Clinical trial NCT03384745
Conditions: Psoriasis
Sponsor: Bond Avillion 2 Development LP
Start date: 2018-07-31; Completion date: 2020-03-26
Enrollment: 313 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center phase 2b study in subjects with moderate to severe chronic plaque-type psoriasis. Approximately 300 subjects will be enrolled at approximately 60 investigator sites in North America and Europe.

Detailed description:

Arms: arm 1: M1095, 30 mg, given at Week 0, 2, 4, 8, 12 and every four weeks. arm 2: M1095, 60 mg, given at Week 0, 2, 4, 8, 12 and every four weeks. arm 3: M1095, 120 mg, given at Week 0, 2, 4, 8, 12 and every eight weeks. arm 4: M1095, 120 mg, given at Week 0, 2, 4, 6, 8, 10, 12 and every four weeks. arm 5: Placebo, given at Week 0, 1, 2, 3, 4, 6, 8 and 10, then M1095, 120mg, given at Week 12, 14, 16, and every four weeks. arm 6: Secukinumab, 300mg, given at Week 0, 1, 2, 3, 4, 8, 12 and every four weeks.
Interventions: intervention 1: M1095 (Sonelokimab) intervention 2: Placebo intervention 3: Secukinumab
Intervention descriptions: intervention 1: M1095 (Sonelokimab) is a trivalent monomeric nanobody® that neutralizes interleukins IL-17A, IL-17F, and IL-17A/F. intervention 2: Placebo contains no active drug. intervention 3: Secukinumab is a human immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds IL-17A.

Protocol documents:
Prot_000.pdf: 
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Protocol Number: AV002                     CONFIDENTIAL               M1095 phase 2b psoriasis study 
 
AV002 – Final protocol, Version 3.0, incorporating CZE-1, dated 16 October 2018 
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Table of Contents 
TABLE OF CONTENTS ........................................................................................................3 
1.0 
PROTOCOL SUMMARY ..........................................................................................7 
1.1 
Synopsis .............................................................................................................7 
1.2 
Schema ............................................................................................................19 
1.3 
Schedule of Activities (SoA) ..........................................................................20 
2.0 
INTRODUCTION......................................................................................................23 
2.1 
Study Rationale ..............................................................................................23 
2.2 
Background ....................................................................................................23 
2.3 
Benefit/Risk Assessment ................................................................................24 
3.0 
OBJECTIVES AND ENDPOINTS ..........................................................................27 
4.0 
STUDY DESIGN ........................................................................................................29 
4.1 
Overall Design ................................................................................................29 
4.2 
Scientific Rationale for Study Design ...........................................................30 
4.3 
Justification for Dose .....................................................................................30 
4.4 
End of Study Definition .................................................................................31 
5.0 
STUDY POPULATION ............................................................................................32 
5.1 
Inclusion Criteria ...........................................................................................32 
5.2 
Exclusion Criteria ..........................................................................................32 
5.3 
Lifestyle Considerations ................................................................................37 
5.3.1 
Meals and Dietary Restrictions .........................................................37 
5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabis/Marijuana .....................37 
5.3.3 
Activity ..............................................................................................37 
5.4 
Screen Failures ...............................................................................................37 
6.0 
STUDY DRUGS .........................................................................................................38 
6.1 
Study Drugs Administered ............................................................................38 
6.2 
Preparation/Handling/Storage/Accountability ...........................................39 
6.3 
Measures to Minimize Bias: Randomization and Blinding........................40 
6.4 
Study Drug Compliance ................................................................................42 
6.5 
Previous and Concomitant Therapy, and Prohibited Medications ...........42 
6.5.1 
Rescue Medicine ...............................................................................43 
6.6 
Dose Modification ..........................................................................................43 
6.6.1 
Week 12 .............................................................................................43 
6.6.2 
Week 24 .............................................................................................44 
6.7 
Treatment after the End of the Study ..........................................................44 
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7.0 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ................................................................45 
7.1 
Discontinuation of Study Drug .....................................................................45 
7.1.1 
Temporary Discontinuation ...............................................................47 
7.1.2 
Rechallenge .......................................................................................47 
7.2 
Subject Withdrawal from the Study ............................................................47 
7.3 
Lost to Follow Up ...........................................................................................48 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ....................................................49 
8.1 
Study Procedures ...........................................................................................49 
8.1.1 
Screening ...........................................................................................49 
8.1.2 
Week 0 / Randomization ...................................................................51 
8.1.3 
Weeks 1, 3, 6, 10 ...............................................................................52 
8.1.4 
Week 2 ...............................................................................................52 
8.1.5 
Week 4 ...............................................................................................53 
8.1.6 
Weeks 8, 44, 52 .................................................................................54 
8.1.7 
Weeks 12, 24, 36, 48 .........................................................................55 
8.1.8 
Week 14 .............................................................................................56 
8.1.9 
Week 16, 20, 28, 32, 40 .....................................................................56 
8.1.10 
Unscheduled Visit .............................................................................57 
8.1.11 
Early Discontinuation ........................................................................57 
8.2 
Efficacy Assessments .....................................................................................59 
8.2.1 
Investigator’s Global Assessment (IGA mod 2011) .........................59 
8.2.2 
Assessment of Total Body Surface Area (BSA) and Psoriasis 
Area and Severity Index (PASI) ........................................................59 
8.3 
Quality of Life Instruments...........................................................................60 
8.3.1 
Dermatology Life Quality Index (DLQI) ..........................................60 
8.3.2 
Short-Form 36 (SF-36) ......................................................................60 
8.3.3 
Euro-Quality of Life Questionnaire for Psoriasis (EQ-PSO) ............60 
8.4 
Safety Assessments .........................................................................................61 
8.4.1 
Physical Examination ........................................................................61 
8.4.2 
Skin Evaluation .................................................................................61 
8.4.3 
Vital Signs .........................................................................................62 
8.4.4 
Electrocardiograms ............................................................................62 
8.4.5 
Clinical Safety Laboratory Assessments ...........................................63 
8.4.6 
Depression and Suicidal Risk Monitoring .........................................63 
8.4.6.1 
Electronic Self Rated Version, Columbia-Suicide 
Severity Rating Scale     (eC-SSRS) ................................64 
8.4.6.2 
Patient Health Questionnaire (PHQ-8) ............................64 
8.5 
Adverse Events (AEs) and Serious Adverse Events (SAEs).......................64 
8.5.1 
Time Period and Frequency for Collecting AE and SAE 
Information ........................................................................................65 
8.5.2 
Method of Detecting AEs and SAEs .................................................65 
8.5.3 
Follow-up of AEs and SAEs .............................................................65 
8.5.4 
Regulatory Reporting Requirements for SAEs .................................65 
8.5.5 
Pregnancy ..........................................................................................66 
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8.5.6 
Cardiovascular and Death Events ......................................................66 
8.5.7 
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs ........................................................66 
8.6 
Overdose and Medication Errors .................................................................66 
8.7 
Pharmacokinetics ...........................................................................................67 
8.8 
Pharmacodynamics ........................................................................................67 
8.9 
Genetics ...........................................................................................................67 
8.10 
Biomarkers .....................................................................................................68 
8.10.1 
Immunogenicity Assessments ...........................................................68 
8.11 
Health Economics...........................................................................................68 
9.0 
STATISTICAL ANALYSIS .....................................................................................69 
9.1 
Statistical Hypotheses ....................................................................................69 
9.2 
Sample Size Determination ...........................................................................70 
9.3 
Populations for Analyses ...............................................................................70 
9.4 
Statistical Analyses.........................................................................................71 
9.4.1 
Efficacy Analyses ..............................................................................71 
9.4.2 
Subject Demographics/Other Baseline Characteristics .....................72 
9.4.3 
Subject Disposition ............................................................................72 
9.4.4 
Treatment Compliance ......................................................................72 
9.4.5 
Safety Analyses .................................................................................73 
9.4.5.1 
Vital Signs .......................................................................73 
9.4.5.2 
ECG Evaluations .............................................................73 
9.4.5.3 
Clinical Laboratory Evaluations ......................................73 
9.4.5.4 
Adverse Events ................................................................73 
9.4.5.5 
Suicidality and Self-Injurious Behavior ..........................73 
9.4.5.6 
Previous and Concomitant Therapy ................................74 
9.4.6 
Other Analyses ..................................................................................74 
9.4.7 
PK Analyses ......................................................................................74 
9.4.8 
Immunogenicity Analyses .................................................................74 
9.5 
Interim Analyses ............................................................................................74 
9.5.1 
Data Monitoring Committee (DMC) .................................................75 
10.0 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .................................................................................................76 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................76 
10.1.1 
Regulatory and Ethical Considerations .............................................76 
10.1.2 
Financial Disclosure ..........................................................................76 
10.1.3 
Informed Consent Process .................................................................76 
10.1.4 
Data Protection ..................................................................................77 
10.1.5 
Study Steering Committee .................................................................77 
10.1.6 
Dissemination of Clinical Study Data ...............................................77 
10.1.7 
Data Quality Assurance .....................................................................78 
10.1.8 
Source Documents .............................................................................78 
10.1.9 
Study and Site Closure ......................................................................78 
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10.1.10 Publication Policy ..............................................................................79 
10.2 
Appendix 2: Clinical Laboratory Tests........................................................80 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................82 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .....................................................................................................88 
10.5 
Appendix 5: HIV, Hepatitis B and Hepatitis C Virus Screening ..............91 
10.6 
Appendix 6: Measures of Psoriasis Area and Severity ...............................92 
10.6.1 
Investigator’s Global Assessment (IGA mod 2011) .........................92 
10.6.2 
Total Body Surface Area (BSA) and Psoriasis Area and 
Severity Index (PASI) .......................................................................93 
10.7 
Appendix 7: Abbreviations ...........................................................................96 
10.8 
Appendix 8: Protocol Amendment History .................................................98 
11.0 
REFERENCES .........................................................................................................101 
12.0 
SIGNATURE OF INVESTIGATOR .....................................................................103 
 
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Protocol Number: AV002                     CONFIDENTIAL               M1095 phase 2b psoriasis study 
 
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1.0 
PROTOCOL SUMMARY 
1.1 
Synopsis 
 
Name of Sponsor: 
Bond Avillion 2 Development LP 
Name of Finished 
Product: 
M1095 
Name of Active 
Ingredient: 
M1095 
Title of Study: 
 
A phase 2b randomized, double-blind, placebo controlled, multi-center 
12-week study with an additional 40-week follow-up assessment of 
efficacy, safety and tolerability of M1095 in subjects with moderate to 
severe chronic plaque-type psoriasis. 
Protocol No: 
 
AV002 
Co-ordinating 
Investigators: 
North America: 
 
 
Europe:
 
 
Study centers: 
Approximately 60 sites, in Europe and North America 
Study duration: 52 weeks 
Phase: 2b 
Objectives: 
Primary: 
• To evaluate the efficacy of four dose regimens of M1095 compared to placebo on 
achievement of an Investigator’s Global Assessment (IGA) score of 0 or 1 after 12 weeks of 
treatment in subjects with moderate to severe chronic plaque-type psoriasis. 
Secondary: 
• To evaluate the efficacy of four dose regimens of M1095 compared to placebo during a 12-
week treatment period on secondary endpoints: Psoriasis Area Severity Index (PASI) 75, 
PASI 90, PASI 100, change in PASI and shift in IGA. 
• To assess the dose-regimen efficacy relationship for M1095 after 12, 24, 36, and 48 weeks of 
treatment. 
• To evaluate the longer-term efficacy of M1095 at Week 24 and at Weeks 36 and 48. 
• To assess the safety and tolerability of M1095.  
 
 
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Exploratory: 
• Assessment of the quality of life and health outcomes of subjects treated with M1095 over 
48 weeks via quality of life instruments evaluated every 12 weeks. 
• Assessment of the population pharmacokinetics (PK) of various doses and dose regimens of 
M1095. 
• Assessment of the development of anti-drug antibodies for various doses and dose regimens 
of M1095. 
• Assessment of change in efficacy from Week 12 to Week 24 in subjects who undergo dose 
escalation. 
• Assessment of M1095 efficacy after being withheld in subjects with an IGA score of 0 at 
Week 24. 
Study Design:  
This is a multi-center phase 2b study in subjects with moderate to severe chronic plaque-type 
psoriasis. Approximately 300 subjects will be enrolled at approximately 60 investigator sites in North 
America and Europe. The study will consist of a 4-week screening period (Week -4 to Week 0), a 12 
week treatment period which is placebo-controlled (Week 0 to Week 12), a 12 week maintenance/ 
escalation period where all subjects are on active treatment (Week 12 to Week 24), a 24 week 
response assessment/dose hold period where active treatment is withheld if subjects being treated 
with M1095 have an IGA score of 0 at the beginning of the period (Week 24 to Week 48) and a final 
assessment period for safety follow up (Week 48 to Week 52). The study will be double-blind up to 
Week 24, with subject- and investigator-blind maintained throughout. 
Subjects will be randomized in a 1:1:1:1:1:1 ratio, with approximately 50 subjects randomized into 
each of six treatment groups as shown below and in Figure 1: 
1. Placebo wk 0, 1, 2, 3, 4, 6, 8, 10 / M1095 120mg wk 12, 14, 16 and q4w. 
2. M1095 30mg wk 0, 2, 4, 8, 12 and q4w.  
3. M1095 60mg wk 0, 2, 4, 8, 12 and q4w. 
4. M1095 120mg wk 0, 2, 4, 8, 12 and q8w. 
5. M1095 120mg wk 0, 2, 4, 6, 8, 10, 12 and q4w. 
6. Secukinumab 300mg wk 0, 1, 2, 3, 4, 8, 12 and q4w. 
Prior to Week 24: 
M1095 subjects in Arms 2 and 3 will receive placebo at Weeks 1, 3, 6, 10 and 14. 
M1095 subjects in Arm 4 will receive placebo at Weeks 1, 3, 6, 10, 14 and 16. 
M1095 subjects in Arm 5 will receive placebo at Weeks 1, 3 and 14. 
Secukinumab subjects in Arm 6 will receive placebo at Weeks 6, 10 and 14.  
Subjects randomized to 30mg or 60mg M1095 who do not achieve an IGA score of 0 or 1 at Week 
12 will be dose escalated to 120mg q4w starting at Week 12. 
Any subjects on M1095 who did not undergo dose escalation at Week 12 and who achieve an IGA 
score of 0 at Week 24 will have study drug withheld and will receive placebo q4w. Subsequently, if 
IGA score is 1 or more, these subjects will re-commence M1095 at the dose they received prior to  
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Protocol Number: AV002                     CONFIDENTIAL               M1095 phase 2b psoriasis study 
 
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Week 24 on a q4w regimen at the visits scheduled by the protocol until the end of the treatment 
period. Dose will not be withheld for a second time, irrespective of subsequent IGA scores.  
Subjects receiving secukinumab will continue to receive 300mg q4w throughout the study. 
The subject blind will be maintained by the use of M1095 and matched placebo. The syringes used 
for all M1095 and placebo doses will be identical. All subjects will receive two injections of 1mL at 
each visit. There is also physical protection of the blind. Subjects will be asked to wear an eye-mask 
for all injections. 
Randomization will be stratified by prior biologic use (yes or no) and weight (≤90kg, >90kg). 
Figure 1 
Flow chart / design diagram 
The last study drug injection is at Week 44, with key safety and efficacy evaluations at Week 48 and 
final safety and efficacy assessments at Week 52. 
Planned number of 
subjects: 
300 
Diagnosis and 
main criteria for 
inclusion: 
Inclusion Criteria:  
1. Ambulatory male and female subjects between 18 and 75 years 
of age at time of consent. 
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Protocol Number: AV002                     CONFIDENTIAL               M1095 phase 2b psoriasis study 
 
AV002 – Final protocol, Version 3.0, incorporating CZE-1, dated 16 October 2018 
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2. Subject has had stable moderate to severe plaque-type psoriasis 
for at least 6 months prior to randomization (e.g., no morphology 
changes or significant flares of disease activity in the opinion of 
the investigator). 
3. Subject must be considered, in the opinion of the investigator, not 
adequately controlled by photo, topical or previous systemic 
treatments and a candidate for systemic biologic therapy. 
4. Subject has IGA ≥3, involved body surface area (BSA) ≥10%, 
and PASI ≥12 at screening and at baseline. 
5. Subject is in the opinion of the investigator able to comply with 
the study procedures. 
6. Following verbal and written information about the study, subject 
must provide signed and dated informed consent before any study 
related activity is carried out. 
Exclusion Criteria:  
1. Subject diagnosed with erythrodermic psoriasis, pustular 
psoriasis, guttate psoriasis, or other skin conditions at the time of 
the screening visit (e.g., eczema) that would interfere with 
evaluations of psoriasis (Note: psoriatic arthritis is NOT 
exclusionary). 
2. Subject has drug-induced psoriasis (i.e. new onset or current 
exacerbation from beta-blockers, calcium channel inhibitors or 
lithium). 
3. Other medical conditions: 
a. At the time of consent, subject has a planned in-patient 
surgical intervention between baseline and the Week 52 
evaluation. 
b. Subject has an active infection or history of infections as 
follows: 
i. Any active infection for which systemic anti-
infectives were used within 28 days prior to 
randomization. 
ii. A serious infection, defined as requiring 
hospitalization or intravenous anti-infectives 
within 8 weeks prior to randomization. 
iii. Any history of bone infection requiring surgical 
intervention and/or intravenous antibiotics. 
iv. Recurrent or chronic infections or other active 
infection that, in the opinion of the investigator, 
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Protocol Number: AV002                     CONFIDENTIAL               M1095 phase 2b psoriasis study 
 
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Page 11 of 103 
 
might cause this study to be detrimental to the 
subject. 
c. Subject has active tuberculosis. 
d. Subject has a positive QuantiFERON®-TB Gold test for 
tuberculosis at screening, or the first test and a repeat test 
are both indeterminate, unless (i) subject has a known 
history of latent TB and has completed a course of 
treatment or (ii) subject has received sufficient treatment 
for latent TB to allow concomitant treatment with a 
biological therapy as per local guidelines (note these 
subjects must continue their concomitant latent TB 
treatment to completion while participating in the study). 
If these subjects are outside of the screening window (>28 
days since consent) when they become eligible to 
participate, they should be fully re-screened for the study.  
e. Subject has an underlying condition (including, but not 
limited to metabolic, hematologic, renal, hepatic, 
pulmonary, neurologic, endocrine, cardiac, infectious or 
gastrointestinal) which in the opinion of the investigator 
places the subject at unacceptable risk for receiving an 
immunomodulatory therapy. 
f. Subject has known history of inflammatory bowel 
disease. 
g. Subject with known chronic liver disease or tests positive 
for hepatitis B virus (HBV) infection or has antibodies to 
hepatitis C virus (HCV) at screening (see Section 10.5, 
Appendix 5 in the protocol main text). 
h. Subject has antibodies to human immunodeficiency 
virus (HIV) at screening (see Section 10.5, Appendix 5 
in the protocol main text). 
i. Subject has history of heart failure, myocardial infarction 
or unstable angina pectoris within the 12 months prior to 
randomization. 
j. Subject has uncontrolled hypertension characterized by 
two blood pressure measurements separated by at least 15 
minutes 
with 
systolic 
>160mmHg 
or 
diastolic 
>100mmHg. 
k. Subject has clinically significant electrocardiogram 
(ECG) abnormalities on centrally read ECG. 
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Protocol Number: AV002                     CONFIDENTIAL               M1095 phase 2b psoriasis study 
 
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l. Subject has any active malignancy, including evidence of 
cutaneous basal or squamous cell carcinoma or 
melanoma. 
m. Subject has history of malignancy within 5 years 
EXCEPT cutaneous squamous or basal cell carcinoma, in 
situ cervical cancer, or in situ breast ductal carcinoma 
which has been treated and considered cured. 
n. Subject has any concurrent medical condition that, in the 
opinion of the investigator, could cause this study to be 
detrimental to the subject. 
4. Subject has laboratory abnormalities at screening, including any 
of the following: 
a. Aspartate 
aminotransferase 
(AST) 
or 
alanine 
aminotransferase (ALT) >2 x the upper limit of normal 
(one 
retest 
is 
allowed 
for 
aminotransferase 
abnormalities). 
b. Serum direct bilirubin >1.5 mg/dL. 
c. White blood cell (WBC) count <3.00 x 103/µL. 
d. Absolute neutrophil count <1.50 x 103/µL. 
e. Absolute lymphocyte count <0.50 x 103/µL. 
f. Platelet count <100,000/µL. 
g. Creatinine clearance of <30mL/min (calculated via 
Cockcroft Gault).     A subsequent 24-hour urine 
collection may be performed with the prior approval of 
the Medical Monitor, and if via urine collection the 
creatinine clearance is >30mL/min the subject is eligible 
for the study.    
AMENDMENT FOR CZECH REPUBLIC               
Creatinine clearance of <60 mL/min (calculated via 
Cockcroft Gault). A subsequent 24-hour urine collection 
may be performed with the prior approval of the Medical 
Monitor, and if via urine collection the creatinine 
clearance is >60mL/min the subject is eligible for the 
study.   
h. Any other laboratory abnormality, which, in the opinion 
of the investigator, will prevent the subject from 
completing the study or will interfere with the 
interpretation of the study results. 
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5. Subject has used topical therapy as follows: 
a. Topical psoriasis treatment within 14 days of 
randomization, 
including, 
but 
not 
limited 
to, 
corticosteroids, anthralin, calcipotriene, topical vitamin D 
derivatives, topical calcineurin inhibitors, retinoids, 
tazarotene, as well as emollients and other non-
prescription topical products that contain urea, >3% 
salicylic acid, or alpha- or beta-hydroxyl acids, and 
medicated shampoos (e.g. those that contain >3% 
salicylic acid, corticosteroids, coal tar, or vitamin D3 
analogues). 
Exceptions: mild/least potent topical steroids are 
permitted during screening for use limited to the face, 
axillae, and/or genitalia but must be discontinued 24 
hours prior to the baseline visit (randomization). 
b. Bland emollients (without alpha or beta hydroxy acids) 
within 24 hours of baseline visit (randomization). Note 
that as per Section 6.5 bland emollients (without alpha 
or beta hydroxy acids) may be used during the study 
but MAY NOT be used within 24 hours prior to any 
study visit. 
6. Subject has used the following within 28 days of randomization: 
ultraviolet A (UVA) light therapy (with or without psoralen); 
ultraviolet B (UVB) light therapy; excimer laser; oral retinoids; 
methotrexate; 
cyclosporine; 
systemically 
administered 
calcineurin inhibitors; azathioprine; thioguanine; hydroxyurea; 
cyclophosphamide; fumarates; apremilast; or oral or parenteral 
corticosteroids 
including 
intramuscular 
or 
intraarticular 
administration (exception: otic, nasal, ophthalmic, or inhaled 
corticosteroids within recommended doses is permitted); other 
non-biologic systemic therapy for psoriasis. 
7. Subject is not willing to limit ultraviolet (UV) light exposure (e.g. 
sunbathing and/or the use of tanning devices) during the study. 
8. Subject has received live vaccine(s) within 6 weeks of 
randomization. 
9. Subject has received prior treatment at any time before screening 
with any compound (marketed or investigational) targeting IL-17 
(i.e. direct inhibitor, receptor blocker, etc.). 
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10. Subject has received prior treatment at any time before screening 
with more than 2 biologic therapies (ustekinumab, tumour 
necrosis factor (TNF) targeting therapies, or investigational 
therapies).  
11. Subject has received TNF targeting therapies in the 12 weeks 
prior to randomization, ustekinumab in the 6 months prior to 
randomization, or investigational biological therapies within 12 
weeks, or 5 half lives of randomization, whichever is the longer. 
12. Subject has known sensitivity to any of the products or 
components to be administered during dosing. 
13. Subject has a history or evidence of suicidal ideation or behavior 
within the 12 months prior to randomization or evidence of severe 
depression at screening or baseline [i.e. severity level 3, 4 or 5 
based on an assessment with the electronic Columbia Suicide 
Severity Rating Scale (eC-SSRS)]. 
14. Subject has a history of chronic alcohol abuse or  chronic drug 
abuse, or has used intravenous (IV) drugs in the past 2 years. 
15. Women of child bearing potential who are not willing to use 
highly effective methods of birth control during treatment and for 
12 weeks after the last dose of study drug. See Section 10.4, 
Appendix 4 in the main protocol text for the definition of child 
bearing potential and guidance on highly effective methods of 
birth control. 
16. Subject has a positive serum pregnancy test during screening or 
a positive urine pregnancy test at baseline (Week 0, 
randomization visit), except those surgically sterile or at least 1 
year postmenopausal.  
17. Subject is pregnant or breast feeding, or planning to become 
pregnant while enrolled in the study and for 12 weeks after the 
last dose of study drug. 
18. Male subjects who are not willing to use contraception during 
treatment and for 12 weeks after the last dose of study drug. See 
Section 10.4, Appendix 4 for definition of permitted methods of 
contraception in male subjects.  
19. Subject will not be available for protocol required study visits or 
procedures, (e.g. venepuncture) to the best of the subject's and 
investigator's knowledge. 
20. Subject has any kind of disorder that, in the opinion of the 
investigator, may compromise the ability of the subject to give 
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informed consent and/or to comply with all required study 
procedures. 
21. Subject is either 
a. Currently 
enrolled 
in 
another 
interventional, 
investigational device or drug study. 
b. Has been in another investigational device or drug 
study(s) in the 30 days prior to consent. 
22. Subject or subject’s immediate family is an employee of the study 
sponsor (Bond Avillion 2 Development LP), Avillion LLP, EMD 
Serono, Merck KGaA or any contract research organization 
(CRO) associated with the study.  
23. Subject or subject’s immediate family is working for or employed 
by the investigator. 
Reference therapy, 
dose, and mode of 
administration: 
1. Placebo, in 2 x 1mL subcutaneous injections, given at Week 0, 1, 2, 
3, 4, 6, 8 and 10. (These subjects will then receive study drug: 
M1095, 120mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study 
drug, 1mL placebo, given at Week 12, 14, 16, and q4w). 
Active therapy, dose 
and mode of 
administration: 
2.  M1095, 30 mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study 
     drug, 1mL placebo, given at Week 0, 2, 4, 8, 12 and q4w.  
     (These subjects will also receive placebo, in 2 x 1mL subcutaneous  
     injections, at Week 1, 3, 6, 10 and 14). 
3.  M1095, 60 mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study  
     drug, 1mL placebo, given at Week 0, 2, 4, 8, 12 and q4w.  
     (These subjects will also receive placebo, in 2 x 1mL subcutaneous  
     injections, at Week 1, 3, 6, 10 and 14). 
4.  M1095, 120 mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study  
     drug, 1mL placebo, given at Week 0, 2, 4, 8, 12 and q8w.  
     (These subjects will also receive placebo, in 2 x 1mL subcutaneous  
     injections, at Week 1, 3, 6, 10, 14, 16, 24, 32 and 40). 
5.  M1095, 120 mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study  
     drug, 1mL placebo, given at Week 0, 2, 4, 6, 8, 10, 12 and q4w.  
     (These subjects will also receive placebo, in 2 x 1mL subcutaneous  
     injections, at Week 1, 3 and 14).  
6.  Secukinumab, 300mg, in 2 x 1mL (150mg/mL) subcutaneous 
     injections, given at Week 0, 1, 2, 3, 4, 8, 12 and q4w.  
     (These subjects will also receive placebo, in 2 x 1mL subcutaneous  
     injections, at Week 6, 10 and 14). 
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The 30mg and 60mg M1095 doses (in arms 2 and 3) will be escalated at 
Week 12 in subjects who have not achieved an IGA score of 0 or 1, as 
described in Section 6.6.1.  
M1095 doses (in arms 1 to 5) may be replaced by placebo at Week 24 as 
described in Section 6.6.2 of the main protocol text.  
Criteria for evaluation: 
Primary Endpoint: 
• IGA score of 0 or 1 at Week 12, with an IGA reduction of at least 2 points from baseline. 
Secondary Endpoints:  
• Efficacy: 
o PASI 75 at Week 12. 
o PASI 90 at Week 12. 
o PASI 100 at Week 12. 
o PASI 75, PASI 90 and PASI 100 beyond Week 12. 
o Change from baseline in PASI score and in total BSA affected by plaque-type 
psoriasis. 
o Shift from baseline in IGA score category. 
• Safety: Adverse events, skin evaluation, laboratory assessments, vital signs, ECGs, drug 
discontinuations, and instruments to assess depression and suicidality [electronic Columbia-
Suicide Severity Rating Scale (eC-SSRS) and Personal Health Questionnaire Depression 
Scale (PHQ-8)]. 
Exploratory Endpoints: 
• Dermatology Life Quality Index (DLQI), Short Form 36 (SF-36) and Euro-Quality of Life 
Questionnaire for Psoriasis (EQ-PSO). 
• Population PK evaluation. 
• Anti-drug antibodies: determination of binding and neutralizing antibodies defined by 
percentage of subjects with antibodies and titers of antibody. 
• Monitoring of pre-existing antibodies against M1095. 
• IGA and PASI endpoints in subjects who dose escalate to 120mg M1095 q4w at Week 12. 
• IGA and PASI endpoints in subjects with an IGA score of 0 for whom M1095 is withheld at 
Week 24. 
 
Statistical Methods 
Sample size: 
A total of approximately 300 subjects will be randomized, approximately 50 per treatment group. 
With this sample size, the study has >99% power to detect a statistically significant difference 
between any treatment arm and placebo in the IGA score of 0 or 1 responder rate at Week 12, with a 
two-sided, unadjusted type I error of 0.05. These calculations assume IGA score of 0 or 1 rates of 
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>88% for study drug and ≤7% for placebo. As this is a phase 2 study, there will be no adjustments 
for multiplicity.  
Exploratory analyses between the different dose regimens of M1095 will also be performed. The 
PASI 100 response rate offers more discriminatory potential for this. Phase 1 data and response 
simulations give a PASI 100 response rate at Week 12 varying from 45 to 72%. With the sample size 
of approximately 50 subjects per group, based on these assumed PASI 100 response rates at Week 
12, the comparison between the highest and lowest M1095 doses has approximately 79% power. 
Analysis sets: 
The Intent to Treat (ITT) population includes all subjects randomly allocated to a treatment. The 
Modified Intent to Treat (MITT) population includes all subjects in the ITT Analysis Set who receive 
at least one dose of study drug, have a baseline, and at least one post baseline efficacy assessments. 
The Per-Protocol (PP) population includes all subjects in the MITT Analysis Set who have no 
important protocol deviations affecting the assessment of efficacy. Membership of the PP Analysis 
Set will be confirmed prior to unblinding the data. The ITT, MITT and PP populations will be 
analyzed per planned treatment.  
The Safety population is all subjects who receive at least one dose of study treatment. The Safety 
population will be analyzed per the actual treatment received. 
Primary analysis: 
The primary endpoint is achievement of an IGA score of 0 or 1 at 12 weeks. The response rate for 
the IGA score of 0 or 1 at Week 12 is defined as the proportion of subjects at Week 12 with an IGA 
score of 0 or 1 and with a reduction from baseline IGA of 2 points or more. Baseline IGA score is 
the last score prior to the first dose of study medication. Any missing IGA score of 0 or 1 response 
will be imputed as a non-response. 
The primary analysis will be based on the ITT Analysis Set. The primary treatment comparisons will 
be made using the two-sided Cochran-Mantel-Haenszel (CMH) test stratified by prior biologic use 
(yes/no) and body weight stratum (≤90kg, >90kg.) 
Sensitivity analyses: 
The primary analysis will be repeated on the MITT and PP Analysis Sets. Furthermore, selected 
sensitivity analyses will be performed on the ITT Analysis Set, including multiple imputation and 
last-observation carried forward. 
Secondary analyses: 
Secondary efficacy and QoL endpoints will be compared between treatments at each visit up to Week 
48 using the CMH test for binary endpoints and an Analysis of Covariance (ANCOVA) model for 
changes from baseline.  
Safety data will be summarized in the Safety Analysis Set by treatment and over time, for each 
treatment period separately and overall. 
 
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Exploratory analyses: 
Exploratory analyses of efficacy will be made for (i) all subjects who were dose-escalated at Week 
12, and (ii) all subjects who had active treatment withheld following an IGA score of 0 at Week 24. 
Subgroup analyses: 
Subgroup analyses of key efficacy and safety data will be performed as appropriate by geographical 
region, prior biological use, weight category, gender and geriatric status. 
Interim analyses: 
An independent Data Monitoring Committee (DMC) will be established to perform and review 
interim analyses during the study. The DMC will be operational prior to enrolment of the first subject 
into the study. The composition and operation of the DMC will be described in a DMC charter. The 
charter will also detail how the communication between the DMC and the sponsor will be firewalled 
to preserve the blinding and integrity of the study.  
The DMC will closely monitor the safety and tolerability data throughout the trial. No formal analysis 
of efficacy is planned during the double-blind, placebo-controlled 12-week induction phase. 
An unblinded interim analysis of 12-week data will occur at the completion of the Week 12 period, 
while the study is still ongoing. These data will be shared with firewalled individuals who are not 
directly involved in the conduct of the study.  
A second interim analysis will occur at the completion of the Week 24 period. All investigators and 
subjects will remain blinded to treatment assignments until the last subject completes the study and 
the final database lock occurs. Once the second interim database lock has occurred after Week 24, 
the sponsor study team will be unblinded.  
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1.2 
Schema 
 
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E. If a urine pregnancy test is positive, study treatment must be withheld. A serum pregnancy test (central) should be performed. See Section 10.4, 
Appendix 4 for details.  
F. Quantiferon TB test must be study specific and can be performed either by the central or local laboratory. If a Quantiferon TB test result is 
‘indeterminate’ the test must be repeated during the Screening period. If any Quantiferon TB test is ‘positive’ or if the first test and the repeat test are 
both ‘indeterminate’, the subject must be referred for tuberculosis workup per local guidelines. The subject is eligible for randomization if (i) they have 
a known history of latent TB and have completed a course of treatment or (ii) they have received sufficient treatment for latent TB to allow concomitant 
treatment with a biological therapy as per local guidelines (note these subjects must continue their concomitant latent TB treatment to completion while 
participating in the study, and if these subjects are outside of the screening window (>28 days since consent) when they become eligible to participate, 
they should be fully re-screened for the study). The subject is not eligible for randomization if either ‘active tuberculosis is present’ or if ‘latent 
tuberculosis is present and is untreated per local guidelines.’  
G. Subjects that test positive for anti-drug antibodies at the last study visit (either Week 52 or Early Discontinuation) may be requested to provide another 
sample approximately 6 to 12 months after study completion. 
H. Patient Reported Outcomes should be conducted at the start of each visit, before other assessments. 
I. 
Chest X-ray within 3 months of consent is considered acceptable. When performed as part of the Screening visit, the chest X-ray should be the last study 
procedure to be completed, as this will prevent unnecessary exposure to radiation if the subject is found to be ineligible following an earlier procedure. 
Investigator should follow up the results of the chest X-ray with the Medical Monitor if clinically indicated. 
J. 
Subjects randomized to M1095 30mg or 60mg who do not achieve an IGA score of 0 or 1 at Week 12 will be dose escalated to 120mg q4w. All study 
drug is allocated via IRT. 
K. Any subjects randomized to M1095 who did not undergo dose escalation at Week 12 and who achieve an IGA score of 0 at Week 24 will have study drug 
withheld and will receive placebo q4w. Subsequently, if IGA score is 1 or more, these subjects will re-commence M1095 at the dose they received prior 
to Week 24 on a q4w regimen at the visits scheduled by the protocol until the end of the treatment period. Dose will not be withheld for a second time, 
irrespective of subsequent IGA scores. All study drug is allocated via the IRT.  
L. The investigator should carefully consider the subject’s response at Week 24 and if there has been a worsening of psoriasis compared to baseline then the 
investigator should consider discontinuing the subject from the study if they are not receiving adequate benefit from their participation. 
 
 
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2.0 
INTRODUCTION 
M1095 is a trivalent monomeric nanobody® that neutralizes interleukins IL-17A, IL-17F, and 
IL-17A/F. A strong scientific and medical rationale exists for the use of M1095 in the treatment 
of autoimmune disease, including psoriasis.  
2.1 
Study Rationale  
Despite several biologic treatment options, the development of new psoriasis therapies is 
important. M1095 is a viable investigational treatment of psoriasis with the potential for a 
similar or improved risk/benefit profile compared to available therapies. This is a phase 2b 
study to evaluate the safety and efficacy of M1095 for the treatment of moderate to severe 
plaque-type psoriasis. 
2.2 
Background 
Psoriasis is a skin condition estimated to affect about 2-4% of the population in western 
countries with a higher prevalence in Caucasians and approximately equal frequency in males 
and females.1 The most common form is psoriasis vulgaris (plaque-type psoriasis) which is 
characterized by lesions which often itch and burn and manifest as raised, inflamed, red skin 
covered with silvery, white scales. The disease can appear anywhere although it is most 
common on extensor surfaces such as elbows and knees, plus the scalp and lower back. Mild 
severity disease can often be managed with topical treatments. As the disease severity 
increases, phototherapy or systemic therapies such as retinoids, methotrexate, cyclosporine, 
apremilast, or biologic immune modifying agents are required for disease control.  
The understanding of the pathophysiology behind psoriatic plaques has expanded markedly 
during the past twenty years leading to an expansion in the armamentarium for disease 
treatment. Cytokines which are known to play a role in psoriasis include, but are not limited 
to, TNF-α, IL-12, IL-23, and IL-17.2 Since 2004, several biologic therapies targeting these 
cytokines have been developed and approved for the treatment of moderate to severe psoriasis. 
The first therapy targeting TNF-α was approved in 2004, a therapy targeting IL-12/IL-23 was 
approved in 2009, the first therapy targeting IL-17 was approved in 2015, and a therapy 
targeting only IL-23 was approved in 2017. While these therapies have significantly improved 
on prior treatments there are still significant unmet needs in psoriasis which drive continued 
development of new therapies. 
IL-17 is a known target for psoriasis treatment and three drugs that target this mechanism are 
currently available. Secukinumab is a human immunoglobulin G1 (IgG1) monoclonal antibody 
that selectively binds IL-17A, ixekizumab is a humanized IgG4 monoclonal antibody that 
selectively binds IL-17A, and brodalumab is a human monoclonal IgG2 antibody that 
selectively binds to the IL-17 receptor inhibiting interactions with IL-17A, IL-17F, IL-17C, 
IL-17A/F and IL-25.3  
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M1095 differs from the approved therapies in several important ways which could provide a 
therapeutic advantage. First, it is a nanobody vs. an antibody. Nanobodies are a novel class of 
proteins that are based on single-domain antibody fragments and therefore are smaller and 
more robust than conventional antibodies.4 Second, M1095 specifically targets IL-17A and IL-
17F. Secukinumab and ixekizumab only interact with IL-17A and it has been reported that IL-
17F also plays a role in psoriasis pathophysiology. Brodalumab does target both IL-17A and 
IL-17F; however, it also blocks the IL-17 receptor from interacting with several other 
cytokines (IL-17C and IL-25) which may account for additional untoward effects that are not 
related to its ability to treat psoriasis. 
M1095 has been evaluated in subjects with psoriasis in study EMR200574-003, “A 
Multicenter, Phase 1, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the 
Safety, Tolerability, Immunogenicity, Pharmacokinetics, Pharmacodynamics and Efficacy of 
Multiple Ascending Doses of Subcutaneous M1095 (Anti-IL17A/F Nanobody) in Male and 
Female Subjects with Moderate to Severe Psoriasis.” The phase 1 study demonstrated that 
M1095 was generally well tolerated with robust efficacy and a pharmacokinetic (PK) profile 
suitable for long-term dosing on a 4 weekly or 8 weekly schedule. Furthermore, the efficacy 
results were suggestive that M1095 at the proposed doses may be able to deliver an 
improvement in Psoriasis Area and Severity Index (PASI) 90 and PASI 100 responses 
compared to what has been described with currently approved IL-17 modulating therapies. A 
full description of the results for this study can be found in the Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
Despite several biologic treatment options, new psoriasis therapies are needed. M1095 is a 
viable candidate treatment with the potential for a similar or improved risk/benefit profile 
compared to available therapies. All subjects in this study will receive M1095 or secukinumab 
as those randomized to placebo will switch to M1095 at Week 12. 
In EMR200574-003, subjects received three doses of M1095 at 2-week intervals over one 
month. Dose levels of 30mg through 240mg were tested. The study demonstrated that  
• M1095 administered up to a dose of 240mg q2w x 3 was generally well tolerated in a 
group of 33 subjects with moderate to severe psoriasis. 
• AUC and Cmax were dose proportional from 30mg to 240mg with a terminal half life 
of 11-12 days. 
• A dose-response relationship was observed with PASI 75/90/100 responses.  
The most common AEs (occurring in 2 or more of the 33 subjects treated with M1095) were 
pruritus, headache, hypertension, nasopharyngitis, somnolence and bronchitis. Two subjects 
discontinued due to AEs (an injection site reaction in a subject receiving 120mg and an 
elevation in aminotransferases in a subject receiving 240mg) and one SAE occurred (acute 
vestibular syndrome, in a subject receiving 30mg, which was deemed unrelated to study drug).  
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Subjects in the study were between 18 and 70 years old with moderate to severe psoriasis of at 
least 6 months duration, a static Physician’s Global Assessment (sPGA) of ≥3, ≥10% body 
surface area and a PASI score of ≥12. PASI 75/90/100 responses at Week 12 (8 weeks after 
the last M1095 injection) ranged from 88%/50%/13% to 100%/100%/56%. Achievement of 
sPGA scores of 0 and 1 at week 12 ranged from 88% to 100%. A full description of the safety 
and efficacy data from this study can be found in the Investigator’s Brochure. 
 
Secukinumab is an IL-17 antagonist that was approved by the Food and Drug Administration 
(FDA) and European Medicines Agency (EMA) in 2015 and is indicated for moderate to 
severe plaque-type psoriasis in adult subjects who are candidates for systemic therapy or 
phototherapy, the same population that will be enrolled in this study. The most common 
adverse reactions (>1%) are nasopharyngitis, diarrhea, and upper respiratory tract infection. 
Warnings and precautions include infections, tuberculosis, inflammatory bowel disease, and 
hypersensitivity reactions. In the pivotal phase 3 studies ERASURE (Efficacy of Response and 
Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year 
Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to 
Determine Efficacy in Psoriasis), at the 300mg secukinumab dose PASI 75 responses ranged 
from 76 to 82% and PASI 90 responses ranged from 54 to 59%.5 A full description of the safety 
and efficacy data for secukinumab can be found in the Prescribing Information6 or Summary 
of Product Characteristics (SmPC).7 
All subjects in this 52-week study will receive active therapy, 1/6 will be exposed to placebo 
for 12 weeks followed by M1095, 4/6 will be randomized to M1095 from the outset and 1/6 
will receive secukinumab at the approved dose. Based on currently available data subjects 
should experience some improvement in their psoriasis with either M1095 or secukinumab. Of 
note, subjects on the lower doses of M1095 who do not achieve an IGA score of 0 or 1 at Week 
12 will be increased to the highest dose.  
The most likely predicted AEs based on the clinical studies conducted to date are infections, 
injection site reactions, and gastrointestinal upset. Less common, but more severe AEs which 
have been reported with other IL-17 modulating agents such as hypersensitivity reactions, 
more severe infections, and suicidality will be managed via inclusion/exclusion criteria, careful 
and frequent monitoring, and administration of all study drug in the clinic.  
In cynomolgus monkeys, non-clinical toxicology studies lasting 26-weeks and 39-weeks 
minimal to mild reddish discoloration of the skin in the axillary and inguinal regions, 
associated with a histopathological diagnosis of superficial perivascular dermatitis, was 
observed. These findings improved but did not completely recover during the recovery period 
in these studies. The overall risk associated with these findings in human study subjects is low. 
If similar findings occur they will be observable on skin evaluation and managed appropriately.  
Subjects will be followed closely (weekly during the first month, biweekly for the second and 
third month and then at least monthly for the remainder of the study) and observed via standard 
assessments including queries about AEs, periodic examinations, and laboratory assessments. 
Subjects who experience notable study drug related AEs or lab abnormalities will be 
discontinued (see Section 7.1).  
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In addition to the assessment of an individual’s benefit-risk there will be an independent Data 
Monitoring Committee (DMC) that will evaluate study data periodically to ensure there are no 
new risks that emerge from the accumulating data. 
 
 
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3.0 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of four dose 
regimens of M1095 compared to placebo 
on achievement of an IGA score of 0 or 1 
after 12 weeks of treatment in subjects 
with moderate to severe chronic plaque-
type psoriasis. 
• IGA score of 0 or 1 at Week 12, with an 
IGA reduction from baseline of at least 2 
points. 
 
Secondary 
• To evaluate the efficacy of M1095 
compared to placebo during a 12-week 
treatment period on secondary endpoints: 
PASI 75, PASI 90, PASI 100, change in 
PASI and shift in IGA. 
• To assess the dose-regimen efficacy 
relationship for M1095 after 12, 24, 36, 
and 48 weeks of treatment. 
• To evaluate the longer-term efficacy of 
M1095 at Week 24 and at Weeks 36 and 
48.  
• To assess the safety and tolerability of 
M1095. 
 
• Efficacy: 
• PASI 75 at Week 12. 
• PASI 90 at Week 12. 
• PASI 100 at Week 12. 
• PASI 75, PASI 90 and PASI 100 
beyond Week 12. 
• Change from baseline in PASI score and 
in total BSA affected by plaque-type 
psoriasis. 
• Shift from baseline in IGA score 
category. 
• Safety:  
• Adverse events, skin evaluation, 
laboratory assessments, vital signs, 
ECGs, drug discontinuations, and 
instruments to assess depression and 
suicidality [electronic Columbia-Suicide 
Severity Rating Scale (eC-SSRS) and 
Personal Health Questionnaire 
Depression Scale (PHQ-8)]. 
Exploratory 
• Assessment of the quality of life and 
health outcomes of subjects treated with 
M1095 over 48 weeks via quality of life 
instruments evaluated every 12 weeks. 
• Assessment of the population PK of 
various doses and dose regimens of 
M1095. 
• Assessment of the development of anti-
drug antibodies for various doses and 
dose regimens of M1095. 
• Dermatology Life Quality Index (DLQI), 
Short Form 36 (SF-36), and EuroQuality of 
Life Questionnaire for Psoriasis (EQ-PSO). 
• Population PK evaluation. 
• Anti-drug antibodies: determination of 
binding and neutralizing antibodies defined 
by percentage of subjects with antibodies 
and titers of antibody. 
• Monitoring of pre-existing antibodies 
against M1095. 
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Objectives 
Endpoints 
• Assessment of change in efficacy from 
Week 12 to Week 24 in subjects who 
undergo dose escalation. 
• Assessment of M1095 being withheld in 
subjects with an IGA score of 0 at Week 
24. 
• IGA and PASI endpoints in subjects who 
dose escalate to 120mg M1095 q4w at 
Week 12. 
• IGA and PASI endpoints in subjects with 
an IGA score at 0 for whom M1095 is 
withheld at Week 24. 
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4.0 
STUDY DESIGN 
4.1 
Overall Design 
This is a multi-center phase 2b study in subjects with moderate to severe chronic plaque-type 
psoriasis. Approximately 300 subjects will be enrolled at approximately 60 investigator sites 
in North America and Europe. The study will consist of a 4-week screening period (Week -4 
to Week 0), a 12 week treatment period which is placebo-controlled (Week 0 to Week 12), a 
12 week maintenance/escalation period where all subjects are on active treatment (Week 12 to 
Week 24), a 24 week response assessment/dose hold period where active treatment is withheld 
if subjects being treated with M1095 have an IGA score of 0 at the beginning of the period 
(Week 24 to Week 48) and a final assessment period for safety follow up (Week 48 to Week 
52). The study will be double-blind up to Week 24, with subject- and investigator-blind 
maintained throughout.  
Subjects will be randomized in a 1:1:1:1:1:1 ratio, with approximately 50 subjects randomized 
into each of six treatment groups as shown below and in Figure 1: 
1. Placebo wk 0, 1, 2, 3, 4, 6, 8, 10 / M1095 120mg wk 12, 14, 16 and q4w. 
2. M1095 30mg wk 0, 2, 4, 8, 12 and q4w.  
3. M1095 60mg wk 0, 2, 4, 8, 12 and q4w. 
4. M1095 120mg wk 0, 2, 4, 8, 12 and q8w. 
5. M1095 120mg wk 0, 2, 4, 6, 8, 10, 12 and q4w. 
6. Secukinumab 300mg wk 0, 1, 2, 3, 4, 8, 12 and q4w. 
Prior to Week 24: 
M1095 subjects in Arms 2 and 3 will receive placebo at Weeks 1, 3, 6, 10 and 14. 
M1095 subjects in Arm 4 will receive placebo at Weeks 1, 3, 6, 10, 14 and 16. 
M1095 subjects in Arm 5 will receive placebo at Weeks 1, 3 and 14. 
Secukinumab subjects in Arm 6 will receive placebo at Weeks 6, 10 and 14.  
Subjects randomized to 30mg or 60mg M1095 who do not achieve an IGA score of 0 or 1 at 
Week 12 will be dose escalated to 120mg q4w starting at Week 12. 
Any subjects randomized to M1095 who did not undergo dose escalation at Week 12 and who 
achieve an IGA score of 0 at Week 24 will have study drug withheld and will receive placebo 
q4w. Subsequently, if IGA score is 1 or more, these subjects will re-commence M1095 at the 
dose they received prior to Week 24 on a q4w regimen at the visits scheduled by the protocol 
until the end of the treatment period. Dose will not be withheld for a second time, irrespective 
of subsequent IGA scores.  
Subjects receiving secukinumab will continue to receive 300mg q4w throughout the study. 
The subject blind will be maintained by the use of M1095 and matched placebo. The syringes 
used for all M1095 and placebo doses will be identical. All subjects will receive two injections 
of 1mL at each visit. There is also physical protection of the blind. Subjects will be asked to 
wear an eye-mask for all injections. 
Randomization will be stratified by prior biologic use (yes or no) and weight (≤90kg, >90kg). 
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4.2 
Scientific Rationale for Study Design 
The study design is similar to that utilized by several biologics in psoriasis for phase 2 and 
phase 3 studies. The evaluation of M1095 versus placebo at Week 12 is consistent with 
regulatory precedents and guidance.8 The overall duration of 52 weeks will enable assessment 
of long term efficacy and safety as well as the effect of treatment withdrawal in subjects with 
an IGA score of 0. All subjects will be eligible for at least 36 weeks of active therapy with 
placebo subjects converting from placebo to M1095 at Week 12.  
As described in the background and thoroughly covered in the Investigator’s Brochure, IL-17 
is a validated target in psoriasis. Furthermore, proof of concept has been obtained via the phase 
1 multiple dose study in subjects with psoriasis. Secukinumab is an approved drug that also 
targets IL-17. 
Inclusion and exclusion criteria described in Sections 5.1 and 5.2 have been developed to 
ensure a well-defined population where efficacy can be determined without introducing any 
unacceptable risks. The study design incorporates frequent visits and evaluations to optimize 
assessment of endpoints and collection of safety data. 
4.3 
Justification for Dose 
The M1095 doses selected for the study (30mg, 60mg, 120mg) are based on the results from 
the phase 1 multiple dose study EMR200574-003 in subjects with moderate to severe psoriasis 
(Figure 2). All doses in study EMR200574-003 showed efficacy based on PASI response, 
however, the lowest dose of 30 mg was less efficacious than the highest dose planned for this 
study, 120mg. This suggests that the doses selected are differentiated and will allow an 
understanding of the dose/exposure response relationship. It is notable that the dosing regimen 
employed in the phase 1 study was administered at Week 0, 2, and 4 followed by endpoint 
evaluation at Week 12. 
In the current phase 2b study, q2w, q4w and q8w regimens will be evaluated. Simulations 
using the efficacy-exposure data from phase 1 suggest that PASI 100 scores at Week 12 will 
vary between approximately 45% to 60% in subjects receiving 30mg M1095 administered at 
Week 0, 2, 4, 8 and 12, and 72% to 85% in subjects receiving 120mg M1095 administered at 
Week 0, 2, 4, 6, 8, 10 and 12. While comparison between each treatment arm will not 
necessarily reveal statistically significant differences, exploratory comparisons between the 
various dose arms will enable exploration of several questions: (1) does the amount of drug 
significantly affect Week 12 response? (comparison of 30 mg, 60mg and 120 mg where drug 
is administered on an identical schedule); (2) does duration and schedule of loading affect 
Week 12 response? (comparison of 120mg administered as q2w x 7 and q2w x 3 followed by 
q4w x 2); (3) does frequency of administration affect longer term results? (comparison of Week 
24 response for the different 120mg dose regimens). 
The highest dose planned in this phase 2b study, 120mg, has shown adequate safety when 
administered q2w for three doses in the phase 1 study and appears to be toward the top of the 
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5.0 
STUDY POPULATION 
Prospective approvals of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, are not permitted. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all the following criteria apply: 
1. Ambulatory male and female subjects between 18 and 75 years of age at time of 
consent. 
2. Subject has had stable moderate to severe plaque-type psoriasis for at least 6 months 
prior to randomization (e.g., no morphology changes or significant flares of disease 
activity in the opinion of the investigator). 
3. Subject must be considered, in the opinion of the investigator, not adequately controlled 
by photo, topical or previous systemic treatments and a candidate for systemic biologic 
therapy. 
4. Subject has Investigator’s Global Assessment (IGA) ≥3, involved body surface area 
(BSA) ≥10% and PASI ≥12 at screening and at baseline. 
5. Subject is in the opinion of the investigator able to comply with the study procedures.  
6. Following verbal and written information about the study, subject must provide signed 
and dated informed consent before any study related activity is carried out. 
5.2 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
1. Subject diagnosed with erythrodermic psoriasis, pustular psoriasis, guttate psoriasis, or 
other skin conditions at the time of the screening visit (e.g., eczema) that would 
interfere with evaluations of psoriasis (Note: psoriatic arthritis is NOT exclusionary.) 
2. Subject has drug-induced psoriasis (i.e. new onset or current exacerbation from beta-
blockers, calcium channel inhibitors or lithium) 
3. Other medical conditions: 
a. At the time of consent, subject has a planned in-patient surgical intervention 
between baseline and the Week 52 evaluation. 
b. Subject has an active infection or history of infections as follows: 
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i. Any active infection for which systemic anti-infectives were used 
within 28 days prior to randomization. 
ii. A serious infection, defined as requiring hospitalization or intravenous 
anti-infectives within 8 weeks prior to randomization. 
iii. Any history of bone infection requiring surgical intervention and/or 
intravenous antibiotics. 
iv. Recurrent or chronic infections or other active infection that, in the 
opinion of the investigator, might cause this study to be detrimental to 
the subject. 
c. Subject has active tuberculosis. 
d. Subject has a positive QuantiFERON®-TB Gold test for tuberculosis at 
screening, or if the first test and a repeat test are both indeterminate, unless (i) 
subject has a known history of latent TB and has completed a course of 
treatment or (ii) subject has received sufficient treatment for latent TB to allow 
concomitant treatment with a biological therapy as per local guidelines (note 
these subjects must continue their concomitant latent TB treatment to 
completion while participating in the study). If these subjects are outside of the 
screening window (>28 days since consent) when they become eligible to 
participate, they should be fully re-screened for the study. 
e. Subject has an underlying condition (including, but not limited to metabolic, 
hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, 
infectious or gastrointestinal) which in the opinion of the investigator places the 
subject at unacceptable risk for receiving an immunomodulatory therapy. 
f. Subject has known history of inflammatory bowel disease. 
g. Subject with known chronic liver disease or tests positive for hepatitis B virus 
(HBV) infection or has antibodies to hepatitis C virus (HCV) at screening. See 
Section 10.5 Appendix 5. 
h. Subject has antibodies to human immunodeficiency virus (HIV) at screening.  
See Section 10.5, Appendix 5. 
i. Subject has history of heart failure, myocardial infarction or unstable angina 
pectoris within the past 12 months prior to randomization. 
j. Subject has uncontrolled hypertension characterized by two blood pressure 
measurements separated by at least 15 minutes with systolic >160mmHg or 
diastolic >100mmHg. 
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k. Subject has clinically significant electrocardiogram (ECG) abnormalities on 
centrally read ECG. 
l. Subject has any active malignancy, including evidence of cutaneous basal or 
squamous cell carcinoma or melanoma. 
m. Subject has history of malignancy within 5 years EXCEPT cutaneous squamous 
or basal cell carcinoma, in situ cervical cancer, or in situ breast ductal carcinoma 
which has been treated and considered cured. 
n. Subject has any concurrent medical condition that, in the opinion of the 
investigator, could cause this study to be detrimental to the subject. 
4. Subject has laboratory abnormalities at screening, including any of the following: 
a. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x the 
upper limit of normal (one retest is allowed for aminotransferase 
abnormalities.) 
b. Serum direct bilirubin >1.5 mg/dL. 
c. White blood cell (WBC) count <3.00 x 103/µL. 
d. Absolute neutrophil count <1.50 x 103/µL. 
e. Absolute lymphocyte count <0.50 x 103/µL. 
f. Platelet count <100,000/µL. 
g. Creatinine clearance of <30mL/min (calculated via Cockcroft Gault). A 
subsequent 24-hour urine collection may be performed with the prior approval 
of the Medical Monitor, and if via urine collection the creatinine clearance is 
>30mL/min the subject is eligible for the study.    
AMENDMENT FOR CZECH REPUBLIC               
Creatinine clearance of <60 mL/min (calculated via Cockcroft Gault). A 
subsequent 24-hour urine collection may be performed with the prior approval 
of the Medical Monitor, and if via urine collection the creatinine clearance is 
>60mL/min the subject is eligible for the study.   
h. Any other laboratory abnormality, which, in the opinion of the investigator, will 
prevent the subject from completing the study or will interfere with the 
interpretation of the study results. 
5. Subject has used topical therapy as follows:  
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a. Topical psoriasis treatment within 14 days of randomization, including, but not 
limited to, corticosteroids, anthralin, calcipotriene, topical vitamin D 
derivatives, topical calcineurin inhibitors, retinoids, tazarotene, as well as 
emollients and other non-prescription topical products that contain urea, >3% 
salicylic acid, or alpha- or beta-hydroxyl acids, and medicated shampoos (e.g. 
those that contain >3% salicylic acid, corticosteroids, coal tar, or vitamin D3 
analogues). 
Exceptions: mild/least potent topical steroids are permitted during screening 
for use limited to the face, axillae, and/or genitalia but must be discontinued 
24 hours prior to the baseline visit (randomization). 
b. Bland emollients (without alpha or beta hydroxy acids) within 24 hours of 
baseline visit randomization. Note that as per Section 6.5 bland emollients 
(without alpha or beta hydroxy acids) may be used during the study but 
MAY NOT be used within 24 hours prior to any study visit. 
6. Subject has used the following within 28 days of randomization: ultraviolet A (UVA) 
light therapy (with or without psoralen); ultraviolet B (UVB) light therapy; excimer 
laser; oral retinoids; methotrexate; cyclosporine; systemically administered calcineurin 
inhibitors; azathioprine; thioguanine; hydroxyurea; cyclophosphamide; fumarates; 
apremilast; or oral or parenteral corticosteroids including intramuscular or 
intraarticular administration (exception: otic, nasal, ophthalmic, or inhaled 
corticosteroids within recommended doses is permitted); other non-biologic systemic 
therapy for psoriasis. 
7. Subject is not willing to limit ultraviolet (UV) light exposure (e.g. sunbathing and/or 
the use of tanning devices) during the study. 
8. Subject has received live vaccine(s) within 6 weeks of randomization. 
9. Subject has received prior treatment at any time before screening with any compound 
(marketed or investigational) targeting IL-17 (i.e. direct inhibitor, receptor blocker, 
etc.). 
10. Subject has received prior treatment at any time before screening with more than 2 
biologic therapies (ustekinumab, tumour necrosis factor (TNF) targeting therapies, or 
investigational therapies).  
11. Subject has received TNF targeting therapies in the 12 weeks prior to randomization, 
ustekinumab in the 6 months prior to randomization, or investigational biological 
therapies within 12 weeks, or within 5 half lives of randomization, whichever is the 
longer. 
12. Subject has known sensitivity to any of the products or components to be administered 
during dosing  
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13. Subject has a history or evidence of suicidal ideation or behavior within the 12 months 
prior to randomization or evidence of severe depression at screening or baseline [i.e. 
severity level 3, 4 or 5 based on an assessment with the electronic Columbia Suicide 
Severity Rating Scale (eC-SSRS)]. 
14. Subject has a history of chronic alcohol abuse or chronic drug abuse, or has used 
intravenous (IV) drugs in the past 2 years. 
15. Women of child bearing potential who are not willing to use highly effective methods 
of birth control during treatment and for 12 weeks after the last dose of study drug. See 
Section 10.4, Appendix 4 for definition of child bearing potential and guidance on 
highly effective methods of birth control. 
16. Subject has a positive serum pregnancy test during screening or a positive urine 
pregnancy test at baseline (Week 0, randomization visit) except those surgically sterile 
or at least 1 year postmenopausal.  
17. Subject is pregnant or breast feeding, or planning to become pregnant while enrolled 
in the study and for 12 weeks after the last dose of study drug. 
18. Male subjects who are not willing to use contraception during treatment and for 12 
weeks after the last dose of study drug. See Section 10.4, Appendix 4 for definition of 
permitted methods of contraception in male subjects.  
19. Subject will not be available for protocol required study visits or procedures, (e.g. 
venepuncture) to the best of the subject's and investigator's knowledge. 
20. Subject has any kind of disorder that, in the opinion of the investigator, may 
compromise the ability of the subject to give informed consent and/or to comply with 
all required study procedures. 
21. Subject is either 
a. currently enrolled in another interventional, investigational device or drug 
study. 
b. has been in another investigational device or drug study(s) in the 30 days prior 
to consent. 
22. Subject is an employee of the study sponsor (Bond Avillion 2 Development LP), 
Avillion LLP, EMD Serono, Merck KGaA or any contract research organization (CRO) 
associated with the study.  
23. Subject or subject’s immediate family is working for or employed by the investigator. 
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5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Subjects should be fasting when they attend for the baseline (randomization) visit, and for 
Weeks 12, 24, 36 and 48. These visits should be conducted in the morning and the subject 
should not have had breakfast.  
5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabis/Marijuana 
There no specific restrictions on caffeine, alcohol, tobacco, or cannabis/marijuana, all of which 
can be used in moderation during the study. Non-smokers should not start smoking during the 
study.  
5.3.3 
Activity 
UV light exposure (e.g. sunbathing and/or the use of tanning devices) must be limited for the 
course of the study.  
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the study but are not 
randomized. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements9 and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) will not 
be rescreened. One central laboratory re-test for ALT and AST is permitted within the 28-day 
screening period. If treatment of latent tuberculosis is instigated and the use of biological 
therapy is permitted per local guidelines the subject may be enrolled into the study. In such 
cases, if the study screening period has extended beyond 28 days since consent, the subject 
should be fully re-consented and re-screened to check they remain eligible for the study. 
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6.0 
STUDY DRUGS 
Study drug is defined as any investigational product, marketed product or placebo, intended to 
be administered to a study subject according to the study protocol. All study drugs in this study 
are considered Investigational Medicinal Products (IMP). 
Study drugs must NOT be used for any purpose other than as described in this protocol, and 
this includes other human studies, animal investigations and in vitro testing. 
Only subjects enrolled in the study may receive study drugs and only authorised site staff may 
prepare, supply or administer study drugs.  
6.1 
Study Drugs Administered 
Study drugs will be administered by subcutaneous injection. Before all injections, the 
appropriate personnel and requirements to treat severe allergic reactions should be available. 
A physician must be available at the time of each injection.  
Treatment Groups 
1. Placebo, in 2 x 1mL subcutaneous injections, given at Week 0, 1, 2, 3, 4, 6, 8 and 10. 
(These subjects will then receive study drug: M1095, 120mg, in 2 x 1mL subcutaneous 
injections, i.e. 1mL study drug, 1 mL placebo, given at Week 12, 14, 16, and q4w). 
2. M1095, 30 mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study drug, 1mL placebo, 
given at Week 0, 2, 4, 8, 12 and q4w. (These subjects will also receive placebo, in 2 x 
1mL subcutaneous injections, at Week 1, 3, 6, 10 and 14). 
3. M1095, 60 mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study drug, 1mL placebo, 
given at Week 0, 2, 4, 8, 12 and q4w. (These subjects will also receive placebo, in 2 x 
1mL subcutaneous injections, at Week 1, 3, 6, 10 and 14). 
4. M1095, 120 mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study drug, 1mL 
placebo, given at Week 0, 2, 4, 8, 12 and q8w. (These subjects will also receive placebo, 
in 2 x 1mL subcutaneous injections, at Week 1, 3, 6, 10, 14, 16, 24, 32 and 40). 
5. M1095, 120 mg, in 2 x 1mL subcutaneous injections, i.e. 1mL study drug, 1mL 
placebo, given at Week 0, 2, 4, 6, 8, 10, 12 and q4w. (These subjects will also receive 
placebo, in 2 x 1mL subcutaneous injections, at Week 1, 3 and 14). 
6. Secukinumab, 300mg, in 2 x 1mL (150mg/mL) subcutaneous injections, given at Week 
0, 1, 2, 3, 4, 8, 12 and q4w. (These subjects will also receive placebo, in 2 x 1mL 
subcutaneous injections, at Week 6, 10 and 14). 
The 30mg and 60mg M1095 doses (in Arms 2 and 3) will be escalated at Week 12 in subjects 
who have not achieved an IGA score of 0 or 1, as described in Section 6.6.1.  
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M1095 doses (in Arms 1 to 5) may be replaced by placebo at Week 24 as described in Section 
6.6.2.  
6.2 
Preparation/Handling/Storage/Accountability 
Further guidance and information can be found in the Study Drug Manual provided for the 
study.  
The investigator is responsible for study drug accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). Study drug storage and 
accountability will be reviewed by the unblinded monitor during routine monitoring visits. 
Study drug will be provided as subject kits each containing 2 vials (A and B) of M1095 of the 
appropriate strength (60mg or 120mg) to reconstitute the randomized dose and/or matching 
placebo, and subject kits containing commercial secukinumab 2 x 150mg pre-filled syringes.  
M1095 and placebo will be supplied as a lyophilized powder in glass vials. The 30mg dose 
will be reconstituted from a 60mg vial with 1mL placebo and 1mL sterile water for injection 
(WFI), the 60mg dose will be reconstituted from a 60mg vial with 1mL sterile WFI, and the 
120mg dose will be reconstituted from a 120mg vial with 1mL sterile WFI. Secukinumab will 
be supplied as commercial pre-filled syringes, over-labelled and packaged for the study.   
All study drug must be stored in a secure, environmentally controlled, and monitored (manual 
or automated) area in accordance with the labelled storage conditions (2 to 8oC, 36 to 46oF) 
with access limited to the investigator and authorized site staff.  
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies must be reported 
and resolved before the study drug is used. 
Investigators and site staff are reminded to check temperatures daily (i.e., manually or by using 
alarm systems to alert of any excursions) and ensure that temperature monitoring device(s) is 
(are) working correctly as required for proper storage of study drug. Any temperature 
excursions should be documented and reported to the sponsor, noting any actions taken. Once 
a deviation is identified, study drug must be quarantined and not used until the sponsor 
provides documentation of permission that the study drug can be used. 
All study drugs will be prepared for injection by an unblinded preparer in syringes with 1mL 
volume. The syringes for injection will be provided to the site approved study drug 
administrator, who is also unblinded (see Section 6.3 for further details). The unblinded 
preparer and the unblinded administrator may be the same person. 
Study drug will be administered via subcutaneous injection. All doses are comprised of two 
injections, each of 1mL, which should be administered at least 5 centimetres apart on any 
quadrant of the abdomen or the upper thigh. The body location for injections should not be 
repeated at consecutive study visits. Injections should not be given in areas where the skin is 
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tender, bruised, erythematous, or indurated. Areas of the skin affected by psoriasis should be 
avoided as injection sites.  
For subjects assigned to M1095 or placebo, the site approved unblinded administrator will be 
instructed to inject the subject with 1ml of solution from vial A and 1ml of solution from vial 
B. Subjects assigned to secukinumab will be dosed with 2 x 150mg/mL pre-filled syringes, as 
directed. Blinded study personnel should not be in attendance while study drug is being 
prepared or administered. Used syringes should be placed immediately out of sight in a sealed 
sharps container.  
Subjects should be observed for approximately 2 hours after the first dose of study drug and 1 
hour for subsequent doses. At Week 12 all subjects should be observed for approximately 2 
hours. If a subject experiences symptoms indicative of an acute hypersensitivity reaction after 
an injection, this should be discussed with the Medical Monitor before the next study 
visit/injection. 
Regulatory agencies require accounting for the disposition of all study drugs received by each 
clinical site. The investigator is responsible for maintaining information related to drug 
disposition which at minimum consists of the date received, date dispensed, quantity dispensed 
and the subject to whom the drug was dispensed. 
At the end of the study, the investigator should return unused study drug and packaging to the 
sponsor’s representative. Local destruction may be permitted with the sponsor’s approval.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
All subjects will be centrally assigned to randomized study drug using an Interactive Response 
Technology System (IRT). Before the study is initiated, the log in information and directions 
for the IRT (including the process for emergency unblinding) will be provided to each site, 
plus a back up telephone number and call-in directions.  
Study drug will be dispensed at the study visits as summarized in the SoA (Section 1.3).  
Any study drug that is prepared but not administered to a subject should not be re-dispensed. 
Unblinding will only occur during the study in the case of subject emergencies where it is 
necessary to determine the subject’s treatment assignment to ensure the best course of medical 
management is taken. The IRT will be programmed with blind-breaking instructions. In case 
of an emergency, the investigator has the sole responsibility for determining if the unblinding 
of a subject’s treatment assignment is warranted. Subject safety must always be the first 
consideration in making such a determination. While not required, it is recommended that the 
investigator should contact the Medical Monitor prior to unblinding unless this could delay 
emergency treatment of the subject. If a subject’s treatment assignment is unblinded, the 
sponsor must be notified within 24 hours of breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and electronic case record 
form (eCRF), as applicable.  
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The outer packaging of study kits will appear identical, but as the M1095 and placebo doses 
require reconstitution, and secukinumab is provided as commercially available pre-filled 
syringes (PFS), it is not possible to blind the study completely. An unblinded study drug 
preparer will be responsible for the reconstitution and dispensation of study drug and will 
endeavor to ensure that there are no differences in the time taken to dispense each arm of the 
study.  
Once syringes for injection have been prepared, they will be provided to the study drug 
administrator, who will also be unblinded.  
The study drug preparer and the study drug administrator may be the same person.  
 
Other than the study drug preparer and administrator, the study team (including the IGA and 
PASI assessors) will be completely blinded throughout the study and will be kept physically 
separate from the preparation and administration of study medication.   
The subject blind will be maintained by the use of M1095 and matched placebo. The syringes 
used for all M1095 and placebo doses will be identical. All subjects will receive two injections 
of 1mL at each visit. There is also physical protection of the blind. Subjects will be asked to 
wear an eye-mask for all injections.  
An unblinded interim analysis of 12-week data will occur at the completion of the 12-week 
period, while the study is still ongoing. This will be managed by an independent DMC and 
statistical analysis group to preserve the blinding. This data will be shared with firewalled 
individuals who are not directly involved in the conduct of the study.  
All members of the sponsor’s study team will be blinded to subject treatment assignments until 
all subjects complete 24 weeks and the database is locked, with all queries through Week 24 
resolved. After Week 24 data has been cleaned and locked, the study statistician and designated 
sponsor team members will be unblinded to perform analysis of key study endpoints. All other 
members of the sponsor’s study team, site staff (except the unblinded preparer) and subjects 
will remain blinded until the end of study. 
An unblinded study monitor will be assigned by the CRO to visit site and check the 
documentation maintained by the unblinded study preparer and administrator and all drug 
accountability records. The unblinded study monitor will not reveal any study details that could 
unblind the study to the blinded study monitor. In the event of a Quality Assurance audit, the 
auditor(s) will also be allowed access to unblinded study drug records at the site(s) to verify 
that randomization/dispensing has been performed accurately. 
Laboratory personnel performing the bioanalytical PK sample analysis may receive an open 
randomization list to enable analysis of relevant samples. In addition, a PK analyst and 
modelling/simulation scientist may receive an open randomization list to enable preparation of 
modelling/simulation activities. These individuals will not interact with site or CRO personnel. 
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Site personnel will enter the IGA score into the IRT prior to the study drug kit being assigned 
at Week 12.  
6.6.2 
Week 24 
Any subjects on M1095 who did not undergo dose escalation at Week 12 and who achieve an 
IGA score of 0 at Week 24 will have study drug withheld and will receive placebo q4w.  
Subsequently, if IGA score is 1 or more, these subjects will re-commence M1095 at the dose 
they received prior to Week 24 on a q4w regimen at the visits scheduled by the protocol until 
the end of the treatment period. Dose will not be withheld for a second time, irrespective of 
subsequent IGA scores.  
At Week 24, subjects on secukinumab will continue to be treated q4w.  
Site personnel will enter the IGA score into the IRT prior to the study drug kit being assigned 
at Week 24, 28, 32, 36, 40 and 44. 
 
At Week 24, the investigator should carefully consider the subject’s response and if there has 
been a worsening of psoriasis compared to baseline then the investigator should consider 
discontinuing the subject from the study if they are not receiving adequate benefit from their 
participation. 
6.7 
Treatment after the End of the Study 
The final dose of study drug will be administered at the Week 44 visit with the final study visit 
occurring at Week 52.  
Subjects that discontinue study treatment during the study should complete Early 
Discontinuation, with visits approximately 4 weeks (28 days) and 8 weeks (56 days) after the 
last dose of study drug (see the SoA, Section 1.3, and Sections 7.2 and 8.1.11). Once the Early 
Discontinuation visits have been completed, subjects will be contacted by telephone as per the 
q4w study schedule.     
After study completion at Week 52, or after completion of the Early Discontinuation visits, 
subjects should be treated as per local guidance and physician recommendation.
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7.0 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL  
Subjects should be discontinued from study drug if any of the criteria described in Section 7.1 
are met. Such subjects will continue to be followed for safety assessments as described in the 
SoA, Section 1.3, and Section 8.1.11.  
 
Subjects may voluntarily withdraw from the study for any reason at any time, or be withdrawn 
by the investigator or the sponsor as per Section 7.2. The investigator should strongly 
recommend that withdrawn subjects return for follow-up visits approximately 28 days and 56 
days after the last dose of study drug to assess their safety and, if willing, to assess duration of 
effect (e.g. rebound assessments). The information to be collected is identical to the Early 
Discontinuation visit, as described in the SoA (Section 1.3) and Section 8.1.11. 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Such subjects will be 
considered to have discontinued the study. 
Subjects who are prematurely discontinued from study treatment, or who have chosen to 
withdraw from the study, or who are lost to follow up, will not be replaced. 
7.1 
Discontinuation of Study Drug 
See the SoA (Section 1.3) and Section 8.1.11 for data to be collected at the time of study drug 
discontinuation, plus follow-up and for evaluations that need to be completed. 
Study treatment must be discontinued under the following circumstances (all cases should be 
discussed with the Medical Monitor): 
• Withdrawal of consent 
• Emergence of the following:  
o AE considered related to study treatment including: 
 Clinically significant systemic hypersensitivity reaction following 
administration of study drug that does not respond to symptomatic 
treatment. 
 Severe (grade 3 or higher Common Terminology Criteria for AEs 
(CTCAE) Version 5.0) anaphylaxis (symptomatic bronchospasm, with 
or without urticaria; parenteral intervention indicated; allergy-related 
edema / angioedema; hypotension).  
 Severe (grade 3 or higher CTCAE Version 5.0) serum sickness (severe 
arthralgia or arthritis; extensive rash, with steroids or intravenous fluids 
indicated). 
• Note that if a subject experiences symptoms consistent with a 
grade 2 serum sickness (moderate arthralgia, fever, rash, or 
urticaria, with antihistamine treatment indicated), and causality 
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by the study drug cannot be ruled out, the subject should return 
to site for an unscheduled visit. There should be a documented 
assessment and physical examination concurrent with the event. 
Grade 2 serum sickness does not require discontinuation of 
study drug, however the Medical Monitor should be informed. 
 Any other severe (grade 3 CTCAE Version 5.0) event that does not 
resolve with supportive care. 
 Any life threatening (grade 4 CTCAE Version 5.0) event. 
o Any other AE that in the judgment of the investigator, and considering the 
subject’s overall status, prevent the subject from continuing to participate in the 
study (for example, sepsis or serious infection). 
o Laboratory findings as follows regardless of CTCAE Version 5.0 grade:  
 Total WBC count <2.00 x 103/µL.  
 Total ANC <1.00 x 103/µL. 
 Platelet count <50,000/µL. 
 Elevated transaminases (ALT or AST) >3 x upper limit of normal 
(ULN) and associated with total bilirubin >2 x ULN (without 
accompanying alkaline phosphatase elevation >2 x ULN suggestive of 
cholestasis) – i.e. subject meets Hy’s Law criteria. 
 Elevated transaminases (ALT or AST) >5 x ULN without clear 
alternative etiology (tests should be repeated within 72 hours to verify 
the result prior to discontinuation.) 
 Any laboratory abnormalities that in the judgment of the investigator, 
taking into consideration the subject’s overall status, prevents the 
subject from continuing participation in the study. 
o Pregnancy (see Sections 8.5.5 and 10.4, Appendix 4).  
o The subject develops a malignancy. (Exception: Subjects may be allowed to 
continue if they develop no more than 2 non-melanoma skin cancers (NMSC) 
during the study) 
o Use of prohibited treatment as per recommendations in Section 6.5. 
• Any other protocol deviation that results in a significant risk to the subject’s safety. 
• Administrative decision by the investigator, the sponsor or it’s designee to stop the 
subject’s study treatment for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and good clinical practice (GCP).  
• Subject noncompliance (significant violation of protocol requirements or missing two 
consecutive visits). 
 
In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given subject if, on balance, continuation would be 
detrimental to the subject’s well-being. The investigator should carefully consider the subject’s 
response at Week 24 and if there has been a worsening of psoriasis compared to baseline then 
the investigator should consider discontinuing the subject from the study if they are not 
receiving adequate benefit from their participation. 
 
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The appropriate personnel from the study site and the sponsor or it’s designee will assess 
whether study treatment should be discontinued for any subject whose treatment code has been 
broken inadvertently for any reason. 
 
Subjects who discontinue study treatment should NOT be considered withdrawn from the 
study. They will continue to be followed up for assessments. See the SoA, Section 1.3 and 
Section 8.1.11 for the required assessments of these subjects after study treatment 
discontinuation. 
 
Subjects should be considered to still be on study unless any of the criteria for study withdrawal 
are met (see Section 7.2). 
7.1.1 
Temporary Discontinuation  
Temporary discontinuations are not permitted in this study. Any missed doses should be 
discussed with the Medical Monitor.  
7.1.2 
Rechallenge 
Rechallenge is defined as the re-introduction of study drug following a temporary withdrawal/ 
dose hold for safety related reasons.  
Rechallenge is not permitted for any reason including after study drug being withheld due to 
related/possibly related AEs; in these circumstances the Medical Monitors should be consulted 
prior to withholding study drug and the subject considered for permanent discontinuation.  
7.2 
Subject Withdrawal from the Study 
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator or the sponsor for safety, behavioral, 
compliance, or administrative reasons. 
 
If the subject withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
 
If a subject withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
 
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information on the applicable eCRF. The withdrawn subjects must return for a follow-up 
visit approximately 28 days after the last dose of study drug to assess their efficacy, safety, 
quality of life (QoL), report any AEs and assess duration of effect (e.g. rebound assessments). 
A further visit/telephone call should be conducted approximately 56 days after the last dose of 
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study drug to follow up on AEs. The information to be collected is identical to the Early 
Discontinuation visit 1 and visit 2, as described in the SoA (Section 1.3) and Section 8.1.11. 
7.3 
Lost to Follow Up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
 
For subjects who are lost to follow-up, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible. The subject should be counselled on the importance of maintaining the 
assigned visit schedule and it should be ascertained whether the subject wishes to 
and/or should continue in the study. 
• Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, three telephone calls 
and, if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
discontinued from the study. 
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8.0 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Study visit 
dates are scheduled relative to Week 0.  
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
study drug. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Patient Reported Outcomes (PROs) during any visit should be conducted before other 
tests, procedures, or consultations.  
• IGA, BSA and PASI during any visit should be conducted after the PROs (if applicable) 
and before other tests, procedures and consultations. As far as possible, the same 
evaluator should perform the IGA, BSA and PASI at all visits for a particular subject, 
especially at Week 0 (randomization), Week 12, and Week 24. 
• The maximum amount of blood collected from each subject over the duration of the 
study, including any extra assessments that may be required, will not exceed 565mL, 
with a maximum 50mL taken at any visit. Repeat or unscheduled samples may be taken 
for safety reasons or for technical issues with the samples. 
8.1 
Study Procedures 
8.1.1 
Screening 
Subjects will attend for a Screening Visit during the 4 weeks (28 days) prior to Week 
0/randomization. This is designed to assess the inclusion/exclusion criteria and establish 
baseline characteristics.  
The approved consent form must be signed and dated by the subject and the consenting 
investigator prior to any study related procedures being conducted. AEs will be collected from 
the time that consent is signed. 
IGA, BSA and PASI should be performed before any other study procedures, assessments or 
consultations. The following assessments will be performed and information collected:- 
• Demographics 
• Inclusion/Exclusion Criteria 
• Psoriasis Medical History 
• Prior Psoriasis Treatments 
• Other Medical History 
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• IGA 
• BSA 
• PASI 
• Adverse events are to be recorded from the time of consent  
• Concomitant Medications 
• Skin Evaluation 
• Physical Examination 
• Vital Signs 
• Laboratory Analysis Chemistry and Haematology (Central Laboratory) 
• Urinalysis (Local) 
• Serum Pregnancy Test (Central Laboratory) 
• ECG (Standard 12 Lead, Central ECG Laboratory) 
• QuantiFERON®-TB Gold Test (Local or Central Laboratory)  
o If a local or central Quantiferon TB test result is 
‘indeterminate’ the test must be repeated during the 
screening period.  
o If any Quantiferon TB test is ‘positive’ or if the first test 
and the repeat test are both ‘indeterminate’, the subject 
must be referred for tuberculosis workup per local 
guidelines.  
o If any Quantiferon TB test is ‘positive’ or if the first test 
and the repeat test are both ‘indeterminate’, the subject is 
eligible for randomization if (i) they have a known history 
of latent TB and have completed a course of treatment or 
(ii) they have has received sufficient treatment for latent 
TB to allow concomitant treatment with a biological 
therapy as per local guidelines (note these subjects must 
continue their concomitant latent TB treatment to 
completion while participating in the study, and if these 
subjects are outside of the screening window (>28 days 
since consent) when they become eligible to participate, 
they should be fully re-screened for the study). 
o If any Quantiferon TB test is ‘positive’ or if the first test 
and the repeat test are both ‘indeterminate’, the subject is 
not eligible for randomization if either ‘active tuberculosis 
is present’ or if ‘latent tuberculosis is present and is 
untreated per local guidelines.’  
• HBV, HCV and HIV Testing (Central Laboratory), Section 10.5,   
Appendix 5 
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• Chest X-Ray (CXR) – CXR within 3 months of consent is considered 
acceptable. When performed as part of the Screening visit, the chest X-
ray should be the last study procedure to be completed, as this will 
prevent unnecessary exposure to radiation if the subject is found to be 
ineligible following an earlier procedure. Investigator should follow up 
the results of the chest X-ray with the Medical Monitor if clinically 
indicated.   
8.1.2 
Week 0 / Randomization 
At Week 0, subjects who meet the inclusion/exclusion criteria will be randomized.  
Fasting blood samples should be obtained, so the visit should be conducted in the morning and 
the subject should not have had breakfast.  
Patient reported outcomes (PRO) i.e. DLQI, EQ-PSO, SF-36, PHQ-8, and eC-SSRS should be 
performed before any other study procedures, assessments or consultations.  
IGA, BSA and PASI should be conducted after the PROs and before other tests, procedures 
and consultations. 
The first dose of study drug should be administered after completion of all other study 
procedures.  
The following assessments will be performed and information collected:- 
• Repeat check of Inclusion/Exclusion Criteria 
• AEs 
• Concomitant Medications 
• DLQI 
• EQ-PSO 
• SF-36 
• PHQ-8 
• eC-SSRS 
• IGA 
• BSA 
• PASI 
• Skin Evaluation 
• Physical Examination 
• Vital Signs 
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• Laboratory Analysis Chemistry and Haematology (Fasting, Central 
Laboratory) 
• Urinalysis (Local) 
• Urine Pregnancy Test (Local) – if positive, study drug must be withheld 
and a Serum Pregnancy Test (Central Laboratory) performed 
• Blood Sample for Immunogenicity (must be pre-dose) 
• Blood Sample for Pharmacokinetics (must be pre-dose) 
• Randomization (via IRT) 
• Study Treatment (allocated via IRT) 
8.1.3 
Weeks 1, 3, 6, 10 
There is a visit window of ±1 day for Weeks 1 and 3, and ±2 days for Weeks 6 and 10.  
IGA, BSA and PASI should be performed before any other study procedures, assessments or 
consultations.  
Study drug should be administered after completion of all other study procedures.  
The following assessments will be performed and information collected:- 
 
• IGA 
• BSA 
• PASI 
• AEs 
• Concomitant Medications 
• Skin Evaluation 
• Vital Signs 
• Study Treatment (allocated via IRT) 
8.1.4 
Week 2 
There is a visit window of ±1 day for the Week 2 visit.  
IGA, BSA and PASI should be performed before any other study procedures, assessments or 
consultations.  
Study drug should be administered after completion of all other study procedures. 
The following assessments will be performed and information collected: 
• IGA 
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• BSA 
• PASI 
• AEs 
• Concomitant Medications 
• Skin Evaluation 
• Vital Signs 
• Laboratory Analysis Chemistry and Haematology (Central Laboratory) 
• Blood Sample for Immunogenicity (must be pre-dose)  
• Blood Sample for Pharmacokinetics (must be pre-dose) 
• Study Treatment (allocated via IRT)  
8.1.5 
Week 4 
There is a visit window of ±1 day for the Week 4 visit. 
Patient reported outcomes (PRO) i.e. PHQ-8, and eC-SSRS should be performed before any 
other study procedures, assessments or consultations.  
IGA, BSA and PASI should be conducted after the PROs and before other tests, procedures 
and consultations. 
Study drug should be administered after completion of all other study procedures. 
The following assessments will be performed and information collected: 
• PHQ-8 
• eC-SSRS 
• IGA 
• BSA 
• PASI 
• AEs 
• Concomitant Medications 
• Skin Evaluation 
• Physical Examination 
• Vital Signs 
• Laboratory Analysis Chemistry and Haematology (Central Laboratory) 
• Urine Pregnancy Test (Local) – if positive, study drug must be withheld 
and a Serum Pregnancy Test (Central Laboratory) performed 
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• Blood Sample for Immunogenicity (must be pre-dose)  
• Blood Sample for Pharmacokinetics (must be pre-dose) 
• Study Treatment (allocated via IRT)  
8.1.6 
Weeks 8, 44, 52 
There is a visit window of ±2 days for Week 8, and ±5 days for Weeks 44 and 52.  
Patient reported outcomes (PRO) i.e. PHQ-8, and eC-SSRS should be performed before any 
other study procedures, assessments or consultations.  
IGA, BSA and PASI should be conducted after the PROs and before other tests, procedures 
and consultations. 
Study drug should be administered after completion of all other study procedures. 
The following assessments will be performed and information collected: 
• PHQ-8 
• eC-SSRS 
• IGA 
• BSA 
• PASI 
• AEs - SAEs and AEs will be followed until resolution, stabilization or 
the event is otherwise explained or the subject is lost to follow up (see 
Section 7.3). AEs not considered serious or as an AESI will be 
considered ongoing if they have not resolved by Week 52. 
• Concomitant Medications 
• Skin Evaluation 
• Vital Signs 
• Laboratory Analysis Chemistry and Haematology (Central Laboratory) 
• Urine Pregnancy Test (Local) – if positive, study drug must be withheld 
and a Serum Pregnancy Test (Central Laboratory) performed 
• Blood Sample for Immunogenicity (must be pre-dose) – subjects 
testing positive at Week 52 may be requested to provide another sample 
6 to 12 months after study completion  
• Blood Sample for Pharmacokinetics (must be pre-dose) 
• Study Treatment (allocated via IRT) with the exception of Week 52 
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• At Week 52, male and female subjects of child bearing potential should 
be reminded that they must use highly effective contraception for a 
further 4 weeks  
8.1.7 
Weeks 12, 24, 36, 48  
There is a visit window of ±2 days for Weeks 12 and 24, and ±5 days for Weeks 36 and 48. 
Fasting blood samples should be obtained, so the visit should be conducted in the morning and 
the subject should not have had breakfast.  
Patient reported outcomes (PRO) i.e. DLQI, EQ-PSO, SF-36, PHQ-8, and eC-SSRS should be 
performed before any other study procedures, assessments or consultations.  
IGA, BSA and PASI should be conducted after the PROs and before other tests, procedures 
and consultations.  
Study drug should be administered after completion of all other study procedures.   
The following assessments will be performed and information collected:- 
• DLQI 
• EQ-PSO 
• SF-36 
• PHQ-8 
• eC-SSRS 
• IGA 
• BSA 
• PASI 
• AEs 
• Concomitant Medications 
• Skin Evaluation 
• Physical Examination 
• Vital Signs 
• Laboratory Analysis Chemistry and Haematology (Fasting, Central 
Laboratory) 
• Urinalysis (Local) 
• Urine Pregnancy Test (Local) – if positive, study drug must be withheld 
and a Serum Pregnancy Test (Central Laboratory) performed 
• ECG (Standard 12 Lead, Central ECG Laboratory) 
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• Blood Sample for Immunogenicity (must be pre-dose) 
• Blood Sample for Pharmacokinetics (must be pre-dose) 
• Study Treatment (allocated via IRT) with the exception of Week 48 
• At Week 24, the investigator should carefully consider the subject’s 
response and if there has been a worsening of psoriasis compared to 
baseline then the investigator should consider discontinuing the subject 
from the study if they are not receiving adequate benefit from their 
participation. 
 
8.1.8 
Week 14 
There is a visit window of ±2 days for the Week 14 visit. 
IGA, BSA and PASI should be performed before any other study procedures, assessments or 
consultations.  
Study drug should be administered after completion of all other study procedures. 
The following assessments will be performed and information collected:- 
• IGA 
• BSA 
• PASI 
• AEs 
• Concomitant Medications 
• Skin Evaluation 
• Vital Signs 
• Laboratory Analysis Chemistry and Haematology (Central Laboratory) 
• Study Treatment (allocated via IRT) 
8.1.9 
Week 16, 20, 28, 32, 40 
There is a visit window of ±2 days for Weeks 16 and 20, and ±5 days for Weeks 28, 32 and 
40.  
Patient reported outcomes (PRO) i.e. PHQ-8, and eC-SSRS should be performed before any 
other study procedures, assessments or consultations.  
IGA, BSA and PASI should be conducted after the PROs and before other tests, procedures 
and consultations. 
Study drug should be administered after completion of all other study procedures. 
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The following assessments will be performed and information collected: 
• PHQ-8 
• eC-SSRS 
• IGA 
• BSA 
• PASI 
• AEs 
• Concomitant Medications 
• Skin Evaluation 
• Vital Signs 
• Laboratory Analysis Chemistry and Haematology (Central Laboratory) 
• Urine Pregnancy Test (Local) – if positive, study drug must be withheld 
and a Serum Pregnancy Test (Central Laboratory) performed 
• Study Treatment (allocated via IRT) 
8.1.10 
Unscheduled Visit  
Subjects may return to site for an Unscheduled Visit as clinically indicated. Laboratory 
assessments performed at an Unscheduled Visit should be sent to the central laboratory.  
All assessments should be documented in the medical record and entered in the eCRF.  
8.1.11 
Early Discontinuation 
The Early Discontinuation Visit involves two contacts with the subjects. The subject should 
attend the study site as close to possible to 4 weeks (28 days) after the last dose of study drug, 
and prior to the initiation of any other biological therapy. The reason for discontinuation should 
be discussed with the Medical Monitor. All subjects should then have further follow up either 
by telephone, or if they have ongoing SAEs or AEs, by attending the study site approximately 
8 weeks (56 days) after the last dose of study drug to report any new, and follow up any existing 
AEs.  
Patient reported outcomes (PRO) i.e. DLQI, EQ-PSO, SF-36, PHQ-8, and eC-SSRS should be 
performed before any other study procedures, assessments or consultations.  
IGA, BSA and PASI should be conducted after the PROs and before other tests, procedures 
and consultations. 
 
The following assessments will be performed and information collected:- 
 
 
Visit 1 – As close as possible to 4 weeks (28 days) after the last dose of study drug, and  
       
prior to the initiation of any other biological therapy. 
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• DLQI 
• EQ-PSO 
• SF-36 
• PHQ-8 
• eC-SSRS 
• IGA 
• BSA 
• PASI 
• AEs  
• Concomitant Medications 
• Skin Evaluation 
• Physical Examination 
• Vital Signs 
• Laboratory Analysis Chemistry and Haematology (Central Laboratory) 
• Urinalysis (Local) 
• Urine Pregnancy Test (Local) 
• ECG (Standard 12 Lead, Central ECG Laboratory) 
• Blood Sample for Immunogenicity – subjects testing positive may be 
requested to provide another sample six to twelve months after study 
completion  
• Blood Sample for Pharmacokinetics 
Visit 2 / Telephone Call – As close as possible to 8 weeks (56 days) after the last dose 
of study drug  
• AEs  
• Concomitant medication  
• Male and female subjects of child bearing potential should be reminded 
that they must use highly effective contraception for a further 4 weeks  
Following completion of the Early Discontinuation visits, subjects will continue to be 
contacted by telephone q4w as per the study schedule up to Week 52. The following 
information will be collected. 
• AEs 
• Concomitant medication 
• Any new treatments for psoriasis 
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8.2 
Efficacy Assessments 
Efficacy evaluations selected for this study are consistent with those used to evaluate other 
therapies for psoriasis.  
The IGA and PASI will be administered by site personnel according to the SoA (Section 1.3). 
All assessors of IGA and PASI must be qualified, experienced in evaluating subjects with 
psoriasis in clinical trials, and have completed study specific training in IGA and PASI rating. 
It is recommended that the same assessor conducts the IGA and PASI at all visits for a 
particular subject, but especially at Week 0 (randomization), Week 12, and Week 24.  
8.2.1 
Investigator’s Global Assessment (IGA mod 2011) 
IGA will be conducted for overall psoriatic disease as indicated in the SoA (Section 1.3).  
The IGA rating scale for overall psoriatic disease is shown in Section 10.6.1, Appendix 6.  
The explanations/descriptions of the points on the scale have been improved to ensure 
appropriate differentiation between the points.10 The IGA mod 2011 is thought to better 
correlate with PASI 90 responses. 
The IGA mod 2011 used in this study is static, i.e. it refers exclusively to the subject’s disease 
state at the time of the assessments, and does not attempt a comparison with any of the subject’s 
previous disease states, whether at baseline or at a previous visit. 
The IGA mod 2011 score will initially be recorded on paper, and then entered in the IRT/eCRF. 
8.2.2 
Assessment of Total Body Surface Area (BSA) and Psoriasis Area and Severity 
Index (PASI) 
The total BSA affected by plaque-type psoriasis will be estimated from the percentages of 
areas affected, including head, trunk, upper limbs and lower limbs (see Section 10.6.2, 
Appendix 6).  
The PASI combines assessments of the extent of body-surface area involvement in 4 
anatomical regions (head, trunk, arms, and legs) and the severity of desquamation, erythema, 
and plaque induration/infiltration (thickness) in each region, yielding an overall score of 0 for 
no psoriasis to 72.0 for the most severe disease.11, 12 See Section 10.6.2, Appendix 6 for details. 
Subjects achieving PASI 75, PASI 90, or PASI 100 are defined as having an improvement of 
at least 75%, 90%, or 100%, respectively, in PASI score from baseline.  
The site will initially record assessments on paper, and will then enter the data into the eCRF, 
which will auto-calculate the PASI score (no manual PASI calculations will be performed by 
the site). 
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The instrument essentially consists of 2 pages – the EQ-5D descriptive system and the EQ 
visual analogue scale (VAS). The EQ-5D descriptive system comprises the following 5 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each 
dimension has 3 response levels: no problems, some problems, severe problems. The subject 
is asked to indicate their health state by ticking in the box against the most appropriate 
statement in each of the 5 dimensions. In the EQ-PSO two additional dimensions, skin irritation 
and self confidence, have been added to make the questionnaire more disease specific for 
psoriasis.17 
The VAS records the subject’s self-rated health on a vertical, VAS where the endpoints are 
labelled ‘Best imaginable health state’ and ‘Worst imaginable helath state.’ This information 
can be used as a quantitative measure of health outcome as judged by the individual 
respondents. 
The EQ-PSO questionnaire will be completed by the subject as indicated in the SoA (Section 
1.3). It will be completed using an electronic tablet device.  
8.4 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3).  
Safety assessments will include collection of AEs, skin evaluation, laboratory values, vital 
signs, ECGs, drug discontinuations, and instruments to assess depression and suicidality 
[electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) and Personal Health 
Questionnaire Depression Scale (PHQ-8)]. Blinded data will be reviewed during the study. An 
independent Data Monitoring Committee (DMC) will have access to unblinded information 
and will conduct periodic scheduled reviews as well as ad hoc reviews as needed. 
8.4.1 
Physical Examination 
A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal and neurological systems. Weight will also be 
measured and recorded. 
Height will be measured at screening only.  
8.4.2 
Skin Evaluation 
Subjects are expected to manifest skin findings associated with psoriasis which may include 
stable disease, worsening disease, or improving disease.  
If a subject develops a clinically significant cutaneous rash that is not typical of a psoriatic 
picture, then the following evaluations should be conducted: 
• 
Photographs  
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o Upper and lower body, front and back, 4 pictures in total. Further close up 
pictures (15cm x 15cm, 6 inches x 6 inches) should be taken of any areas of 
interest.  
• 
Skin biopsy  
o Two ≥4mm punch biopsies, one of normal skin, one within the rash. 
• 
Skin culture 
Detailed instructions for these evaluations will be provided as Skin Evaluation Instructions 
for the study. 
The Medical Monitor should be notified if photographs/skin biopsy/skin culture are being 
conducted and the subject should be treated as indicated while he/she continues study 
therapy. 
8.4.3 
Vital Signs 
Vital signs will be measured after at least 5 minutes rest, and will include temperature (oral, 
axillary, core, temporal, or tympanic), sitting or supine blood pressure and heart rate. 
8.4.4 
Electrocardiograms 
12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  
At each time point, triplicate ECGs are required. Three individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes. 
ECG should also be performed at any time in the study if clinically indicated. 
Digital ECGs will be transmitted to a central vendor who will assess ECG measurements for 
screening requirements prior to randomization.  
The investigator is to assess ECG measurements for safety and should report any clinically 
significant findings as adverse events.  
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8.4.5 
Clinical Safety Laboratory Assessments 
See Section 10.2, Appendix 2 for the list of clinical laboratory tests to be performed by the 
central laboratory and the SoA (Section 1.3) for the timing and frequency.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. 
Laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the subject's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within eight weeks after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or Medical Monitor. 
o All protocol-required laboratory assessments, as defined in Section 10.2, 
Appendix 2, must be conducted in accordance with the laboratory manual and 
the SoA (Section 1.3).  
o If laboratory values from non-protocol specified laboratory assessments 
performed at the study site’s local laboratory require a change in subject 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE or dose modification), then the values must be recorded in the 
eCRF.  
8.4.6 
Depression and Suicidal Risk Monitoring  
In studies of brodalumab, there have been reports of suicidal ideation or behavior. The sponsor 
considers it important to monitor for such events before and during this clinical study. 
Subjects being treated in this study should be monitored appropriately and observed closely 
for suicidal ideation and behavior or any other unusual changes in behavior. Consideration 
should be given to discontinuing study drug in subjects who experience signs of suicidal 
ideation or behavior.  
Families and caregivers of study subjects should be instructed to monitor for the emergence of 
unusual changes in behavior, as well as the emergence of suicidal ideation and behavior, and 
to report such symptoms immediately to the study investigator. 
Baseline assessment of suicidal ideation and behavior and treatment-emergent suicidal ideation 
and behavior will be assessed during the study using the electronic Columbia Suicide Severity 
Rating Scale (e-C-SSRS). Depression will be assessed using the Patient Health Questionnaire-
8 (PHQ-8).  
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8.4.6.1 
Electronic Self Rated Version, Columbia-Suicide Severity Rating Scale     
(eC-SSRS) 
The eC-SSRS is a standardized and validated instrument developed for the assessment of the 
severity and frequency of suicidal ideation and behavior.18, 19, 20 Subjects respond to 
standardized clinical questions that are presented in a uniform fashion. The eC-SSRS defines 
five subtypes of suicidal ideation and behavior in addition to self-injurious behavior with no 
suicidal intent. The eC-SSRS takes approximately 3 to 10 minutes to complete. 
The eC-SSRS questionnaire will be completed by the subject as indicated in the SoA (Section 
1.3). It will be completed using an electronic tablet device.  
 
8.4.6.2 
Patient Health Questionnaire (PHQ-8) 
The PHQ-8 is a validated and widely used eight-item version of the Patient Health 
Questionnaire depression scale designed to clinically assess subjects for symptoms and signs 
of depression.21, 22 The PHQ-8 takes approximately 3 minutes to complete and will be 
completed by the subject as indicated in the SoA (Section 1.3). It will be completed using an 
electronic tablet device. 
8.5 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
The definitions of an AE or SAE can be found in Section 10.3, Appendix 3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or 
that caused the subject to discontinue the study drug. 
Adverse events of special interest (AESI) include cytopenias, liver function test 
changes/enzyme elevations, infections, injection-site reactions, allergic/hypersensitivity 
reactions, cerebrocardiovascular events, malignancies, depression, Crohn’s disease and 
ulcerative colitis.  These events are based on Phase 1 data and findings with other IL-17 
modulating drugs.  Additional adverse events may be identified as being of special interest 
during the study and prior to the first unblinding.  Formal pre-specified evaluations beyond the 
discontinuation criteria in Section 7.1 are not planned at this time. 
If a subject reports symptoms consistent with a grade 2 serum sickness while between study 
visits, and causality by the study drug cannot be ruled out, the subject should return to site for 
an unscheduled visit if symptoms recur after the next dose. There should be a documented 
assessment and physical examination concurrent with the event 
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8.5.1 
Time Period and Frequency for Collecting AE and SAE Information  
AEs will be collected from the signing of the informed consent form (ICF).  
Medical conditions that begin before the start of study drug but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section, unless related to study procedures. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Section 10.3, Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after the conclusion of 
a subject’s study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a subject has been discharged from the study, and he/she considers the 
event to be reasonably related to the study drug or study participation, the investigator must 
promptly notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3, 
Appendix 3. 
8.5.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.5.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. SAEs and AEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3). 
AEs not considered serious or as an AESI will be considered ongoing if they have not resolved 
by Week 52. Further information on follow-up procedures is given in Section 10.3, Appendix 
3. 
8.5.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
drug under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
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regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. AEs/SAEs must be followed up and reported as appropriate for at 
least 8 weeks (5 terminal half lives) after the last study dose. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC if appropriate 
according to local requirements.  
8.5.5 
Pregnancy 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment and until at least 12 weeks (>5 terminal half lives) 
after the last study dose.  
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4, Appendix 
4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and should be reported to the sponsor or 
designee within 24 hours. 
8.5.6 
Cardiovascular and Death Events 
Cardiovascular AEs should be reported as AEs/SAEs as described in Sections 8.5 and 10.3, 
Appendix 3.  
Any subject deaths that occur during the study should be considered SAEs and reported as per 
Sections 8.5 and 10.3, Appendix 3. If a death occurs, the investigator may be asked to provide 
a copy of any post-mortem findings including histopathology. 
8.5.7 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs 
All AEs and outcomes should be reported as described in Sections 8.5 and 10.3, Appendix 3.  
8.6 
Overdose and Medication Errors 
There is no data regarding overdose of M1095.  
Secukinumab doses of up to 30 mg/kg intravenously have been administered in clinical trials 
without dose-limiting toxicity. In the event of overdosage, it is recommended that the subject 
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be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic 
treatment be instituted immediately. 
Medication errors may result, in this study, from the administration of an unassigned treatment 
to the wrong subject, errors related to storage requirements, or administration of an expired 
product. All overdoses occurring to a study subject are to be captured on the AE page of the 
eCRFs and on the SAE form when appropriate. In the event of medication dosing error, the 
sponsor should be notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• 
Medication errors involving subject exposure to the study drug.  
• 
Potential medication errors or uses outside of what is foreseen in the protocol that do or do 
not involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error, and, if applicable, any associated AE(s) is captured on an 
AE eCRF page.  
8.7 
Pharmacokinetics 
Pharmacokinetic samples will be collected at the timepoints specified on the SoA (Section 
1.3). 
Samples will be shipped initially to the study’s central laboratory and tested by the sponsor or 
sponsor's designee. 
Serum M1095 levels will be assessed at trough (i.e. before study drug is given) at the following 
visits: Weeks 0, 2, 4, 8, 12, 24, 36, 44, 48, 52 and Early Discontinuation. M1095 serum 
concentrations will be summarized at these timepoints.  
Drug concentration information will not be reported to investigative sites or blinded personnel 
until the study has been unblinded. 
Details of the analysis will be provided either in the Statistical Analysis Plan (SAP), or in a 
separate PK Plan, prior to the analysis taking place. 
8.8 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.9 
Genetics 
Planned genetic analysis is not performed in this study. Unscheduled genomic biomarkers may 
be assessed as described in Section 8.10. 
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8.10 
Biomarkers 
Biomarkers are not routinely evaluated in this study. However, if a subject develops a clinically 
significant cutaneous rash that is not typical of psoriasis, two ≥4mm punch biopsies, one of 
normal skin, and one from skin within the rash will be obtained. The biopsies will be prepared 
and sent to a specialist laboratory for analysis of genomic biomarkers, specifically the 
expression of inflammatory mediators that characterize various immune reactions.  
8.10.1 
Immunogenicity Assessments 
Antibodies to M1095 will be evaluated in serum samples collected at the timepoints specified 
on the SoA (Section 1.3)  
Samples will be shipped initially to the study’s central laboratory and tested by the sponsor or 
sponsor's designee. 
Serum anti-drug antibodies will be assessed at trough (i.e. before study drug is given) at the 
following visits: Weeks 0, 2, 4, 8, 12, 24, 36, 44, 48, 52 and Early Discontinuation.   
Serum samples will be screened for antibodies binding to M1095 and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to M1095 and/or further characterize the immunogenicity of M1095. 
The detection and characterization of antibodies to M1095 will be performed using a validated 
assay method by or under the supervision of the sponsor. All samples collected for detection 
of antibodies to study drug will also be evaluated for M1095 serum concentration (see Section 
8.7) to enable interpretation of the antibody data. Positive samples for anti-drug antibodies will 
be evaluated to determine if the antibodies are neutralizing or non-neutralizing.   
If a subject’s final anti-drug antibody sample is positive (i.e. sample from Week 52 or sample 
from an Early Discontinuation visit) then the sponsor may request an addition sample be 
collected approximately six to twelve months after completion of the study. Subjects will be 
informed of this in the consent form and will have the option to refuse this additional sample.   
With a subject’s consent, samples may be stored following the last subject’s last visit for the 
study at a facility selected by the sponsor to enable further analysis of immune responses to 
M1095.  
8.11 
Health Economics 
This study will not collect data for Health Economics.  
 
 
 
 
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9.0 
STATISTICAL ANALYSIS  
Statistical analysis of this study will be the responsibility of the sponsor or its designee.  
Continuous data will be summarized in terms of the number of observations (n); mean; 
standard deviation and/or standard error of the mean, if applicable; median; minimum; and 
maximum. 
Categorical data will be summarized in terms of the number of observations (n), frequency 
count, and percentages. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05 unless otherwise 
stated. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be 
described in the clinical study report (CSR). Additional exploratory analyses of the data will 
be conducted as deemed appropriate. Complete details of the planned analyses will be 
documented in the SAP. 
9.1 
Statistical Hypotheses 
The primary endpoint is achievement of an IGA score of 0 or 1 at Week 12, with an IGA 
reduction of at least 2 points from baseline. The proportion of subjects in the Intent to Treat 
(ITT) Analysis Set with an IGA score of 0 or 1 at Week 12 will be used to compare treatment 
arms. The following null hypotheses will be tested at Week 12: 
• 
H1: M1095 30mg q2w x 3, followed by 30mg q4w x 1, is not different from placebo 
with respect to achievement of IGA scores of 0 or 1. 
• 
H2: M1095 60mg q2w x 3, followed by 60mg q4w x 1, is not different from placebo 
with respect to achievement of IGA scores of 0 or 1. 
• 
H3: M1095 120mg q2w x 3, followed by 120mg q4w x 1, is not different from placebo 
with respect to achievement of IGA scores of 0 or 1. 
• 
H4: M1095 120mg q2w x 6 is not different from placebo with respect to achievement 
of IGA scores of 0 or 1. 
The primary analysis method will be performed on the ITT Analysis Set and the treatment 
arms will be compared with the Cochran-Mantel-Haenszel test stratified by prior biologic use 
(yes/no) and body weight stratum (≤90kg, >90kg). Significance for each hypothesis will be 
assessed at the 2-sided 5% level. No adjustment for multiple comparisons will be made. 
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9.2 
Sample Size Determination  
A sufficient number of subjects will be screened, so that a total of approximately 300 subjects 
will be randomized (approximately 50 per treatment group.) 
With this sample size, the study has >99% power to detect a statistically significant difference 
between any treatment arm and placebo in the IGA score of 0 or 1 rate at Week 12, with a two-
sided, unadjusted type I error of 0.05. These calculations assume IGA score of 0 or 1 rates of 
>88% for study drug and ≤7% for placebo.6 As this is a phase 2 study, there will be no 
adjustments for multiplicity.  
Exploratory analyses between the different dose levels of M1095 will also be performed. The 
PASI 100 response rate offers more discriminatory potential for this. Phase 1 data and response 
simulations give a PASI 100 response rate at Week 12 varying from 45 to 72%. With the 
sample size of 50 subjects per group, based on these assumed PASI 100 response rates at Week 
12, the comparison between the highest and lowest M1095 doses has approximately 79% 
power. 
Power calculations have been performed with SAS v.9.4 Proc Power using the methodology 
for a two-group chi square test of equal proportions. 
Randomization will be stratified by prior biologic use (yes, no) and weight (≤90kg, >90kg).  
9.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
All subjects who sign informed consent 
Intent to Treat 
(ITT)  
The Intent to Treat (ITT) population includes all subjects randomly 
allocated to a treatment. Subjects will be analyzed according to 
planned treatment.  
Modified Intent 
To Treat (MITT) 
The Modified Intent to Treat (MITT) population includes all subjects 
in the ITT Analysis Set who receive at least one dose of study drug, 
have a baseline, and at least one post baseline efficacy assessments. 
Subjects will be analyzed according to planned treatment. 
Per-Protocol (PP) 
The Per-Protocol (PP) population includes all subjects in the MITT 
Analysis Set who have no important clinical protocol deviations 
affecting the assessment of efficacy. Membership of the PP Analysis 
Set will be confirmed prior to unblinding the data. Subjects will be 
analyzed according to planned treatment. 
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The primary analysis set for efficacy data will be the ITT Analysis Set.  
The primary analysis will be repeated on the MITT and PP Analysis Sets. Furthermore, 
selected sensitivity analyses will be performed on the ITT Analysis Set, including multiple 
imputation and last-observation carried forward. Safety data will be analyzed using the Safety 
Analysis Set. 
9.4 
Statistical Analyses 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. A comprehensive SAP will provide full details on all planned analyses for this study 
prior to the first interim data analysis.  
The primary analysis is at Week 12 and key secondary analyses are at Week 24. 
9.4.1 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary endpoint is achievement of an IGA score of 0 or 1 at Week 12. 
Response rates of IGA score of 0 or 1 at Week 12 will be used to compare the 
treatment arms. The response rate of IGA score of 0 or 1 at Week 12 is defined 
as the proportion of subjects at Week 12 with an IGA score of 0 or 1 and with 
an IGA reduction from baseline of 2 points or more. Baseline IGA score is the 
last score prior to the first dose of study medication. Any missing IGA score of 
0 or 1 response will be imputed as a non-response. 
The primary analysis will be based on the ITT Analysis Set. The primary 
treatment comparisons will be made using the two-sided Cochran-Mantel-
Haenszel (CMH) test stratified by prior biologic use and body weight stratum. 
Secondary 
The key secondary endpoints are the PASI 75, PASI 90 and PASI 100 at Week 
12. Secondary efficacy and QoL endpoints will be compared between 
randomized treatments in the ITT Analysis Set at each visit up to Week 12 and 
at Weeks 24, 36 and 48 using the CMH test for binary endpoints and for the 
shift from baseline in IGA and an Analysis of Covariance (ANCOVA) model 
Safety 
The Safety population includes all subjects who receive at least one 
dose of study treatment. The Safety population will be analyzed per 
the actual treatment received. 
Pharmacokinetic 
The Pharmacokinetic (PK) population includes all subjects who 
receive at least one dose of M1095 with valid (i.e. not flagged for 
exclusion) PK data and no protocol deviation with an impact on PK. 
The PK population will be analyzed per the actual treatment 
received. 
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for changes from baseline. The ANCOVA model will include treatment, prior 
biologic use and weight stratum as factors and the baseline value as a covariate. 
Descriptive summaries will be provided in tabular and graphical formats by 
treatment and over time. 
Analysis of the primary and key secondary endpoints will also be performed 
using the MITT and the PP populations. The impact of missing data on efficacy 
results will be assessed using multiple imputation, last-observation carried 
forward and worst-case imputation methods.  
Exploratory 
Exploratory analyses of efficacy will be made for subjects who (i) were dose-
escalated at Week 12, and (ii) who stopped treatment following IGA score of 0 
at Week 24. 
For the primary and secondary endpoints, comparisons will be made to placebo (all arms), and 
between the M1095 treatment arms. Dose response and dosing frequency response trend 
testing will be performed involving selected M1095 arms and placebo. No formal statistical 
testing will be done between M1095 treatment arms and secukinumab as the secukinumab arm 
is for reference only. Secukinumab will be compared to placebo using the same methods as the 
primary analysis.  
9.4.2 
Subject Demographics/Other Baseline Characteristics 
All data for background and demographic variables will be listed by treatment group and 
subject. For these parameters summary statistics will be provided by treatment group. 
 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject. 
9.4.3 
Subject Disposition 
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. 
Subject disposition will be summarized for each treatment period and overall. Reasons for 
discontinuation from the study will be summarized.  
9.4.4 
Treatment Compliance 
Treatment compliance with study drug will be summarized for each treatment period. Subject 
compliance with study drug will be assessed at each visit. A subject will be considered overall 
compliant for each study period if he/she is missing no more than 20% of the expected doses 
and not missing 2 consecutive doses. Proportions of subjects compliant by visit and overall 
compliance will be summarized by treatment groups. 
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9.4.5 
Safety Analyses 
Safety data will be summarized in the Safety Analysis Set by treatment. AEs will be 
summarized for each treatment period separately and overall. Treatment periods are described 
in Section 4.1. No statistical analyses of the safety data are planned. 
9.4.5.1 
Vital Signs 
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics, for 
absolute values and change from baseline, will be provided by treatment and visit/time. 
9.4.5.2 
ECG Evaluations 
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics, for absolute values and change from baseline, will be provided by 
treatment and visit/time. 
9.4.5.3 
Clinical Laboratory Evaluations 
All laboratory data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time. 
9.4.5.4 
Adverse Events 
All information obtained on adverse events will be displayed by treatment and subject. 
Treatment-Emergent AEs (TEAEs) are AEs that emerge while on study treatment, having been 
absent pre-treatment, or that worsen during study treatment relative to the pre-treatment state. 
Serious TEAEs including deaths, TEAEs that led to investigational product discontinuation, 
and TEAEs by maximum severity and relationship to investigational product will be 
summarized by the Medical Dictionary for Regulatory Activities (MedDRA) system organ 
class and preferred term. The number and percentage of subjects with TEAEs will be tabulated 
by body system and preferred term. A subject with multiple AEs within a body system is only 
counted once towards the total of the body system. A subject with multiple AEs within the 
same preferred term is only counted once towards the total of the preferred term. 
AESI will also be presented and summarized. AESI include cytopenias, liver function test 
changes/enzyme elevations, infections, injection-site reactions, allergic/hypersensitivity 
reactions, cerebrocardiovascular events, malignancies, depression, Crohn’s disease and 
ulcerative colitis. Additional adverse events may be identified as being of special interest 
during the study and prior to first unblinding. 
9.4.5.5 
Suicidality and Self-Injurious Behavior 
Suicide-related thoughts and behaviors and self-injurious behavior with no suicidal intent, 
based on the eC-SSRS, will be listed by subject. 
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9.4.5.6 
Previous and Concomitant Therapy 
Previous and concomitant therapies will be listed by treatment group and subject. Concomitant 
medications will be summarized by treatment. 
9.4.6 
Other Analyses  
As possible, subgroup analyses of key efficacy and safety data will be performed by 
geographical region, prior biological use, weight category, gender and geriatric status. 
Detailed description of the subgroup variables and detailed analysis methodology will be 
defined in the SAP. Additional subgroup analyses may be performed as deemed necessary.  
9.4.7 
PK Analyses 
An exploratory population PK analysis may be performed to model M1095 pharmacokinetics. 
The modelling effort should provide guidance about the design of further studies in terms of 
dose and regimen. 
Full details of the PK analysis will be provided either in the SAP, or in a separate PK plan prior 
to the analysis taking place. The population PK analysis will be presented separately from the 
main CSR. 
9.4.8 
Immunogenicity Analyses 
Binding and neutralizing antibodies will be defined by the percentage of subjects with 
antibodies and the titers of antibody. These data will be summarized. 
9.5 
Interim Analyses  
An unblinded interim analysis of complete 12-week data will occur at the end of the Week 12 
period, while the study is still ongoing. This will be managed by an independent DMC and 
statistical analysis group to preserve the blinding. This data will be shared with firewalled 
individuals who are not directly involved in the conduct of the study.  
A second interim analysis will occur at the completion of the Week 24 period. All investigators 
and subjects will remain blinded to treatment assignments until the last subject completes the 
study and the final database lock occurs. Once the second interim database lock has occurred 
after Week 24, the study statistician, statistical programmers, and designated sponsor team 
members will be unblinded to perform analysis of key study endpoints.   
The study will not be terminated early on the basis of positive efficacy after the first or the 
second interim database locks. 
Information that may unblind the study during the analyses will not be reported to study sites 
or the blinded study team until the study has been unblinded. All investigators and subjects 
will remain blinded to treatment assignments until the last subject completes the study and the 
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final database lock occurs. Once the second interim database lock has occurred after Week 24, 
the sponsor study team will be unblinded.  
The SAP will specify the analyses to be performed and the tables, figures and listings (TFLs) 
to be generated at each interim analysis. The SAP will be finalized prior to the first unblinding.  
9.5.1 
Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee (DMC) will be established to closely monitor the 
safety and tolerability data throughout the study and review interim analyses during the study. 
The DMC will be operational prior to enrolment of the first subject into the study. The 
composition and operation of the DMC will be described in a DMC charter. The charter will 
also detail how the communication between the DMC and the sponsor will be firewalled to 
preserve the blinding and integrity of the study.  
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10.0 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Council for Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects.  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European Clinical Trials Directive 2001/20/EC, and all other applicable 
local regulations. 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year 
after completion of the study. 
10.1.3 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding 
the study.  
• Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that 
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meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study site.  
• The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign the 
ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• Separate ICFs will be used to document agreement for skin evaluation (including 
assessments of genomic biomarkers) should this be required as per Section 8.4.2, and 
to document agreement to collect information from a study subject’s partner in case of 
pregnancy.  
• A separate ICF may also be used to document agreement for HIV testing, depending 
on local requirements. 
• A separate ICF may also be used to document agreement for use of a subject expense 
reimbursement system, depending on local requirements. 
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
10.1.4 
Data Protection 
• Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be 
transferred.  
• The subject must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject.  
• The subject must be informed that his/her medical records may be examined by study 
monitors, Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5 
Study Steering Committee  
A Study Steering Committee will be utilized for the study. Membership will include an overall 
Principal Investigator as well as regional lead investigators. The scope of the Study Steering 
Committee will be described in its applicable Charter. 
10.1.6 
Dissemination of Clinical Study Data 
Key design elements of this protocol will be made publicly available via the European Clinical 
Trials Database (EudraCT) and www.ClinicalTrials.gov. On study completion and finalization 
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of the CSR, the results of this study will be either submitted for publication and/or made 
publicly available via the EudraCT database and www.ClinicalTrials.gov.  
10.1.7 
Data Quality Assurance 
• All subject data relating to the study will be recorded on an eCRF (printed pages are 
acceptable only if the eCRF is unavailable) unless transmitted to the sponsor or 
designee electronically (e.g., laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor.  
10.1.8 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records. Also, 
current medical records must be available. 
• Definition of what constitutes source data can be found in the Source Data Agreement 
agreed with each investigator prior to site initiation. 
10.1.9 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the investigator 
• Discontinuation of further study intervention development 
Study recruitment will be stopped at a site when the total requested number of subjects for the 
study has been obtained, irrespective of the specific site’s inclusion number. Investigators will 
be informed when recruitment is to cease. 
When study analyses are complete the investigators will receive information about the 
treatment allocation for the subjects randomised at their respective sites. 
The sponsor may stop the study prematurely after consultation with the investigator, e.g., if the 
subject recruitment is so slow that the study cannot be completed within a reasonable time 
frame. Such premature termination/suspension of the study will be notified to Regulatory 
Authorities and IECs/IRBs as required. 
 
10.1.10 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 
 
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10.2 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 2 will be performed by the central laboratory.  
• Local laboratory results are only required if central laboratory results are not available 
in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that a sample for central analysis is obtained at 
the same time. Additionally, if local laboratory values are used to make either a study 
intervention decision or response evaluation, the values must be entered into the eCRF. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5.0 of the protocol. 
• Additional tests may be performed at any time during the study as deemed necessary 
by the investigator or required by local regulations. 
• Review of each laboratory report must be documented by an investigator.  
Table 2: Protocol-Required Safety Laboratory Assessments 
Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
Red Blood Cell (RBC) count 
• 
White Blood Cell (WBC) count with differential 
o 
Lymphocytes 
o 
Monocytes 
o 
Neutrophils 
o 
Bands 
o 
Eosinophils 
o 
Basophils 
• 
Platelets 
• 
ESRA 
Chemistry 
• 
Albumin 
• 
Alkaline phosphatase 
• 
ALT 
• 
AST 
• 
Total CO2 
• 
Total bilirubin 
o 
Direct bilirubin (if Total bilirubin is out of range) 
• 
Urea 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
Potassium 
• 
Total protein 
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• 
Sodium 
• 
Plasma GlucoseA 
• 
High sensitivity CRPA 
• 
LipidsA 
o 
Total cholesterolA 
o 
LDLA 
o 
HDLA 
o 
Total cholesterol to HDL ratioA 
o 
TriglyceridesA 
Urinalysis 
• 
Blood 
• 
White blood cells 
• 
Glucose 
• 
Protein 
• 
Ketones 
• 
pH 
Serology 
• 
Anti-HBVB 
• 
Anti-HCVB 
• 
Anti-HIVB 
• 
QuantiFERON®-TB GoldC 
Pregnancy Test 
• 
hCG (in serum)D  
• 
hCG (in urine)D 
 
A – Additional tests performed at Weeks 0 (randomization), 12, 24, 36 and 48. This must be a FASTING blood 
sample. ESR will be performed at the study site using a kit provided by the central laboratory.  
 
B – Screening only. See Section 10.5, Appendix 5 for details. 
 
C – Screening only. Sample to be sent to central or local laboratory. 
 
D – Pregnancy test in serum at Screening only, unless subsequent local urine pregnancy test is positive, in which 
case a central laboratory serum test should be repeated (See Section 10.4, Appendix 4).  
 
 
 
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10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Contraceptive guidance is given as per the Clinical Trial Facilitation Group recommendations 
related to contraception and pregnancy testing in clinical trials.24 
Women are considered not of child bearing potential if they are surgically sterile or post-
menopausal defined as 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms).  
Highly effective contraception must be used by all female subjects considered women of child 
bearing potential throughout the study and for 12 weeks following the last dose of study drug.  
 Highly effective contraception is defined as:  
i. Total abstinence: When this is in line with the preferred and usual 
lifestyle of the subject. [Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception]. 
ii. Female sterilization: have had a surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up 
hormone level assessment 
iii. Male partner sterilization (with the appropriate post-vasectomy 
documentation of absence of sperm in the ejaculate). (For female 
subjects on the study, the vasectomized male partner should be the sole 
partner for that subject). 
iv. Use of established oral, intravaginal, transdermal, injectable or 
implantable hormonal methods of contraception associated with 
inhibition of ovulation.  
v. Intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS). 
Male subjects must also use contraception throughout the study and for 12 weeks following 
the last dose of study drug. The following methods of contraception are permitted for male 
study subjects. 
i. Condom 
ii. Sterilization (with the appropriate post-vasectomy documentation of 
absence of sperm in the ejaculate). 
iii. Contraception taken by female partners if considered women of child 
bearing potential.  
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At each study visit, female and male subjects will be reminded that they must follow the 
study’s contraceptive guidance. This includes the final study visit, either Week 52 or the 
Early Discontinuation – Visit 2, when subjects will be reminded that they must follow the 
study’s contraceptive guidance for at least 4 more weeks, and that they should inform the 
investigator immediately should they or their partner become pregnant in this time.  
Pregnancy Testing 
• 
Women of child bearing potential should only be included in the study after a confirmed 
menstrual period and a negative highly sensitive serum pregnancy test, performed by the 
study’s central laboratory as part of study screening. 
• 
Local pregnancy testing should be performed at the baseline (randomization) visit, and at 
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, plus the Early Discontinuation 
Visit. Pregnancy testing will also be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected. A urine dipstick test will be performed locally by 
the study site personnel.  
• 
If at any stage, a local pregnancy test is positive, a highly sensitive serum pregnancy test 
should be performed via the study’s central laboratory.  
Collection of Pregnancy Information: 
Male subjects with partners who become pregnant  
• 
The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study.  
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor’s designee within 24 hours of learning of the partner’s pregnancy. 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female subjects who become pregnant  
• 
The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a subject's pregnancy. 
The subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the subject and the neonate and the information will 
be forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
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• 
Any female subject who becomes pregnant while participating in the study will 
discontinue study drug.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion 
is always considered to be an SAE and will be reported as such. Any post-study pregnancy 
related SAE considered reasonably related to the study intervention by the investigator will be 
reported to the sponsor as described in Section 8.5.4. While the investigator is not obligated to 
actively seek this information in former study subjects, he or she may learn of an SAE through 
spontaneous reporting.  
 
 
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Based on this scale, a subject will be eligible to participate in the study if the subject has an 
IGA score at baseline of 3 or 4. 
Based on this scale, a subject will be considered as an IGA 0 or 1 responder if the subject 
achieves a score of 0 or 1. 
10.6.2 
Total Body Surface Area (BSA) and Psoriasis Area and Severity Index 
(PASI) 
The total BSA affected by plaque-type psoriasis will be estimated from the percentages of 
areas affected, including head, trunk, upper limbs and lower limbs (see below for PASI 
assessment).  
The site will initially record assessments on paper and will then enter the data into the eCRF, 
which will auto-calculate the PASI score (no manual PASI calculations will be required by the 
site). 
Rounding should occur (e.g. 9.49% = 9 and 9.5% = 10) except in any instance where the 
percentage is just above 0 (i.e. 0.25% should round up to 1, not down to 0).  
A PASI score will be derived as indicated in Table 4.11, 12 The head, trunk, upper limbs and 
lower limbs are assessed separately for erythema, thickening (plaque elevation, induration), 
and scaling (desquamation). The average degree of severity of each sign in each of the four 
body regions is assigned a score of 0-4. The area covered by lesions on each body region is 
estimated as a percentage of the total area of that particular body region. Further practical 
details help the assessment: 
• The neck is assessed as part of the head. 
• The axillae and groin are assessed as part of the trunk. 
• The buttocks are assessed as part of the lower limbs. 
• When scoring the severity of erythema, scales should not be removed. 
 
 
 
 
 
 
 
 
 
 
 
 
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The investigator is only responsible for collecting the components or scoring signs and total 
regional area. PASI calculations, including changes over time will be calculated via the PASI 
Score eCRF.  
Based on PASI, to be eligible a subject must have a score of 12 or more at baseline. 
Based on total BSA, to be eligible, a subject must have 10% or more total BSA involved at 
baseline. 
Definitions of efficacy variables based on PASI 
The following definitions are used in this study, see Committee for Medicinal Products for 
Human Use (CHMP) guidelines for psoriasis.8 
• PASI 75 response: subjects achieving ≥ 75% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 75 responders 
• PASI 90 response: subjects achieving ≥ 90% improvement (reduction) in PASI score 
• PASI 100 response / remission: complete clearing of psoriasis (PASI=0) 
• Relapse: when the achieved maximal PASI improvement from baseline is reduced by 
>50% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.7 
Appendix 7: Abbreviations 
AE 
 
 
Adverse Event 
AESI  
 
Adverse Event of Special Interest 
ALT 
 
 
Alanine Aminotransferase 
ANC  
 
Absolute Neutrophil Count 
ANCOVA 
 
Analysis of Covariance 
AST 
 
 
Aspartate Aminotransferase 
AUC  
 
Area Under the Curve 
BSA  
 
Body Surface Area 
Cmax  
 
Maximum Concentration 
CFR 
 
 
Code of Federal Regulations 
CIOMS 
 
Council for International Organizations of Medical Sciences 
CMH  
 
Cochran-Mantel-Haenszel  
CONSORT 
 
Consolidated Standards of Reporting Trials 
CRO  
 
Contract Research Organization 
CRP 
 
 
C-Reactive Protein 
CS 
 
 
Corticosteroids 
CSR 
 
 
Clinical Study Report 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CXR  
 
Chest X-Ray 
D/C 
 
 
Discontinuation 
DLQI  
 
Dermatology Life Quality Index 
DMC  
 
Data Monitoring Committee 
DNA  
 
Deoxyribonucleic Acid 
ECG  
 
Electrocardiogram 
eCRF  
 
Electronic Case Record Form 
eC-SSRS 
 
Electronic Columbia Suicide Severity Rating Scale 
EMA  
 
European Medicines Agency 
EQ-POS 
 
Euro-Quality of Life Questionnaire for Psoriasis 
ESR 
 
 
Erythrocyte Sedimentation Rate 
EudraCT 
 
European Clinical Trials Database 
FDA  
 
Food and Drug Administration 
FSH 
 
 
Follicle Stimulating Hormone 
GCP  
 
Good Clinical Practice 
HBV  
 
Hepatitis B Virus 
hCG 
 
 
Human Chorionic Gonadotropin 
HCV  
 
Hepatitis C Virus 
HDL  
 
High Density Lipoprotein 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HIV 
 
 
Human Immunodeficiency Virus 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Council for Harmonization 
IEC 
 
 
Independent Ethics Committee 
IGA 
 
 
Investigator’s Global Assessment 
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IgG 
 
 
Immunoglobulin G 
IL 
 
 
Interleukin 
IMP 
 
 
Investigational Medicinal Product 
IRB 
 
 
Institutional Review Board 
IRT 
 
 
Interactive Response Technology 
ITT 
 
 
Intent to Treat 
IUD 
 
 
Intrauterine Device 
IUS 
 
 
Intrauterine System 
IV 
 
 
Intravenous 
LDL 
 
 
Low Density Lipoprotein 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MITT  
 
Modified Intent to Treat 
PASI  
 
Psoriasis Area and Severity Index 
PFS 
 
 
Pre-Filled Syringe 
PHQ-8  
 
Patient Health Questionnaire-8 
PK 
 
 
Pharmacokinetics 
PP 
 
 
Per Protocol 
PRO  
 
Patient Reported Outcomes 
PUVA  
 
Photochemotherapy (Psoralens and UVA) 
QoL 
 
 
Quality of Life 
q2w 
 
 
Every 2 weeks 
q4w 
 
 
Every 4 weeks 
q8w 
 
 
Every 8 weeks 
RBC  
 
Red Blood Cell 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SF-36  
 
Short-Form 36 
SmPC  
 
Summary of Product Characteristics 
SoA 
 
 
Schedule of Activities 
sPGA  
 
Static Physician’s Global Assessment 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
TB 
 
 
Tuberculosis 
TEAE  
 
Treatment Emergent Adverse Event 
TNF 
 
 
Tumour Necrosis Factor 
ULN  
 
Upper Limit of Normal 
UV 
 
 
Ultraviolet 
UVA  
 
Ultraviolet A (longwave) 
UVB  
 
Ultraviolet B (shortwave) 
VAS  
 
Visual Analogue Scale 
WBC  
 
White Blood Cell 
WFI 
 
 
Water for Injection 
 
 
 
 
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10.8 
Appendix 8: Protocol Amendment History 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Details of changes made 
02 
3.0 
inc. CZE-1 
16-Oct-2018 
• Change of office address for 
Avillion LLP 
• Clarification of eligibility 
regarding tuberculosis, and 
permission of re-screening if 
subjects become eligible after 
instigating treatment of latent TB 
• Creatinine clearance may be 
measured via 24-hour urine 
collection, in addition to 
calculation via Cockcroft-Gault 
• FOR CZECH REPUBLIC ONLY 
Exclusion criterion 4g amended to 
exclude subjects with a calculated 
creatinine clearance (via Cockcroft 
Gault) of <60mL/min 
• Exclusion criterion 13 amended to 
include suicidal behavior 
• Clarification of chronic drug abuse 
and IV drugs 
• Exclusion criterion 15 amended to 
clarify the requirement for highly 
effective contraceptive methods in 
women of child bearing potential 
• New exclusion criterion (18) to 
capture requirements for male 
contraception 
• Clarification of PASI endpoints 
• Addition of total BSA to secondary 
endpoints 
• Clarification of IGA endpoints 
• Urine pregnancy test every 4 
weeks 
• Updates to systemic and topical 
prior and prohibited treatments for 
psoriasis 
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AV002 – Final protocol, Version 3.0, incorporating CZE-1, dated 16 October 2018 
 
• Consideration of subject’s response 
at Week 24 and benefit from 
participating in study 
• Clarification that male sterilization 
is a permitted form of 
contraception in male subjects 
• Clarification on use of 
cannabis/marijuana 
• Clarification on release of 
randomization codes for PK 
analysis 
• Efficacy assessments to be 
recorded on paper, and clarification 
of who will perform assessments 
and rounding rules 
• Correction of the null hypothesis 
H4 and clarification of the other 
null hypotheses 
• Update to the statistical methods 
for the secondary endpoints 
• Clarification of visits for which 
treatment comparisons will be 
made 
• Clarification of unblinding at Week 
24 to allow analysis of key study 
endpoints 
• Update to use CTCAE Version 5.0 
• Addition of a separate ICF, per 
local requirements, to agree to the 
use of a subject expense 
reimbursement system. 
• Clarification at Week 52 regarding 
contraception for the next 4 weeks 
• Clarification of requirement to 
capture overdose/medication errors 
on AE eCRF 
• Typos and consistency in wording 
CZE-1 
2.0 
31-Aug-2018 
• Exclusion criterion 4g amended to 
exclude subjects with a calculated 
creatinine clearance (via Cockcroft 
Gault) of <60mL/min 
• Exclusion criterion 15 amended to 
clarify the requirement for highly 
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AV002 – Final protocol, Version 3.0, incorporating CZE-1, dated 16 October 2018 
 
effective contraceptive methods in 
women of child bearing potential 
• New exclusion criterion (18) to 
capture requirements for male 
contraception 
• Clarification that male sterilization 
is a permitted form of 
contraception in male subjects 
01 
2.0 
03-Apr-2018 
• www.ClinicalTrials.gov NCT 
number added 
• Co-ordinating Investigators added  
• Clarify the method used to blind 
injections to study subjects  
• ECG performed during Screening, 
and not at Week 0 
• HIV test added at Screening 
• Clarify the reconstitution of 30mg 
dose  
• ESR performed at study site using 
a kit provided by central laboratory 
• Clarify that there will be separate 
ICFs for skin evaluation and 
pregnant partners, and that there 
may be a separate ICF for HIV 
testing 
 
 
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AV002 – Final protocol, Version 3.0, incorporating CZE-1, dated 16 October 2018 
 
11.0 
REFERENCES 
1. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM; Identification and Management of 
Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology 
of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013 
Feb; 133 (2): 377–85.  
2. Bartlett HS and Million RP. Targeting the IL-17-T(H)17 pathway. Nat Rev Drug 
Discov. 2015 Jan; 14(1):11-2. 
3. Wasilewska A, Winiarska M, Olszewska M, Rudnicka L; Interleukin-17 inhibitors. A 
new era in treatment of psoriasis and other skin diseases. Postepy Dermatol Alergol. 
2016 Aug; 33(4):247-52. 
4. Ablynx website, accessed 27feb2017. http://www.ablynx.com/technology-
innovation/understanding-nanobodies/ 
5. Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, 
Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, 
Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C; ERASURE Study 
Group; FIXTURE Study Group; Secukinumab in plaque psoriasis--results of two 
phase 3 trials. N Engl J Med. 2014 Jul 24;371(4):326-38.  
6. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/cosenty
x.pdf  
7. https://ec.europa.eu/health/documents/community-
register/2015/20150115130444/anx 130444 en.pdf 
8. EMA guidance: GUIDELINE ON CLINICAL INVESTIGATION OF MEDICINAL 
PRODUCTS INDICATED FOR THE TREATMENT OF PSORIASIS. 
EMEA/CHMP/EWP/2454/02. 
9. http://www.consort-statement.org/ 
10. Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C; The 5-point 
Investigator’s Global Assessment (IGA) Scale: A modified tool for evaluating plaque 
psoriasis severity in clinical trials. J Dermatolog Treat. 2015 Feb; 26(1):23-31. 
11. Fredriksson T, Pettersson U; Severe psoriasis – oral therapy with a new retinoid. 
Dermatologica. 1978; 157(4):238-44. 
 
12. Weisman S, Pollack CR, Gottschalk RW; Psoriasis disease severity measures: 
comparing efficacy of treatments for severe psoriasis. J Dermatolog Treat. 2003 Sep, 
14(3):158-65. 
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Page 102 of 103 
AV002 – Final protocol, Version 3.0, incorporating CZE-1, dated 16 October 2018 
 
13. Finlay AY, Khan GK; Dermatology Life Quality Index (DLQI) – a simple practical 
measure for routine clinical use. Clin Exp Dermatol. 1994 May; 19(3):210-6.  
14. Ware JE, Brook RH, Williams KN, et al.; Conceptualisation and Measurement of 
Health for Adults in the Health Insurance Study, Vol 1. Model of Health and 
Methodology, 1980 Santa Monica, CA. Rand Corp 
15. Garratt AM, Ruta DA, Abdalla MI, Buckingham JK, Russell IT; The SF36 health 
survey questionnaire: an outcome measure suitable for routine use within the NHS? 
BMJ. 1993 May 29; 306(6890):1440-4.  
16. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X; 
Development and preliminary testing of the new five-level version of EQ-5D (EQ-
5D-5L). Qual Life Res. 2011 Dec; 20(10):1727-36. 
17. Swinburn P, Lloyd A, Boye KS, Edson-Heredia E, Bowman L, Janssen B; 
Development of a disease-specific version of the EQ-5D-5L for use in patients 
suffering from psoriasis: lessons learned from a feasibility study in the UK. Value 
Health. 2013 Dec; 16(8):1156-62. 
18. Mundt JC, Greist JH, Gelenberg AJ, Katzelnick DJ, Jefferson JW, Modell JG; 
Feasibility and validation of a computer-automated Columbia-Suicide Severity Rating 
Scale using interactive voice response technology. J Psychiatr Res. 2010 Dec; 
44(16):1224-8.  
19. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier 
GW, Melvin GA, Greenhill L, Shen S, Mann JJ; The Columbia-Suicide Severity 
Rating Scale: initial validity and internal consistency findings from three multisite 
studies with adolescents and adults. Am J Psychiatry. 2011 Dec; 168(12):1266-77. 
20. Mundt JC, Greist JH, Jefferson JW, Federico M, Mann JJ, Posner K; Prediction of 
suicidal ideation and behaviour ascertained by the electronic Columbia-Suicide 
Severity Rating Scale. J Clin Psychiatry. 2013 Sep; 74(9):887-93. 
21. Kroenke K, Spitzer RL; The PHQ-9: a new depression diagnostic and severity 
measure. Psychiatr Ann. 2002 Sep; 32(9);509-15.  
22. Kroenke K, Strine TW, Spitzer RL, Williams JB, Berry JT, Mokdad AH; The PHQ-8 
as a measure of current depression in the general population. J Affect Disord. 2009 
Apr; 114(1-3):163-73.  
23. https://evs.nci.nih.gov/ftp1/CTCAE/About.html 
24. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
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12.0 
SIGNATURE OF INVESTIGATOR  
PROTOCOL TITLE: A phase 2b randomized, double-blind, placebo controlled, multi-center 
12-week study with an additional 40-week follow-up assessment of efficacy, safety and 
tolerability of M1095 in subjects with moderate to severe chronic plaque-type psoriasis. 
PROTOCOL NO: 
AV002  
This protocol is a confidential communication of Bond Avillion 2 Development LP. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol. I will 
also work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with good clinical practices and the applicable laws and 
regulations. Acceptance of this document constitutes my agreement that no unpublished 
information contained herein will be published or disclosed without prior written approval 
from Bond Avillion 2 Development LP. 
 
Instructions to the investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the 
name/address of the center in which the study will be conducted. Return the signed copy to the CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
 
 
Signature 
 
Title  
 
 
 
 
 
 
Printed Name 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name/Address of Center 
 
 
 
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SAP_001.pdf: 
Statistical Analysis Plan (SAP) 
M1095 
M1095 phase 2b psoriasis study 
A phase 2b randomized, double-blind, placebo controlled, 
multicenter 12-week study with an additional 40-week 
follow-up assessment of efficacy, safety and tolerability of 
M1095 in subjects with moderate to severe chronic plaque-
type psoriasis. 
Version: Final 4.0 24-Sep-19, Effective 24-Sep-2019 
Author(s): 
Document type: 
Document status: 
Release date(s): 
Number of pages:
Identifying 
Numbers: 
 Trial Statistician 
SAP Documentation  
Final 
Version 1.0, 29-Jan-2019 
Amendment 1, version 2.0, 04-Jun-2019 
Amendment 2, version 3.0, 17-Jul-2019 
Amendment 3, version 4.0, 24-Sep-2019 
77 
ClinicalTrials.Gov NCT03384745
Confidential Information 
The information contained in this Statistical Analysis Plan (SAP) is confidential and the information contained within it may not be 
reproduced or otherwise disseminated without the approval of Clinbay or its representatives,  
This document and the information in it is the property of Bond Avillion 2 Development LP and it may not, in full or in 
part, be disclosed, distributed, reproduced, published or otherwise used without the express permission of Bond 
Avillion 2 Development LP. 
Confidential Notice
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Protocol Number: AV002                
CONFIDENTIAL 
M1095 phase 2b psoriasis study 
 
                      
Page 2 of 77  
 
AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
Table of Contents 
Section 
Page 
Table of Contents .......................................................................................... 2 
List of Tables ................................................................................................ 5 
List of Figures ............................................................................................... 7 
Abbreviations ................................................................................................ 8 
Revision History ......................................................................................... 10 
1 
Introduction ........................................................................................... 16 
1.1 
Scope of Document .......................................................................... 16 
1.2 
Study Reference Documentation ..................................................... 16 
1.3 
Study Objectives .............................................................................. 16 
1.3.1 
Primary Objective .................................................................... 16 
1.3.2 
Secondary Objectives .............................................................. 16 
1.3.3 
Exploratory Objectives ............................................................ 17 
1.4 
Study Design .................................................................................... 17 
2 
Interim Analyses ................................................................................... 21 
3 
Analysis Populations ............................................................................. 23 
4 
Statistical Methods ................................................................................ 25 
4.1 
General Considerations .................................................................... 25 
4.1.1 
Imputation Methods for Missing Data..................................... 27 
4.1.1.1 
Complete Cases (CC)......................................................... 31 
4.1.1.2 
Non-Responder Imputation (NRI) ..................................... 31 
4.1.1.3 
Last-Observation Carried Forward (LOCF) ...................... 31 
4.1.1.4 
Multiple Imputation (MI)................................................... 31 
4.1.1.5 
Tipping Point Analysis ...................................................... 34 
4.2 
Efficacy ............................................................................................ 36 
4.2.1 
Primary Analysis ..................................................................... 36 
4.2.1.1 
Variable .............................................................................. 36 
4.2.1.2 
Descriptive Analyses ......................................................... 36 
4.2.1.3 
Inferential Analyses ........................................................... 36 
4.2.1.4 
Sensitivity Analyses ........................................................... 37 
4.2.2 
Secondary Analyses ................................................................. 38 
4.2.2.1 
Variables ............................................................................ 39 
4.2.2.2 
Descriptive and Inferential Analyses ................................. 40 
4.2.3 
Exploratory Analyses .............................................................. 41 
4.2.3.1 
Exploratory Analyses after Escalation at Week 12 ........... 41 
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M1095 phase 2b psoriasis study 
 
                      
Page 3 of 77  
 
AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
4.2.3.2 
Exploratory Analyses after Withholding/Restarting 
M1095 from Week 24 ........................................................ 45 
4.3 
Quality of Life .................................................................................. 48 
4.3.1 
Variables .................................................................................. 48 
4.3.2 
Descriptive Analyses and Inferential Analyses ....................... 48 
4.4 
Subject Demographics/Other Baseline Characteristics ................... 48 
4.4.1 
Variables .................................................................................. 49 
4.4.2 
Descriptive Analyses ............................................................... 49 
4.5 
Analysis Populations ........................................................................ 50 
4.5.1 
Variables .................................................................................. 50 
4.5.2 
Descriptive Analyses ............................................................... 50 
4.6 
Subject Disposition .......................................................................... 51 
4.6.1 
Variables .................................................................................. 51 
4.6.2 
Descriptive Analyses ............................................................... 51 
4.6.3 
Graphical Presentation ............................................................. 52 
4.7 
Treatment Compliance ..................................................................... 52 
4.7.1 
Variables .................................................................................. 52 
4.7.2 
Descriptive Analyses ............................................................... 54 
4.8 
Previous and Concomitant Therapy ................................................. 55 
4.9 
Safety and Tolerability Data ............................................................ 56 
4.9.1 
Variables .................................................................................. 59 
4.9.2 
Descriptive Analyses ............................................................... 59 
4.9.2.1 
Vital Signs.......................................................................... 59 
4.9.2.2 
Skin Evaluations ................................................................ 59 
4.9.2.3 
ECG Evaluations................................................................ 59 
4.9.2.4 
Clinical Laboratory Evaluations ........................................ 60 
4.9.2.5 
Adverse Events .................................................................. 61 
4.9.2.6 
Depression and Suicidality/Self-Injurious Behavior ......... 63 
4.9.3 
Graphical Presentation ............................................................. 63 
4.10 Pharmacokinetic (PK) Parameters ................................................... 63 
4.10.1 
Variables .................................................................................. 63 
4.10.2 
Descriptive Analyses ............................................................... 63 
4.11 Immunogenicity Data ....................................................................... 64 
4.12 Subgroup Analyses .......................................................................... 64 
4.12.1 
Variables .................................................................................. 64 
4.12.2 
Descriptive and Inferential Analyses ....................................... 65 
4.12.2.1 
Binary and Categorical Variables ...................................... 65 
4.12.2.2 
Continuous Variables ......................................................... 65 
4.12.2.3 
Safety Variables ................................................................. 66 
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AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
5 
Sample Size Calculation ....................................................................... 67 
6 
Reference List ....................................................................................... 68 
7 
Appendices ............................................................................................ 70 
7.1 
Appendix A: Scoring of DLQI ........................................................ 70 
7.2 
Appendix B: Derivation of EQ-PSO ................................................ 71 
7.3 
Appendix C: Scoring of SF-36 (Version 2 Standard) ...................... 72 
7.4 
Appendix D: Scoring of PHQ-8 ....................................................... 76 
7.5 
Appendix E: Derivation of eC-SSRS ............................................... 77 
 
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Protocol Number: AV002                
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M1095 phase 2b psoriasis study 
 
                      
Page 5 of 77  
 
AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
List of Tables 
Table 2.1 List of assessments and timeframes analyzed for interim analyses ........................ 22 
Table 3.1: Definition of Analysis Populations ........................................................................ 24 
Table 4.1: Randomized Planned Treatment Groups and their Labels for each Treatment 
Period for Primary, Secondary Efficacy Analyses and Exploratory Analyses of QoL 
Variables. ................................................................................................................................. 25 
Table 4.2: Actual Treatment Groups for the Induction Period and their Labels for Safety 
Analyses of the Induction Period ............................................................................................ 26 
Table 4.3: Actual Treatment Groups for the Overall Period and their Labels for Safety 
Analyses of the Overall Period ................................................................................................ 26 
Table 4.4: Analysis Populations and Imputation Approaches to Handle Missing Data in 
Function of Efficacy Variables ................................................................................................ 28 
Table 4.5: Secondary Efficacy Endpoints and Variables ........................................................ 39 
Table 4.6: Exploratory Endpoints and Variables Related to Post-Week 12 Dose 
Escalation/Maintenance Analyses ........................................................................................... 42 
Table 4.7: Planned Treatment Groups with Dose Escalation and their Labels for each 
Treatment Period for Exploratory Analyses after Week 12. ................................................... 43 
Table 4.8: Definition of Additional Analysis Population for Exploratory Analyses .............. 45 
Table 4.9: Exploratory Endpoints and Variables Related to Post-Week 24 Dose Hold/Restart 
Analyses .................................................................................................................................. 46 
Table 4.10: Planned Treatment Groups with Dose Escalation/Hold and their Labels for each 
Treatment Period for Exploratory Analyses after Week 24. ................................................... 47 
Table 4.11: Analysis Populations in Function of Demography Variables .............................. 50 
Table 4.12: First M1095 Dose and Calculation of Dose Hold Duration Depending on 
Treatment Group ..................................................................................................................... 54 
Table 4.13: Actual Treatment Groups and their Labels for Pooled Safety Analyses of the 
Overall Period .......................................................................................................................... 57 
Table 4.14: Actual Treatment Groups and their Labels for Safety Analyses of the 
Maintenance/Escalation Period ............................................................................................... 58 
Table 4.15: Actual Treatment Groups and their Labels for Safety Analyses of the Response 
Assessment/Dose Hold Period ................................................................................................ 58 
Table 4.16: List of Efficacy Endpoints for Subgroup Analyses and Variables ...................... 64 
 
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Date: 24-Sep-2019 
 
Table 7.1: Names, Labels in SDTM Format and Range of Values for each Item .................. 72 
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Page 7 of 77  
 
AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
List of Figures 
Figure 1.1: Flow chart / Study Design Diagram ..................................................................... 20 
Figure 4.1: Multiple Imputation Process when Imputing n Datasets ...................................... 33 
 
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Protocol Number: AV002                
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M1095 phase 2b psoriasis study 
 
                      
Page 8 of 77  
 
AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
Abbreviations 
 
ADaM 
Analysis Data Model 
AE  
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA  
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BSA 
Body Surface Area 
CC 
Complete Cases 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
csv 
Comma-separated values 
CV 
Coefficient of Variation 
DAG 
Data Analysis Group 
DBL 
Database Lock 
DLQI 
Dermatology Life Quality Index 
DMC  
Data Monitoring Committee 
ECG 
Electrocardiogram 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
EQ-5D-5L 
Euro-Quality of Life-5 dimension-5 levels 
EQ-POS 
Euro-Quality of Life Questionnaire for Psoriasis 
HR 
Heart Rate 
IA 
Interim Analysis 
IA1 
First Interim analysis 
IA2 
Second Interim analysis 
IGA  
Investigator’s Global Assessment 
IMP 
Investigational Medicinal Product 
IRT 
Interactive Response Technology 
ITT 
Intent to Treat 
LLOQ 
Lower Limit Of Quantification 
LOCF 
Last Observation Carried Forward 
LOQ 
Limit Of Quantification 
LS 
Least-Squares 
LSM 
Least-Squares Means 
MAR 
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MITT12 
Modified Intent to Treat up to Week 12 
MITT24 
Modified Intent to Treat up to Week 24 
MITT48 
Modified Intent to Treat up to Week 48 
N/A 
Not Applicable 
NRI 
Non-Responder Imputation 
OR 
Odds Ratio 
PASI  
Psoriasis Area and Severity Index 
PCS 
Physical Component Summary 
PHQ-8 
Personal Health Questionnaire-8 
PK 
Pharmacokinetics 
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PP 
Per Protocol 
PP12 
Per Protocol up to Week 12 
PP24 
Per Protocol up to Week 24 
PP48 
Per Protocol up to Week 48 
PRO 
Patient Reported Outcomes 
PT 
Preferred Term 
Q2W 
Every 2 weeks 
Q4 
Every 4 weeks 
Q4W 
Every 4 weeks 
Q8 
Every 8 weeks 
Q8W 
Every 8 weeks 
QC 
Quality Control 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SF-36 
Short-Form 36 
SI 
International System of Units 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
TPA 
Tables, Figures, Listings 
Tipping Point Analysis 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
wk 
week 
 
 
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Protocol Number: AV002                
CONFIDENTIAL 
M1095 phase 2b psoriasis study 
 
                      
Page 10 of 77  
 
AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
Revision History 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Section title impacted (Current number): Outline of 
change 
29-JAN-19 
Prior to 
unblinding at 
Week 12 
(first Interim 
Analysis) 
Creation of 
initial version 
NA 
17-MAY-19 Prior to 
unblinding at 
Week 12 
(first Interim 
Analysis) 
The SAP was 
amended to 
clarify/modify 
some 
analyses.  
Section 1.3.2 Secondary Objectives: Clarification of 
the key secondary objectives for consistency purposes 
with the protocol.   
 
Section 1.4 Study Design: Clarification of treatment 
groups in the response assessment/dose hold period. 
 
Section 2 Interim Analyses (Table 2.1):  
• 
Clarification of data presented for each interim 
analysis (IA). 
• 
Clarification of DMC meetings occurring before 
IA1. 
 
Section 3 Analysis Populations: Clarification of the 
period for the three per protocol populations.  
 
Section 4.1 General Considerations (Table 4.2 and 
Table 4.3):  
• 
Clarification of derivation of actual treatments 
for the safety analyses of the induction and 
overall periods.  
• 
Clarification of reporting of efficacy and QOL 
data. 
 
Section 4.1.1 Imputation Methods for Missing Data:  
• 
Table 4.4: Clarification of the timeframe for 
each IA and of the variables and changes in the 
planned analyses for these IA. 
• 
Clarification of the use of stratifications factors 
as assigned at randomization (in IRT) in the 
efficacy analyses. 
• 
Clarification of the definition of missing data. 
 
Section 4.1.1.3 Last-Observation Carried Forward 
(LOCF): Clarification of the assumption made for LOCF 
approach in case a subject misses a visit.  
 
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M1095 phase 2b psoriasis study 
 
                      
Page 11 of 77  
 
AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
Date 
Time point 
Reason for 
update 
Section title impacted (Current number): Outline of 
change 
 
Section 4.1.1.5.1 Imputation Phase: Clarification 
regarding the fact that the response probabilities 
specified in this section are provided to explain the 
methodology.  
 
Section 4.2 Efficacy: Clarification of using the 
stratifications factors as assigned at randomization (in 
IRT) 
 
Section 4.2.1.3 Inferential Analyses: Clarification of 
using the stratifications factors as assigned at 
randomization (in IRT) in the analyses.  
 
Section 4.2.1.4 Sensitivity Analyses: Clarification that 
sensitivity analyses are optional.  
 
Section 4.2.2.1 Variables (Table 4.5): Clarification of 
endpoints and their type.  
 
Section 4.2.2.2 Descriptive and Inferential Analyses: 
Addition of a sensitivity analysis because the subgroup 
analysis per actual stratification factors cannot serve as 
sensitivity analysis in case of stratification errors. 
 
Section 4.2.2.2.2 Time-to-event Variables: 
Clarification of the time to be used if median time is not 
estimable.  
 
Section 4.2.3 Exploratory Analyses: Clarification 
regarding the fact that sensitivity analyses of the 
exploratory analyses may not be performed.  
 
Section 4.2.3.1.1 Variables (Table 4.6): Clarification of 
type of variables. 
 
Section 4.2.3.1.2 Descriptive Analyses (Table 4.7): 
Clarification of the descriptive comparisons and of the 
displayed treatments for exploratory analyses after 
Week 12.  
 
Section 4.2.3.1.5 Time-to-event Variables: 
Clarification of the time to be used if median time is not 
estimable. 
 
Section 4.2.3.1.6 Subset Analyses: Clarification of the 
reasons to use the MITT48 population for exploratory 
analyses after Week 12.  
 
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Date 
Time point 
Reason for 
update 
Section title impacted (Current number): Outline of 
change 
Section 4.2.3.2.1 Variables (Table 4.9): Clarification of 
type of variables. 
 
Section 4.2.3.2.2 Descriptive Analyses:  
• 
Clarification of the analysis population for the 
exploratory analyses after Week 24.  
• 
Table 4.10: Clarification of the treatments 
presented in the exploratory analyses after 
Week 24. 
• 
Table 4.15: Clarification of treatment labels for 
M1095 120mg. 
 
Section 4.3.2: Descriptive Analyses and Inferential 
Analyses: Clarification of the use of stratifications 
factors as assigned at randomization (in IRT) in the 
analyses of quality of life data. 
 
Section 4.4.1 Variables:  
• 
Clarification of the variables and/or visits to be 
presented in the table of demographics and 
other baseline characteristics 
• 
Clarification of the analysis populations for the 
laboratory assessments. 
 
Section 4.5.1 Variables: Correction of the analysis 
populations to be presented in the disposition table.  
 
Section 4.7: Treatment Compliance: Clarification of 
the definition of subject-years.  
 
Section 4.8: Previous and Concomitant Therapy: 
Change in the analysis population. 
 
Section 4.9 Safety and Tolerability Data: 
• 
Table 4.13, Table 4.14 and Table 4.15: 
Clarification of derivation of actual treatments. 
• 
Table 4.15: Clarification of treatment labels for 
M1095 120mg. 
 
Section 4.9.2.5 Adverse Events:  
• 
Clarification of TEAEs per treatment period. 
• 
Change of wording for actual treatments. 
• 
Clarification that only serious TEAEs will be 
presented in summary tables and that incidence 
tables by PT will not be produced.  
• 
The identification of common TEAEs were 
clarified.  
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AV002 – Final SAP, Version 4.0 
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Date 
Time point 
Reason for 
update 
Section title impacted (Current number): Outline of 
change 
 
Section 4.10 Pharmacokinetic (PK) Parameters:  
• 
Clarification regarding the fact that the PK 
analyses may be reported in a separate report.  
• 
Clarification of treatment groups to be used for 
PK analyses. 
 
Section 4.12 Subgroup Analyses:  
• 
Clarification of using the actual stratifications 
factors in the subgroup analyses. 
• 
Clarifications that the subgroup analyses can be 
used as sensitivity analyses only if there were 
no stratifications errors.  
 
Section 4.12.1 Variables (Table 4.16): Clarifications of 
type of variables. 
 
Editorial and administrative changes have been made 
throughout the document.  
 
17-JUL-19 
Prior to 
unblinding at 
Week 12 
(first Interim 
Analysis) 
The SAP was 
amended to 
clarify/modify 
some 
analyses.  
Section 2 Interim Analyses (Table 2.1): Clarification of 
analyses to be performed at Interim Analyses 1 and/or 
2. 
 
Section 3 Analysis Populations: Adding a reference 
to a supplement to the SAP. 
 
Section 4.1.1 Imputation Methods for Missing Data:  
• 
Table 4.4: Clarification of analyses to be 
performed at Interim Analysis 2. 
• 
Change of the factors to be used for the efficacy 
analyses: use of weight category and prior use 
of biologic therapy stratum derived from the 
observed values rather than the stratum as 
assigned at randomization. 
 
Section 4.2 Efficacy: Use of the actual stratification 
factors for all efficacy analyses using a CMH test or an 
ANCOVA and for the descriptive analyses presenting 
the stratification factors. 
 
Section 4.2.1.4.1 Sensitivity Analysis to 
Stratification Factors: Addition of a sensitivity analysis 
of the primary endpoint using the randomized stratum in 
case of a large number of stratification errors. 
 
Section 4.2.1.1 Variables: Clarification of the IGA 
categories for the shift analysis. 
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AV002 – Final SAP, Version 4.0 
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Date 
Time point 
Reason for 
update 
Section title impacted (Current number): Outline of 
change 
 
Section 4.2.1.4.3 Sensitivity Analyses to Missing 
Data: Clarification of how the extent of missing IGA data 
will be summarized. 
 
Section 4.2.2.2.1 Binary and Categorical Variables:  
• 
Addition of a sensitivity analysis of the key 
secondary endpoints in case of a large number 
of stratification errors. 
• 
Removal of the assessment of the homogeneity 
assumption because this assessment is 
covered by the subgroup analyses.  
• 
Removal of the pairwise comparisons for the 
shift analyses to keep all possible shift 
categories.  
 
Section 4.2.3.1.1 Variables and Section 4.2.3.2.1 
Variables: Clarification of the IGA categories for the 
shift analysis. 
 
Section 4.3 Quality of Life: Use of the actual 
stratification factors for all analyses using an ANCOVA. 
 
Section 4.9.2.1 Vital Signs: Clarifications of the way to 
identify vital signs abnormalities.   
 
Section 4.12 Subgroup Analyses: Clarification of the 
subgroup analyses that can be used for sensitivity 
analyses due to the change of efficacy analyses.  
 
Editorial and administrative changes have been made 
throughout the document. 
 
24-SEP-19 
Prior to 
unblinding of 
study 
statistician, 
programmers 
and 
designated 
sponsor team 
members at 
Week 24 
(second 
Interim 
Analysis) 
The SAP was 
amended to 
clarify some 
points.   
Section 2 Interim Analyses:  
• 
Clarification of tasks to be performed for each 
designated role (study statistician, statistical 
programmers and designated sponsor team 
members). 
• 
Table 2.1: Clarification that shift analysis from 
baseline in IGA (secondary endpoint) as well as 
PK and immunogenicity analyses (exploratory 
endpoint) will not be reported after Week 24 for 
Interim Analysis 2. 
 
Section 4.1.1 Imputation Methods for Missing Data 
(Table 4.4):  
• 
Correction of the imputation method of the 
secondary analysis of PASI responses and IGA 
score of 0 or 1 from Week 24 in the MITT48 
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M1095 phase 2b psoriasis study 
 
                      
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AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
Date 
Time point 
Reason for 
update 
Section title impacted (Current number): Outline of 
change 
population. 
• 
Completion of the imputation method when 
there was a change in the population but not in 
the analysis period (exploratory (escalation): 
IGA score of 0 or 1, IGA score of 0, PASI 
responses from Week 12 to Week 24 and 
exploratory (escalation): shift from Week 12 in 
IGA score category from Week 12 to Week 24),  
• 
Removal of the reporting of the shift from 
baseline in IGA imputed with LOCF from Week 
24 to Week 52 for Interim Analysis 2.  
 
Section 4.2.2.2.1 Binary and Categorical Variables: 
Correction of the presented visits for the categorical 
analyses displaying the shift from baseline in IGA score 
category to be consistent with Table 4.5.  
 
Section 4.9.1 Variables: Clarification of the data 
presented in the section.   
 
Section 4.12 Subgroup Analyses: Clarification of the 
subgroups of IGA at baseline.  
 
Editorial and administrative changes have been made 
throughout the document. 
 
  
 
 
 
 
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AV002 – Final SAP, Version 4.0 
Date: 24-Sep-2019 
 
1 Introduction 
1.1 Scope of Document 
The Statistical Analysis Plan (SAP) describes the implementation of the planned statistical 
analysis that will be included in the Clinical Study Report (CSR) for protocol No. AV002: A 
phase 2b randomized, double-blind, placebo controlled, multicenter 12-week study with an 
additional 40-week follow-up assessment of efficacy, safety and tolerability of M1095 in 
subjects with moderate to severe chronic plaque-type psoriasis.  
1.2 Study Reference Documentation 
Final study protocol (Version 3.0, incorporating CZE-1, dated 16th October 2018) is available 
at the time of finalization of the SAP. 
1.3  Study Objectives 
1.3.1 Primary Objective  
Type of Objective 
Study Objective 
Primary Objective 
• To evaluate the efficacy of four dose regimens of M1095 
compared to placebo on achievement of an Investigator’s 
Global Assessment (IGA) score of 0 or 1 after 12 weeks of 
treatment in subjects with moderate to severe chronic plaque-
type psoriasis. 
 
1.3.2 Secondary Objectives 
Type of Objective 
Study Objective 
Key Secondary 
Objectives  
• To evaluate the efficacy of four dose regimens of M1095 
compared to placebo during a 12-week treatment period on 
secondary endpoints: Psoriasis Area and Severity Index 
(PASI) 75, PASI 90, PASI 100, change in PASI and shift in 
IGA. 
Secondary 
Objectives 
• To assess the dose-regimen efficacy relationship for M1095 
after 12, 24, 36 and 48 weeks of treatment. 
• To evaluate the longer-term efficacy of M1095 at Week 24 
and at Weeks 36 and 48. 
• To assess the safety and tolerability of M1095. 
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AV002 – Final SAP, Version 4.0 
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1.3.3 Exploratory Objectives  
Type of Objective 
Study Objective 
Exploratory 
Objectives 
• Assessment of the quality of life and health outcomes of 
subjects treated with M1095 over 48 weeks via quality of life 
instruments evaluated every 12 weeks. 
• Assessment of the population pharmacokinetics (PK) of 
various doses and dose regimens of M1095.  
• Assessment of the development of antidrug antibodies for 
various doses and dose regimens of M1095. 
• Assessment of change in efficacy from Week 12 to Week 24 
in subjects who undergo dose escalation. 
• Assessment of M1095 being withheld in subjects with an IGA 
score of 0 at Week 24. 
 
1.4 Study Design 
This is a multi-center, randomized phase 2b study in subjects with moderate to severe chronic 
plaque-type psoriasis. Approximately 300 subjects will be enrolled at approximately 60 
investigator sites in North America and Europe.  
At the end of the initial 4-week screening period (Week -4 to Week 0), all eligible subjects 
will be randomized within strata of prior biologic use (yes/no) and weight (≤ 90 kg/> 90 kg) 
in a 1:1:1:1:1:1 ratio with approximately 50 subjects randomized into each of six treatment 
groups as shown below and in Figure 1.1: 
1. Placebo at weeks 0, 1, 2, 3, 4, 6, 8, 10 / M1095 120mg at weeks 12, 14, 16 and Q4W. 
2. M1095 (30 mg) at weeks 0, 2, 4, 8, 12 and Q4W. 
3. M1095 (60 mg) at weeks 0, 2, 4, 8, 12 and Q4W. 
4. M1095 (120 mg) at weeks 0, 2, 4, 8, 12 and Q8W. 
5. M1095 (120 mg) at weeks 0, 2, 4, 6, 8, 10, 12 and Q4W. 
6. Secukinumab (300 mg) at weeks 0, 1, 2, 3, 4, 8, 12 and Q4W. 
After randomization at Week 0, the study will consist of:  
• 3 consecutive treatment periods: 
A: Induction: a 12-week treatment period (Week 0 to Week 12), which is 
placebo-controlled,  
B: Maintenance/escalation: a 12-week maintenance/escalation period (Week 12 
to Week 24) where all subjects are on active treatment, 
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C: Response assessment/dose hold: a 24 week response assessment/dose hold 
period (Week 24 to Week 48) where active treatment is withheld in subjects 
who have been administered M1095 during the maintenance period and have 
an IGA score of 0 at the start of this period i.e. at Week 24,  
• followed by a final assessment period (Week 48 to Week 52) for safety/efficacy 
follow-up. 
The study will be double-blinded, subject- and investigator- blinded, during all treatment 
periods up to Week 52 (refer to the unblinding plan for further information about the 
timepoints when specific teams will be unblinded during the study). Blinding will be 
maintained prior to Week 52 using masking techniques. Therefore, up to Week 24, subjects 
randomized to 30 and 60 mg M1095 (Arms 2 and 3) will be administered placebo at Weeks 
1, 3, 6, 10 and 14 in order to preserve the blinding. Similarly, subjects randomized to 120 mg 
M1095 (Arm 4) will receive placebo at Weeks 1, 3, 6, 10, 14 and 16 and subjects randomized 
to 120 mg M1095 (Arm 5) will receive placebo at Weeks 1, 3 and 14. Subjects randomised to 
Secukinumab (Arm 6) will receive placebo at Weeks 6, 10 and 14.  
At the end of the treatment induction period (Week 12), the subjects randomized to 30 mg or 
60 mg M1095 who do not achieve an IGA score of 0 or 1 will be dose-escalated to 120 mg 
Q4W at Week 12.  
Subjects who enter the maintenance/escalation period will receive one of the following 
treatments until Week 24 and before the dose injection at Week 24: 
• Placebo at weeks 0, 1, 2, 3, 4, 6, 8, 10 and M1095 120 mg at weeks 12, 14, 16 and 
Q4W. 
• M1095 30 mg at weeks 0, 2, 4, 8, 12 and Q4W         
• M1095 60 mg at weeks 0, 2, 4, 8, 12 and Q4W         
• M1095 30 mg at weeks 0, 2, 4, 8 and M1095 120 mg at 
week 12 and Q4W  
• M1095 60 mg at weeks 0, 2, 4, 8 and M1095 120 mg at 
week 12 and Q4W  
• M1095 120 mg at weeks 0, 2, 4, 8, 12 and Q8W 
• M1095 120 mg at weeks 0, 2, 4, 6, 8, 10, 12 and Q4W 
• Secukinumab 300 mg at weeks 0, 1, 2, 3, 4, 8, 12 and Q4W. 
At the end of the maintenance/escalation period (Week 24), any subjects on M1095 treatment 
groups who did not undergo dose escalation at Week 12 and achieve an IGA score of 0 at 
Week 24 will have the study treatment withheld. To maintain the blinding after Week 24, 
these subjects will receive placebo Q4W. Subjects receiving secukinumab in the first 
treatment period will continue to receive it at the same dose 300 mg Q4W throughout the 
study. 
Subjects who enter the response assessment/dose hold period will receive one of the 
following treatments until Week 44 (or until when the IGA score of subjects with M1095 
if IGA Week12 ≤ 1 
if IGA Week12 > 1 
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treatment held at Week 24 subsequently increases to 1 or more* at which time these subjects 
will be re-administered the study treatment M1095 at the dose they received prior to Week 
24): 
• Placebo at weeks 0, 1, 2, 3, 4, 6, 8, 10 and M1095 
120 mg at weeks 12, 14, 16 and Q4W  
• Placebo at weeks 0, 1, 2, 3, 4, 6, 8, 10 and M1095 
120 mg at weeks 12, 14, 16 and Q4W until Week 20 
and Placebo Q4W*         
• M1095 30 mg at weeks 0, 2, 4, 8, 12, 
and Q4W until Week 20 and Placebo 
Q4W*         
• M1095 60 mg at weeks 0, 2, 4, 8, 12, 
and Q4W until Week 20 and Placebo 
Q4W*         
• M1095 30 mg at weeks 0, 2, 4, 8, 12 and 
Q4W  
• M1095 60 mg at weeks 0, 2, 4, 8, 12 and 
Q4W 
• M1095 30 mg at weeks 0, 2, 4, 8 and M1095 120 mg at week 12, 
and Q4W  
• M1095 60 mg at weeks 0, 2, 4, 8 and M1095 120 mg at week 12, 
and Q4W  
•  M1095 120 mg at weeks 0, 2, 4, 8, 12 and Q8W until Week 20, 
and Placebo Q4W* 
•  M1095 120 mg at weeks 0, 2, 4, 6, 8, 10, 12 and Q4W until 
week 20, and Placebo Q4W*  
• M1095 120 mg at weeks 0, 2, 4, 8, 12 and Q8W 
• M1095 120 mg at weeks 0, 2, 4, 6, 8, 10, 12 and Q4W 
• Secukinumab 300 mg at weeks 0, 1, 2, 3, 4, 8, 12 and Q4W 
*If the IGA score of these subjects subsequently increases to 1 or more at any time after 
Week 24, these subjects will be re-administered the study treatment M1095 at the dose they 
received prior to Week 24 on a Q4W regimen at the scheduled visits as per protocol until the 
end of the treatment period. Dose will not be withheld for a second time, irrespective of 
subsequent IGA scores. 
if IGA Week24 > 0 
if IGA Week12 ≤ 1 and IGA Week24 = 0  
if IGA Week12 > 1 
if IGA Week24 = 0 
if IGA Week24 > 0 
if IGA Week12 ≤ 1 and IGA Week24 > 0 
if IGA Week24 = 0 
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Figure 1.1: Flow chart / Study Design Diagram 
 
 
Exposure to Placebo will be limited to a maximum of 12 weeks during the induction period 
and a maximum of 20 weeks after Week 24 (i.e. during the response assessment/dose hold 
period) provided that the subjects maintain a complete remission (i.e. achieving an IGA = 0). 
All subjects, irrespective of whether they completed or discontinued the study, will be 
followed up for safety and potential sustainability of efficacy, for an additional 8 weeks (56 
days) after receiving the last dose of study treatment. In addition, subjects who discontinued 
prior to Week 52 will be contacted monthly as per the study schedule (up to Week 52) to 
report any AEs, concomitant medications and any new psoriasis treatments. 
 
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2  Interim Analyses 
Two Interim Analyses (IAs) are planned during this trial: 
1. IA1: the first unblinded IA of complete 12-week data for all randomized subjects will 
occur at the end of the induction period, while the study is still ongoing,  
2. IA2: the second IA will occur at the completion of the maintenance/escalation period 
at Week 24, while the study is still ongoing. 
The purpose of both interim analyses is to closely monitor the safety and tolerability data 
throughout the study. The study will not be terminated early on the basis of either positive 
efficacy or futility after the review of the first or the second interim analyses. The two interim 
analyses are also conducted to gather preliminary efficacy information to make possible 
executive decisions concerning the clinical project.  
The first unblinded IA will be managed by an independent Data Monitoring Committee 
(DMC) and an independent Data Analysis Group (DAG) to preserve the blinding. This data 
will be shared with firewalled individuals who are not directly involved in the conduct of the 
study. The DMC will be operational prior to enrolment of the first subject into the study. The 
composition and operation of the DMC will be described in a DMC charter. The charter will 
also detail how the communication between the DMC and the sponsor will be firewalled to 
preserve the blinding and integrity of the study. The analyses that will be included in the first 
interim analysis are described in Table 2.1 (refer to the corresponding sections of this SAP 
for further information about the analyses and to Table 4.4 for the imputation methods to be 
used for each assessment of this planned interim analysis). Unblinded results of IA1 will be 
reviewed by the DMC members.  
The DMC members will meet regularly to review blinded safety data and may decide to carry 
out additional unblinded safety review, as necessary. In addition, the DMC members will 
hold two DMC meetings with review of unblinded safety data before IA1.  
Laboratory personnel performing the bioanalytical PK sample analysis may receive an open 
randomization list to enable analysis of relevant samples prior to IA2. In addition, a PK 
analyst and modelling/simulation scientist may receive an open randomization list to enable 
preparation of modelling/simulation activities. These individuals will not interact with site or 
CRO personnel, who is blinded. 
For the second unblinded IA, all investigators and subjects will remain blinded to treatment 
assignments. Once the second interim database lock has occurred after the last subject 
completed the visit at Week 24 or early discontinued before Week 24 and all data up to Week 
24 are cleaned, the study statistician, statistical programmers and designated sponsor team 
members will be unblinded to perform and/or review analysis of key study endpoints (please 
refer to the unblinding plan for further details). All sponsor or CRO personnel in direct 
contact with study sites will remain blinded and be firewalled to prevent accidental 
unblinding. The second interim analysis will consist of all planned analyses described in 
Table 2.1. It will present data for all subjects up to Week 24 (Visit 13) that is the minimum 
analysis cutoff visit for interim 2 and data beyond Week 24 (please refer to Table 4.4 for 
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3  Analysis Populations 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
All subjects who sign informed consent. 
Intent-to-Treat 
(ITT)  
The Intent-to-Treat (ITT) population includes all subjects 
randomly allocated to a treatment. 
Subjects will be analyzed according to planned treatment in the 
induction period (up to Week 12).  
Modified Intent-
To-Treat (MITT) 
including MITT12, 
MITT24 and 
MITT48 
The Modified Intent-to-Treat up to Week 12 (MITT12) 
population includes all subjects in the ITT population who 
receive at least one injection, have a baseline, and at least one 
post-baseline efficacy assessments up to Week 12. 
Two additional MITT populations will be defined for exploratory 
analyses after Week 12 and after Week 24: 
• MITT24 that includes all MITT12 subjects who received 
at least one injection during the escalation/maintenance 
period from Week 12 to Week 24,  
• MITT48 that includes all MITT12 subjects who received 
at least one injection during the response assessment/dose 
hold period from Week 24 to Week 48.  
Subjects will be analyzed according to planned treatment: 
• in the induction period (up to Week 12) for MITT12, 
• in the maintenance/escalation period (from Week 12 to 
Week 24) for MITT24, 
• in the response assessment/response hold period (from 
Week 24 to Week 48) for MITT48. 
 
 
 
 
 
Per-Protocol (PP) 
including PP12, 
PP24 and PP48 
 
 
 
 
 
The Per-Protocol (PP) population includes all subjects in the 
MITT population who have no important clinical protocol 
deviations affecting the assessment of efficacy.  
Three PP populations will be defined: 
• PP12 population: PP population up to Week 12 including 
subjects in the MITT12 population 
• PP24 population: PP population up to Week 24 including 
subjects in the MITT24 population 
• PP48 population: PP population up to Week 48 including 
subjects in the MITT48 population. 
 
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Population 
Description 
 
 
 
 
 
 
Per-Protocol (PP) 
including PP12, 
PP24 and PP48 
The PP populations up to Week 12 and Week 24 will be defined 
during the blinded data review meeting prior to unblinding at 
Weeks 12 and 24 respectively. Membership of the PP population 
after Week 24 will be determined based on new protocol 
deviations occurring after Week 24.  
 
Subjects will be analyzed according to planned treatment: 
• in the induction period (up to Week 12) for PP12, 
• in the maintenance/escalation period (from Week 12 to 
Week 24) for PP24, 
• in the response assessment/response hold period (from 
Week 24 to Week 48) for PP48. 
Safety 
The Safety population includes all subjects who receive at least 
one dose of study treatment. 
The Safety population will be analyzed per the actual treatment 
received using a conservative approach that will be described 
further in Section 4.1. 
Pharmacokinetic 
(PK) 
The Pharmacokinetic (PK) population includes all subjects who 
receive at least one dose of M1095 with valid (i.e. not flagged for 
exclusion) PK data and with no occurrence of important protocol 
deviation impacting the PK results during the study. 
The PK population will be analyzed per the actual treatment 
received. 
Table 3.1: Definition of Analysis Populations 
The primary population for efficacy data will be the ITT population. The primary analysis 
will be repeated on the MITT12 and PP12 analysis populations.  
Safety data will be analyzed using the Safety population and PK data using the PK 
population. 
All protocol deviations (PDs) will be tracked and their categorization will be reviewed and 
evaluated during the blinded data review meetings. Important PDs are defined as deviations 
from the protocol that are likely to have an impact on the subject’s rights, safety, well-being, 
and/or on the validity of the data for analysis. However, only selected clinically important 
PDs affecting the assessment of efficacy will be excluded from statistical analyses in the PP 
populations (refer to the supplement to the SAP: Protocol Deviations Exclusion List).   
The PP12 and PP24 populations and the PK population will be finalized during the blinded 
data review meetings.  
The precise list of important PDs will be documented and approved at Weeks 12 and 24 
before unblinding and at Week 48.   
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All primary/secondary efficacy and exploratory QoL endpoints will be presented in tables 
including visits from Week 0 to Week 52 as follows: 0, 1, 2, 3, 4, 6, 8, 10, 12, // 14, 16, 20, 
24, // 28, 32, 36, 40, 44, 48 and 52 (each week number, written in bold, indicates the weeks, 
at which the pairwise treatment comparisons will be made and // indicates the boundary for 
the study periods). In regard to interim analyses, only visits up to Week 12 will be included 
for IA1. IA2 will include data up to Week 24 for all subjects and beyond Week 24 for some 
subjects depending on the cut-off date (see Section 2). The analyses may be split by period or 
by combined periods depending on the tables produced for IA1 and IA2. 
For all efficacy and quality of life analyses unless specified otherwise, baseline will be 
defined as the last non-missing assessment prior to the first dose of study medication 
(planned at Week 0).  
For safety analyses, baseline will be defined differently according to the treatment period: 
• Induction period: baseline will be defined as the last non-missing assessment prior to 
the first dose of study medication (planned at Week 0). 
• Maintenance/Escalation period, Response Assessment/Dose Hold period and Overall 
study (all combined periods): baseline will be defined as the last non-missing 
assessment prior to the first dose of study medication (planned at Week 0) for all 
subjects randomized to M1095 or Secukinumab. For the subjects randomized to 
placebo, baseline will be the last non-missing assessment prior to the first dose of 
M1095 (planned at Week 12).  
Unless otherwise stated, continuous data will be summarized by treatment group at each 
scheduled visit (including baseline) using the following summary statistics: number of non-
missing observations (n), arithmetic mean, standard deviation, median, minimum and 
maximum. In general, summary plots over time will present means and standard errors. The 
number of decimal places for these statistics will be determined by the number of decimal 
places of the raw data or derived data where applicable: minimum and maximum will be 
presented with the same number of decimal places as for the raw data, mean and median with 
an additional decimal place and the standard deviation and/or standard error with two 
additional decimal places compared to the raw data.  
Categorical data will be summarized in terms of the number of non-missing observations in 
the analysis population, frequency counts and percentages. Percentages will be displayed 
with one decimal place.  
All statistical analyses will be performed using SAS v9.4 or higher.  
4.1.1 Imputation Methods for Missing Data 
Intercurrent events, inducing missing assessments, may occur during the course of the study 
for various reasons such as: 
• treatment discontinuation due to an adverse event or a lack of efficacy, 
• treatment discontinuation due to subject noncompliance (protocol deviations, missing 
two consecutive visits).  
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4.1.1.1 Complete Cases (CC) 
Where stated, efficacy and quality of life data will be analyzed without any imputation using 
complete cases to assess the imputation approaches. A complete case will be a subject with 
no missing data at the considered timepoint and who did not discontinue treatment during this 
period before this timepoint. 
4.1.1.2 Non-Responder Imputation (NRI) 
Where specified, missing dichotomous categorical efficacy data (such as clinical response) 
will be imputed with Non-Responder Imputation (NRI). NRI will assume a non-response for 
the considered endpoint at any assessment that is missing. This may arise because of a missed 
assessment, discontinuation due to any reasons from study treatment or study at any time 
point prior to the cutoff analysis date regardless of whether the subject was a responder at the 
time of dropout.   
NRI will be the primary imputation approach for the primary and key secondary analyses (as 
specified in Table 4.4).  
4.1.1.3 Last-Observation Carried Forward (LOCF) 
Where stated, missing categorical and continuous efficacy data will be imputed with Last 
Observation Carried Forward (LOCF). LOCF approach will consist in carrying forward the 
value of the last observed non-missing post-baseline assessment to the subsequent scheduled 
and missing assessment. In case of missing baseline i.e. of absence of an observed assessment 
prior to the first administration of treatment at Week 0, no imputation of baseline will be 
performed. In addition, if a subject did not have at least one observed post-baseline 
assessment during the considered period, no LOCF will be performed on the missing post-
baseline assessments.  
This approach will assume that any subjects who withdraw the treatment or study due to any 
reasons maintain the same value that was observed at the last non-missing post-baseline 
assessment before withdrawing. Similarly, for subjects who miss an assessment, the approach 
will assume that they maintain the same value that was observed at the last non-missing post-
baseline assessment until they return to a visit and a new value is observed.     
4.1.1.4 Multiple Imputation (MI)  
Missing pre-specified categorical and continuous efficacy data will be imputed with MI under 
Missing at Random (MAR) assumption using the ITT population (Enders, 2010). MI method 
will be applied on the data of a given endpoint that are assumed to be MAR.  
The current assumption on which the primary analysis is based is that all subjects with a 
missing response at a given timepoint and/or with missing responses after treatment 
withdrawal are regarded as non-responder, non-response is assumed regardless of whether the 
subject responded to the treatment at the time of the drop-out. The secondary analyses using 
LOCF approach assume that all subjects with missing data at a given timepoint and/or after 
treatment withdrawal maintain their last observed assessment over time.  
 
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MI under MAR assumption assumes that dropouts behave similarly to other subjects in the 
same treatment group who did not withdraw and continued to be treated with the study 
treatment. In terms of efficacy, this will estimate the effect of treatment as if all subjects were 
treated as randomized.   
 
MI will be implemented in three steps using SAS®, version 9.4 or higher (see Figure 4.1.). 
Depending on the nature of data, some of the steps may have some specificities (Demirtas et 
al., 2008). MI method assumes a multivariate normal distribution for the continuous variable 
of interest (e.g. PASI percent change) at each visit. 
4.1.1.4.1 Step 1: Imputation Phase  
1.a. Initialization  
Create a dataset with only one record per subject containing all scheduled assessments at each 
visit including the baseline assessment, the planned treatment group and all covariates of the 
imputation model to use SAS® PROC MI. The covariates of the imputation model will be the 
stratification factors as randomized at the least. Other covariates such as sites, gender may be 
considered to be added.   
1.b. Exploration of the Missing Data Pattern 
Check the pattern of missing data. The pattern of missing data may be intermittent or non-
monotone, i.e. that a subject may miss an assessment at a planned visit and may return for 
assessment at the subsequent visits before study completion or treatment withdrawal. That 
will be the assumption by default. However, the pattern might be monotone for shorter 
periods such as the induction period up to Week 12 i.e. no subjects miss a scheduled visit 
before withdrawing treatment or completing the period.  
If the pattern for the considered period is intermittent, please go to Step 1.c. Otherwise, go to 
Step 1.d. 
1.c. Partial Imputation of intermittent Missing Data  
Generate n datasets with a monotone missing pattern using a Markov Chain Monte Carlo 
(MCMC) method with one single chain, 1000 burn-in iterations at least, and a non-
informative Jeffreys prior for each treatment group. The model will include weight category 
and prior use of biologic therapy stratum derived from the observed values (actual stratum), 
the baseline and post-baseline assessments. Each intermittent missing value will be imputed 
using independent samples that are generated by MCMC from the posterior distribution.  
The chosen n will be 100 imputed datasets at least. A larger number for n such as 500 or 1000 
might be considered depending on the computational cost. If the baseline assessment was 
missing, the baseline will be imputed at this step.  
1.d. Imputation of Monotone Missing Data  
Impute the monotone missing data using a Bayesian framework for each treatment group. 
The model will include the explanatory variables of actual weight and prior use of biologic 
therapy stratum, the assessment at baseline and the assessments at all visits. If step 1.c. was 
skipped, the n datasets will be generated at that stage.  
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2.a. Binary Variables 
The analysis model and the displayed statistics will be identical to those described for the 
primary or secondary analyses (refer to Sections 4.2.1.3 and 4.2.2.2.1 for further details). 
Briefly, a CMH analysis with the actual weight category and prior use of biologic therapy 
stratum as the stratification factors will be performed for each imputed dataset yielding n 
common CMH ORs with their 95% CI and n p-values for each pairwise treatment 
comparison at a given visit where applicable.  
2.b. Continuous Variables 
Treatment comparisons will be made for each imputed dataset using an ANCOVA model 
including planned treatment group, actual weight category and prior use of biologic therapy 
stratum as factors and the baseline value as a covariate in the model as described in Section 
4.2.2.2.3. The Least-Squares Means (LSM) along with the SE and 95% CI for each treatment 
group and the differences in LSM for each pairwise treatment comparison, their associated 
SE, 95% CI and p-value will be computed for the n datasets at the specified visits.  
4.1.1.4.3 Step 3: Pooling Phase 
The analysis results from the n imputed datasets will be combined into an overall result for 
each treatment comparison and visit using SAS® PROC MIANALYZE.  
3.a. Binary Variables 
Rubin’s rules for combining results from multiple imputed datasets are based on the 
assumption that the statistics estimated from each imputed dataset are normally distributed 
(Rubin D., 1976). Therefore, estimates of ORs that follow a log normal distribution will be 
pooled after using a log transformation. Similarly, a Wilson-Hilferty transformation will be 
applied before combining the p-values given that the CMH test is based on a chi-square 
distributed statistic (Ratitch, B., Lipkovich, I. & O’Kelly, M., 2013). 
3.b. Continuous Variables 
The LSM along with the SE and 95% CI and the differences in LSM, their associated SE, 
95% CI and p-value for each treatment comparison will be combined using Rubin’s rule 
(Rubin D., 1976).  
4.1.1.5 Tipping Point Analysis  
The tipping point analysis will only be performed on the primary analysis. It will test the null 
hypotheses of no treatment effect vs. placebo at Week 12 for the primary endpoint (IGA 
score of 0 or 1 at Week 12, with an IGA reduction from baseline of at least 2 points) as 
specified in Section 4.2.1.3 for a range of deviations from Missing At Random (MAR) 
assumption for the control group and the active treatment groups independently. It will 
include scenarios where the dropout on active treatment has worse outcomes than dropouts 
on the placebo group.  
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The purpose of the tipping point analysis is to assess how severe a departure from MAR has 
to be to overturn the conclusions drawn from the primary analysis. If the departures from 
MAR assumption to change the statistical significance (evidence of treatment effect) to 
statistical insignificance (no evidence of treatment effect) are deemed implausible, the tipping 
point analysis will give supportive evidence to the primary objective under Missing Not At 
Random (MNAR) assumption (Liublinska, V. and Rubin, D.B., 2014).  
4.1.1.5.1 Step 1: Imputation Phase  
1.a. Initialization  
Create n copies of the analysis dataset and combine these datasets. The analysis dataset 
should be identical in structure and content to the dataset created for MI (refer to Section 
4.1.1.4.1).   
1.b. Imputation  
For any active or control treatment group, different response probabilities (e.g. 0%, 20%, 
40% 60%, 80% and 100%) will be applied successively to impute the missing values of IGA 
response at Week 12 and similarly for the placebo group. Missing IGA responses at Week 12 
will be randomly imputed with 0 (i.e. non-responder) and 1 (i.e. responder) with the chosen 
response probabilities. The different steps below will be described with the aforementioned 
response probabilities provided as an example: 0%, 20%, 40% 60%, 80% and 100%. 
 
This imputation will be performed by generating random numbers from a Bernoulli 
distribution to perform the imputation on the missing IGA responses at Week 12 in two steps: 
i. Impute the missing values of the placebo group by generating random numbers from a 
Bernoulli distribution using a response probability of 0% for example. 
ii. Impute the active/control treatment groups with the same methodology using a 
response probability of 20% for example. 
4.1.1.5.2 Step 2: Analysis Phase 
Analyze the n imputed datasets separately using a CMH analysis as described in Section 
4.1.1.4.2. 
4.1.1.5.3 Step 3: Pooling Phase 
The analysis results from the n imputed datasets will be combined into an overall result for 
each treatment comparison and visit using SAS® PROC MIANALYZE as described in 
Section 4.1.1.4.3 - binary variables.  
4.1.1.5.4 Step 4: Repetition Phase 
Return to Step 1 using the next combination of response probability for the missing IGA 
response at Week 12: 0% for the placebo group and 40% for the active/control treatment 
group (0/0.4) and so forth.  
 
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For the following response probability combinations 0/0, 0/1, 1/0, 1/1, missing data will be 
imputed using one single dataset and analyzed as described in Section 4.1.1.4.2. 
4.2 Efficacy  
4.2.1 Primary Analysis 
The primary objective is to assess the efficacy of four dose regimens of M1095 versus 
placebo on IGA score in subjects with moderate to severe chronic plaque-type psoriasis at 
Week 12. 
All subjects within the ITT population will be included in the primary efficacy analysis.  
4.2.1.1  Variable 
The primary variable is the response rate for the IGA score at Week 12, which is defined as 
the proportion of subjects who achieve an IGA score of 0 or 1 at Week 12 and with an IGA 
reduction from baseline of 2 points or more at Week 12. This variable will be denoted by 
“IGA response” in subsequent sections.  
Baseline IGA score is defined as the last non-missing IGA score prior to the first dose of 
study medication. 
IGA response for subjects with missing baseline and/or Week 12 IGA score will be imputed 
using NRI approach. NRI consists in imputing any missing IGA score response as a non-
response (see Section 4.1.1.2 for further information).  
4.2.1.2 Descriptive Analyses 
Descriptive summary of the proportion of subjects achieving the primary endpoint will be 
tabulated by treatment group and also by treatment group and actual stratum (≤ 90 kg and 
prior biologic use, ≤ 90 kg and no prior biologic use, > 90 kg and prior biologic use, > 90 kg 
and no prior biologic use) i.e. derived from the observed values of body weight and prior 
biologic use for all visits up to Week 12. Summary statistics will include the number and 
percentage of subjects achieving an IGA response for all visits up to Week 12.  
The 95% confidence intervals of the binomial proportions will be estimated using the 
Clopper-Pearson exact interval.  
The primary variable will also be listed by treatment group, subject and visit.  
Bar plots of IGA responder rates (95% CI) by treatment group overall and for each stratum 
will be created.  
4.2.1.3 Inferential Analyses 
The IGA responder rates at Week 12 will be compared between treatment groups using CMH 
test stratified by actual prior use of biologic therapy (yes/no) and body weight stratum 
(≤ 90 kg, > 90 kg) as observed at baseline. The following four null hypotheses will be 
individually tested at the unadjusted two-sided 5% significance level: 
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• H1: M1095 30 mg Q2W × 3, followed by 30 mg Q4W × 1, is not different from 
placebo with respect to achievement of IGA response, 
• H2: M1095 60 mg Q2W × 3, followed by 60 mg Q4W × 1, is not different from 
placebo with respect to achievement of IGA response, 
• H3: M1095 120 mg Q2W × 3, followed by 120 mg Q4W × 1, is not different from 
placebo with respect to achievement of IGA response, 
• H4: M1095 120 mg Q2W × 6 is not different from placebo with respect to 
achievement of IGA response 
resulting in the following comparisons at Week 12 between the treatment groups/regimens: 
• M1095 30 mg wk 0, 2, 4, 8 
• M1095 60 mg wk 0, 2, 4, 8                               
• M1095 120 mg wk 0, 2, 4, 8                             
• M1095 120 mg wk 0, 2, 4, 6, 8, 10 
The CMH Odds Ratio (OR) for the comparison of each M1095 treatment arm to placebo will 
be presented along with its 95% CI and associated p-value.  
4.2.1.4 Sensitivity Analyses 
Several sensitivity analyses may be performed to assess the robustness of the primary 
analysis to changes among stratification factors as randomized, analysis population, missing 
data and definition of the primary endpoint (refer to Table 4.4 and Section 4.1.1). 
4.2.1.4.1 Sensitivity Analysis to Stratification Factors  
The assumption of homogeneity of the OR over the actual strata will be tested by the 
Breslow-Day statistic at a 10% significance level for each pairwise comparison to placebo. 
In the event of non-homogeneity of the OR for a particular test, the corresponding treatment 
OR will be calculated separately with its 95% confidence interval for each stratum. Owing to 
the limited sample size in each stratum, no p-value will be reported, the main purpose of this 
assessment being to evaluate the relative magnitude of the treatment difference in each 
stratum. 
In case of a large number of stratification errors, the primary analysis may be repeated as 
described in Section 4.2.1.3 but using the per randomized stratum i.e. as entered by the sites 
into the IRT system at the randomization.  
4.2.1.4.2 Sensitivity Analyses to Analysis Population 
Sensitivity analyses will be performed identically to the primary analysis but using the 
following populations: MITT12 and PP12.  
 
vs. placebo wk 0, 1, 2, 3, 4, 6, 8, 10. 
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4.2.1.4.3 Sensitivity Analyses to Missing Data 
The primary analysis may be replicated using the ITT population: 
• with missing data being imputed with:  
o LOCF (see Section 4.1.1.3), 
o MI (see Section 4.1.1.4)  
o Tipping point analysis (see Section 4.1.1.5)  
• on complete cases (see Section 4.1.1.1) 
(refer to Table 4.4 for further details about the pre-planned analyses). 
 
In addition, the extent of missing IGA data will be summarized by visit and treatment group.    
 
Figures of individual raw IGA as well as mean raw IGA may be provided for the subgroups 
of complete cases and cases with missing IGA assessment at Week 12, by treatment group 
and over time up to Week 12. 
4.2.1.4.4 Sensitivity Analysis to Endpoint Definition 
To assess the robustness of inferences to the definition of the primary endpoint, the same 
analysis as in Section 4.2.1.3 will be repeated by considering a different definition for an IGA 
responder: “complete IGA response” where a complete IGA response is defined as an IGA 
score of 0 and with an IGA reduction from baseline of 3 points or more. 
4.2.2 Secondary Analyses 
All subjects in the ITT population will be included in the secondary efficacy analyses.  
The main estimands of the secondary objectives of longer-term efficacy after Week 12: 
• for the binary endpoint IGA (and the key secondary endpoints PASI 75 / PASI 90 / 
PASI 100) is the difference in response proportions between treatment conditions at: 
o Week 24,  
o Week 36, 
o Week 48  
• for the continuous endpoint PASI score (and the other secondary endpoint percentage 
of total BSA affected by plaque-type psoriasis) is the difference in means between 
treatment conditions in the change from baseline to: 
o Week 24,  
o Week 36, 
o Week 48  
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100 responder will be a subject achieving a complete clearing of psoriasis at a post-baseline 
visit that is a PASI score of 0. 
 
An improvement in PASI is represented by a decrease in PASI score from baseline. Percent 
change in PASI from baseline will be computed by dividing the change from baseline in 
PASI by the baseline PASI score and multiplying this result by 100.  
The methods to handle missing binary, shift and continuous secondary efficacy variables are 
summarized in Table 4.4. 
In the next subsections, the analysis of the secondary variables will be handled according to 
the type of variables: binary for proportions, categorical for shift from baseline, or continuous 
for change from baseline and/or percent change variables.  
4.2.2.2 Descriptive and Inferential Analyses 
4.2.2.2.1 Binary and Categorical Variables 
The proportions of the binary variables will be summarized by treatment group at each visit 
up to Week 52. Pairwise comparisons vs. placebo and pairwise comparisons across M1095 
treatment arms will be made at each visit up to Week 12 and at Weeks 24, 36 and 48 using 
the CMH test of 2-by-2 tables stratified by actual prior use of biologics (yes/no) and body 
weight stratum (≤ 90 kg, > 90 kg) in the same way as for the primary analysis (please refer to 
Section 4.2.1.3). No formal statistical testing will be performed between M1095 treatment 
arms and Secukinumab as the Secukinumab arm is for reference only. However, 
Secukinumab will be compared to placebo using the same methodology. In case of a large 
number of stratification errors, the key secondary analyses might be repeated as described in 
Section 4.2.1.3 but using the per randomized stratum as entered into the IRT system by the 
sites.  
The assumption of homogeneity of association between treatment and the binary variables in 
the different actual strata will be tested at Weeks 12, 24, 36 and 48 for all pairwise 
comparisons M1095 vs. placebo at 10% significance level using the Breslow-Day test as 
explained in Section 4.2.1.4.  
For the categorical analyses, the proportion and number of subjects in each IGA category at a 
given visit from baseline will be presented by treatment group and over time at each visit up 
to Week 12 for the induction period, from Week 12 to Week 24 for the 
maintenance/escalation period and from Week 24 to Week 48 for the response 
assessment/dose hold period.  
Bar plots and line plots of the responder rates with 95% CI will be provided by treatment 
group and over time up to Week 48 overall.  
 
The binary secondary efficacy variables will be listed by treatment group and over time.  
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4.2.2.2.2 Time-to-event Variables 
Time-to-event variables will be presented by treatment group with tables of Kaplan-Meier 
(KM) estimates as well as KM curves. For KM curves, the number of subjects that are still at 
risk (Pocock et al, 2012) will also be displayed under the time axis. In addition, the following 
descriptive statistics will be presented by treatment group: the number and percentage of IGA 
response, complete IGA response and censored data at each visit and the median time (or 
other estimable percentile (say 75%) if median is not estimable) to IGA response or complete 
IGA response along with its 95% confidence interval. 
4.2.2.2.3 Continuous Variables 
The raw PASI score, absolute change and percent change from baseline in PASI score will be 
presented by treatment group and over time for all visits up to Week 52 using summary 
statistics and listings. Mean of change from baseline in PASI and its associated standard error 
will be displayed graphically over time by treatment group.  
For the percent change in PASI, treatment comparisons vs. placebo and between M1095 
treatment groups will be tested at each specified visit up to Week 48. The treatment LSM 
along with the corresponding SE, 95% CI and the LSM differences along with its SE, 95% CI 
and p-value will be obtained at each visit separately using an analysis of covariance 
(ANCOVA) model. The ANCOVA will include the planned treatment group, actual prior 
biologic and weight stratum as factors and the baseline value as a covariate. The residuals 
from the ANCOVA model will be examined to check that the assumptions of normality, 
independence and homoscedasticity hold.  
4.2.3 Exploratory Analyses 
The exploratory analyses are planned: 
• After Week 12: to evaluate the change in efficacy from Week 12 to Week 24 in 
subjects who undergo dose escalation or maintenance at Week 12 in the MITT 
population who enter the maintenance/escalation period (MITT24), 
• After Week 24: to explore the effect of withholding M1095 at Week 24 in IGA score 
of 0 responders in the MITT population who enter the response assessment/dose hold 
period (MITT48). 
Sensitivity analyses for the exploratory analyses after Week 12 and Week 24 will not be 
performed unless deemed necessary. 
4.2.3.1 Exploratory Analyses after Escalation at Week 12 
At Week 12, subjects randomized to M1095 30 mg or M1095 60 mg are planned to undergo a 
dose escalation to M1095 120 mg if they fail to achieve an IGA response i.e. if they have an 
IGA > 1.  
The assessment of change in efficacy from Week 12 to Week 24 will be investigated in the 
subgroup of subjects who were randomized to 30 mg and 60 mg M1095 at Week 0 and who 
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No formal inferential analyses will be conducted. Comparisons of treatment groups (1), (4), 
(5) and (6) will be presented elsewhere. For treatment groups (2) and (3) after Week 12, 
comparisons will be biased due to the Week 12 treatment change being based on post-
randomization unfavorable event of lack of efficacy. Comparisons after Week 12 based on 
descriptive statistics will be made between treatment groups of subjects who dose escalated 
in subjects who were initially randomized to M1095 30 mg and M1095 60 mg at Week 0.  
4.2.3.1.3 Binary and Categorical Variables  
The number and proportion of subjects for each binary variable of Table 4.6 will be described 
in a tabulated and graphical manner per treatment group for each visit with the time in weeks 
since Week 12. The 95 % exact CI of the proportion will also be presented.  
Line plots will present the responder proportions (and its 95% CI) by treatment group and 
over time from Week 12 and possibly, from Week 0.  
For the shift analyses, the proportion and number of subjects in each category will be 
presented by treatment group and over time. 
4.2.3.1.4 Continuous Variables  
The raw PASI score, absolute and percent change from baseline will be described for all 
visits in the same tabular and graphical way as in Section 4.2.2.2.3 per treatment group.  
Means of absolute change from baseline in PASI and their associated standard error will be 
displayed graphically over time by treatment group. 
These descriptive statistics above will also be produced for change and percent change from 
Week 12 in PASI.  
A mean/SE plot of improvement in PASI over time will also be created, showing the effect of 
dose escalation from Week 12. 
4.2.3.1.5 Time-to-event Variables 
Time-to-event variables will be graphically presented by treatment group using Kaplan-Meier 
curves. The number of subjects that are still at risk (Pocock et al, 2012) will also be displayed 
under the time axis. In addition, the following descriptive statistics will be presented by 
treatment group:  
• The number and percentage of IGA response, complete IGA response and censored 
data at each visit, 
• The median time (or other percentile) to IGA response or complete IGA response 
along with its 95% confidence interval. 
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4.2.3.1.6 Subset Analyses 
The exploratory post-Week 12 analyses will be repeated to assess the longer-term efficacy in 
the MITT48 population that includes the MITT subjects who completed the maintenance/ 
escalation period and who entered the dose assessment/dose hold period.  
Given the study design that allows subjects to dose escalate to the highest dose of M1095 at 
Week 12 following post-randomization efficacy assessments, selected exploratory analyses 
may be performed in a subset of subjects with similar post-baseline efficacy characteristics. 
The purpose of this population is to investigate the differences in a descriptive manner 
between subjects with similar post-baseline efficacy characteristics at the start of the 
considered period who had a dose change and those who did not have a dose change. 
Therefore, an additional population may be derived for this purpose: 
Population 
Description 
Week 12 IGA 
Non-Responder 
Population 
Week 12 IGA non-Responder Population is a subset of MITT12 
population. This population includes all MITT12 subjects who are 
classified as IGA non-responders at Week 12 (i.e. with IGA > 1). 
Subjects will be analyzed according to planned treatment in the 
maintenance/escalation period (from Week 12 to Week 24). 
 
Table 4.8: Definition of Additional Analysis Population for Exploratory Analyses 
The exploratory post-Week 12 analyses may be repeated in the Week 12 IGA non-Responder 
Population. The aim is to compare all treatment groups from Week 12 to Week 24 in the 
MITT subjects who enter the maintenance/escalation period but who had an unfavorable 
efficacy event at Week 12 (all treatment groups will be included except for (2a) and (3a) – 
refer to Table 4.7).  
4.2.3.2 Exploratory Analyses after Withholding/Restarting M1095 from 
Week 24 
From Week 24, subjects receiving M1095 who were not escalated from M1095 30 mg or 
M1095 60 mg at Week 12 will have their M1095 treatment withheld (placebo will be given) 
if their IGA score equals 0 at Week 24. If their IGA score is 1 or more at Week 24, these 
subjects will stay on current dose. 
Then, withheld subjects will restart M1095 at the previous dose level (Q4W) at the first visit 
post-Week 24 when their IGA is 1 or more. 
The exploratory analyses after Week 24 will be conducted in the MITT48. 
4.2.3.2.1 Variables  
The post-Week 24 exploratory objectives will be explored with these variables: 
 
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4.3 Quality of Life 
All subjects in the ITT population will be selected for the analyses of Quality of Life (QoL) 
variables. 
4.3.1 Variables  
The QoL variables are: 
• Change from baseline in Dermatology Life Quality Index (DLQI) total score and in 
DLQI subscales, 
• Achievement of DLQI of 0 or 1 (binary variable),  
• Change from baseline in the norm-based Short Form 36 (SF-36) scores for the eight 
sections and for the physical and mental summary components, 
• Change from baseline in EuroQuality of Life Questionnaire for Psoriasis (EQ-PSO) as 
measured by VAS and EQ-PSO score for the 7 dimensions. 
The derivations of QoL scores are described in the Appendices on page 68.  
LOCF will be used to impute any missing values for the continuous variables and NRI for the 
binary variable (refer to Section 4.1.1.3). 
4.3.2 Descriptive Analyses and Inferential Analyses  
The raw continuous QoL variables at baseline and post-baseline visits as well as their change 
from baseline will be presented by randomized treatment group at each visit up to Week 48 
using summary statistics, listings and appropriate graphical methods.  
Treatment comparisons of continuous QoL variables will be assessed at all visits up to Week 
12 by an ANCOVA including planned treatment group, actual prior biologic and weight 
stratum as factors and the baseline value as a covariate in the model. The treatment LSM, the 
corresponding SE and 95% CI and the pairwise LSM difference, the corresponding SE, 95% 
CI and p-value will be presented. This analysis will be replicated at Weeks 24, 36 and 48.  
The proportions of the binary variable will be examined and reported as described in Section 
4.2.2.2.1. 
The analyses of QoL variables may be replicated using complete cases. Additional 
exploratory analyses of QoL may be performed. 
4.4 Subject Demographics/Other Baseline Characteristics 
The subject demographics and other baseline characteristics will be reported in the analysis 
populations specified in Table 4.11. 
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4.4.1 Variables 
The variables are the demographics of subjects plus all data for background and other 
baseline characteristics such as relevant medical history, results of laboratory screens, drug 
tests and any other relevant information. 
The demographics of subjects include: 
• continuous age (in years) along with categorical age (< 45, ≥ 45 - < 65, ≥ 65), gender, 
race and ethnicity,  
• country, geographical region (Europe, North America), 
• height (in cm) at screening, continuous weight (in kg) as well as categorical weight 
(≤ 90 kg, > 90 kg) and Body Mass Index (BMI) (in kg/m²) at baseline. BMI will be 
calculated by dividing weight in kilograms by height in meters squared. 
• randomized prior biologic use and weight stratum (as entered into IRT system by the 
sites).  
Other baseline characteristics consist of: 
• psoriasis medical history i.e. the number of significant flares of disease activity in the 
last 6 months, the time since diagnosis and the actual prior biologic use,  
• results of laboratory screens, drug tests at baseline, 
• IGA score, PASI score and percentage of BSA affected by psoriasis at baseline, 
• DLQI total score, EQ-PSO total score (VAS), SF-36 physical and mental component 
summaries at baseline, 
• PHQ-8 and eC-SSRS total score at baseline. 
The variables of subject demographics and other baseline characteristics will be performed in 
the ITT population. Besides, these variables will be reported in other analysis populations to 
evaluate the differences between non-randomized treatment groups that are assigned on the 
basis of post-randomization efficacy results in the exploratory analyses after Week 12 and 
Week 24. All subjects within the ITT population and/or safety population will be included in 
the analysis of the results of laboratory screens, drug tests, PHQ-8 and eC-SSRS total score 
(refer to Table 4.11 for further details). 
4.4.2 Descriptive Analyses 
All data for background and demographic variables, psoriasis medical history, results of 
laboratory screens and drug tests, IGA score, PASI score and percentage of BSA as well as 
QoL and Patient Reported Outcomes (PRO) data will be summarized by treatment group as 
specified in Table 4.11 at screening and/or baseline visit. No treatment comparisons will be 
performed. This data will also be listed by treatment group and subject.   
 
 
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each analysis population with the primary reason for exclusion whenever available will be 
produced.  
4.6 Subject Disposition  
Subject disposition will be analyzed in the enrolled population unless stated otherwise.  
4.6.1 Variables 
Subject disposition will be described by: 
• the number and percentages of subjects who are screened, randomized, treated, who 
completed the treatment period and/or study, who discontinued along with the 
primary reason for early discontinuation for the study overall as well as for each 
treatment period separately. 
• the number and percentages of subjects who dose escalated from Week 12 or of 
subjects who had dose withheld from Week 24 for the maintenance/escalation period 
and the response assessment/dose hold period respectively, 
• the number and percentage of subjects with important protocol deviations in the ITT 
population overall and grouped into categories for the study overall as well as for each 
treatment period separately, 
• the number and percentages of subjects in analysis populations and excluded from the 
analysis populations, 
• the time in weeks to study drug discontinuation due to any reasons and due to an AE 
for the induction period. 
 
To assess the exploratory analyses after Week 12 and 24, the disposition of subjects after the 
post-randomization treatment assignment at Week 12 or Week 24 will be explored in the 
MITT24 or MITT48 populations and by assigned treatment sequence for the 
maintenance/escalation period or dose assessment/response hold period respectively using 
these variables:  
• the number and percentage of subjects completing the maintenance/escalation period 
or dose assessment/response hold period, 
• discontinuing the treatment during the maintenance/escalation period or dose 
assessment/response hold period and by primary discontinuation reason.   
4.6.2 Descriptive Analyses 
Subject disposition variables will be summarized by treatment group.  
In addition, a listing of important protocol deviations will be presented by subject and 
treatment broken down by center. 
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4.6.3 Graphical Presentation 
The time in weeks to study drug discontinuation due to any reasons and due to an AE will be 
represented graphically with Kaplan-Meier plots by treatment groups for the ITT population 
during the induction period.  
The time to subject discontinuation in days for the induction period will be defined as the 
difference in days between the withdrawal date if occurring in the induction period and the 
date of first dose of study drug plus an additional day. The subject who will complete the 
induction period will be censored at the completion date of the induction period i.e. at the 
date of Week 12. For other subjects who did not withdraw during the induction period and 
did not complete the period, they will be censored at the date of the last known study visit 
during this period when they last received study treatment.  
This graphical presentation and descriptive statistics will be repeated overall.  
4.7 Treatment Compliance 
All subjects within the safety population will be included in the data analysis.  
4.7.1 Variables  
Treatment exposure will be characterized by the following variables: 
• the duration of study exposure that corresponds to the period from the date of the first 
dose of study drug to either the date of last study visit (Week 52) for the subjects who 
completed the study or the date of discontinuation for subjects who discontinued 
during the study,   
• the duration of treatment exposure in days and in subject-years including the duration 
of dose hold in days for the response assessment/dose hold period (subject-years is 
calculated by adding the number of subjects in the group and multiplying that number 
by the years that subjects were on treatment),  
• the frequency of treatment exposure determined by the number of injections received, 
• the actual amount/dose in mg received by the subjects as well as the percentage of the 
scheduled dose that was actually received, 
Treatment compliance will also be described with: 
• the number and proportion of subjects receiving the complete dose as scheduled,  
• the number and proportion of subjects that are compliant and non-compliant in each 
treatment group.  
For the induction and maintenance/escalation periods, the duration of treatment exposure is 
the difference in days between the date of last study visit in the considered treatment period 
unless subjects have discontinued during this period and the date/time of the first dose of 
study drug in the same period.  
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Exposure [period x] = last study visit date [period x] – 1st study drug dose date/time [period x].  
For subjects who have discontinued from placebo at or prior to the last visit of the induction 
period, the duration of exposure will be the sum of the number of days between the date/time 
of the first dose and the date of treatment discontinuation.  
For subjects who have discontinued from M1095/Secukinumab treatment at or prior to the 
last visit of the induction or maintenance/escalation periods, the duration of exposure will be 
the sum of the number of days between the date/time of the first dose in the considered period 
and the date of the last dose before discontinuation and 56 days that correspond to the longest 
period of washout for M1095/Secukinumab. If the study discontinuation occurred within the 
56 days after the last dose received, the duration of exposure will be defined as the difference 
in days between the date of study discontinuation and the date of first dose of study drug.   
Exposure [period x] = last dose date/time [period x] – 1st study drug dose date/time [period x] + 56 days. 
The treatment exposure of response assessment/dose hold period will be described by several 
variables:  
• the number of subjects who have dose of study drug being withheld at Week 24, 
• the duration in days of the dose being withheld during the period i.e. the difference in 
days between the date of the visit at Week 24 and the date/time of M1095 re-
commencement,  
• the total duration in days of the dose being withheld since the last dose of M1095 i.e. 
the difference in days between the date of the last dose of study drug before dose of 
Week 24 being withheld i.e. at Week 20 and the date/time of M1095 re-
commencement (see Table 4.12). 
The duration of exposure to M1095/secukinumab treatment overall during the combined 
induction, maintenance/escalation and response assessment/dose hold periods be calculated 
as follows: 
Secukinumab: Exposure [overall] = date/time of last dose – date/time of 1st dose + 56 days. 
M1095: Exposure [overall] = date/time of last dose – date/time of 1st dose – d1 + 56 days. 
with the date/time of the first dose as described in Table 4.12 for the different treatment 
groups and subtracting the dose hold duration for the overall period while considering the 5 
half lives of the M1095 treatment (d1) as explained in Table 4.12. This duration will also be 
expressed in subject-years by adding the amount of times in days that subjects spent on 
treatment for all subjects divided by the total number of days in a year i.e. 365.25.  
A subject being administered the complete dose at a given visit is a subject who received the 
planned number of injections and the planned dosage in mg per injection. A subject being 
administered the complete dose overall is a subject who received the cumulative number of 
injections and the cumulative dosage in mg as planned.  
A subject will be considered overall compliant for each study period or overall if this subject 
is missing no more than 20% of the planned treatment and not missing two or more 
consecutive planned dosing occasions of the considered period or overall. Although subjects 
will receive two injections at each visit, the two injections at the same visit will be regarded 
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All descriptive analyses on treatment compliance will be also summarized for the three 
treatment periods and for the overall study. The number and proportion of subjects having 
received the complete dose administered will be presented by each dose administered and 
overall by treatment group. Proportions of subjects compliant and non-compliant with study 
drug will be summarized by treatment group.  
Data for study drug administration will be listed by treatment group and subject. 
4.8 Previous and Concomitant Therapy  
Data of previous and concomitant therapies will be summarized in the ITT Population.  
Prior and concomitant therapies will be coded according to World Health Organization Drug 
Dictionary (WHO-DD version of March 2018). Prior therapies are defined as all therapies 
that ended prior to randomization at Week 0. Concomitant therapies are all medications: 
• that started or continued on the day of or after randomization for the induction period 
and the overall period (from Week 0 to 52), 
• or that started or continued on the day of or after the first dose of study drug of the 
considered period i.e.: 
o at Week 12 for the maintenance/escalation period, 
o at Week 24 for the response assessment/dose hold period.  
In case of missing start and end dates, the medication will be considered as concomitant 
medication for the whole duration of study. If either the start date or the end date is missing 
or both dates are incomplete, the available information about the data will be used to infer 
from the randomization date/time if the therapy was taken prior to randomization or 
concomitantly: 
• If the end date is missing and: 
o the start date is available and complete and: 
▪ after or on the day of randomization, the medication will be considered 
as concomitant,  
▪ prior to randomization, the medication will be regarded as concomitant 
therapy. 
o the start date is partial and: 
▪ the partial part of the start date is after the randomization date, the 
medication will be inferred as concomitant,  
the partial part of the start date is prior to or the same as the 
comparable part of the randomization date, the medication will be 
concomitant medication. 
• If the start date is missing and:  
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o the end date is available and complete and: 
▪ on the day of or after randomization, the medication will be considered 
as concomitant,  
▪ prior to randomization, the medication will be inferred as a prior 
therapy. 
o the end date is partial and: 
▪ the partial part of the end date is the same as or after the comparable 
part of the randomization date, the medication will be concomitant,  
▪ the partial part of the end date is prior to the comparable part of the 
randomization date, this medication will be regarded as previous. 
• If both start and end dates are incomplete, 
o If the partial part of the end date is before randomization, the medication will 
be classified as prior, 
o If the partial part of the start date is the same as or after the comparable part of 
the randomization date, the medication will be classified as concomitant. 
The same rules will apply for the other treatment periods but using the first dose of study 
drug of the considered period as the reference date.  
The number and percentage of subjects taking previous medications and previous psoriasis 
medications will be summarized by treatment group, Anatomical Therapeutic Class (ATC) 
and preferred name. Similarly, the concomitant medications will be summarized by treatment 
group, by ATC and preferred name for the induction period separately and for the study 
overall.  
Previous and concomitant therapies will be listed by treatment group and subject. The 
therapies will be listed with dose, unit, frequency, route of administration (if applicable), 
indication, start and end dates and the ongoing status.  
A listing of any new treatments for psoriasis in subjects who early discontinued will be 
produced by treatment group and subject. 
4.9 Safety and Tolerability Data 
Safety data will be summarized in the Safety Population by actual treatment group.  
Unless indicated otherwise, safety variables will be summarized separately for the induction 
period (Week 0 to 12) and the overall study (Week 0 to Week 52) per actual treatment group 
(refer to Table 4.2 and Table 4.3 for details about defining actual treatment groups). Overall 
study corresponds to the time interval from Week 0 to Week 52 for the subjects who 
completed the study or from Week 0 to the last follow-up for subjects who discontinued. 
Please note that for the overall safety analyses, the baseline for subjects who were 
randomized to placebo will be the last non-missing assessment before the first dose of 
M1095. 
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4.9.1 Variables 
Safety and tolerability data encompass vital signs, skin evaluations, ECGs, laboratory values, 
number and severity of adverse events, instruments to assess depression and suicidality such 
as electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) and Personal Health 
Questionnaire Depression Scale (PHQ-8). 
4.9.2 Descriptive Analyses 
4.9.2.1 Vital Signs 
All vital signs data (systolic and diastolic Blood Pressure (BP), Heart Rate (HR), weight) will 
be listed up to Week 52 by treatment group, subject, and visit/time and when reference ranges 
are available, abnormalities will be flagged. Summary statistics for absolute values and 
change from baseline, will be provided by treatment group and visit/time. The number and 
percentage of subjects within each baseline category (low, normal, high and missing) versus 
the post-baseline category (low, normal, high and missing) of vital signs will also be 
summarized at all post-baseline visits (the low, normal and high categories will be defined as 
follows for these parameters: heart rate: <60 beats/min, 60-100 beats/min, >100 beats/min, 
systolic blood pressure: <90 mmHg, 90-139 mmHg, >139 mmHg, diastolic blood pressure: 
<60 mmHg, 60-89 mmHg, >89 mmHg and temperature: <36.5°C, 36.5-37.3°C, >37.3°C). 
4.9.2.2 Skin Evaluations 
All skin evaluation data including any findings not typical of psoriasis, conduction of further 
skin assessments such as biopsy will be listed by treatment group, subject and visit up to 
Week 52.  
4.9.2.3 ECG Evaluations  
The ECG evaluations will be reported by treatment group for the induction period and the 
overall study. The number and proportions of subjects with a normal, abnormal, abnormal 
clinically significant or unevaluable overall 12-lead ECG evaluation will be reported by 
treatment group. In addition, summary statistics for the absolute values and change from 
baseline for ECG parameters will be provided by treatment group and visit/time. ECG 
parameters comprise HR, PR interval, QRS, QT interval and the corrected QT intervals i.e. 
QTcB using Bazett’s correction and QTcF using Fridericia’s correction QTcB is calculated 
by dividing the QT interval by the square root of the preceding R-R interval while QTcF is 
calculated by dividing the QT interval by the cube root of the preceding R-R interval.  
A shift analysis from baseline will be implemented for PR, QRS, QT, QTcB and QTcF 
intervals and HR describing the change from baseline (normal, abnormal) to end of 
period/study (normal, abnormal, abnormal clinically significant or unevaluable) in ECG 
parameters.  
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The number and proportion of subjects with abnormal elevated QT, QTcB and QTcF 
intervals i.e. exceeding the upper limit value of 450 ms, 480 ms and 500 ms will be 
summarized by treatment group. The number and proportion of subjects who experience an 
increase from baseline in QT, QTcB and QTcF interval greater than 30 ms and 60 ms will 
also be reported by treatment group. 
 
All ECG data will be listed by treatment, subject and visit/time up to Week 48, abnormalities 
will be flagged. 
4.9.2.4 Clinical Laboratory Evaluations  
All laboratory data up to Week 52 including serology tests (at screening only), pregnancy 
tests (women only) and urinalyses will be listed by treatment, subject, and visit/time. If 
reference normal ranges are available, laboratory abnormalities will be flagged and the 
CTCAE grade included.  
Summary statistics of hematology, chemistry and urinalysis data and their change from 
baseline in SI units will be provided by treatment group and visit/time. Unscheduled 
measurements e.g. laboratory re-test due to abnormal laboratory results or unplanned visits 
due to safety concerns will be excluded from this analysis.  
In addition, the number and percentage of subjects with abnormal, high or low, hematology, 
chemistry and urinalysis values will be summarized by treatment group.   
Individual subject changes from baseline to worst post-baseline assessment in laboratory 
parameters graded using CTCAE will be summarized using shift tables by treatment group 
for the induction and overall period. The worst post-baseline laboratory assessment will 
correspond to the worst post-baseline CTCAE grade observed on-treatment over all visits 
(including scheduled and unscheduled measurements). 
For non-graded laboratory parameters, shift tables will present the number and percentages of 
subjects within each baseline category (low, normal, high and missing) versus the post-
baseline category (low, normal, high and missing). The categories will be defined by using 
the minimum and maximum values. Minimum/maximum baseline value will be the 
lowest/highest non-missing value observed during the baseline period i.e. before the first dose 
of study treatment. The minimum/maximum post-baseline laboratory assessment will be 
determined relative to the reference normal ranges i.e. to on-treatment lowest decrease and 
highest increase from minimum/maximum baseline over all visits (including scheduled and 
unscheduled measurements) for the considered period. In addition, a shift table from 
normal/high baseline category to low post-baseline category will be produced using the 
minimum value. Similarly, a shift table from low/normal baseline category to high post-
baseline category will be produced using the maximum value. 
Scatterplots of minimum/maximum absolute laboratory values during baseline vs. minimum/ 
maximum absolute laboratory values during the treatment period will be presented with lines 
indicating the reference limits (Lower Limit Normal, Upper Limit Normal and absence of 
change from baseline).   
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4.9.2.5 Adverse Events  
Treatment-Emergent AEs (TEAEs) per treatment period are AEs that emerge while on study 
treatment during a given treatment period (e.g. induction period), having been absent pre-
treatment, or that worsen during the considered period (e.g. induction period) relative to the 
pre-treatment state i.e. after baseline and on or prior to the date of the last visit of the 
considered period (e.g. Week 12 for the induction period). On study treatment during a 
treatment period is defined as the period from the first study treatment administration at the 
start of period (e.g. Week 0 for the induction period) up to the last visit of the treatment 
period for subjects who did not discontinue treatment during the considered period (e.g. 
Week 12 for the induction period) or for subjects who discontinued during the considered 
period, up to the end of the considered period or up to 8 weeks after the last dose of study 
treatment, whichever occurs first. TEAEs will be assigned to the actual treatment period to 
which they are considered treatment-emergent.  
When considering the study overall, treatment-Emergent AEs (TEAEs) are AEs that emerge 
while on study treatment i.e. from the first study treatment administration up to 8 weeks after 
the last dose of study treatment, having been absent pre-treatment, or that worsen during 
study treatment relative to the pre-treatment state i.e. after baseline.  
If the classification of an AE cannot be clearly established because of missing or incomplete 
date/time of AE, the AE will be classified as treatment-emergent. No imputation of missing 
or partial AE start and end dates will be performed. 
To determine whether an AE is pre-treatment, on-treatment or post-treatment in case of 
partial or missing AE dates, the rules below will be followed:  
• If the start date is incomplete and either the end date is incomplete or available:  
o if the non-missing part of the start date infers that the AE occurred post-
treatment, the AE will be considered as post-treatment.  
o If the partial or complete end date indicates that the AE occurred prior to the 
first dose of study drug, the AE will be considered as pre-treatment. 
o If the partial start date does not give any evidence as to when the AE occurred 
during the study, and the end date infers that the AE stopped after the first 
dose of study drug, the AE will be flagged as on-treatment for all periods for 
which the first dose of study drug was started before the end of the AE.  
o If the partial or complete start and end dates do not indicate as to when the AE 
started and ended compared to the first dose of study drug of any period, the 
AE will be flagged on-treatment for all periods.  
• If both start and end dates are both missing: the AE will be considered on-treatment 
and therefore a TEAE for all periods. 
To determine the worsening of an AE during study treatment, the maximum severity for each 
AE during the baseline period will be considered. In case of missing severity, the 
conservative approach below will be followed: 
• If an AE has a missing severity during the study treatment, it will be defined as 
treatment-emergent.  
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• If the severity of an AE is missing at baseline and this event continues during the 
study treatment, this AE will be considered as treatment-emergent.  
Adverse events of Special Interest (AESI) include cytopenias, liver function test 
changes/enzyme elevations, infections, injection-site reactions, allergic/hypersensitivity 
reactions, cerebrocardiovascular events, malignancies, depression, Crohn’s disease and 
ulcerative colitis. Additional adverse events may be identified as being of special interest 
during the study and prior to first unblinding.  
An overview table will present the number and percentage of subjects experiencing these 
types of AEs below by treatment: 
• TEAEs, 
• TEAEs by relationship to investigational product, 
• serious TEAEs including deaths,  
• TEAEs by maximum severity,  
• deaths,  
• and TEAEs leading to study treatment discontinuation.  
This table will be produced for all separate treatment periods and the overall periods (refer to 
Table 4.3, Table 4.13, Table 4.14 and Table 4.15). 
For the overall period, the exposure-adjusted incidence per 100 subject-years will also be 
presented. The exposure-adjusted incidence will be calculated by dividing the number of 
subjects with AEs by the total person years of exposure during the treatment period (refer to 
Section 4.7). This result will be multiplied by 100 to obtain the exposure-adjusted incidence 
per 100 subject-years.  
The AESI will also be displayed with an overview table by treatment for each treatment 
period and the overall periods. 
The incidence of subjects with TEAEs will be summarized by the Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ class (SOC) and Preferred Term (PT) and by 
treatment group. A subject with multiple AEs in the same SOC (or with the same PT) will 
only be counted once for that SOC (or PT). The PTs will be presented in decreasing order of 
frequency over all treatment groups within the SOC. Similarly, incidence tables will be 
produced for treatment-related TEAEs, for serious TEAEs, for TEAEs by maximum severity, 
for TEAEs leading to deaths and study drug discontinuations. In addition, the number and 
percentage of subjects with AESI will be presented by treatment group classed by SOC and 
PT. An additional summary table will be created to include the relatively common TEAEs i.e. 
with an incidence greater than 5%. All information obtained on adverse events will be listed 
by treatment group and subject. A listing of deaths will be also provided by indicating the 
study period in which the deaths occurred in the enrolled population.  
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4.9.2.6 Depression and Suicidality/Self-Injurious Behavior  
Suicide-related thoughts and behaviors and self-injurious behavior with no suicidal intent 
based on the eC-SSRS, and depression based on the PHQ-8 will be listed by subject and visit 
up to Week 52.  
In addition, the frequency and percentage of subjects with at least one post-baseline eC-SSRS 
assessment with suicidal ideation, suicidal behavior, suicidal ideation or behavior, treatment-
emergent suicidal ideation and emergence of suicidal behavior will be summarized by 
treatment group (see Section 7.5 – Appendix E: Derivation of eC-SSRS for further 
information). The total PHQ-8 score and absolute change from baseline will be described by 
a by-treatment summary table for each visit (see Section 7.4 – Appendix D: Scoring of PHQ-
8). 
4.9.3 Graphical Presentation  
Boxplots to visualize trends and data distributions in longitudinal continuous safety data 
(vital signs, ECG parameters, laboratory parameters) will be produced by treatment group 
and visit. 
4.10 Pharmacokinetic (PK) Parameters 
All subjects within the pharmacokinetic population will be included in the PK parameter 
analysis and may be reported in a separate report. 
4.10.1 Variables 
M1095 serum concentrations in ng/mL will be assessed at the following visits: Weeks 0, 2, 4, 
8, 12, 24, 36, 44, 48 and 52.   
4.10.2 
Descriptive Analyses 
Descriptive summary statistics of serum concentration will be provided for each treatment 
period by treatment sequence of the considered period and visit/sampling time point (the 
induction period summaries will present all treatment groups of Table 4.2 except for 
Secukinumab (6), Placebo (1) and total M1095, the maintenance/escalation period summaries 
will present all treatment groups of Table 4.14 in addition to Plac/120mg (x4), Q4, 30mg 
(x4), Q4/No Esc, 60mg (x4), Q4/No Esc, 120mg (x4), Q8, 120mg (x6), Q4, the response 
assessment/dose hold period summaries will present all treatment groups of Table 4.14 and 
Table 4.15). The summary statistics will include arithmetic and geometric means, SD, 
arithmetic and geometric CV, minimum, median, and maximum and the frequency (number 
of subjects and percentage) of concentrations below the LLOQ. All concentrations below 
LLOQ will be treated as zero in summary statistics for concentration data. The geometric 
mean will not be reported if the data include zero values. Serum concentrations will also be 
listed by treatment group, subject and visit/sampling time point. Graphical methods will be 
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4.12.2 
Descriptive and Inferential Analyses  
4.12.2.1 
Binary and Categorical Variables  
The number and proportion of responders will be reported by treatment group and visit for 
each subgroup category and overall.  
 
At each visit, proportions will be compared between treatment group using a logistic 
regression. The model will include the treatment and subgroup as categories as well as the 
treatment-by-subgroup interaction. The treatment-by-subgroup interaction will be tested at 
the 15% significance level. A forest plot will be produced for each endpoint and treatment 
comparison of interest. The following comparisons will be reported: pairwise comparison of 
each treatment arm to Plac/120mg (x4), Q4 at Weeks 12, 24, 36 and 48. 
The forest plots will show the predicted proportions in each treatment group estimated from 
the models for each subgroup category and overall. Treatment comparisons will also be 
reported on the plots. Owing to the low sample size in the subgroups, some analyses may not 
be feasible. Further, no p-values will be produced, but the 95% confidence intervals on mean 
treatment ORs will be presented, if possible.  
The calculated ORs in the forest plot for each stratum of the subgroup of combined prior 
biological use and weight category will also serve as the sensitivity analyses for the CMH 
tests of secondary efficacy analyses in case that the assumption of OR homogeneity was not 
met.  
4.12.2.2 
Continuous Variables  
Each treatment comparison vs. placebo will be assessed using an ANCOVA with treatment, 
subgroup, the subgroup-by-treatment interaction as factors and the baseline value as a 
covariate in the model. Significance of the interaction will be tested at the 15% level. The 
LSM differences along with 95% CI for each pairwise comparison vs. placebo will be 
calculated at Week 12 in each category of the subgroup. This inferential analysis will be 
repeated for Weeks 24, 36 and 48.  
The subgroup analysis of actual prior biological use and weight stratum will be used as 
sensitivity analyses of the secondary endpoints in case of some imbalance between the 
treatment groups that is solely due to chance, particularly if the imbalance is such that any 
M1095 groups may have a better prognosis than the control group. This will assess the 
robustness of the conclusions drawn from the secondary analyses based on the ANCOVA 
analysis. Additional analyses may be performed to adjust for other baseline covariates if 
deemed necessary.  
 
A forest plot displaying the LSM differences and the 95% CI in each category of subgroups 
will be produced for each pairwise treatment comparison. The p-value of the treatment-by-
subgroup interaction will also be displayed and tested at the 15% level.  
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4.12.2.3 
Safety Variables 
The number and percentage of subjects with AESI will be summarized by treatment group 
classed by SOC and PT for each category of the subgroup for the induction and overall period 
(refer to Section 4.9.2.5). 
 
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5 Sample Size Calculation 
A sufficient number of subjects will be screened, so that a total of approximately 300 subjects 
will be randomized (approximately 50 per treatment group). 
With this sample size, the study has > 99% power to detect a statistically significant 
difference between any treatment arm and placebo in the IGA score of 0 or 1 rate at Week 12, 
with a two-sided, unadjusted type I error of 0.05. These calculations assume IGA score of 0 
or 1 rates of > 88% for study drug and ≤ 7% for placebo. As this is a phase 2 study, there will 
be no adjustments for multiplicity. 
Exploratory analyses between the different dose levels of M1095 will also be performed. The 
PASI 100 response rate offers more discriminatory potential for this. Phase 1 data and 
response simulations give a PASI 100 response rate at Week 12 varying from 45 to 72%. 
With the sample size of 50 subjects per group, based on these assumed PASI 100 response 
rates at Week 12, the comparison between the highest and lowest M1095 doses has 
approximately 79% power. 
Power calculations have been performed with SAS v.9.4 Proc Power using the methodology 
for a two-group chi square test of equal proportions. 
Randomization will be stratified by prior biologic use (yes, no) and weight (≤ 90 kg, 
> 90 kg). 
 
 
 
 
 
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6  Reference List 
Abraha, Iosief & Montedori, Alessandro. (2010). Modified intention to treat reporting in 
randomised controlled trials: Systematic review. BMJ (Clinical research ed.). 340. c2697. 
10.1136/bmj.c2697. 
Basra, M.K.A., Salek, M.S., Camilleri, L., Sturkey, R. and Finlay, A.Y., 2015. Determining 
the minimal clinically important difference and responsiveness of the Dermatology Life 
Quality Index (DLQI): further data. Dermatology, 230(1), pp.27-33. 
Committee for Medicinal Products for Human Use, 2017. Guideline on immunogenicity 
assessment of therapeutic proteins. London: European Medicines Agency. 
Committee for Proprietary Medicinal Products (CPMP), Points to Consider on Adjustment 
for Baseline Covariates (2003). Stat Med, 23(5), pp.701-709. 
Demirtas, H., Freels, S.A. and Yucel, R.M., 2008. Plausibility of multivariate normality 
assumption when multiply imputing non-Gaussian continuous outcomes: a simulation 
assessment. Journal of Statistical Computation and Simulation, 78(1), pp.69-84. 
Enders, C.K., 2010. Applied missing data analysis. Guilford press. 
Finlay, A.Y. and Khan, G.K., 1994. Dermatology Life Quality Index (DLQI)—a simple 
practical measure for routine clinical use. Clinical and experimental dermatology, 19(3), 
pp.210-216. 
Gassmann-Mayer C, Jiang K, McSorley P, Arani R, DuBrava S, Suryawanshi S, Webb DM, 
Nilsson M. Clinical and Statistical Assessment of Suicidal Ideation and Behavior in 
Pharmaceutical Trials. Clin Pharmacol Ther 2011; 90(4): 554-560. 
Horton, N.J., Lipsitz, S.R. and Parzen, M., 2003. A potential for bias when rounding in 
multiple imputation. The American Statistician, 57(4), pp.229-232. 
Kroenke, K., Strine, T.W., Spitzer, R.L., Williams, J.B., Berry, J.T. and Mokdad, A.H., 2009. 
The PHQ-8 as a measure of current depression in the general population. Journal of affective 
disorders, 114(1-3), pp.163-173. 
Liublinska, V. and Rubin, D.B., 2014. Sensitivity analysis for a partially missing binary 
outcome in a two‐arm randomized clinical trial. Statistics in medicine, 33(24), pp.4170-4185. 
Mundt, J.C., Greist, J.H., Gelenberg, A.J., Katzelnick, D.J., Jefferson, J.W. and Modell, J.G., 
2010. Feasibility and validation of a computer-automated Columbia-Suicide Severity Rating 
Scale using interactive voice response technology. Journal of psychiatric research, 44(16), 
pp.1224-1228. 
Nilsson, M., Suryawanshi, S., Gassmann-Mayer, C., Dubrava, S., McSorley, P. and Jiang, K. 
(2013). Columbia–Suicide Severity Rating Scale Scoring and Data Analysis Guide (Version 
2). 
[online] 
Cssrs.columbia.edu. 
Available 
at: 
http://cssrs.columbia.edu/wp-
content/uploads/ScoringandDataAnalysisGuide-for-Clinical-Trials-1.pdf [Accessed 17 Jul. 
2018]. 
 
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Pocock, S.J., Clayton, T.C. and Altman, D.G., 2002. Survival plots of time-to-event outcomes 
in clinical trials: good practice and pitfalls. The Lancet, 359(9318), pp.1686-1689. 
Ratitch, B., Lipkovich, I. and O'Kelly, M., 2013. Combining analysis results from multiply 
imputed categorical data. PharmaSUG 2013-Paper SP03, pp.1-10. 
Rubin, D.B., 1976. Inference and missing data. Biometrika, 63(3), pp.581-592. 
Ware, J.E., Kosinski, M., Bjorner, J.B., Turner-Bowker, D.M., Gandek, B. and Maruish, 
M.E., 2011. User's manual for the SF-36v2 Health Survey (3rd ed.). Lincoln (RI): Quality 
Metric. 
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7.2 Appendix B: Derivation of EQ-PSO 
EQ-PSO, based on EQ-5D-3L, is a generic instrument to assess the health status of subjects 
suffering from psoriasis. This instrument comprises 7 dimensions: mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression, skin irritation and self-confidence, the last two 
being the two psoriasis-specific dimensions. For each dimension, there will be 3 response 
levels: no problems, some problems and severe problems coded as follows: 
• Level 1 or “no problems”:  
 
 
coded as 1  
• Level 2 or “some problems”:   
 
coded as 2 
• Level 3 or “severe problems”:  
 
coded as 3. 
The EQ-PSO (VAS) based on vertical VAS is a score ranging from 0 to 100 (in mm), with 0 
being the worst imaginable health state and 100 the best imaginable health state. An 
improvement in EQ-PSO will be described by a positive change from baseline since a higher 
score at a post-baseline visit indicates a better subject’s health status.    
 
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7.4 Appendix D: Scoring of PHQ-8 
The PHQ-8 is an eight-item version of the Patient Health Questionnaire depression scale 
designed to clinically assess subjects for symptoms and signs of depression (Kroenke et al., 
2009).  
No missing items within a questionnaire are expected since this questionnaire is handled 
using an electronic tablet device.  
Each item will have 4 possible responses: 
• Not at all:  
 
 
 
 
scored as 0  
• Several days:   
 
 
 
scored as 1 
• More than half the days: 
 
 
scored as 2 
• Nearly every day: 
 
 
 
scored as 3. 
The total PHQ-8 score will be obtained by summing the scores of all 8 items resulting in a 
total score between 0 and 24 points. Missing questionnaire at a scheduled visit will not be 
imputed. Higher the PHQ-8 score, more severe the depression is. Therefore, an improvement 
in PHQ-8 will be expressed by a negative change from baseline.  
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7.5 Appendix E: Derivation of eC-SSRS 
The eC-SSRS is a standardized and validated instrument developed for the assessment of the 
severity and frequency of suicidal ideation and behavior (Mundt et al., 2010). 
Each standardized clinical question below has a binary response (yes/no) and is classified 
into categories re-ordered from the original eC-SSRS scale: 
Suicidal Ideation: 
 
  
 
  
 
 
  
 
  
 
  
Suicidal Behavior: 
 
  
 
  
 
  
 
  
 
 
 
 
 
The eC-SSRS defines 5 subtypes of suicidal ideation and behavior in addition to self-
injurious behavior with no suicidal intent. The following variables (Nilsson et al., 2013) 
based on the above categories will be derived: 
• Suicidal ideation: a “yes” response at any time to any of the 5 suicidal ideation 
questions (Categories from 1-5) during the considered visit/period, 
• Suicidal behavior: a “yes” response at any time to any of the 5 suicidal behavior 
questions (Categories 6-10) during the considered visit/period, 
• Suicidal ideation or behavior: a “yes” response at any time during treatment to any of 
the 10 suicidal ideation questions (Categories 1-10) during the considered visit/period, 
• Suicidal ideation score that is the maximal suicidal ideation category (Categories 1-5) 
reported by subjects at the assessment. If no suicidal ideation is present at the 
assessment, a score of 0 will be assigned.  
 
Missing eC-SSRS data will not be imputed.  
 
Treatment-emergent suicidal ideation will be defined as an increase in the maximal suicidal 
ideation score after the first dose of study drug and during treatment compared to the 
maximal suicidal ideation score observed prior to treatment. “Lifetime” scores from the 
Baseline eC-SSRS scale and any “Since Last Visit” scores from the Since Last Visit C-SSRS 
scales will be considered to determine the maximal suicidal ideation score prior to treatment. 
Emergence of suicidal behavior (Categories 6-10) will be defined as the on-treatment 
occurrence of suicidal behavior from not having suicidal behavior prior to treatment.  
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