| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe chronic plaque psoriasis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate to severe chronic plaque psoriasis |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071117 |
| E.1.2 | Term | Plaque psoriasis |
| E.1.2 | System Organ Class | 100000004858 |
|
| 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 a DMF/NB-UVB PT combination regimen and DMF treatment alone in patients with moderate-to-severe chronic plaque psoriasis, as assessed by PASI 75 or PASI ≤3. |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the efficacy of a DMF/NB-UVB PT combination regimen and DMF treatment alone (as assessed by PASI, BSA, and PGA.
2. To assess the time to achieve a clinically meaningful improvement (as assessed by PASI) of a DMF/ NB-UVB PT combination regimen and DMF treatment alone.
3. To assess the efficacy of DMF/ NB-UVB PT combination regimen and DMF treatment alone according to patient-reported outcomes (PRO) (DLQI, Skindex-16, pruritus-VAS, and WPAI).
4. To assess cost-effectiveness (as assessed by health resources utilisation [HRU] and EQ-5D) of a DMF/ NB-UVB PT combination regimen and DMF treatment alone.
5. To assess the safety and tolerability of a DMF/ NB-UVB PT combination regimen and DMF treatment alone.
6. To assess adherence rate and patient satisfaction of a DMF/ NB-UVB PT combination regimen and DMF treatment alone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1- Ability to understand and comply with the requirements of the study and communicate with the Investigator, and written, signed and dated informed consent given before any study related activity is performed.
2-Male or female must be at least 18 years of age at the time of Screening Visit.
3-Patients diagnosed with chronic plaque psoriasis of at least 6 months prior to the Screening Visit, and stable active plaque-type psoriasis (defined as without clinically significant flares during the 12 weeks before randomisation).
4-Patients with the severity of psoriasis at Screening and Baseline visits defined by PASI score >5.
5-Candidates whose disease is eligible for systemic treatment and PT (i.e. with lesions in areas that can be irradiated) at the Screening Visit.
6-Patients who are PT naïve or who have not had PT at least 6 months before the Screening Visit.
7-General good health, or a stable medical condition not considered likely to interfere with the conduct of the clinical study, as determined by the Investigator based upon results of medical history, laboratory results (within normal or clinically acceptable range limits) and physical examination (no clinical significant abnormal findings). Investigators are encouraged to consult with the Sponsor if there are questions regarding the significance of any out of range values.
8-Complete record of at least the last 12 months prior to the Screening Visit of anti-psoriatic previous topical, PT and non-biologic systemic treatments, if any.
9-Unlikely to conceive, as indicated by at least one “yes” answer to the following questions
-Patient is a male
-Patient is a surgically sterilized female by hysterectomy or bilateral tubal ligation
-Patient is a postmenopausal female ≥45 years of age with >1 year since last menses. If a patient is <45 years of age, or cessation of menses is more than 3 months and less than 1 year, follicle stimulating hormone must be documented as elevated into the postmenopausal range (>60 mIU/mL) at the Screening visit
-Patient is a non-sterilized and pre-menopausal female using a highly effective medically accepted method of contraception, during the study period and for 30 days after the last dose of the study drug
Explanatory note: Highly effective methods of birth control are defined as a method with less than 1% failure rate per year which include:
combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation1 (oral, injectable, implantable2), intrauterine device, intrauterine hormone-releasing system 2, bilateral tubal occlusion 2, vasectomised partner 2,3, and sexual abstinence 4.
1 Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraception method.
2 Contraception methods that are considered to have low user dependency (according to the CTFG recommendations on contraception and pregnancy testing).
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the woman who is considered of childbearing potential study participant and that the vasectomised partner has received medical assessment of the surgical success.
4 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of the risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.
10-For female patients of child-bearing potential, a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit. Additionally, they must agree to have urine pregnancy tests while on study medication.
11-Patients willing to keep sun exposure of the trunk and limbs to none or minimal, occasional and unintentional, and not to use tanning booths or other ultraviolet (UV) light sources for the duration of the trial. |
|
| E.4 | Principal exclusion criteria |
1-Female patients who are currently pregnant, who intend to become pregnant during the course of the study, or who are breastfeeding, unwillingness/inability to use appropriate measures of contraception
2- Patients with a diagnosis of flexural, guttate, erythrodermic or pustular psoriasis
3- Patients with a diagnosis and/or signs/symptoms suggestive of active psoriatic arthritis
4- Drug-induced psoriasis (i.e., a new onset or current exacerbation of psoriasis from beta-blockers, calcium channel blockers, or lithium)
5-History or evidence of skin disease (atopic dermatitis, eczema) or conditions (scarring, open wounds) other than chronic plaque-type psoriasis that might interfere with the study conduct or evaluations, or which exposes the patient to unacceptable risk by study participation
6-Patients with a haematological abnormality at the Screening Visit as follows: platelet count <100,000/mm3, white blood cells (WBC) count < 3,000 cells/ mm3, lymphocyte count < 1,000/μL, haemoglobin, haematocrit, or red blood cell count outside 30% of the upper or lower limits of normal
for the laboratory.
7-History or concurrent malignancy (excluding successfully treated basal cell carcinoma, squamous cell carcinoma of the skin in situ, squamous cell carcinoma with no evidence of recurrence within 5 years or carcinoma in situ of the cervix that has been adequately treated).
8- Presence of severe photodamage, actinic keratosis and/or clinically/histologically atypical moles.
9- Patients suffering from active significant gastrointestinal problems (ulcers, diarrhoea, etc.).
10-Patients with severe renal impairment (creatinine clearance <30 mL/min, estimated glomerular filtration rate (eGFR) using CKD-EPI Creatinine Equation or significant proteinuria (3+ or higher)
11-Patients with abnormal liver enzymes:
-if an enzyme was >3x the upper limit of the normal range (ULN): aspartate amino transferase (AST or SGOT), alanine amino transferase (ALT or SGPT), gamma-glutamyl-transferase (GGT), alkaline phosphatase (ALP)
- if bilirubin was >2x ULN, for the other liver enzymes >2x ULN was exclusionary
12-Patients with active infectious disease
13- Patients on systemic therapy
14- Patients with concomitant treatment with immunomodulating or immunosuppressive medication, or systemic corticosteroids
15- History of hypersensitivity or allergy to the study drugs or its excipients
16- Patients with history or evidence/indication of current drug and/or alcohol abuse or dependence, according to the judgment of the Investigator
17- Patients with HIV-positive status or any other immunosuppressive disease
18-Patients who have had a live vaccination within 4 weeks prior to the Baseline Visit, or intend to have a live vaccination during the course of the study, or have participated in a vaccine clinical study within 12 weeks of randomization
19-Patient who intend to use any concomitant medication not permitted by this study or who have not undergone the required washout period, prior to the Baseline Visit, for a particular prohibited medication:
-Topical psoriasis treatment (e.g. topical corticosteroids, vitamin A analogues, vitamin D analogues, coal tar, anthracene derivatives, salicylic acid preparations): 2 weeks
-PT (other than the study PT, e.g. Psoralen-UVA therapy, tanning salon or homeadministered UVB): 6 months
-Conventional systemic anti-psoriatic drugs, excluding fumarate-based drugs and PT: 4 weeks
-Any other immunosuppressive medication (e.g. cytostatics, etc.): 6 months
20- Patients who are hypersensitive to ingredients of the study drugs
21- Patients previous enrolled in this study or participating in any other drug investigational trial within the 30 days (or five half-lives whichever is longer) prior to enrollment.
22- Concurrent systematic therapy
23- Patients with photosensitivity: hypersensitivity to sunlight or UVB light of any type; history of Lupus, polymorphic light eruption (PMLE), or any disease known to be worsened by UV light exposure
24- Patients that intake concomitant medications that are known to be able to induce photosensitivity
25-Patients with previous exposure to fumarate-based drug or a biologic systemic treatment (e.g. tumour necrosis factor-alpha inhibitors, IL-17 inhibitors, IL-17R inhibitors, IL-12/23 p40 inhibitors, IL-23p19 inhibitors or experimental biological product)
26- Patients who failed to respond, did not tolerate, had relevant side-effects or with contra-indication to NB-UVB in the past
27- Patients who are not eligible for PT according to the Investigator (e.g. patients with severe involvement of the scalp and/or skin folds).
28- Patients who do not have logistic availability to fulfil all the PT sessions required in the study
29- Patients previously randomised in the current study
30- Patient who is part of the study team at the research site
31-Patient with any other serious or uncontrolled physical or mental dysfunction |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients achieving “PASI 75 response OR PASI ≤3” at 24 weeks of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints
-Proportion of patients achieving a PASI 75 response at 24 weeks of treatment.
-Proportion of patients achieving an absolute PASI score of ≤3 at 24 weeks of treatment.
-Proportion (and number) of patients achieving PASI 75, PASI 90 responses as well as absolute PASI score of ≤5, ≤3 and ≤1 all visits*.
-Absolute PASI score and percentage change from baseline in the absolute PASI score at all visits*.
-Proportion (and number) of patients with a PGA score of 0 or 1 (‘clear’ or ‘almost clear’) at all visits*.
-Absolute PGA score and change from baseline in the absolute PGA score at each visit*.
-Absolute BSA score and change from baseline in the absolute BSA score at each visit*.
-Time to achieve the primary composite endpoint (PASI 75 response OR to PASI score ≤3)
-Time to PASI 75 response.
-Time to PASI score ≤ 3.
-Absolute DLQI score and percentage change from baseline in the absolute DLQI score at all visits*.
-Proportion of patients achieving a DLQI score of 0 or 1 at all visits*.
-Absolute Skindex-16 score and change from baseline in the absolute Skindex-16 score at all visits*.
-Absolute pruritus-VAS score and change from baseline in the absolute pruritus-VAS score at all visits*.
-Absolute WPAI score and change from baseline in the absolute WPAI score at all visits*
* When the data is collected
-HRU related to psoriasis collected at Week 24:
• Number of visits related to psoriasis (including unscheduled)
• Treatments related to psoriasis (including dose, route, frequency, duration, onset date, end date, and reasons for onset and discontinuation
• Number of hospitalisation/s related to psoriasis (if any, number of hospitalisations and length [days])
• Number of unscheduled/emergency room visits to the general practitioner/dermatologist related to psoriasis (if any, number [days]
• Diagnostic procedures related to psoriasis (clinical examination, laboratory controls, biopsy [if any], others)
• Percentage of HRU related to adverse reactions (ARs) to psoriasis-treatments generating costs (i.e. concomitant treatments, etc.)
- Quality Adjusted Life Year (QALY) for 24 weeks of treatment will be calculated using the EQ-5D score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Dimethyl Fumarate as monotherapy |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| 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 | 6 |
| 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 | 0 |
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