A Study to Evaluate the Efficacy, Safety, and Tolerability of NDI-034858 in Subjects With Active Psoriatic Arthritis

Study Overview
=================
Brief Summary
-----------------
This study is designed to evaluate the efficacy, safety, and tolerability of NDI-034858 in subjects with active Psoriatic Arthritis (PsA).

Detailed Description
-----------------
This is a Phase 2b, Randomized, Multi-center, Double-Blind, Placebo-Controlled, Multiple Dose Study . Randomization to one of the treatments with NDI-034858 Dose 1, 2, 3 or placebo once daily (QD) will be based on a 1:1:1:1 scheme. The maximum study duration per subject is approximately 20 weeks, including up to 30 days for the screening period, a 12-week treatment period, and a 4-week safety follow-up period. Efficacy will be assessed using the ACR20 composite measure (including tender and swollen joint count, patient assessment of PsA pain visual analog scale (VAS), patient global PsA assessment VAS, physician global PsA assessment, HAQ-DI, and hsCRP) as well as the additional components. Efficacy for psoriasis among subjects who have ≥ 3% BSA) involvement on Day 1, will be measured using PASI, PGAs, and BSA. Safety will be assessed by collecting AEs, recording vital signs, performing physical examinations, and evaluating clinical laboratory and ECGs results.

Official Title
-----------------
A Phase 2b, Randomized, Multi-Center, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Efficacy, Safety, and Tolerability of NDI-034858 in Subjects With Active Psoriatic Arthritis

Conditions
-----------------
Psoriatic Arthritis

Intervention / Treatment
-----------------
* Drug: NDI-034858
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject has PsA on the basis of the Classification Criteria for Psoriatic Arthritis with peripheral symptoms at the screening visit. Subject has a history of PsA symptoms for ≥ 6 months prior to the screening visit. Subject has ≥ 3 tender joints and ≥ 3 swollen joints at screening and Day 1 visits. Subject has at least one lesion of plaque psoriasis ≥ 2 cm in diameter, nail changes characteristic of psoriasis, or a documented history of plaque psoriasis. Subject has active PsA despite previous standard doses of non-steroidal anti-inflammatory drug (NSAIDs) administered for ≥ 4 weeks, or traditional disease-modifying anti-rheumatic drug (DMARDs) (including methotrexate and sulfasalazine) administered for ≥ 3 months, or tumor necrosis factor inhibitor (TNFi) agents administered for ≥ 3 months, or subjects are intolerant to NSAIDs or DMARDs or TNFi agents. If subject is on concurrent PsA treatments, they must be on stable doses. All female subjects should followed the protocol defined contraceptive method. Exclusion Criteria: Subject has other disease(s) that might confound the evaluations of benefit of NDI-034858 therapy, including but not limited to rheumatoid arthritis (RA), axial spondyloarthritis (this does not include a primary diagnosis of PsA with spondylitis), systemic lupus erythematosus, Lyme disease, or fibromyalgia. Subject has a history of lack of response to any therapeutic agent targeting IL-12, IL17, and/or IL23 at approved doses after at least 12 weeks of therapy, and/or received one of these therapies within 6 months prior to baseline (Day 1). Subject has a history of lack of response to > 1 therapeutic agent targeting tumor necrosis factor. Subject has received infliximab, golimumab, adalimumab, or certolizumab pegol, or any biosimilar of these agents, within 8 weeks prior to baseline (Day 1). Subject has received etanercept, or any biosimilar of etanercept, within 4 weeks prior to baseline (Day 1). Subject has received rituximab or any immune-cell-depleting therapy within 6 months prior to baseline (Day 1). Subject has received any marketed or investigational biological agent, other than those specified in other inclusion/exclusion criteria, within 12 weeks or 5 half-lives prior to baseline (Day 1). Subject is currently receiving a non-biological investigational product or device or has received one within 4 weeks prior to baseline (Day 1). Subject has received apremilast or other non-biologic systemic treatment for PsA within 4 weeks prior to baseline (Day 1), other than methotrexate (MTX), sulfasalazine, corticosteroids, NSAIDs, or paracetamol/acetaminophen, which are allowed at stable doses as described in Inclusion Criterion 7. For subjects not receiving MTX and sulfasalazine at screening, MTX and sulfasalazine are excluded within 4 weeks prior to baseline (Day 1). Subject has received leflunomide within 8 weeks of baseline (Day 1) if no elimination procedure was followed or adhere to an elimination procedure. For subjects not receiving MTX and sulfasalazine at Screening, MTX and sulfasalazine are excluded within 4 weeks prior to baseline (Day 1). Subject has received intraarticular injection (including corticosteroids), intramuscular steroids, intralesional steroids, or intravenous steroids within 4 weeks prior to baseline (Day 1). For subjects not receiving MTX and sulfasalazine at screening, MTX and sulfasalazine are excluded within 4 weeks prior to baseline (Day 1). For subjects not receiving MTX and sulfasalazine at screening, MTX and sulfasalazine are excluded within 4 weeks prior to baseline (Day 1). Subject has received high potency opioid analgesics (eg, methadone, hydromorphone, or morphine) within 2 weeks prior to baseline (Day 1). Subject has used any topical medication that could affect PsA or psoriasis (including corticosteroids, retinoids, vitamin D analogues (such as calcipotriol), JAK inhibitors, or tar) within 2 weeks prior to baseline (Day 1). Subject has used any systemic treatment that could affect PsA or psoriasis (including oral retinoids, immunosuppressive/immunomodulating medication, cyclosporine, oral JAK inhibitors, or apremilast) within 4 weeks prior to baseline (Day 1). Subject has received any ultraviolet (UV)-B phototherapy (including tanning beds) or excimer laser within 4 weeks prior to baseline (Day 1). Subject has had psoralen and UV A (PUVA) treatment within 4 weeks prior to baseline (Day 1). Subject has received Chinese traditional medicine within 4 weeks prior to baseline (Day 1) Subject has received any live-attenuated vaccine, including for COVID-19, within 4 weeks prior to baseline (Day 1) or plans to receive a live-attenuated vaccine during the study and up to 4 weeks or 5 half-lives of the study drug, whichever is longer, after the last study drug administration. Subject is currently being treated with strong or moderate cytochrome P450 3A (CYP3A4) inhibitors, such as itraconazole or has received moderate or strong CYP3A4 inhibitors within 4 weeks prior to baseline (Day 1). Subject has consumed grapefruit or grapefruit juice within 1 week prior to baseline (Day 1). Subject has used tanning booths within 4 weeks prior to baseline (Day 1), has had excessive sun exposure, or is not willing to minimize natural and artificial sunlight exposure during the study. Subject is a female who is breastfeeding, pregnant, or who is planning to become pregnant during the study. Subject has evidence of erythrodermic, pustular, predominantly guttate psoriasis, or drug-induced psoriasis. Subject has a history of skin disease or presence of skin condition that, in the opinion of the investigator, would interfere with the study assessments. Subject has any clinically significant medical condition, evidence of an unstable clinical condition, psychiatric condition, 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. Subject had a major surgery within 8 weeks prior to baseline (Day 1 or has a major surgery planned during the study. Subject has a history of Class III or IV congestive heart failure as defined by New York Heart Association Criteria. Subject has an estimated creatinine clearance of < 40 mL/min based on the Cockcroft-Gault equation or a history of renal failure. Subject was hospitalized in the 3 months prior to screening for asthma, has ever required intubation for treatment of asthma, currently require oral corticosteroids for the treatment of asthma, or has required more than one short-term (≤ 2 weeks) course of oral corticosteroids for asthma within 6 months prior to baseline (Day 1). Subject has a history of cancer or lymphoproliferative disease within 5 years prior to baseline (Day 1). 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. Subject has a history of fever, inflammation, or systemic signs of illness suggestive of systemic or invasive infection within 4 weeks prior to baseline (Day 1). Subject has an active bacterial, viral, fungal, mycobacterial infection, or other infection (including TB or atypical mycobacterial disease), or any major episode of infection that required hospitalization or treatment with intravenous antibiotics within 12 weeks prior to baseline (Day 1), or oral antibiotics within 4 weeks prior to baseline (Day 1). Subject has a history of chronic or recurrent infectious disease, including but not limited to chronic renal infection, chronic chest infection, recurrent urinary tract infection, fungal infection (with the exception of superficial fungal infection of the nailbed), or infected skin wounds or ulcers. Subject has a history of an infected joint prosthesis or has received antibiotics for a suspected infection of a joint prosthesis, if that prosthesis has not been removed or replaced. Subject has active herpes infection, including herpes simplex 1 and 2 and herpes zoster within 8 weeks prior to Day 1. Subject has a history of known or suspected congenital or acquired immunodeficiency state or condition that would compromise the subject's immune status (eg, history of splenectomy, primary immunodeficiency). Subject has positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B core antigens (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Samples testing positive for HCV antibodies will require polymerase chain reaction (PCR) qualitative testing for HCV RNA. Subject has clinical or laboratory evidence of active or latent TB infection at screening as assessed by QuantiFERON-TB Gold (or a purified protein derivative [PPD] skin test or equivalent, or both if required per local guidelines) and chest X-ray. The PPD skin test should be utilized only when a QuantiFERON-TB Gold Test is not possible for any reason (unless local guidelines require both tests). Chest X-ray may be taken at screening or completed within 3 months prior to the screening visit, with documentation showing no evidence of infection or malignancy as read by a qualified physician. Subject has a known or suspected allergy to NDI-034858 or any component of the investigational product, or any other significant drug allergy (such as anaphylaxis or hepatotoxicity). Subject has a known history of clinically significant drug or alcohol abuse in the last year prior to baseline (Day 1).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NDI-034858 study drug - Dose 1<br>NDI-034858 study drug will be orally administered QD for 12 weeks | Drug: NDI-034858<br>* Randomized participants will receive NDI-034858 capsule orally<br>* Other names: TAK-279;|
| Experimental: NDI-034858 study drug - Dose 2<br>NDI-034858 study drug will be orally administered QD for 12 weeks | Drug: NDI-034858<br>* Randomized participants will receive NDI-034858 capsule orally<br>* Other names: TAK-279;|
| Experimental: NDI-034858 study drug - Dose 3<br>NDI-034858 study drug will be orally administered QD for 12 weeks | Drug: NDI-034858<br>* Randomized participants will receive NDI-034858 capsule orally<br>* Other names: TAK-279;|
| Placebo Comparator: Placebo<br>Placebo will be orally administered QD for 12 weeks | Other: Placebo<br>* Randomized participants will receive placebo orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving at least an American College of Rheumatology (ACR) 20 response | The ACR20 is a composite measure defined as both improvement of 20% in the number of tender (68) and number of swollen (66) joints, and a 20% improvement in three of the following five criteria: patient global assessment of psoriatic arthritis, physician global assessment of psoriatic arthritis, patient pain scale, disability history questionnaire (ie, HAQ-DI) and an acute phase reactant (ie, erythrocyte sedimentation rate [ESR] or hsCRP). For this primary endpoint, hsCRP will be used. | Day 1 to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving at least an ACR-50 or ACR-70 response | The ACR-50 and ACR-70 are a composite measure defined as both improvement of 50% or 70%, respectively, in the number of tender (68) and number of swollen (66) joints, and a 50% or 70%, respectively, improvement in three of the following five criteria: patient global assessment of psoriatic arthritis, physician global assessment of psoriatic arthritis, patient pain scale, disability history questionnaire (ie, HAQ-DI) and an acute phase reactant (ie, ESR or CRP). | Day 1 to Week 16 | 
| Change from baseline in tender joint count (TJC) | The TJC 68 are a total score of points assigned for presence of tenderness in the following: Temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, hip, knee, ankle, tarsus, typically assigned 2 points each; Metacarpophalangeal, finger proximal interphalangeal, metatarsophalangeal, toe proximal interphalangeal, typically assigned 10 points each; Distal interphalangeal, typically assigned 8 points. | From screening until Week 12 | 
| Change from baseline in swollen joint count (SJC) | The SJC 66 (SJC minus hip joints, which cannot be assessed for swelling) are a total score of points assigned for presence of swelling in the following: Temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, knee, ankle, tarsus, typically assigned 2 points each; Metacarpophalangeal, finger proximal interphalangeal, metatarsophalangeal, toe proximal interphalangeal, typically assigned 10 points each; Distal interphalangeal, typically assigned 8 points. | From screening until Week 12 | 
| Change from baseline in Patient Global Assessment of Psoriatic Arthritis | Subjects will rate their assessment of their PsA using a VAS where 0 is 'very good, no symptoms' and 100 is 'very poor, severe symptoms'. | Day 1 to Week 16 | 
| Change from baseline in Patient Global Assessment of Psoriatic Arthritis pain | Subjects will rate their assessment of their PsA using a VAS where 0 is 'no pain' and 100 is 'most severe pain'. | Day 1 to Week 16 | 
| Change from baseline in Physician Global Assessment of Psoriatic Arthritis | The patients' overall disease status will be assessed, taking into account signs, symptoms, and function, of all components of joint and skin which is affected at the time of the visit and will rate this overall status using a VAS scale where 0 is 'very good, asymptomatic, and no limitation of normal activities' and 100 is 'very poor, very severe symptoms which are intolerable, and inability to carry out all normal activities'. | Day 1 to Week 16 | 
| Change from baseline in Health Activities Questionnaire - Disability Index (HAQ-DI) score | The HAQ-DI is comprised of eight domains: dressing, arising, eating, walking, hygiene, reach, grip, and activities. There are two or three questions per section. Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). For each section the score given to that section is the worst score within the section (ie, if one question is scored 1 and another 2, then the score for the section is 2). | Day 1 to Week 16 | 
| Change from baseline in dactylitis count | The dactylitis count consists of totaling the number of single digits in the hands and feet with tenderness. | Day 1 to Week 16 | 
| Change from baseline in Leed's Enthesitis Index (LEI) | The LEI is comprised of review of six bilateral sites: Achilles tendon insertions, medial femoral condyles, and lateral epicondyles of the humerus. Tenderness at each site is quantified on a dichotomous basis: 0 means nontender and 1 means tender. | Day 1 to Week 16 | 
| Change from baseline in Physician Global Assessment of Psoriasis | The PGA is measured using a 0 to 4 scale with a 0 score meaning cleared and a 4 score meaning severe and a ≥ 2 grade improvement from baseline. | Day 1 to Week 16 | 
| Change from baseline in Disease Activity Score 28 with CRP(DAS28-CRP) | The DAS28-CRP describes the severity of PsA using clinical and laboratory data, specifically hsCRP. The DAS scores indicate how active a subject's psoriatic arthritis is currently and can be trended over time. | Day 1 to Week 16 | 
| Incidence of AEs and TAEs | The safety and tolerability of NDI-034858 will be assessed. | Day 1 to Week 16 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Placebo-Controlled, Double-blind, Multiple-dose study