| 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 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071117 |
| E.1.2 | Term | Plaque psoriasis |
| E.1.2 | System Organ Class | 100000004858 |
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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 establish proof of efficacy of namilumab in moderate to severe plaque psoriasis, as measured by the proportion of subjects achieving a reduction in Psoriasis Area and Severity Index (PASI) scores ≥ 75% from baseline (hereafter referred to as PASI75) response rate at week 12. |
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| E.2.2 | Secondary objectives of the trial |
• To investigate efficacy on skin involvement - measured as mean change from Baseline in PASI score at Week 12.
• To investigate efficacy on skin involvement - measured as PASI50, PASI75 and PASI90 response rates.
• To investigate efficacy on skin involvement - measured as mean change from Baseline to Week 12 in static Physician’s Global Assessment score (sPGA).
• To investigate efficacy on skin involvement - measured as the proportions of subjects achieving ≥ 2 point improvement in sPGA score and complete psoriasis clearance (sPGA scores 0-1) respectively between Baseline and Week 12.
• To investigate efficacy on skin and joint involvement from Baseline to Week 12 using daily VAS assessment of itching, pain and joint stiffness, together with assessment of morning stiffness duration.
• Nail Psoriasis Severity Index (NAPSI) score from Baseline to Week 12.
• To investigate the optimal, minimally efficacious doses.
• To evaluate safety, tolerability.
See protocol for complete list |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biopsy sub-study.
Biopsies will be taken from a subset of consenting subjects (at selected study sites), approximately 5 from each dosing group. Biopsies will be taken from a single lesion/plaque at Baseline, Week 2 and Week 12. A non-lesional biopsy will also be taken at Baseline.
Objectives:
To explore the mechanism of namilumab action using skin biopsies.
(1). Investigation of lesional cellular infiltrates and epidermal proliferation/differentiation assessed by histology and immunohistochemistry (IHC).
(2). Investigation of lesional cytokine mRNA expression.
Pharmacogenomic Study.
Optional peripheral whole blood RNA and DNA samples will be collected from consenting subjects. As the field of pharmacogenomics in psoriasis is evolving, samples may be tested for disease- and/or drug-related biomarker hypothesis generating/validation and diagnostic development. |
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| E.3 | Principal inclusion criteria |
1. The subject is male or female aged 18 to 70 years, inclusive.
2. The subject is suffering from stable plaque psoriasis (for at least 6 months) involving ≥10% of their body surface area, PASI score ≥12.
3. The subject must have been a candidate for, or have received, ≥1 phototherapy or systemic psoriasis therapy at the time of inclusion.
4. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
5. The subject signs and dates a written informed consent form and any required privacy authorization prior to the initiation of any study procedures.
6. A male subject who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of the informed consent throughout the duration of this study (including the treatment period and 18 weeks after last dose of study medication).
7. A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent throughout the duration of this study (including the treatment period and 18 weeks after last dose of study medication). |
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| E.4 | Principal exclusion criteria |
1.The subject has received any investigational agent during an interval equivalent to 5 half-lives for that agent, or an interval of 30 days if longer, prior to the study Baseline clinic visit. Alternatively, the subject is participating or planning to participate in any other clinical study during this study.
2.The subject has received namilumab, any other GM-CSF / G-CSF receptor blocker or signaling inhibitor either in a previous clinical study or as a therapeutic agent.
3.The subject is required to take excluded medications (see Section 7.3 below).
4.The subject has a history of hypersensitivity or allergies to any of the contents of the namilumab formulation.
5.The subject has other forms of psoriasis (eg drug-induced psoriasis, pustular, erythrodermic, exfoliative, inverse and/or guttate psoriasis).
6.Evidence of skin conditions other than psoriasis (e.g., eczema) at the time of the Screening clinic visit, or between the Screening visit and study drug initiation, that would interfere with evaluations of the effect of investigational product on psoriasis.
7.The subject has a history or evidence of a clinically significant disorder (including but not limited to cardiopulmonary, oncologic, renal, metabolic, hematologic or psychiatric), condition or disease that, in the opinion of the investigator and/or Takeda physician would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
8.Evidence of clinically uncontrolled respiratory disease (including sarcoidosis) on the basis of data from the subjects’ respiratory assessments - including chest X-ray, lung function tests (forced expiratory volume in one second [FEV1], forced vital capacity [FVC], peak expiratory flow rate [PEFR]) and pulse oximetry performed at Screening. The subjects must have SpO2 ≥ 94%, FEV1 and/or FVC ≥ 60 % of predicted values at Screening and Baseline and no uncontrolled lung disease. Subject treatment initiated or modified to control lung disease within 24 weeks prior to Screening must be considered exclusionary.
9.History of clinically significant interstitial lung disease – e.g. chronic or recurrent pulmonary infection where macrophages are important for the clearance of the infection (such as Pneumocystis (carinii) jiroveci pneumonia, allergic bronchopulmonary aspergillosis, Nocardia infections, Actinomyces infection).
10.Presence of active TB. History of active tuberculosis (TB) or latent TB infection where no anti-TB treatment has been given or where successful completion of an appropriate course of anti-TB therapy cannot be documented.
11.A positive QuantiFERON-TB Gold test and / or evidence of active or latent TB by chest X-ray, not accompanied by initiation of an approved regimen of anti-TB therapy at least 12 months prior to the Baseline clinic visit.
12.The subject has a history of severe chronic obstructive pulmonary disease (COPD) and / or history of severe COPD exacerbation(s), or a history of asthma with exacerbations requiring hospitalization (including emergency or acute care treatments), within the last 12 months prior to the Screening visit.
13.History of methotrexate treatment-associated lung toxicity.
14.The subject has a history of cancer within the last 10 years except for adequately managed basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured.
15.The subject has a history of treatment with anti-cancer chemotherapy (e.g. alkylating agents, anti-metabolites, purine analogues) and/or monoclonal antibodies, or has received GM-CSF / G-CSF treatment associated with chemotherapy within the last 5 years.
16. The subject has an underlying condition that predisposes to infections (e.g. immunodeficiency, history of poorly controlled diabetes mellitus, splenectomy).
17. The subject has any clinically significant illness within 4 weeks prior to the first dose of study medication or during the study - including acute or chronic infectious disease, which in the opinion of the investigator may influence the outcome of the study.
18. The subject has a known history of infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV), or has serological findings at the Screening visit which indicate active or latent hepatitis B, hepatitis C or HIV infection.
19.The subject has , in the judgment of the investigator, clinically significant abnormal clinical laboratory parameters at Screening including, but not limited to:
Hemoglobin <8.5 g/dL
Neutrophils <1500/mm3
Platelet count <75 000 cells/mm3
AST or ALT >2 x ULN
20. The subject has a history of drug abuse (defined as any illicit drug use), or a history of alcohol abuse within 2 years prior to the Screening visit.
21. Any other condition that, in the judgment of the investigator, might cause this study to be detrimental to the subject’s health.
See Protocol for complete list.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for the study is the proportion of subjects achieving a PASI75 improvement from baseline at week 12. Data comparisons will be made to evaluate superiority in efficacy of each of the four namilumab dose levels to placebo. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Proportion of subjects who achieve PASI75, assessed at all applicable post-Baseline visits up to and including Week 10.
• Mean change from Baseline in PASI score, assessed at all applicable post-Baseline visits up to and including Week 12.
• Proportion of subjects who achieve PASI50, assessed at all applicable post-Baseline visits up to and including Week 12.
• Proportion of subjects who achieve PASI90, assessed at all applicable post-Baseline visits up to and including Week 12.
• Proportion of subjects achieving ≥ 2 point improvement in sPGA score, assessed (using a 6-point rating scale with range 0 = Clear to 5 = Very severe) at all applicable post-Baseline clinic visits up to and including Week 12.
• Proportion of subjects achieving sPGA clear or almost clear/minimal (sPGA = 0 or 1 using the 6-point rating scale with range 0 = Clear to 5 = Very severe), assessed at all applicable post-Baseline visits up to and including Week 12.
• Mean change from Baseline in sPGA score, assessed (using a 6-point rating scale with range 0 = Clear to 5 = Very Severe) at all applicable post-baseline visits up to and including Week 12.
• Mean change from Baseline in affected body surface area (BSA), assessed at all applicable post-Baseline visits up to and including Week 12.
• Mean change from Baseline in Visual Analogue Scale (VAS) itching, assessed at all applicable post-Baseline visits up to and including Week 12.
• Mean change from Baseline in VAS joint pain, assessed at all applicable post-Baseline visits up to and including Week 12.
• Mean change from Baseline in VAS morning stiffness and duration of morning stiffness, assessed at all applicable post-Baseline visits up to and including Week 12.
• Change in score from Baseline to Week 12 in Dermatology Life Quality Index (DLQI).
• Change in score from Baseline to Week 12 in Short Form 36 Health Survey (SF-36 v. II).
• Change in score from Baseline to Week 12 in EuroQoL Health Questionnaire (EQ-5D).
• Mean change from Baseline for Nail Psoriasis Severity Index (NAPSI) - finger nail assessments at all applicable post-Baseline visits up to and including Week 12. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please see E.5.2 for timepoints corresponding to each secondary endpoint. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose-Finding - Proof of Concept period + Open label treatment period |
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| 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 | 5 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Canada |
| Denmark |
| Germany |
| Latvia |
| Poland |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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