| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Psoriatic arthritis (PsA) is a chronic, systemic inflammatory disease that manifests as peripheral arthritis, axial disease, dactylitis, enthesitis, and skin and nail lesions. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037160 |
| E.1.2 | Term | Psoriatic arthritis |
| E.1.2 | System Organ Class | 100000004859 |
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| 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 |
| To assess the efficacy of NDI-034858 orally administered QD at 5 mg, 15 mg, or 30 mg for 12 weeks on the rheumatological signs, symptoms and function in subjects with active psoriatic arthritis (PsA) |
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| E.2.2 | Secondary objectives of the trial |
· To assess additional evaluations of efficacy of NDI-034858 orally administered QD at 5 mg, 15 mg, or 30 mg for 12 weeks in subjects with active PsA
· To assess the safety and tolerability of NDI-034858 orally administered QD at 5 mg, 15 mg, or 30 mg for 12 weeks in subjects with active PsA
·To evaluate the plasma concentration of NDI-034858 orally administered QD at 5 mg, 15 mg, or 30 mg in subjects with active PsA
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is male or female, aged ≥18 years, at the time of consent.
2. Subject has PsA on the basis of the CASPAR with peripheral symptoms at the screening visit, as assessed by the investigator.
3. Subject has PsA symptoms for ≥ 6 months prior to screening, as assessed by the investigator.
4. Subject has ≥ 3 tender joints and ≥ 3 swollen joints at screening and Day 1 visits, as assessed by the investigator.
5. 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.
6. Subject has active PsA despite previous standard doses of NSAIDs administered for ≥ 4 weeks, or traditional DMARDs (including methotrexate and sulfasalazine) administered for ≥ 3 months, or TNFi agents administered for ≥ 3 months, or subjects are intolerant to NSAIDs or DMARDs or TNFi agents, as assessed by the investigator.
7. If subject is on concurrent PsA treatments, they must be on stable doses as described below and for the duration of the study:
a. Methotrexate (MTX): subject must have received treatment for ≥ 3 months, with stable dose and stable route of administration (not to exceed 25 mg MTX per week) for ≥ 4 weeks prior to Day 1 until Week 16 (EOS); subjects on MTX should be taking folic acid supplementation according to local standard of care to minimize the likelihood of MTX associated toxicity.
b. Sulfasalazine: Maximum dose of 3 gm/day. Minimum duration of therapy 2 months and dose stable for 4 weeks prior to Day 1.
c. Other traditional DMARDs not listed may be considered on a case-by-case basis after discussion with the medical monitor.
d. Oral corticosteroids: the subject must be on a stable dose, not to exceed the equivalent of 10 mg of prednisone per day, for ≥ 2 weeks prior to Day 1. If subject is not currently using oral corticosteroids, must not have received for at least 2 weeks prior to Day 1.
a. NSAIDs or paracetamol/acetaminophen as needed: the subject must be on a stable dose for ≥ 2 weeks prior to Day 1. If not currently using NSAIDs, must not have received for at least 2 weeks prior to Day 1.
8. For female subjects of childbearing potential involved in any sexual intercourse that could lead to pregnancy: the subject must agree to use a highly effective contraceptive method from screening until at least 4 weeks after the last study drug administration. Highly effective contraceptive methods include hormonal contraceptives (eg, combined oral contraceptive, patch, vaginal ring, injectable, or implant), intrauterine devices or intrauterine systems, vasectomized partner(s) (provided vasectomy was performed ≥ 4 months prior to screening), tubal ligation, or double barrier methods of contraception (eg, male condom with cervical cap, male condom with diaphragm, and male condom with contraceptive sponge) in conjunction with spermicide.
9. Female subjects of childbearing potential must have had a negative serum pregnancy test at screening and negative urine pregnancy test at Day 1.
10. For male subjects involved in any sexual intercourse that could lead to pregnancy, subject must agree to use one of the highly effective contraceptive methods listed in Inclusion Criterion 9, from Day 1 until at least 12 weeks after the last study drug administration. If the female partner of a male subject uses any of the hormonal contraceptive methods listed above, this contraceptive method should be used by the female partner from at least 4 weeks before Day 1 until at least 12 weeks after the last study drug administration.
11. Subject has a body mass index (BMI) of >18 kg/m2, inclusive, (BMI = weight (kg)/[height (m)]2), and total body weight >50 kg (110 lb).
12. Subject is willing to participate and is capable of giving informed consent. Note: Signed, dated, written informed consent must be obtained prior to any study-related procedures.
13. Subjects must be willing to comply with all study procedures and must be available for the duration of the study.
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| E.4 | Principal exclusion criteria |
1. Other disease(s) that might confound the evaluations of benefit of NDI-034858 therapy, including but not limited to rheumatoid arthritis, axial spondyloarthritis (this does not include a primary diagnosis of PsA with spondylitis), systemic lupus erythematosus, Lyme disease or fibromyalgia.
2. History of lack of response to any therapeutic agent targeting interleukin (IL)-12, IL-17, and/or IL-23 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).
3. History of lack of response to >1 therapeutic agent targeting tumor necrosis factor.
4. Received infliximab, golimumab, adalimumab, or certolizumab pegol, or any biosimilar of these agents, within 8 weeks or 5 half-lives, whichever is longer, prior to baseline (Day 1).
5. Received etanercept, or any biosimilar of etanercept, within 4 weeks prior to baseline (Day 1).
6. Received rituximab or any immune-cell-depleting therapy within 6 months prior to baseline (Day 1).
7. Received any marketed or investigational biological agent, other than those specified in other inclusion/exclusion criteria, within 12 weeks or 5 half-lives (whichever is longer) prior to baseline (Day 1).
8. Currently receiving a non-biological investigational product or device or has received one within 4 weeks prior to baseline (Day 1).
9. Received apremilast or other non-biologic systemic treatment for PsA within 4 weeks prior to baseline (Day 1), other than MTX, sulfasalazine, corticosteroids, NSAIDs, or paracetamol/acetaminophen, which are allowed at stable doses as described in Inclusion Criterion 7. Subject has received leflunomide within 95 days of baseline (Day 1) if no elimination procedure was followed or adhere to an elimination procedure (eg, 11 days with cholestyramine or 30 days washout with activated charcoal as per local label). For subjects not receiving MTX and sulfasalazine at Screening, MTX and sulfasalazine are excluded within 4 weeks prior to baseline (Day 1).
10. 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).
11. Received high potency opioid analgesics (eg, methadone, hydromorphone, or morphine) within 2 weeks prior to baseline (Day 1).
12. Used any topical medication that could affect PsA or psoriasis (including corticosteroids, retinoids, vitamin D analogues [such as calcipotriol], Janus kinase [JAK] inhibitors, or tar) within 2 weeks prior to baseline (Day 1).
13. 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), unless otherwise excluded or allowed by protocol.
14. Received any ultraviolet (UV)-B phototherapy (including tanning beds) or excimer laser within 4 weeks prior to baseline (Day 1).
15. Had psoralen and ultraviolet A (PUVA) treatment within 4 weeks prior to baseline (Day 1).
16. Received Chinese traditional medicine within 4 weeks prior to baseline (Day 1).
17. Received any live-attenuated vaccine, including for Coronavirus Disease-19 (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.
18. 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).
19. Consumed grapefruit or grapefruit juice within 1 week prior to baseline (Day 1).
20. 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.
21. Subject is a female who is breastfeeding, pregnant, or who is planning to become pregnant during the study.
22. Evidence of erythrodermic, pustular, predominantly guttate psoriasis, or drug-induced psoriasis.
23. History of skin disease or presence of skin condition that, in the opinion of the investigator, would interfere with the study assessments.
24. Any clinically significant medical condition, evidence of an unstable clinical condition (eg cardiovascular, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, or local active infection/infectious illness), 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.
(List not exhaustive. Full list of Exclusion criteria can be found in Protocol Section 5.2.) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects achieving at least an American College of Rheumatology (ACR) 20 response at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For time-point(s) see section E.5.1 |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
- Proportion of subjects achieving ACR-50 response at Week 12
- Proportion of subjects achieving ACR-70 response at Week 12
- Change from baseline (Day 1) in tender joint count at Week 12
- Change from baseline (Day 1) in swollen joint count at Week 12
- Change from baseline (Day 1) in Patient Global Assessment of Psoriatic Arthritis at Week 12
- Change from baseline (Day 1) in Patient Global Assessment of Psoriatic Arthritis pain at Week 12
- Change from baseline (Day 1) in Physician Global Assessment of Psoriatic Arthritis at Week 12
- Change from baseline (Day 1) in Health Activities Questionnaire – Disability Index (HAQ-DI) score at Week 12
- Change from baseline (Day 1) in dactylitis count at Week 12, among subjects who have dactylitis at Day 1
- Change from baseline (Day 1) in Leed's Enthesitis Index (LEI) at Week 12, among subjects who have enthesitis at Day 1
- Proportion of subjects with Minimal Disease Activity (MDA) at Week 12
- Change from baseline (Day 1) in Disease Activity Index for Psoriatic Arthritis (DAPSA) at Week 12
- Proportion of subjects achieving 75% improvement from baseline (Day 1) in Psoriasis Area Severity Index [(PASI)-75] at Week 12 among subjects with ≥ 3% body surface area (BSA) psoriatic involvement at Day 1
- Proportion of subjects achieving a Physician Global Assessment of Psoriasis of 0 or 1 and at least a 2-point improvement from baseline (Day 1) at Week 12.
Secondary Endpoints - Safety
- Incidence of TEAEs, TESAEs, TEAESIs
- Assessment of clinically relevant changes in vital signs, clinical laboratory parameters, and proportion of subjects with clinically relevant abnormal ECGs, and physical examinations
Secondary Endpoints – Pharmacokinetics
- Measurement of plasma concentrations of NDI-034858 in subjects receiving 5 mg, 15 mg, or 30 mg of NDI-034858
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary Efficacy Endpoints: For time-point(s) see section E.5.2 |
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| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Czechia |
| Germany |
| Poland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The EOS is defined as completion of the last visit or procedure shown in the Schedule of Events for the last enrolled subject in the study globally for all study sites. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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