Efficacy and Safety Study of HRO350 in Patients with Mild-to-moderate Psoriasis (the 'HeROPA' Study).

The PASI assesses efficacy in moderate-to-severe psoriasis and quantifies the severity of a participant's psoriasis based on both, "lesion severity" and the "percentage of body surface area (BSA)" affected. To be included on the study, patients Psoriasis Area and Severity Index (PASI) score needs to be ≥ 3 and ≤ 10, indicating mild-to-moderate Psoriasis.

The proportion of patients with ≥50% reduction in Psoriasis Area and Severity Index (PASI) from baseline to week 26 will be compared between: HRO350 2100 mg and placebo, and HRO350 1050 mg and placebo.

Comparing proportions of patients with PASI50 from baseline to Week 4, 12, 39, 52 and 60. Comparing proportions of patients with PASI75 from baseline to Week 4, 12, 26, 39, 52 and 60.

The PASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores representing greater severity of Psoriasis.

The BSA is a measurement of involved skin over the whole body. Assessment of BSA with psoriasis will be estimated by means of the handprint method, where the full palmar hand of the participant (fully extended palm, fingers and thumb together) represents approximately 1% of the total BSA. The surface area of the whole body is made up of approximately 100 palms or "handprints" (each entire palmar surface or "handprint" equates to approximately 1% of total body surface area). A negative change from baseline indicates a reduction of affected BSA.

The study will look at: percentage of participants with a ≥ 75 percent (%) improvement from baseline in affected BSA (at Week 12, 26, 39, 52 and 60), percent change from baseline in total BSA with psoriasis (at Week 12, 26, 39, 52 and 60), and percentage of participants who achieved BSA ≤ 3% for participants with baseline affected BSA >3% (at Week 12, 26, 39, 52 and 60).

The static Physician's Global Assessment (sPGA) will be scored periodically to confirm the severity of psoriasis and to assess efficacy of HRO350/placebo. sPGA is an average assessment of all psoriatic lesions, based on erythema, scaling and induration. The total score will be calculated as average of the 3 severity scores and rounded to the nearest whole number score to determine the PGA score and category (0=clear; 1=almost clear; 2=mild; 3=moderate; and 4=severe). An sPGA response is defined as sPGA score of clear (0) or almost clear (1).

The study will look at: percentage of Participants with sPGA Score of 'Clear' or 'Almost Clear' (at week 4, 12, 26, 39, 52 and 60), percentage of Participants with sPGA Score 0, 1, 2, 3 and 4, respectively, percentage of Participants with static Physician Global Assessment (sPGA) of Psoriasis Score of 'Clear' or 'Almost Clear' and with at least a 2-point reduction from baseline at Week 12, 26, 39, 52 and 60.

The product of sPGA and BSA (sPGAxBSA) has been suggested by several groups as an alternative to PASI in this patient group as it accounts for both extent and severity of psoriasis providing an accurate global assessment of disease. The sPGAxBSA score will be calculated by multiplying the static PGA score by the BSA; i.e. with a range from 0 to 400, as the maximum sPGA = 4, and the maximum BSA = 10.

The study will look at mean change from baseline in sPGAxBSA score at Week 4, 12, 26, 39, 52 and 60.

For patients whose psoriasis involves the scale the ScPGA will be employed. The ScPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), incorporating an Investigator's assessment of the severity of the three primary signs of the disease: erythema, scaling, and induration of the overall scalp. An ScPGA response is defined as an ScPGA score clear (0) or almost clear (1) with at least a 2-point reduction from baseline among participants with a baseline ScPGA score ≥ 2.

The study will look at percentage of Participants with a Scalp Physician Global Assessment (ScPGA) Response at Week 4, 12, 26, 39, 52 and 60 among Participants with Baseline ScPGA Score ≥ 2.

Each patient will have available standardised rescue medication for use if the symptoms of psoriasis are not adequately managed by the study medication (HRO350/placebo). Rescue medication in this study is betamethasone valerate 0.1% w/w ointment and may be used for the relief of inflammatory and pruritic manifestations of the psoriasis on an ad hoc basis. Each patient will be dispensed betamethasone valerate at the study start.

At the end of the study, all returned rescue medication will be weighed. The use of rescue medication will be calculated. The study will look at mean use of rescue medication (measured as grams used) during study; from baseline to end-of-treatment. And, mean number of days, from baseline to end-of-treatment, rescue medication was used; absolute and proportion of days.

36-Item Short-Form Health Survey (SF-36) is a standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects are summarized as physical and mental health summary scores. The score range for the physical and mental health scores is 0-100 (100=highest level of functioning).

The study will look at mean change from baseline for the Physical Component in SF-36 at Week 26 and 52, and mean change from baseline for the Mental Component in SF-36 at Week 26 and 52.

The DLQI (Finlay and Khan, 1994) is a self-administered general dermatology questionnaire that consists of 10 items that assess health related quality of life (daily activities, personal relationships, symptoms and feelings, leisure, work and school, and treatment). It is calculated by summing the score for each question, resulting in a total score ranging from a maximum of 30 to a minimum of 0 with 30 corresponding to the worst health-related quality of life, and 0 corresponding to the best score. The minimum clinically important difference (MCID) between scores for the DLQI has been defined as a score difference of 4 (Basra et al., 2015).

The study will look at: DLQI Total Score, mean change from baseline in DLQI Total Score, proportion of patients who achieve a ≥4-point reduction in DLQI, and mean change from baseline in DLQI for each of 10 items at Week 4, 12, 26, 39, 52 and 60.

The Psoriasis Symptom Inventory (PSI) is a validated patient-reported outcome measure assessing patients' perception of 8 different psoriasis signs and symptoms: itch, redness, scaling, burning, stinging, cracking, flaking and pain (Martin et al., 2013; Bushnell et al., 2013; Revicki et al., 2014). Patients will assess the severity of each item on a 5-point Likert-type rating scale from 0 ('not at all') to 4 ('very severe'). The scores for all 8 items are then summed to give a total score with a range of 0-32. In this study, it is the 7-day recall version of the PSI that will be used.

The study will look at mean change from baseline in PSI Total Score, and mean change from baseline in PSI for each of 8 items at Week 4, 12, 26, 39, 52 and 60.

The patient's overall satisfaction to treatment of their psoriasis will be assessed at screening and every 3 months using a simple one-dimensional 5-point Likert scale in which the patient will be questioned: 'How satisfied are you with your current treatment for psoriasis today?', and will be asked to rate their satisfaction by a choice between the categories:

• very dissatisfied
• dissatisfied
• neither satisfied nor dissatisfied
• satisfied
• very satisfied The study will look at mean change from screening in the treatment satisfaction score at Week 12, 26, 39, 52 and 60.

The number and rate of patients discontinuing from the study prior to planned completion (i.e., not completing the 52 weeks of treatment and the 8 weeks follow-up period) will be presented, categorized by reasons for discontinuation as an indirect measure of efficacy.

Frequency tables of all safety variables will be analysed and will i.a. include:

• Frequency of any Treatment-emergent Adverse Events (TEAEs) and SAEs.
• Frequency of any TEAE by system organ class (SOC), preferred term (PT), severity and relationship of TEAEs to investigational medicinal product.
• Discontinuation rate: any or due to TEAEs.
• Frequency of each safety laboratory variable categorised as

• Below normal range (clinically significant)
• Below normal range (not clinically significant)
• Within normal range
• Above normal range (not clinically significant)
• Above normal range (clinically significant)

Further, full narratives of any SAEs will be described in the study report.