An Open Label Phase 1b Study of Secukinumab in Patients With Moderate to Severe Papulopustular Rosacea
Phase: PHASE1
Conditions: Papulopustular Rosacea
Sponsor: Anne Chang

An Open Label Phase 1b Study of Secukinumab in Patients With 
Moderate to Severe Papulopustular Rosacea 
Study Protocol and Statistical Analysis Plan 
NCT03079531 
 August 15, 2017 
 
 
 

An open label phase 1b study of secukinumab in patients with moderate to 
severe papulopustular rosacea 
 
 
 
 
 
 
Principal Investigator: Anne Lynn S. Chang, MD 
Associate Professor of Dermatology 
Stanford University School of Medicine 
450 Broadway Street, MC5334 
Redwood City, CA 94063 
Phone: (650) 644 7318 
alschang@stanford.edu 
 
Version 08152017 
 
 
 
 

I.  Background  
Rosacea is a common inflammatory skin disease affecting up to 10% of adults. 
Despite this, the etiology of rosacea is unclear, although there may be a genetic 
predisposition (Chang et al., 2015). Currently, there is no cure. Rosacea can lead 
to scarring, itching, burning, and is associated with anxiety and depression 
(Moustafa et al., 2015), significantly affecting quality of life. 
II.    Study Rationale  
Rosacea is a common inflammatory skin disease affecting up to 10% of adults. 
Despite this, the etiology of rosacea is unclear, although there may be a genetic 
predisposition (Chang et al., 2015). Currently, there is no cure. Rosacea can lead 
to scarring, itching, burning, and is associated with anxiety and depression 
(Moustafa et al., 2015), significantly affecting quality of life. 
Secukinumab is an antibody that binds to a protein (interleukin (IL)-17A) that is 
involved in inflammation. When IL-17A is bound to secukinumab, it cannot bind to 
its receptor, thereby inhibiting its ability to feed the inflammatory response. In 
clinical trials, secukinumab has been effective for moderate to severe psoriasis 
(Blauvelt et al., 2015).  Recently, human data from all types of rosacea have shown 
Th1/Th17 polarization profile of the T-cell response, suggesting that anti-IL-17 
therapy may be beneficial for rosacea (Buhl et al., 2015). Hence, secukinumab 
could be effective against rosacea. This proposal is a proof-of-concept study to 
use secukinumab in open label design for moderate to severe papulopustular 
rosacea. 
III.  Objective and endpoints 
Primary objective:  
To assess whether secukinumab can reduce the number of papules and/or 
pustules in moderate to severe papulopustular rosacea after 16 weeks of 
use. 
Secondary objective 1: To assess whether secukinumab can reduce the 
number of papules and/or pustules in moderate to severe papulopustular 
rosacea after 12 weeks of use. 
 
Secondary objective 2: To assess whether secukinumab can reduce the overall 
severity of rosacea by global assessment combining patient reported symptoms 
and clinical inspection. 
 

Secondary objective 3: To assess whether secukinumab can reduce on 
erythema in patients with moderate to severe papulopustular rosacea after 16 
weeks of use. 
 
Secondary objective 4: To assess whether secukinumab can significantly 
improve quality of life measures in patients with moderate to severe 
papulopustular rosacea after 16 weeks of usage. 
 
Secondary objective 5: To assess whether secukinumab leads to any adverse 
events ≥ grade 3 in rosacea patients during the 16 weeks of the study. 
 
Secondary objective 6: To assess whether secukinumab leads to any changes 
in immune infiltrate in papulopustular rosacea lesions after 16 weeks. 
 
Secondary endpoint 1: Change in the number of papulopustular lesion count on 
the face due to rosacea before and after 12 weeks of secukinumab. 
 
Secondary endpoint 2: Change in composite global assessment of rosacea 
using the clinical scorecard measures as shown in Appendix 2.  
 
Secondary endpoint 3: Change in the area of involvement of erythema on the 
face due to rosacea before and after 16 weeks of secukinumab, as assessed by 
blinded and independent 
photographic assessor using the visual scale in Appendix 3. 
 
Secondary endpoint 4: Change in any of the quality of life scores before and 
after 16 weeks of secukinumab using the questionnaire in Appendix 4. 
 
Secondary endpoint 5: Describe the incidence and severity of adverse events 
while on secukinumab for rosacea from baseline to week 16. 
 
Secondary endpoint 6: Describe and quantitate changes in the level and 
composition of the peri-follicular immune infiltrate in rosacea lesions before and 
after 16 weeks of secukinumab.  
IV.       Study design  

This is an open label single arm study whose primary objective is to assess 
whether secukinumab can significantly reduce the number of papule/pustules after 
16 weeks of use. After Stanford Human Subjects Panel approval and written 
Informed Consent, study participants will use secukinumab 300 mg weekly x 5 
weeks (Dose at Week 0, 1, 2, 3, and 4) followed by 2 additional monthly injections 
(a total of seven 300mg doses), according to the Visit Table. Adverse events will 
be graded and recorded according to Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0. To avoid investigator bias, a board certified 
dermatologist blinded to the before or after status of the participant will assess the 
facial photographs for papulopustule count and erythema. As this is not a 
crossover study, participants are certainly at risk for reporting bias, however, future 
larger studies may address this issue. (Because rosacea takes at least 16 weeks 
to reach maximal clinical response, a crossover study with washout between 
treatment intervals would be estimated to take 28 weeks, which is a long duration 
for an exploratory study.) Study participants will follow the procedures as outlined 
in the Visit Table. Our team has experience administering rosacea quality of life 
surveys (Chang et al., 2012). 
Biomarkers for response such as type and degree of inflammatory infiltrate before 
and after treatment (16 weeks) will be assessed from 4 mm Keyes punch biopsies 
of rosacea papules. The tissue will be fixed in formalin and embedded in paraffin 
for staining with hematoxylin and eosin. Histological assessments will be made by 
a dermatopathologist blinded to the before or after treatment status of the tissue 
assessed. Severity of inflammation will be assessed using a 5 point Likert scale, 
and the numbers of neutrophils, lymphocytes and Langerhans cells will be assess 
be high powered field. 
V.       Patient population  
Adults (N=24) with moderate or severe papulopustular rosacea who meet 
the eligibility criteria as outlined below. 
Key inclusion criteria  
1) Moderate to severe papulopustular rosacea defined clinically using the 
grading system of Wilkin et al. (2004) as having at least ten lesions (either 
papules or pustules) on face at time of enrollment  
2) Age 18 years or greater 
3) Willing and able to understand and sign informed consent form 
Key exclusion criteria  
1) Known hypersensitivity to secukinumab 
2) Topical or oral anti-rosacea medication usage for 28 days prior to 
enrollment 
3) Active Crohn’s disease, as secukinumab may exacerbate this disease 

4) Active infection including tuberculosis, hepatitis B or C, human 
immunodeficiency virus 
5) Participants with latent tuberculosis will need to have treatment initiated 
prior to starting study drug 
6) Pregnant or lactating 
7) Active and/or uncontrolled medical conditions that may interfere with study 
procedures or obscure rosacea assessment such as cutaneous lupus 
8) Use of retinoids within past 4 weeks of enrollment.  
a. Use of topical retinoids within past 3 months of enrollment is allowed 
if the regimen is stable for 1 month prior to enrollment and subject 
agrees to keep regimen unchanged for duration of study 
9) Use of antibiotics within 4 weeks of enrollment 
10) Use of light based or laser treatment to face within 8 weeks of enrollment 
11) Use of systemic steroids within 4 weeks of enrollment 
a. Use of topical steroids is allowed if the regimen is unchanged for 2 
weeks prior to enrollment and is unchanged for the duration of the 
study 
12) Acne conglobate, acne fulminans, chloracne, severe acne requiring 
systemic treatment 
VI.       Treatment  
This is an open label study using secukinumab 300 mg subcutaneously 
weekly x5 weeks (Dose at Week 0, 1, 2, 3, and 4) then monthly x2 
months (a total of seven doses of 300mg). 
VII.       Drug administration  
Subcutaneous injection  
VIII.       Dosing guidelines  
This study will use a flat dose that is the FDA approved dose for psoriasis 
(see Package Insert) 
IX.       Visit schedule and Assessments 
 
Visit 1 (Week -4 to Baseline) 
 

Following written informed consent, a past medical history, concomitant 
medications, and physical examination will be performed. Vitals signs will be 
taken and peripheral blood draw will be performed to assess for blood counts, 
kidney function, and tuberculosis exposure (See Study Calendar). 
 
Visit 2 Week 0 (Baseline) 
 
After verification of eligibility, participants will undergo vital signs, physical 
examination, adverse event determination, concomitant medication review, 
photography, skin biopsy and questionnaire administration. Biopsy will be sent 
for histology and immunohistochemistry. Study drug will be dispensed with a 
study diary and instructions on self administration. 
 
Visit 3 Week 4 
Adverse events and concomitant medication changes will be ascertained. Drug 
diary will be reviewed for correct study agent usage. Unused drug and sharps 
containers will be collected. Vitals signs and physical examination will be 
performed and photographs taken. Rosacea Questionnaire will be administered. 
Study drug will be dispensed.  
 
Visit 4 Week 12 
Adverse events and concomitant medication changes will be ascertained. Drug 
diary will be reviewed for correct study agent usage. Unused drug and sharps 
containers will be collected. Vitals signs and physical examination will be 
performed and photographs taken. Rosacea Questionnaire will be administered. 
Study drug will be dispensed.  
 
Visit 5 Week 16 (End of treatment) 
 
Adverse events and concomitant medication changes will be ascertained. Drug 
diary will be reviewed for correct study agent usage. Unused drug and sharps 
containers will be collected. Vitals signs and physical examination will be 
performed and photographs taken. Rosacea Questionnaire will be administered. 
Biopsy will be performed and sent for histology and immunohistochemistry. 
 
Evaluation schedule:  
TABLE OF VISITS 

Visit number 
1 
2 
3 
4 
5 
Time of Visit 
Week -4 to BL 
W0 (BL) 
W4 
W12¥ 
W16¥ 
Inclusion/Exclusion criteria 
x 
x 
 
 
 
Information & Informed consent 
x 
 
 
 
 
Vital signs 
x 
x 
x 
x 
x 
Physical examination 
x 
x 
x 
x 
x 
Lab test: CBC, MetC, UA 
x 
x** 
 
 
x 
Quantiferon 
x 
 
 
 
 
Dispense study medication 
 
x 
x 
x 
 
Self-administration of study drug 
 
x* 
x 
x 
 
Adverse events 
 
x 
x 
x 
x 
Concomitant medications evaluation 
x 
x 
x 
x 
x 
Rosacea clinical assessment 
(Appendix 1-3) 
x 
x 
x 
x 
x 
Facial photography 
 
x 
x 
x 
x 
RoseQOL questionnaire (Appendix 4) 
 
x 
x 
x 
x 
Skin Biopsy 
 
x 
 
 
x 
Histology & immunohistochemistry 
 
x 
 
 
x 
*In addition to self-administration at the study site at baseline (BL) under study staff 
supervision, study participants will be provided with three additional doses and a 
sharps container for weekly self-administration at home. Study participants will be 
asked to fill out a study diary to assess for compliance and adverse events. 
¥Week 16 time point was selected to compare the primary endpoint of papule and 
pustule count with baseline due to previous studies suggesting this time point is 
needed to achieve significant differences in papule and pustule count using 
systemic anti-inflammatory treatment with doxycycline (Theobald et al., 2007) and 
the 16 week time period observed for maximal therapeutic impact for secukinumab 
in psoriasis. (Langley et al., 2014) We also include a 12 week time point to assess 
for therapeutic benefit as another study (Sanchez et al., 2005) indicated that this 
time period is sufficient to detect therapeutic benefit using another systemic agent 
for rosacea, doxycycline.  
 ** If screening labs within 7 days of baseline, can use screening labs as baseline 
labs 
 
 

APPENDIX 1. Severity grading of papulopustular rosacea, adapted from 
Sanchez et al., 2005.  
 
Severity 
Papules/Pustules 
Study Score 
Mild 
1-9 
1 
Moderate 
10-14 
2 
Severe 
15+ 
3 
 
APPENDIX 2. Clinical score for assessing rosacea severity, reproduced from 
Sanchez et al., 2005. 
 
 
 
 
 

 
APPENDIX 3. Visual scoring system for erythematotelangiectatic rosacea, a 
secondary endpoint. 0=none, 1=mild (panel A), 2=moderate (panel B), and 
3=severe (panel C). Top table reproduced from Sanchez et al., 2005; bottom 
figure reproduced from Wilkin et al., 2004. 
 
 
 
 
 
 
Appendix 4. Rosacea quality of life survey derived from Nicholson et al., 2007. 
The response choices for the questions below are as follows: 1=never, 2=rarely, 
3=sometimes, 4=often, 5=all the time. The items below are reliable and have 
good discriminant ability. 
 
 

 
10.   Safety monitoring and reporting 
Serious adverse events, drug misuse or abuse, reports of drug exposure during 
pregnancy, and any other information that may suggest a change in the benefit-
risk profile of secukinumab, and where required, copes of the Investigator 
Notifications for suspected unexpected serious adverse events (SUSAR) and 
copies of the Development Safety Update Report, as appropriate.  
We will perform an adverse event reconciliation between the Sponsor’s trial 
database and an output from the Novartis safety database periodically 
throughout the trial. 
11.   Statistical methods and Data analysis  
This study is powered for the primary endpoint of significant reduction of 
papule/pustule count at baseline versus week 16.  
The null hypothesis is that there will be no difference in papule/pustule count at 
baseline and after 16 weeks of secukinumab due to known chronic and incurable 
nature of rosacea and that when used for psoriasis, maximum therapeutic effect 
is seen at 16 weeks. Because of the risk profile of the study medication in 
suppressing the immune system, we estimate that any reduction in 
papule/pustule count less than 20% would not be clinically meaningful. Since 10 
papules/pustules are required to enroll, the difference in papule/pustule count 
would have to be at least 2 (assuming a standard deviation of 3). Using an 
alpha=0.05 and power=0.80 (two sided test), sample size needed is 20. 
Assuming a dropout rate of 20% from 20 patients, we would need to enroll 24 
patients to achieve sufficient sample size. This is consistent with a study by 
Sanchez et al., 2005 for oral doxycycline in which 20 individuals were enrolled 
and achieved statistical significance. (Calculation by Shufeng Li, MS, Stanford 
Dermatology biostatistician)