-23, IL-17, or IL-23 (eg, ustekinumab, secukinumab, tildrakizumab, ixekizumab, or guselkumab) within 6 months prior to Day 1. b) TNF inhibitor(s) (eg, etanercept, adalimumab, infliximab, certolizumab) within 2 months prior to Day 1. c) Agents that modulate integrin pathways to impact lymphocyte trafficking (eg, natalizumab) or agents that modulate B cells or T cells (eg, alemtuzumab, abatacept, or visilizumab) within 3 months prior to Day 1. d) Rituximab or other immune cell-depleting therapy within 6 months prior to Day 1. 11. Subject has used medicated shampoo and/or body wash, including formulations containing but not limited to salicylic acid, corticosteroids, coal tar, vitamin D3 analogues, or other compounds used for the management of psoriasis within 2 weeks prior to Day 1. 12.Subject has used any topical medication that could affect psoriasis presentation (including but not limited to corticosteroids, salicylic acid, urea, alpha- or beta-hydroxy acids, anthralin, retinoids, vitamin D analogues [such as calcipotriol], methoxsalen, trimethylpsoralen, calcineurin inhibitors [eg, tacrolimus], tapinarof, roflumilast, JAK inhibitors, or tar) within 2 weeks prior to Day 1 Note: Low-potency topical steroids (World Health Organization Class VI and VII) are permitted on the palms, soles, face, and intertriginous areas but should not be used within 24 hours before any study visit. Low-potency topical steroids may be used to treat acute non-psoriatic conditions (eg, contact dermatitis) on all body regions for no more than 2 weeks but should not be used within 24 hours before any study visit. Low-potency topical steroids co-formulated with other topicals that may affect the presentation of psoriasis are not permitted. Bland emollients (defined as emollients containing only ingredients that are pharmacologically inactive) are allowed on all body regions but should not be used within 24 hours before any study visit.13. "Subject has used any systemic nonbiologic treatment that could affect psoriasis presentation (including oral, intravenous, intramuscular, intra-articular, intrathecal, or intralesional corticosteroids; oral retinoids; immunosuppressive/immunomodulating medication; methotrexate; azathioprine; 6-thioguanidine; mercaptopurine; mycophenolate mofetil; hydroxyurea; cyclosporine; 1,25-dihydroxyvitamin D3 analogues; psoralens; sulfasalazine; fumaric acid derivatives; JAK inhibitors) within 4 weeks prior to Day 1, or 5 half-lives, whichever is longer. Note: Intranasal corticosteroids, inhaled corticosteroids, and eye and ear drops containing corticosteroids are permitted. 14. Subject has used leflunomide within 6 months prior to Day 1. 15. Subject has received phototherapy (including ultraviolet B [UV-B], psoralen and ultraviolet A [PUVA], tanning beds, therapeutic sunbathing) or excimer laser within 4 weeks prior to Day 1.
5. 16. Subject has used botanical preparations (eg, herbal supplements or traditional medicines, including traditional Chinese medicines, derived from plants, minerals, or animals) intended to treat psoriasis or other immunological diseases within 4 weeks prior to Day 1. 17. Subject has any previous exposure to TAK-279 (also known as NDI-034858), other TYK inhibitors, including deucravacitinib, or subject participated in any study that included a TYK2 inhibitor (eg, deucravacitinib, VTX958, GLPG3667, etc), unless subject has documentation of post-trial unblinding that confirms the subject did not receive a TYK2 inhibitor, or subject has any prior exposure to apremilast. 18. Subject has received lithium, antimalarials, or intramuscular gold therapy within 4 weeks prior to Day 1. 19. Subject is currently being treated with strong or moderate CYP3A4 inhibitors (such as itraconazole) or strong or moderate CYP3A4 inducers (such as rifampin, carbamazepine, or phenytoin), or has received strong or moderate CYP3A4 inhibitors or strong or moderate CYP3A4 inducers within 4 weeks or 5 half-lives of the inducer or inhibitor, whichever is longer, prior to Day 1, or is anticipated to require treatment with strong or moderate CYP3A4 inducers or inhibitors during the trial period (see Appendix A). Note: This includes consumption of food or beverages containing grapefruit and/or Seville oranges within 1 week of Day 1. Subjects must be counseled to avoid food or beverages containing grapefruit and/or Seville oranges for the duration of the study. 20. "Subject has received any live-attenuated vaccine within 60 days prior to Day 1 or plans to receive a live-attenuated vaccine during the study and up to 4 weeks after the last study drug administration. Note: Non–live-attenuated vaccines or boosters for coronavirus disease-2019 (COVID-19) or influenza are permitted during the study. 21. Subject received an investigational antibody or biologic therapy within 6 months prior to Day 1. 22. Subject is currently receiving a nonbiological study drug or device or has received one within 4 weeks prior to Day 1.
6. 23. Subject is currently enrolled in a clinical trial or anticipates enrollment in a clinical trial during the course of the study. 24. Subject has any of the following laboratory values at the screening visit: a) AST or ALT values ˃3 times the ULN b) Total bilirubin (unconjugated and/or conjugated) ˃1.5 times the ULN. c) Hemoglobin <9.0 g/dL (<90.0 g/L). d) Absolute white blood cell count <3.0 × 109/L (<3000/mm3). e) Absolute neutrophil count of <1.0 × 109/L (<1000/mm3). f) Absolute lymphocyte count of <0.5 × 109/L (<500/mm3). g) Platelet count <100 × 109/L (<100,000/mm3). h) Thyroid-stimulating hormone outside the normal reference range AND free thyroxine (T4) or triiodothyronine (T3) outside the normal reference range. i) Estimated creatinine clearance <45 mL/min based on the Cockcroft-Gault calculation. j) 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. 25. 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. 26. Subject does not tolerate venipuncture or inability to be venipunctured. 27. Subject has history of significant drug allergy (such as anaphylaxis). 28. Subject has any contraindications listed in the country-specific label for apremilast (such as presence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption). 29. Subject has a known or suspected allergy to TAK-279, apremilast, or any of their components. 30. Subject has a positive pregnancy test result or plans to become pregnant during the study period, or subject is pregnant or lactating/nursing.
7. 31. 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 course of the study. 32. Subject is compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness, or is committed to an institution (eg, prison) by virtue of an order issued either by judicial or administrative authorities. 33. Subject is a study site employee, an immediate family member (eg, spouse, parent, child, sibling), or is in a dependent relationship with study site employee who is involved in the conduct of this study, or may consent under duress. 34. In Germany, subject is incapable of giving consent or otherwise meets criteria in Sections 136 or 137 of the Verordnung zum Schutz vor der schädlichen Wirkung ionisierender Strahlung – Strahlenschutzverordnung. 35. In the 7 days prior to randomization, subject has not completed at least 4 of 7 PSSD entries, or subject is unable or unwilling to complete daily PSSD diary for the duration of the study, in the opinion of the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Static Physician's Global Assessment (sPGA) 0/1 response: Assessed as proportion of subjects achieving an sPGA of clear (0) or almost clear (1) with a ≥2-point decrease from baseline at Week 16
2. Psoriasis Area and Severity Index (PASI)-75 response: Assessed as proportion of subjects achieving ≥75% improvement from baseline in PASI score at Week 16.

Secondary endpoints 4

1. PASI Response: Proportion of subjects achieving PASI-75 (versus apremilast), PASI-90, or PASI-100 at Week 16 or Week 24.
2. Enhanced sPGA response: Proportion of subjects achieving an sPGA of clear (0) at Week 16
3. Changes in severity of psoriasis on the scalp, nail, body surface area, hands and feet using ssPGA, NAPSI, BSA, and PGA of the hands and/or feet
4. Time to relapse until Week 60 for PASI-75 Responders at Week 40

Investigational products

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

Test 1

Comparator 4

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

95 Hayden Avenue

City

Lexington

Postcode

02421-7942

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 18

Locations

9 EU/EEA countries · 98 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 289 files

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

Application history

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