|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Moderate to Severe Plaque Type Psoriasis
|E.1.1.1||Medical condition in easily understood language ||
|E.1.1.2||Therapeutic area ||Diseases [C] - Immune System Diseases [C20]
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10037153
|E.1.2||System Organ Class ||10040785 - Skin and subcutaneous tissue disorders
|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 ||
|The primary objective of the study is to demonstrate that Super-Responders (SRe; defined as psoriasis subjects who receive on-label guselkumab treatment until week 20 and respond with a Psoriasis Area and Severity Index [PASI] score = 0 at weeks 20 and 28) maintain control of disease until week 68 with prolonged treatment intervals of 16 weeks (100 mg q16w).
|E.2.2||Secondary objectives of the trial ||
|Secondary objectives are to evaluate
• whether subjects with short disease duration (≤2 years) show a more rapid and better guselkumab response compared to subjects with longer disease duration and whether subjects with shorter disease are more likely to maintain drug-free control of disease after guselkumab withdrawal. To be evaluated in Study Parts 1, 2 and 3.
• whether different treatment intervals (weeks 28 to 60: guselkumab 100 mg q8w vs. guselkumab 100 mg q16w) affect the maintenance of drug-free control of disease after 68 weeks of guselkumab treatment. To be evaluated in Study Part 3.
• the safety and tolerability of guselkumab in subjects with moderate-to-severe plaque-type psoriasis.
|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||
|Substudies (part of the final protocol dated 05-Jul-2018):
Four substudies are planned to further evaluate pharmacologic effects of guselkumab and evaluate various pharmacologic/clinical response relationships allowing assessment of inter-individual variability in clinical outcomes and possible identification of subject population groups that may respond differently to guselkumab. The substudies will also aim to further define the mechanism of action (MoA) of guselkumab at the molecular and cellular levels during and after treatment. Changes in gene expression as well as quantitative and qualitative changes in different types of immune cells will be evaluated in skin biopsies and blood.
- Substudy 1 (Cellular MoA substudy)
- Substudy 2 (Gene expression substudy)
- Substudy 3 (Serum analysis)
- Substudy 4 (Genetic analyses)
The following objectives are to be explored in the mechanistic biomarker substudies:
• characterization of the immune cellular and molecular composition at baseline (week 0) and changes (quantitative and qualitative characterization) in the lesional skin of subjects during treatment with guselkumab as determined by fluorescence activated cell sorting (FACS)-based analysis. To be explored in substudy 1
• characterization of the immune cellular changes (quantitative and qualitative characterization) in the blood of subjects at baseline (week 0), during and after treatment with guselkumab as determined by FACS-based analysis. To be explored in substudy 1
• characterization of molecular (gene expression) changes during treatment with guselkumab in the skin of subjects treated with guselkumab as determined by RNA sequencing (RNAseq) and quantitative polymerase chain reaction (qPCR). To be explored in substudy 2
• characterization of the tissue immunopathological changes in the skin of subjects during and after treatment with guselkumab as determined by immunohistochemistry (IHC)/ immunofluorescence (IF)/ in situ hybridization (ISH). To be explored in substudy 2
• characterization of the effects of guselkumab treatment on serum biomarkers as determined by immunoassays. To be explored in substudy 3
• characterization of the association between changes in the various exploratory biomarker endpoints and 1) efficacy of guselkumab, 2) duration of psoriasis, 3) maintenance of response after stopping guselkumab treatment, and 4) ability to achieve a PASI 100 response at weeks 20 and 28 (super responder status). To be explored in all substudies
|E.3||Principal inclusion criteria ||
|1. Male or female with at least 18 years of age.
2. Has a disease duration of plaque psoriasis of either ≤2 years or >2 years calculated from date at which first symptoms [plaque] were reported by subject to date of screening visit at screening; approximately 40% subjects must have a disease duration ≤2 years.
3. Has moderate-to-severe plaque-psoriasis defined by a PASI score >10 or affected BSA >10% and additionally a DLQI score >10 at baseline (week 0).
4. Is a candidate for systemic treatment for psoriasis.
5. Before first administration of study drug, a woman must be:
a. Not of childbearing potential
b. Of childbearing potential and practicing a highly effective method of contraception
6. A woman of childbearing potential must have a negative urine pregnancy test at baseline and agree to urine pregnancy testing before receiving injections and at safety follow-up.
7. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 12 weeks after receiving the last administration of guselkumab.
8. A male subject must wear a condom when engaging in any activity that allows for passage of ejaculate to another person.
9. A male subject must agree not to donate sperm for the purpose of reproduction
10. TB-related inclusion criteria:
Subjects are considered eligible according to the following TB screening criteria:
a. Have no history of latent or active TB before screening.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c. Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB before the first administration of study drug.
d. Within 2 months before baseline, have a negative QuantiFERON®-TB Gold test result, or have a newly identified positive QuantiFERON-TB Gold test result) in which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated before baseline.
e. Have a chest radiograph (posterior-anterior and lateral views, or per country regulations where applicable), taken within 3 months before the first administration of study drug and read by a qualified radiologist, with no evidence of current, active TB or old, inactive TB.
11. Agrees not to receive a live virus or live bacterial vaccination during the study, or within 3 months after the last administration of study drug.
12. Agrees not to receive a BCG vaccination during the study, or within 12 months after the last administration of study drug.
13. Clinical laboratory-related inclusion criteria:
Has screening laboratory test results within the following parameters, if one or more of the laboratory parameters is out of range, a single retest of laboratory values is permitted:
a. Hemoglobin ≥10 g/dL (SI: ≥100 g/L)
b. White blood cells ≥3.5 x 103/μL (SI: ≥3.5 GI/L)
c. Neutrophils ≥1.5 x 103/μL (SI: ≥1.5 GI/L)
d. Platelets ≥100 x 103/μL (SI: ≥100 GI/L)
e. Serum creatinine ≤1.5 mg/dL (SI: ≤137 μmol/L)
f. Aspartate aminotransferase ≤2 × upper limit of normal (ULN)
g. Alanine aminotransferase ≤2 × ULN
h. Alkaline phosphatase ≤2 × ULN
14. Agrees to avoid prolonged sun exposure and avoid use of tanning booths or other ultraviolet (UV) light sources during study.
15. Be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
16. Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
17. Must sign a separate ICF if he or she agrees to provide an optional DNA sample or skin biopsy samples for research (where local regulations permit). Refusal to give consent for the optional substudies does not exclude a subject from participation in the main study.
|E.4||Principal exclusion criteria||
|1 clinical active psoriasis arthritis which needs systemic therapy beyond NSAIDs
2 diagnosed or reported history or current signs or symptoms indicating severe, progressive, or uncontrolled hepatic, renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances, which are detected at screening assessments 3 unstable cardiovascular disease, defined as a recent clinical deterioration or a cardiac hospitalization within the last 3 months, diagnosed or reported by the subject
4 transplanted organ
5 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
6 pregnant, nursing, or planning a pregnancy while enrolled in this study and within 16 weeks following the last administration of study drug
7 non-plaque form of psoriasis
8 current drug-induced psoriasis
9 major surgery, within 8 weeks before screening
10 substance abuse problem within the previous 12 months
11 known allergy or sensitivity to products containing latex
12 previously received any therapeutic agent directly targeted to IL-23
13 received any anti-TNF-α biologic therapy within 3 months before the first administration of study drug
14 received any therapeutic agent directly targeted to IL-12/23, IL-23, IL-17A or IL-17R within 3 months of the first administration of study drug
15 received natalizumab, belimumab, or agents that modulate B cells or T cellswithin 12 months of the first administration of study drug
16 received any systemic immunosuppressant or anakinra within 4
weeks of the first administration of study drug
17 received phototherapy or any systemic medications/treatments that could affect psoriasis or IGA evaluations within 4 weeks of the first administration of study drug
18 used topical treatments that could affect psoriasis or IGA evaluations within 2 weeks of the first administration of study drug
19 currently receiving lithium, antimalarials, or intramuscular gold, or
has received lithium, antimalarials, or IM gold within 4 weeks of the first study drug administration
20 received an experimental antibody or biologic therapy within the
previous 6 months
21 received, or is expected to receive, any live virus or bacterial
vaccination within 3 months before the first administration of study drug
22 had a BCG vaccination within 12 months of screening
23 known intolerance or hypersensitivity to any biologic medication, or known allergies or clinically significant reactions to murine, chimeric, or human proteins, mAbs, or antibody fragments
24 known allergies, hypersensitivity, or intolerance to guselkumab or its excipients
25 a history of chronic or recurrent infectious disease
26 history of active granulomatous infection before study start
27 chest radiograph within 3 months before the first administration of study drug
28 nontuberculous mycobacterial infection or opportunistic infection.
Subjects with a history of esophageal candidiasis or thrush would also be exceptions to this criterion
29 persistently indeterminate QuantiFERON-TB® Gold test results
30 infected with HIV
31 Tests positive for hep B virus infection or who are seropositive for
antibodies to hep C virus
32 serious infection, was hospitalized or received intravenous antibiotics for an infection during 2 months before baseline
33 herpes zoster within the 2 months before baseline
34 known malignance or has a history of malignancy within 5 years
before study start
35 history of lymphoproliferative disease; a history of monoclonal
gammopathy of undetermined significance; or signs and symptoms
suggestive of possible lymphoproliferative disease
36 unable or unwilling to undergo multiple venipunctures because of
poor tolerability or lack of easy access to veins
37 Lives in an institution on court or authority order
38 condition that, in the opinion of the investigator, would participation not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments
39 Is an employee of the investigator or study site, with direct
involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator
40. a potential participant with the following features will be excluded from participating in the study protocol:
o During the 6 weeks prior to baseline, have had ANY of (a) confirmed SARS-CoV-2 infection, OR (b) suspected SARS-CoV-2 infection, OR (c) close contact with a person with known or suspected SARS-CoV-2 infection
(i) obtained at least 2 weeks after conditions (a), (b), (c) above
(ii) with absence of ALL conditions (a), (b), (c) above during the period between the negative test result and the baseline study visit
Please refer to the protocol pages 40-43 for all exclusion criteria
|E.5 End points
|E.5.1||Primary end point(s)||
|The primary endpoint of the main study is the proportion of subjects in study groups 2a and 2b who achieve an absolute PASI score <3 at week 68.
|E.5.1.1||Timepoint(s) of evaluation of this end point||
|E.5.2||Secondary end point(s)||
|Major secondary endpoints of this study are:
• Time to improvement from baseline (week 0) in PASI (PASI 75/90/100 response and absolute PASI score = 0) for subjects with short (≤ 2 years) and longer (>2 years) disease duration per study group (1, 2a 2b, and 2c)
• Proportion of subjects with short (≤2 years) and longer (>2 years) disease duration who achieve an absolute PASI score of 0, ≤1 and <3 at weeks 20, 28, 68 and 116 per study group (1, 2a, 2b, 2c, 3a and 3b)
• Proportion of subjects who retain disease control (ie, absolute PASI score <3 at all visits) from week 68 through week 116 for subjects with short (≤ 2 years) and longer (>2 years) disease duration per study group (3a and 3b).
Other secondary endpoints of this study are:
• Proportion of subjects who achieve a PASI 75/90/100 response at weeks 20, 28, 68 and 116 per study group (1, 2a, 2b, 2c, 3a and 3b)
• Time to loss of disease control (absolute PASI score >5 at any visit) after treatment withdrawal beyond week 68 per study group (3a and 3b)
• Proportion of subjects with an absolute PASI score = 0 at all of the following visits: weeks 12, 16, 20 and 28 (study group 1)
• The change from baseline (week 0) in Dermatology Life Quality Index (DLQI) score at weeks 28 and 68 per study group (1, 2a, 2b, and 2c)
• Proportion of subjects who achieve a DLQI score 0/1 and <5 at weeks 28 and 68 per study group (1, 2a, 2b, and 2c)
• The change from baseline (week 0) in affected Body Surface Area (BSA) at weeks 12, 28, 52, 68, 80, and 104 (all study groups)
• The change from baseline (week 0) in the Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA) score at weeks 28, 68 and 116 among subjects with nail psoriasis at baseline (week 0) (1, 2a, 2b, 2c, 3a and 3b).
• The change from baseline (week 0) in the signs and symptoms aggregate scores of the Psoriasis Symptoms and Signs Diary (PSSD) at weeks 28, 68 and 116 (1, 2a, 2b, 2c, 3a and 3b)
• The proportion of subjects who achieve a PSSD sign score = 0 at week 68 among subjects with a PSSD sign score ≥1 at week 28 per study group (2a, 2b and 2c).
• The association between trough serum concentration and efficacy or serum biomarker level
• The association between trough serum guselkumab levels at weeks 20, 28, 36 and 68 and achieving a PASI score <3 at week 68 per study group (2a and 2b)
• Proportion of subjects who were re-treated due to loss of disease control (PASI >5) and regain control of disease (PASI <3) 24 weeks after start of re-treatment (study groups 2d and 3c)
• Safety and tolerability with regard to adverse events (AEs) and abnormal laboratory results (all study groups).
|E.5.2.1||Timepoint(s) of evaluation of this end point||
|Weeks 12, 16, 20, 28, 36, 52, 68 & 116
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| Yes
|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.184.108.40.206||Other trial type description||
|E.7.2||Therapeutic exploratory (Phase II)|| No
|E.7.3||Therapeutic confirmatory (Phase III)|| Yes
|E.7.4||Therapeutic use (Phase IV)|| No
|E.8 Design of the trial
|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.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || Yes
|E.8.2.4||Number of treatment arms in the trial||3
The trial involves single site in the Member State concerned
|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||90
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||100
|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
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||5
|E.8.9.1||In the Member State concerned months||2
|E.8.9.1||In the Member State concerned days||0