Clinical trial NCT05150587
Conditions: Papulopustular Rosacea
Sponsor: Alfasigma S.p.A.
Start date: 2021-10-05; Completion date: 2022-10-20
Enrollment: 216 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Rosacea is a common chronic inflammatory relapsing-remitting skin condition almost exclusively affecting the central area of the face and the eyes.

Preliminary evidence suggests that treatment with rifaximin, a poorly absorbed oral antibiotic drug may be beneficial in patients with rosacea, particularly in those with papulopustular phenotype and positivity to Lactulose Breath Test (L-BT).

The objective of this study is twofold:

1. To explore the safety and efficacy of 2 doses of oral Rifaximin versus placebo in adults with moderate-to-severe papulopustular rosacea.
2. To assess the pharmacokinetics (PK) of these two dose regimens in a sub-group of patients.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Rifaximin intervention 2: Placebo
Intervention descriptions: intervention 1: Rifaximin tablets intervention 2: Placebo tablets

Protocol documents:
Prot_000.pdf: 
St u d y c o d e:  R E- R O S 2 0 0 2- 2 0 2 1
E u dr a C T n o. N. A.
Fi n al V er si o n 2. 0 – 2 5 M ar c h 2 0 2 2
C O N FI D E N TI A L
P a g. 1 | 9 4
S t u dy  c o d e: R E -R O S 2 0 0 2 -
S T U D Y P R O T O C O L
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St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2
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C o nfi d e nti al                                                    P a g. 2 | 9 4
SI G N A T U R E P A G E ( 1/ 3)
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t hi s cli ni c al st u d y pr ot o c ol,
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Study code: RE-ROS2002-2021 
 
Final Version 2.0 25 March 2022 
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SIGNATURE PAGE (2/3) 
 
 
STUDY COORDINATOR’S SIGNATURE  
 
 
Declaration of Coordinating Investigator   
  
Title: A phase IIa, multicenter, double blind, placebo controlled, randomized clinical 
trial to assess safety, efficacy and pharmacokinetics of Rifaximin Delayed-Release 
(Rifaximin-EIR) in patients with moderate-to-severe papulopustular rosacea 
 
 
This study protocol was subjected to critical review. The information it contains is consistent with 
current knowledge of the risks and benefits of the investigational product, as well as with the moral, 
ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki, 
the guidelines on Good Clinical Practice, and other applicable national and local laws and 
regulations. 
 
 
 
Prof./Dr. _______________________   
 
 
______________________________ 
______________________________ 
______________________________
______________________________  
Tel: ___________________________ 
e-mail: _________________________ 
 
 
  
 
 
 
 Date  
(dd/mm/yyyy) 
 
Signature 
 
 
 
 
 


 
 
 
 
Study code: RE-ROS2002-2021 
 
Final Version 2.0 25 March 2022 
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SIGNATURE PAGE (3/3) 
 
Declaration of the Investigator 
 
Title: A phase IIa, multicenter, double blind, placebo controlled, randomized clinical 
trial to assess safety, efficacy and pharmacokinetics of Rifaximin Delayed-Release 
(Rifaximin-EIR) in patients with moderate-to-severe papulopustular rosacea 
 
 
All documentation for this study supplied to me, which has not been previously published, will be 
kept in the strictest confidence. This documentation includes this study protocol, Investigator’s 
Brochure, Case Report Forms, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
No changes will be made to the study protocol without the prior written approval of the Sponsor and 
the IRB or IEC, except where necessary to eliminate an immediate hazard to the subjects. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
 
Responsible Investigator of the local study centre: 
 
 
Name: 
  
 
 
Title: 
Institution: 
Telephone: 
 
  
 
 
 
 Date  
(dd/mm/yyyy) 
 
Signature 
 
 
 
 
 
 


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  5 | 9 4 
 
E M E R G E N C Y I N S T R U C TI O N S 
 
 
All S eri o u s a d v er s e e v e nt s 
 
All a d v er s e e v e nt s t h at c o ul d aff e ct t h e s af et y of t h e st u d y p arti ci p a nt s or t h e c o n d u ct of t h e 
tri al m u st b e r e p ort e d wit hi n 2 4 h o ur s t o o n e of t h e f oll o wi n g: 
 
 
 
Alf a si g m a S. p. A., 
 
E- m ail: 
 
 
F a x: 
 
 
 
 
D uri n g a n e m er g e n c y t h e i n v e sti g at or m a y u n bli n d t h e s u bj e ct vi a i nt er a cti o n r e s p o n s e 
t e c h n ol o g y (I R T) if t h e k n o wl e d g e of t h e a s si g n e d tr e at m e nt i s n e c e s s ar y t o tr e at t h e 
s u bj e ct a d e q u at el y.  
 
 
D efi niti o n of S eri o u s A d v er s e E v e nt s a n d S eri o u s A d v er s e Dr u g R e a cti o n:   
A s eri o u s a d v er s e e v e nt ( S A E) or s eri o u s a d v er s e dr u g r e a cti o n ( S A D R) i s a n y u nt o w ar d m e di c al 
o c c urr e n c e t h at at a n y d o s e i s: 
 f at al  
 lif e-t hr e at e ni n g  
  r e s ulti n g i n or pr ol o n gi n g i n- p ati e nt h o s pit ali s ati o n 
  s e v er el y or p er m a n e ntl y di s a bli n g or i n c a p a cit ati n g 
  a c o n g e nit al a n o m al y/ birt h d ef e ct 
  ot h er e v e nt( s) c o n si d er e d m e di c all y i m p ort a nt 
 
 
 
 
 
P P D
P P D
P P D


 
 
 
 
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SYNOPSIS 
 
 
Study Title: 
A phase IIa, multicenter, double blind, placebo controlled, randomized 
clinical trial to assess safety, efficacy and pharmacokinetics of 
Rifaximin 
Delayed-Release 
(Rifaximin-EIR) 
in 
patients 
with 
moderate-to-severe papulopustular rosacea 
Study Code: 
RE-ROS2002-2021 
Study Centre(s):    Approximately 40 centers in the USA 
Drug on the study  Rifaximin is a negligibly absorbed, broad spectrum oral antibiotic 
currently used to treat specific intestinal infections. Rifaximin-EIR is a 
delayed release formulation of Rifaximin that contains enteric-coated 
microgranules of Rifaximin.  
The new formulation used in this trial, Rifaximin-EIR 250mg tablet (not 
yet on the market), has been developed to optimize Rifaximin 
intestinal concentration and therapeutic effect. 
Rationale and 
Objectives: 
Rosacea is a common chronic inflammatory relapsing-remitting skin 
condition almost exclusively affecting the central area of the face and 
the eyes. 
Based on its main clinical manifestations rosacea has been classically 
divided into the following four subtypes: i) erythematotelangectic, ii) 
papulopustular, iii) phymatous, and iv) ocular. Recent modifications of 
international clinical guidelines however have focused on individual 
features rather than combination of features. This contemporary 
“phenotype” approach is based on two rosacea features that are 
independently diagnostic (persistent central facial erythema and 
phyma), and other major features that are diagnostic when in 
combination (i.e. papules and pustules, facial telangiectasia excluding 
alar involvement, transient central facial erythema, otherwise known 
as flushing, and specific ocular manifestations). 
Preliminary evidence suggests that treatment with rifaximin, a poorly 
absorbed oral antibiotic drug may be beneficial in patients with 
rosacea, specifically in those with papulopustular phenotype. 
  
The objective of this study is twofold: 
1) to explore the safety and efficacy of two doses of oral 
Rifaximin delayed-release (750mg/day and 1500mg/day) 
administered t.i.d. for 30 days versus placebo in adults with 
moderate-to-severe papulopustular rosacea.   
2) in a sub-group of patients, to assess the pharmacokinetics 
(PK) of the 750mg/daily and 1500mg daily dose of Rifaximin-
EIR 250mg administered using a t.i.d. schedule.  
Phase  
IIa 
Experimental 
design: 
This is Proof of Concept, phase IIa, multicenter, double-blind, 
placebo-controlled, randomized clinical trial. 
 


 
 
 
 
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Two hundred one (201) eligible subjects are planned to participate in 
the main study while a subgroup of 18-36 (a minimum of 6 and a 
maximum of 12 subjects per arm) are planned to participate in the PK 
sub-study. Patients participating in the PK study will be randomly 
selected from the whole population.  
 
At randomization visit, subjects will be 1:1:1 randomized to receiving 
any of the two daily doses of active treatment or placebo. TID doses 
of the assigned treatment will be administered from Day 1 to Day 30. 
On Day 30, just the first daily dose will be administered. 
 
The randomization will be stratified based on Lactulose Breath Test 
(L-BT) status, i.e. negative (L-BT result with H2 ≤10 ppm by 90 
minutes compared to time 0) vs. positive (L-BT H2 >10 ppm) and PK 
sub-study participation (yes or not). 
 
Subjects participating in the PK sub-study, at Day 30 will stay 
overnight to complete the PK assessments.   
Venous blood samples for PK analysis will be collected on: 
x 
Day 1: Pre1st dose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post 
dosing. 
x 
Day 30: Pre-dose (single dose in the morning), and at 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 12, 22, 24, 30 hours post dosing.  
 
Prospective participants can be recruited using two different 
strategies:  
x 
social media recruitment;  
x 
on-site recruitment  
Based on the recruitment strategy, subjects will follow a different path 
(Study Schedule A [social media recruitment] or B [on-site 
recruitment]). 
 
A - Social media recruitment  
Specific advertisements targeted to papulopustular rosacea subjects 
posted in selected social media will re-direct subjects interested in 
participating in the study to a dedicated study website.  
Remote data recording (V0): In a dedicated study website, a 
prospective participant will be asked to:  
x 
review a concise study description, 
x 
provide online pre-screening informed consent,  
x 
provide contact details,  
x 
provide demographics (e.g., age, gender, etc.), 
x 
complete an online medical history and concomitant 
medication questionnaire,  
x 
upload either three pictures of their face (one frontal and two 


 
 
 
 
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lateral [right and left side] photos) or a short video of the face.  
Central Reader Validation:  
This task will be performed no later than 2 working days after V0. A 
Central reader (expert dermatologist) will: 
x 
check preliminary compliance with inclusion/exclusion criteria 
based on the 
o review of personal and clinical data (including medical 
history, concomitant medications etc.) posted on the 
website,   
o review of patient’s images downloaded on the website,  
x 
confirm the preliminary eligibility of pre-screened candidates 
and refer them via a dedicated website to the clinical team. 
Phone contact with the subject:  
This task will be performed no later than 1 week after the candidate 
validation has been occurred.  
The investigational team will call the prospective participant and in 
case the subject accepts to move forward, a clinic visit will be 
scheduled (V1).  
 
On the Screening visit (V1) the Site Investigator will conduct formal 
informed consent process and proceed with the procedures foreseen 
by the visit. All subsequent visits (Randomization visit, V2; End of 
Treatment visit, V3; End of Study visit, V4) will be identical for both 
recruitment paths (social media and on site). 
 
B - On-site recruitment  
Subjects presenting at the Investigational Site with moderate or 
severe papulopustular rosacea will be informed about the possibility 
to participate in the trial and if they are interested the Investigator will 
provide further information on the study and, if the subject is 
interested to participate, he will schedule the Screening visit (V1). All 
other visits will be performed as the social media recruitment path 
(see above). 
 
Number of 
Subjects: 
As described in Section 16.1 (Determination of Sample Size), two 
hundred one (201) eligible subjects (67 per arm) with moderate-to-
severe papulopustular rosacea, with a cap of 33 subjects per arm 
having negative L-BT at screening (i.e., a test showing an increase 
≤10 ppm of H2 by 90 minutes compared to time 0) are planned to be 
enrolled. 
Plasma samples will be collected in a sub-group of 6-12 subjects 
(minimum and maximum, respectively) per arm for pharmacokinetics 
assessments.  
Study Population: 
Inclusion criteria 


 
 
 
 
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All the following criteria must be met both at the Screening and 
Randomization visits unless otherwise specified. 
1. Men and women aged 18 years or older at screening (V1) 
2. Female participants are eligible if they are: 
of non-childbearing potential, i.e.: i) post-menopausal (at least 
2 years without spontaneous menses), or ii) surgically sterile 
(bilateral tubal occlusion, or hysterectomy), or iii) ablation of 
both ovaries),  
or  
of childbearing potential with a negative pregnancy test result 
at screening and randomization and agreeing to use a highly 
effective method of contraception (i.e. with failure rate of less 
than 1% per year) until 72 hours after taking the last study 
treatment dose.  
Note 1. Based on Clinical Trial Facilitation Group recommendations, 
highly effective methods of contraception are the following:  
x 
intrauterine device (IUD);  
x 
intrauterine hormone-releasing systems (IUS) or;  
x 
combined hormonal contraceptives (i.e. estrogen and 
progestogen) in oral, intravaginal or transdermal form, with 
inhibition of ovulation as primary mode of action or; 
x 
progestogen-only hormonal contraceptives in oral, injectable 
or implantable form, with inhibition of ovulation as primary 
mode of action or;  
x 
absolute and continuous sexual abstinence from Day 1 
included (first day of treatment) until 72 hours after taking the 
last study treatment dose. 
Note 2. In each case of delayed menstrual period (over one month 
between menstruations), female participants of child-bearing potential 
will be strongly recommended a confirmation of absence of 
pregnancy. This recommendation applies also to women of child-
bearing potential with infrequent or irregular menstrual cycles.  
3. Presence of rosacea, papulopustular phenotype, defined as 
papules and/or nodules with or without pustules of rosacea, 
without comedones, plus: centrofacial persistent erythema or 
phyma or transient episodic facial erythema (flushing) or facial 
telangiectasia (excluding peri-alar regions) or major ocular 
rosacea features (i.e. lid margin telangiectasia, interpalpebral 
conjunctival injection, spade-shaped infiltrates in the cornea, 
scleritis and sclerokeratitis). 
4. Presence of ≥11 and ≤ 70 facial papules and/or pustules. 
5. Moderate (Grade 3) or severe (Grade 4) rosacea based on 
Investigator’s Global Assessment based on Investigator’s 
judgement.     
6. Patients accepting to provide and legally capable of providing 


 
 
 
 
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free and informed consent to all procedures included in the 
protocol (including facial skin photography). 
Exclusion criteria 
None of the following criteria must be met both at the Screening visit 
and at the Randomization visit (Day 1) unless otherwise specified: 
1. Granulomatous rosacea or rosacea fulminans.  
2. Erythematoteleangectatic, phymatous or ocular rosacea only. 
Patients with these subtypes associated with papulopustular 
rosacea can be enrolled.  
3. Rosacea with IGA grade ≤2 based on Investigator’s judgment.  
4. Anticipated need for proctoscopy or colonoscopy within two 
weeks after lactulose breath test. 
Note 3: Subjects undergoing unanticipated proctoscopy or 
colonoscopy within a week from lactulose breath test should have a 
thorough bowel cleansing with a non-fermentable solution. 
5. Subjects requiring a low galactose diet. 
6. Hypersensitivity or intolerance to lactulose or any excipient of 
the lactulose preparation to be used for L-BT. 
7. History of inflammatory bowel disease (Crohn’s disease or 
ulcerative colitis) or other conditions characterized by severe 
intestinal ulcers.  
8. History of coeliac disease. 
9. Patients with intestinal obstruction or partial intestinal 
obstruction. 
10. Presence of diarrhoea associated with fever and/or blood in 
the stool. 
11. Severe kidney impairment (i.e. estimated glomerular filtration 
rate <30 ml/min). 
12. Severe hepatic impairment (i.e. Child-Pugh B or C).  
13. Cancer or any cancer-related treatment within 5 years prior to 
screening (excluding non-melanoma skin-cancer).  
14. History of alcohol or drug abuse within a year prior to 
screening, based on Investigator’s judgement. 
15. Facial skin conditions that can interfere with reliable 
assessment of rosacea throughout the study (e.g. facial hair, 
tattoos, other facial adornments, keloids, hypertrophic 
scarring, recent facial surgery, excessive sun exposure 
including use of tanning beds)   
16. Any other significant health condition (e.g. cardiovascular, 
respiratory, 
renal, 
hepatic, 
neurologic, 
psychiatric, 
hematologic, oncologic, immune etc.) or non-health condition 
that in the investigator’s judgement may: 
i) jeopardize the patient’s safe participation in the trial or 
ii) make unlikely the patient’s completion of the study or  
iii) make unlikely the patient’s compliance with the study 


 
 
 
 
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procedures (e.g. highly anticipated need of non-
permitted treatments, terminal illness, etc.). 
17. History of hypersensitivity to rifaximin, rifamycin-derivatives, 
any of the rifaximin-EIR or placebo excipients.  
18. Treatment 
with 
biologic 
immunomodulatory 
and/or 
immunosuppressive drugs (e.g. anti-TNF drugs) within 6 
months prior to randomization.  
19. Treatment with non-biologic immunomodulatory and/or 
immunosuppressive drugs (e.g. cyclosporine, methotrexate 
etc.) within 30 days prior to randomization.  
20. Treatment with warfarin (or other coumarins) within 14 days 
prior to randomization.  
21. Treatment with niacin within 30 days prior to randomization.   
22. Topical facial or systemic antibiotics within 30 days before 
randomization; 
23. Treatment with neomycin or other low-absorbable oral 
antibiotics (such as marketed rifaximin) within 90 days before 
randomization. 
24. Topical facial, inhaled or systemic corticosteroids within 30 
days prior to randomization.  
25. Topical facial retinoids within 30 days before randomization. 
26. Systemic retinoids within 6 months before randomization. 
27. Any other topical or systemic treatment for rosacea within 30 
days before randomization (including also laser and pulsed 
light, etc.). 
28. Over-the-counter 
intestinal 
or 
topical 
skin 
probiotics 
(functional food is allowed), within 30 days before 
randomization. 
29. Any experimental treatment within 6 months prior to 
randomization. 
30. Current swab-positive or suspected (under investigation) 
Covid-19 infection;  
or fever and one or more of the following respiratory disease 
signs or symptoms: cough, sputum production, shortness of 
breath within the last 14 days;  
or contact with people with Covid-19 infection within the last 
14 days.  
31. Women who are pregnant, breast-feeding or planning a 
pregnancy during the trial period. 
32. Subjects who are investigational site staff members and their 
family members, site staff members otherwise supervised by 
the investigator, or patients who are Alfasigma’s employees. 


 
 
 
 
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Test products 
(dose and mode of 
administration) 
and reference 
therapy/placebo 
(dose and mode of 
administration): 
Rifaximin-EIR 250 mg tablets or placebo. 
Patients will be randomly allocated into the following treatment arms: 
x 
Group A: two tablets of Rifaximin-EIR 250 mg TID (1500 mg 
daily) for 29 days (morning, afternoon, night); on Day 30 they 
will receive two tablets of Rifaximin-EIR 250 mg in single 
administration in the morning. 
x 
Group B: one tablet of Rifaximin-EIR 250 mg (750 mg daily) + 
one tablet of placebo TID for 29 days (morning, afternoon, 
night); on Day 30 they will receive one tablet of Rifaximin-EIR 
250 mg and one tablet of placebo in single administration in 
the morning. 
x 
Group C: two tablets of placebo TID for 29 days (morning, 
afternoon, night); on Day 30 they will receive two tablets of 
placebo in single administration in the morning. 
 
Prohibited and 
permitted 
medications: 
Prohibited Medications 
Initiation of beta-blocker treatment is not allowed from the screening 
visit (V1) to the end of follow-up (Day 60; V4) included. Patients 
already on chronic treatment with beta-blockers at the screening visit 
can be enrolled in the study.  
Initiation of any oestroprogestinic or progestogen contraceptive or 
oestroprogestinic or progestogen replacement therapy is not allowed 
from 
V1 
to 
V4 
included. 
Patients 
already 
treated 
with 
oestroprogestinic or progestogen contraceptives or oestroprogestinic 
or progestogen replacement therapy before V1 can be enrolled in the 
study.   
 
The following medication will not be permitted from V1 to V4 included:  
x 
Biologic 
or 
non-biologic 
immunomodulatory 
or 
immunosuppressive drugs; warfarin (or other coumarins); 
niacin; topical facial or systemic antibiotic treatments; 
neomycin or any other low-absorbable oral antibiotics (such 
as marketed rifaximin); topical facial, inhaled or systemic 
corticosteroids; topical and systemic retinoids; any other 
topical or systemic treatment for rosacea (including also laser 
and pulsed light, etc.). 
x 
Any cancer-related treatment. 
x 
“over the counter” formulations including topical skin or 
intestinal probiotics. 
x 
Any other experimental treatment  
 
Permitted Medications: 
All other medications for concomitant chronic conditions are allowed 
and should be maintained constant throughout the whole study. 


 
 
 
 
Study code: RE-ROS2002-2021 
 
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Duration of the 
study: 
Overall, including all parts from sites activation, the study will last 
approximately 14 months (study period for a single subject: 1 month 
for screening, 1 month for treatment, 1 month for follow-up).  
Criteria for 
evaluation:  
 
 
 
 
Co-primary efficacy endpoint: 
The following co-primary efficacy endpoints will be clinically assessed 
by the Investigator: 
1. Absolute change from baseline in number of rosacea 
inflammatory lesions (papules and pustules) at the end of 
treatment (Day 30) AND 
2. Percent of subjects showing treatment success, defined as an 
IGA score of 0 (clear) or 1 (almost clear) with at least a 2-grade 
improvement from baseline at the end of treatment (Day 30). 
Investigator’s Global Assessment (IGA) score 
Grade Description Amount and size of inflammatory lesions 
present 
0 
Clear 
None 
1 
Almost Clear Very few, small papules/pustules 
2 
Mild 
Few small papules/pustules 
3 
Moderate 
Several small or large papules/pustules 
4 
Severe 
Numerous small and/or large papules/pustules 
 
Secondary efficacy endpoints: 
1. Mean change from Baseline (V2) in number of inflammatory 
lesions (papules and pustules) at V3. 
2. Percent of participants showing treatment success (i.e. IGA 
score of 0 or 1) at V3 and V4. 
3. Percent of participants with IGA score of 0 (clear) at V3 and 
V4.   
4. Change from Baseline (V2) in the following rosacea additional 
features at V3 and V4: 
x pain, burning/stinging and itching [measured using a 0-10 
cm Visual Analogue Scale (VAS)]  
x telangiectasia (absent=0, mild=1, moderate=2, severe=3) 
x ocular manifestations (absent=0, mild=1, moderate=2, 
severe=3),  
x phymatous changes (absent=0, mild=1, moderate=2, 
severe=3).   
5. Change from Baseline in facial non-transient erythema at V3 
and V4 (absent=0, mild=1, moderate=2, severe=3).  
6. Change from baseline in abdominal pain score at V3 and V4. 
7. Change from baseline in abdominal distension score at V3 


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  1 4 | 9 4 
 
a n d V 4. 
8.  C h a n g e fr o m b a s eli n e i n b o w el h a bit s ati sf a cti o n s c or e at V 3 
a n d V 4. 
9.  C h a n g e  fr o m  b a s eli n e  i n  gl o b al  s e v erit y  of  a b d o mi n al  
s y m pt o m s s c or e at V 3 a n d V 4. 
1 0. P er c e nt of p arti ci p a nt s s h o wi n g tr e at m e nt s u c c e s s a c c or di n g 
t o  a  M o difi e d  I G A  s c al e  e x cl u di n g  p a p ul e s/ p u st ul e s  b ut  
i n cl u di n g er yt h e m a (i. e. s c or e of 0 or 1) at V 3 a n d V 4. 
1 1. P er c e nt of p arti ci p a nt s h o wi n g tr e at m e nt s u c c e s s a c c or di n g t o 
a M o difi e d I G A s c al e i n cl u di n g er yt h e m a a n d p a p ul e s/ p u st ul e s 
at V 3 a n d V 4. 
P h ar m a c o ki n eti c a s s e s s m e nt s ( P K s u b- st u d y o nl y): 
1 2. P h ar m a c o ki n eti c s of t h e si n gl e d o s e (i. e. at D a y 1 aft er t h e 
fir st d o s e a d mi ni str ati o n) a n d t h e r e p e at e d d o s e s (i. e. at D a y 
3 0 aft er t h e l a st d o s e) of Rif a xi mi n- EI R 2 5 0 m g. 
S af et y  
S af et y a s s e s s m e nt s: 
  
C o m pl et e P h y si c al E x a mi n ati o n i n cl u di n g h ei g ht, w ei g ht, 
B MI;  
 
Vit al si g n s (i n cl u di n g  h e art r at e, bl o o d pr e s s ur e, a n d b o d y 
t e m p er at ur e);  
 
R o uti n e l a b or at or y p ar a m et er s ( h a e m at ol o g y, bi o c h e mi str y, 
uri n al y si s);  
  
A d v er s e e v e nt s ( A E s);  
  
Wit h dr a w of s u bj e ct s fr o m st u d y d u e t o a d v er s e e v e nt s.    
St ati sti c al 
M et h o d s:  
A d et ail e d St ati sti c al A n al y si s Pl a n ( S A P) will b e i s s u e d aft er t h e st u d y 
st art s.   
S A S s oft w ar e ( V. 9. 3 or s u b s e q u e nt) will b e u s e d f or t h e st ati sti c al 
a n al y s e s.  
C o nti n u o u s  v ari a bl e s  will  b e  s u m m ari z e d  b y  d e s cri pti v e  st ati sti c s  
( n u m b er of c a s e s, m e a n a n d st a n d ar d d e vi ati o n, m e di a n, mi ni m u m, 
1 st a n d  3
r d q u artil e,  m a xi m u m).  C at e g ori c al  v ari a bl e s  will  b e  
s u m m ari z e d u si n g a b s ol ut e fr e q u e n ci e s a n d p er c e nt a g e s.  
All t h e st ati sti c al t e st s will b e c o n d u ct e d at t h e t w o -si d e d α  = 0. 0 5 
si g nifi c a n c e l e v el. D u e t o t h e e x pl or ati v e p ur p o s e s of  t hi s tri al, n o 
a dj u st m e nt  of si g nifi c a nt l e v el f or m ulti pli cit y will b e a p pli e d. 
S a m pl e si z e e sti m ati o n 
T h e  s a m pl e  si z e  e sti m ati o n  i s  b a s e d  o n  t h e  c o -pri m ar y  effi c a c y  
e n d p oi nt s, i. e. m e a n c h a n g e fr o m b a s eli n e i n n u m b er of i nfl a m m at or y 
l e si o n s a n d p er c e nt of p ati e nt s s h o wi n g tr e at me nt s u c c e s s. 
: 
C CI


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  1 5 | 9 4 
 
B a s e d o n t h e s e a s s u m pti o n s, 5 1 p ati e nt s w er e t o b e e nr oll e d i n e a c h 
tr e at m e nt ar m a s s h o w n i n t h e t a bl e s b el o w. 
 
T h e t ot al s a m pl e si z e ( 1 5 3) w as a dj u st e d t o 1 7 1 p ati e nt s ( 5 7 i n e a c h 
tr e at m e nt gr o u p) c o n si d eri n g a n e xp e ct e d dr o p o ut r a t e of a b o ut 1 0 % 
( u si n g  Fr e e d m a n’ s  f or m ul a  ( C o ntr ol  Cli n  Tri al s,  1 9 9 0):  n’ =  
1 0 0* n/( 1 0 0 - x), w h er e x i s t h e e xp e ct e d dr o p o ut r at e). 
T h e i niti al l y pl a n n e d s a m pl e si z e h a s b e e n i n cr e a s e d t o a t ot al of 2 0 1 
p ati e nt s ( 6 7 i n e a c h tr e at m e nt gr o u p) t o miti g at e t h e i m p a ct o n t h e 
st ati st i c al p o w er of t h e tr e at m e nt kit mi s all o c ati o n t h at o c c urr e d f or 1 5 
p ati e nt s o ut of t h e i niti al 3 0 p ati e nt s r a n d o mi z e d.  
A n al y si s P o p ul ati o n s  
T h e f oll o wi n g a n al y si s p o p ul ati o n s will b e d efi n e d:  
S cr e e n e d P o p ul ati o n, d efi n e d a s all p ati e nt s e nr oll e d i nt o a s cr e e ni n g 
p h a s e aft er i nf or m e d c o n s e nt.  
S af et y A n al y si s S et ( S A F), d efi n e d a s all  r a n d o mi s e d p ati e nt s h a vi n g 
t a k e n at l e a st o n e d o s e of t h e i n v e sti g ati o n al tr e at m e nt.  
C CI
C CI


 
 
 
 
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Confidential                                                    Pag. 16 | 94 
 
Full Analysis Set (FAS), defined as all patients in the SAF who have 
at least one post-baseline measurement for any primary endpoint.  
Modified Full Analysis Set (mFAS), defined as all patients in the FAS 
excluding the initial 30 patients randomized. 
Per Protocol Set (PPS), defined as all patients in the FAS who fulfil 
the study protocol requirements with no major deviations that may 
affect study results.  
PK Set, defined as all randomized patients who received at least one 
dose of Rifaximin and had a suitable PK profile.  
Analysis of the efficacy endpoints will be performed on the FAS and 
the PPS. Results on the FAS will be considered primary. Results on 
the PPS population will be used as supportive. 
Analysis of the safety and tolerability endpoints will be performed on 
the SAF. 
Efficacy Statistical Analysis 
 
Each active group will be compared with the placebo group.  
Statistical tests will be performed at the two-sided α =0.05 level. 
Considering the Proof of Concept purposes of this trial, no adjustment 
for multiplicity will be applied. 
The first co-primary efficacy endpoint (i.e.: mean change from 
Baseline in number of inflammatory lesions at Day 30) will be 
analysed by means of an Analysis of Covariance (ANCOVA) model, 
with change from Baseline to Day 30 as dependent variable, 
treatment group and stratification factor as explicative factors, and 
baseline number of inflammatory lesions as covariate. The adjusted 
mean differences will be presented with 95% CIs and p-values. 
The second co-primary efficacy endpoint (i.e.: percent of patients 
showing treatment success (IGA score of 0 or 1) with at least a 2-
grade improvement from baseline at Day 30) will be analysed by 
means of a stratified Cochran Mantel-Haenszel (CMH) chi square 
test. The Breslow-Day test for stratified tables will be applied. A two-
sided 95% CI for difference in success rate between the treatment 
groups (each active group vs placebo) will also be computed. 
The primary statistical analysis on the FAS will be performed 
according to the actual treatment received. 
In addition, two sensitivity analyses will be implemented: 
x 
The first by analyzing the FAS according to the “randomized 
treatment”, as originally planned 
x 
The second on the mFAS according to the “randomized 
treatment”. 


 
 
 
 
Study code: RE-ROS2002-2021 
 
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PK analysis 
PK parameters will be assessed according to a non-compartmental 
approach. At least the following PK parameters will be calculated:   
x 
Cmax, Tmax, AUC0-tau, t1/2;  
x 
Accumulation factor after the last dose;  
Rifaximin-EIR individual and mean plasma concentrations at each 
sampling time point will be presented by listings and descriptive 
summary statistics including arithmetic means, geometric means, 
medians, quartiles, ranges, standard deviations and coefficients of 
variation 
(arithmetic 
and 
geometric). 
Individual 
and 
mean 
concentrations versus time will be plotted on linear and log-linear 
scales. Descriptive statistics and graphs will be also performed for the 
PK parameters.  
Safety analysis 
With reference to the safety parameters, standard statistical analyses 
will be conducted on vital signs, physical examination, laboratory 
parameters and AEs at the relevant visits. 
 
Note: Full details of study design and schedule of assessment are reported in Section 11 of the 
study protocol (“Study Procedures”) 
 


 
 
 
 
Study code: RE-ROS2002-2021 
 
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TABLE OF CONTENTS 
 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................... 21 
2. 
ETHICS ..................................................................................................................................... 22 
2.1 
INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW BOARD (IRB) ................ 22 
2.2 
ETHICAL CONDUCT OF THE STUDY ........................................................................................ 22 
2.3 
SUBJECT INFORMATION AND CONSENT ................................................................................. 22 
3. 
GENERAL INFORMATION ...................................................................................................... 24 
4. 
BACKGROUND AND RATIONALE ......................................................................................... 25 
5 
STUDY OBJECTIVES AND PURPOSE ................................................................................... 30 
5.1 
CO-PRIMARY EFFICACY ENDPOINT ........................................................................................ 30 
5.2 
SECONDARY ENDPOINTS ...................................................................................................... 30 
6. 
OVERALL STUDY DESIGN AND PLAN.................................................................................. 32 
7. 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS ... 33 
8. 
BENEFIT-RISK EVALUATION ................................................................................................. 34 
9. 
SELECTION OF STUDY POPULATION .................................................................................. 36 
9.1 
NUMBER OF PARTICIPANTS ................................................................................................... 36 
9.2 
INCLUSION CRITERIA ............................................................................................................ 36 
9.3 
EXCLUSION CRITERIA ........................................................................................................... 37 
9.4 
PREMATURE DISCONTINUATION FROM THE STUDY PER SUBJECT ............................................ 38 
10. TREATMENTS .......................................................................................................................... 40 
10.1 
TREATMENTS TO BE ADMINISTERED ...................................................................................... 40 
10.2 
INVESTIGATIONAL PRODUCTS ............................................................................................... 40 
10.2.1 
Test preparation ........................................................................................................ 40 
10.2.2 
Labelling and Packaging .......................................................................................... 40 
10.2.3 
Storage, Dispensing, Use and Disposal of the compound during and at the end 
of the study .............................................................................................................................. 41 
10.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS / RANDOMISATION ..................... 41 
10.4 
SELECTION OF DOSES IN THE STUDY ..................................................................................... 42 
10.5 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT ............................................................ 42 
10.6 
BLINDING ............................................................................................................................. 43 
10.7 
TREATMENT COMPLIANCE .................................................................................................... 43 
10.8 
PRIOR AND CONCOMITANT THERAPY ..................................................................................... 43 
11. STUDY PROCEDURES ............................................................................................................ 45 
11.1 
VISIT SCHEDULE ................................................................................................................... 45 
11.2 
STUDY EVALUATIONS/PROCEDURES ..................................................................................... 47 
11.2.1 
Remote data recording ............................................................................................. 47 
11.2.2 
Central reader validation .......................................................................................... 47 
11.2.3 
Phone contact with the subject ............................................................................... 47 
11.2.4 
Screening Visit .......................................................................................................... 48 
11.2.5 
Randomization Visit .................................................................................................. 49 
11.2.6 
End of Treatment Visit .............................................................................................. 49 
11.2.7 
End of Study Visit ..................................................................................................... 50 
11.2.8 
Early Termination Visit ............................................................................................. 51 
11.2.9 
Unscheduled Visit ..................................................................................................... 51 
11.3 
LABORATORY TESTS ............................................................................................................ 52 
11.3.1 
Handling of Biological Samples .............................................................................. 54 
11.4 
DECODING OF RANDOMISATION IN CASE OF EMERGENCY ........................................................ 54 
11.5 
SUBJECT DIARY ................................................................................................................... 52 
12. EFFICACY AND SAFETY ASSESSMENT............................................................................... 56 


 
 
 
 
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12.1 
ASSESSMENT OF EFFICACY .................................................................................................. 56 
12.1.1 
Co-primary Efficacy Endpoint .................................................................................. 56 
12.1.2 
Secondary Efficacy Endpoints ................................................................................ 56 
12.2 
ASSESSMENT OF SAFETY ..................................................................................................... 56 
12.3 
APPROPRIATENESS OF MEASUREMENTS ............................................................................... 56 
13. PHARMACODYNAMIC ENDPOINTS ...................................................................................... 60 
14. PHARMACOKINETIC ENDPOINTS ......................................................................................... 60 
14.1 
PHARMACOKINETIC BLOOD SAMPLING .................................................................................. 60 
14.2 
PHARMACOKINETIC PARAMETERS ......................................................................................... 60 
15. SAFETY ASPECTS .................................................................................................................. 62 
15.1 
ADVERSE EVENTS ................................................................................................................ 62 
15.1.1 
Definition of Adverse Events ................................................................................... 62 
15.1.2 
Definition of Serious Adverse Events ..................................................................... 62 
15.1.3 
Protocol-Specified Serious Adverse Events .......................................................... 63 
15.1.4 
Change of Laboratory Parameters .......................................................................... 64 
15.1.5   Classification and Coding of the Causal Relationship and Severity .................... 64 
15.1.6 
Documentation of Adverse Events ......................................................................... 65 
15.1.7 
Prompt Reporting of SAE to the Sponsor .............................................................. 65 
15.1.8 
Reportable events ..................................................................................................... 66 
15.1.9 
Post study AEs and SAEs ........................................................................................ 66 
15.2 
WARNINGS AND PRECAUTIONS ............................................................................................. 67 
16. STATISTICAL PLAN AND DETERMINATION OF SAMPLE SIZE ......................................... 68 
16.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 68 
16.2 
DEFINITION OF STUDY POPULATIONS .................................................................................... 69 
16.2.1 
Screened Population ................................................................................................ 69 
16.2.2 
Safety Population ...................................................................................................... 69 
16.2.3 
Full Analysis Set (FAS) ............................................................................................. 69 
16.2.4 
Modified Full Analysis Set (FAS) ............................................................................. 69 
16.2.5 
Per Protocol Set (PPS) ............................................................................................. 69 
16.2.6 
PK Set ......................................................................................................................... 70 
16.2.7 
Disposition................................................................................................................. 70 
16.2.8 
Demographic and Other Baseline Variables .......................................................... 70 
16.3 
STATISTICAL AND ANALYTICAL PLANS .................................................................................. 70 
16.3.1 
Primary Efficacy Endpoints and Statistical Model of Analysis ............................ 70 
16.3.2 
Secondary Efficacy Endpoints and Statistical Model of Analysis ....................... 71 
16.3.3 
Safety Laboratory Statistical Analysis ................................................................... 72 
16.3.4 
Statistical Analysis of Adverse Events ................................................................... 73 
16.3.5 
Statistical Analysis of Lactulose Breath Test Results .......................................... 74 
16.3.6 
Statistical Analysis of Vital Signs and Body Weight ............................................. 74 
16.3.7 
Statistical Analysis of Physical Examination ......................................................... 74 
16.3.8 
Handling of Missing and Incomplete Data ............................................................. 73 
16.4 
ADDITIONALLY PLANNED STATISTICAL ANALYSES ................................................................. 74 
16.4.1 
Interim Analyses and Data Monitoring Committee ............................................... 74 
16.4.2 
Multicentre study ...................................................................................................... 74 
16.4.3 
Examination of Subgroups ...................................................................................... 74 
17. DOCUMENTATION, RECORD ACCESS AND ARCHIVING................................................... 75 
17.1 
DOCUMENTATION OF ESSENTIAL DOCUMENTS/SUPPLEMENTS AT STUDY CENTRE DURING THE 
TRIAL 75 
17.2 
SCREENING/ENROLLMENT LOG ............................................................................................. 75 
17.3 
DOCUMENTATION OF SUBJECTS’ PARTICIPATION ................................................................... 75 
17.4 
DATA PROTECTION ............................................................................................................... 75 
17.5 PERSONAL DATA BREACH .................................................................................................... 76 
17.6 
SOURCE DOCUMENTS ........................................................................................................... 77 
17.7 
SUBJECTS' RECORDS ........................................................................................................... 77 


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  2 0 | 9 4 
 
1 7. 8  C A S E R E P O R T F O R M S  .......................................................................................................... 7 7 
1 7. 9  D A T A M A N A G E M E N T  ............................................................................................................ 7 8 
1 7. 1 0  D A T A B A S E P R O C E S SI N G  ...................................................................................................... 7 8 
1 7. 1 1  A R C HI VI N G R E Q UI R E M E N T S F O R S P O N S O R A N D IN V E S TI G A T O R  ............................................. 7 8 
1 8  P R O J E C T M A N A G E M E N T  ...................................................................................................... 8 0 
1 8. 1  IN V E S TI G A T O R IN F O R M A TI O N A N D T R AI NI N G  .......................................................................... 8 0 
1 8. 2  Q U A LI T Y A S S U R A N C E A N D Q U A LI T Y C O N T R O L  ...................................................................... 8 0 
1 8. 2. 1  
A u dit a n d S u p er vi si o n of t h e St u d y  ........................................................................ 8 0 
1 8. 2. 2  
M o nit ori n g  .................................................................................................................. 8 0 
1 8. 3  T RI A L S T E E RI N G C O M MI T T E E  ................................................................................................. 8 1 
1 8. 4  D A T A M O NI T O RI N G C O M MI T T E E  ............................................................................................. 8 1 
1 8. 5  A M E N D M E N T S T O T H E P R O T O C O L  ......................................................................................... 8 1 
1 8. 6  C L O S U R E O R D I S C O N TI N U A TI O N O F S T U D Y A N D S I T E............................................................. 8 1 
1 8. 7  P R E M A T U R E D I S C O N TI N U A TI O N O F T H E S T U D Y I N A T RI A L S I T E .............................................. 8 2 
1 8. 8  P R E M A T U R E D I S C O N TI N U A TI O N O F T H E W
H O L E S T U D Y  ......................................................... 8 3 
1 8. 9  IN S U R A N C E F O R S U B J E C T S  .................................................................................................. 8 3 
1 8. 1 0  D I S C L O S U R E O F A L L IN F O R M A TI O N A N D R E S U L T S  ................................................................. 8 3 
1 8. 1 1  P U B LI C A TI O N P O LI C Y  ............................................................................................................ 8 3 
1 8. 1 2  O W N E R S HI P  ......................................................................................................................... 8 3 
1 8. 1 3  C O N T R A C T S , F I N A N C E S ........................................................................................................ 8 3 
1 9.  R E P O R TI N G  ............................................................................................................................. 8 4  
2 0.  R E F E R E N C E LI S T .................................................................................................................... 8 5 
2 1.  A P P E N DI C E S  … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … …... … 8 8  
C CI


 
 
 
 
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1. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse Event 
AL 
Alfasigma S.p.A. 
b.i.d. 
Bis In Die (twice a day) 
BMI 
Body Mass Index 
CDAD 
Clostridium Difficile Associated Diarrhoea 
CH4 
Methane 
CI 
Confidence Interval 
CRF 
Case Report Form 
DLQI 
Dermatology Life Quality Index 
GCP 
Good Clinical Practice 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicine Agency 
ePRO 
Electronic Patient Reported Outcome 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
G-BT 
Glucose Breath Test 
IB 
Investigator's Brochure 
IBD 
Irritable Bowel Disease 
IBS 
Irritable Bowel Syndrome 
IBS-SSS 
Irritable Bowel Syndrome - Symptom Severity Scale 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
H2 
Hydrogen 
IEC 
Independent Ethics Committee 
IGA 
Investigator’s Global Assessment 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
L-BT 
Lactulose Breath Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
PMC 
Pseudomembranous Colitis 
ppm 
Parts Per Million 
PPS 
Per Protocol Set 
PT 
Preferred Term 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAF 
Safety Analysis Set 
SIBO 
Small Intestinal Bacterial Overgrowth 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t.i.d. 
Three Times Daily 


 
 
 
 
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2. 
ETHICS 
2.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
Before initiating the trial, Alfasigma S.p.A. (AL) and the investigator(s)/institution(s) must obtain 
written and dated approval/favourable opinion from the IRB(s)/IEC(s) for the trial protocol, written 
informed consent form, subject recruitment procedures (e.g. adverts), and any other written 
information to be provided to subjects. As part of the investigator(s)’/institution(s)’ written application 
to the IRB/IEC, Alfasigma will provide the IRB(s)/IEC(s) with a current copy of the Investigator's 
Brochure (IB). If the IB is updated during the trial, AL will supply a copy of the updated IB to the 
IRB(s)/IEC(s). 
Alfasigma S.p.A and the investigator(s)/institution(s) must obtain approval/favourable opinion from 
the IRB(s)/IEC(s) for change(s) to any aspect of the trial, such as modification(s) of the protocol, 
written Informed Consent Form (ICF), written information to be provided to subjects, and/or other 
procedures. 
Alfasigma S.p.A must promptly report any new information that may affect the safety of the subjects 
or the conduct of the trial to the IRB(s)/IEC(s). 
Alfasigma S.p.A will submit safety update reports to the IRB(s)/IEC(s) and to the Competent 
Authorities periodically, in accordance with the applicable laws. Upon completion of the trial, 
Alfasigma S.p.A will provide the IRB(s)/IEC(s) and the Competent Authorities with a brief report of 
its outcome (synopsis). 
(See also chapter "EMERGENCY INSTRUCTIONS") 
2.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association’s Declaration of Helsinki in its revised edition (64th 
WMA General Assembly, Fortaleza, Brasil, October 2013), the Guidelines of Good Clinical Practice 
(EMA/CPMP/ICH/135/1995 R2, 1 December 2016) and the Directives 2001/20/EC and 2005/28/EC 
as well as demands of the national drug and data protection laws will be strictly followed. 
(See also chapters: "Insurance for Subjects, "Data Protection"  and "Documentation of Subjects’ 
Participation"  
2.3 
Subject Information and Consent 
The investigator is responsible for not admitting subjects to the trial before informed consent has 
been given. Consent means that the person involved has the legal capacity to give consent and is 
able to exercise free power of choice. Consent should be given as written informed consent after 
receiving detailed information. The subjects who refuse to give informed consent must not be 
included in this trial.   
Subjects will be given a written "Subject information and consent form”.  
Before signing the ICF the subject will be informed in detail by a physician about the following items: 
a. 
the aim and rationale of the trial 
b. 
the nature of the treatment and the allocation of subjects to the different treatment groups 
c. 
other therapeutic alternatives 
d. 
expected therapeutic effects of the medication 
e. 
known adverse drug reactions and other risks or inconvenience during the clinical trial 
f. 
the trial procedures to be followed, including all invasive procedures 
g. 
compensation and/or treatment available to the subject in the event of trial-related injury 
h. 
anticipated prorated payment and expenses to the subjects for participating in the trial (if 
applicable) 
i. 
subject's right to withdraw at any time without justification and without penalty or loss of 
benefits to which the subject is otherwise entitled 
j. 
the subject's responsibilities 


 
 
 
 
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k. 
availability of more detailed information before and during the trial 
l. 
information about data protection 
m. person(s) to contact in the event of trial-related injury 
n. 
foreseeable circumstances and/or reasons under which the subject’s participation in the 
trial may be terminated 
o. 
the expected duration of the subject’s participation in the trial 
p. 
the approximate number of subjects involved in the trial 
 
The subject must be given ample time to inquire about the details of the trial. The ICF is signed by 
the informing physician and by the subject. Persons who withdraw their informed consent must not 
continue the trial. 
 
The filled-in and signed ICF will be kept and archived in original by the investigator in the 
“Investigator’s Study File”. (See chapter 17.1). The subject will be provided with a copy.  
 
 


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  2 4 | 9 4 
 
3.
 G E N E R A L
 
I N F O R M A TI O N
 
S p o n s or 
Alf a si g m a S. p. A. , Vi a R a g a z zi d el ‘ 9 9, 5, I- 4 0 1 3 3 B ol o g n a, It al y 
 
S p o n s or P er s o n n el: 
Cli ni c al R e s e ar c h P h y si ci a n 
 
T el.:
F a x:
E- m ail: 
 
 
S e ni or Cli ni c al S ci e nti st 
 
T el.: 
 
E- m ail: 
  
 
Cli ni c al St u d y M a n a g er  
 
T el.: 
 
E- m ail: 
 
 
Cli ni c al S af et y U nit M a n a g er  
 
T el: 
F a x:
E- m ail: 
  
 
S e ni or St ati sti ci a n 
 
T el.: 
 
E- m ail: 
 
 
Pr e- cli ni c al & Cli ni c al P h ar m a c ol o g y H e a d  
 
T el.:  
 
 
E- m ail: 
 
 
C R O:  
Bi or a si   
 
I n v e sti g at or s 
A li st of all I n v e sti g at or s i n v ol v e d i n t h e St u d y will b e pr o vi d e d a s a s e p ar at e d o c u m e nt. 
 
L a b or at ori e s  
P K bi o a n al y si s: P y x a nt 
Cli ni c al L a b or at or y: Bi or a si ( or d el e g at e d l a b or at or y)  
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P
D
P P D


 
 
 
 
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4. 
BACKGROUND AND RATIONALE 
Rosacea  
Rosacea is a common chronic skin disease that almost exclusively affects the central area of the 
face and the eyes. This condition affects 0.09 to 20% of the population (depending on the 
geographical areas and genetic predisposition) with typical age of onset of 30 to 50 years although 
can be found also in younger adults. Rosacea is slightly more prevalent among women, populations 
of Northern Europe and/or Celtic heritage, and less frequent among Asians and African Americans 
(Steinhoff et al., 2011). In a recent systematic review using available global data on rosacea 
epidemiology (including 32 studies, 41 populations, more than 26 million individuals), the global 
prevalence of rosacea has been estimated to be 5.5%. (Gether et al., 2018). 
Based on its main clinical manifestations rosacea has been classically divided into the following four 
phenotypes: 1) erythematotelangjectatic, 2) papulopustular, 3) phymatous, and 4) ocular (Wilkin et 
al 2014, Steinhoff et al., 2013).  
Recently, a phenotype system has been developed to address shortcomings of the previous 
diagnosis and subtyping classification system. With the phenotype system, diagnosis of rosacea can 
be established by the following: either fixed centrofacial erythema or phymatous changes 
independently; or in their absence, the presence of any 2 major features (flushing, papules and 
pustules, telangiectasias and specific ocular manifestations). Minor features (burning, stinging, 
edema, dryness, scaling) are not diagnostic (Gallo et al. 2018, Tan J et. al. 2017)). The advantage 
of the latter is that it allows diagnosis and treatment more closely based on signs and symptoms as 
well as pathophysiology (Buddenkotte and Steinhoff, 2018). 
While the pathogenesis of rosacea is still largely unknown, there is convincing evidence that several 
genetic and environmental factors may contribute to the development of rosacea, such as adaptive 
and innate immune dysregulation, neurovascular changes, and chronic inflammation (Holmes and 
Steinhoff., 2017). Among the environmental factors, microorganisms and/or their products may have 
an important part in the genesis of the disease: Helicobacter pylori, Staphylococcus epidermidis, 
Chlamydia pneumoniae, Bacillus olenorius and, more convincingly, Demodex folliculorum, a skin 
parasite, have been hypothesized to have a significant role in the pathogenesis of rosacea 
(Lazaridou et al., 2011), particularly in patients with papules and pustules, the phenotype with the 
most intense inflammatory component (Holmes and Steinhoff., 2017). Thus, involvement of bacteria 
in the pathogenesis is possibly one of the reasons why antibiotics have been traditionally proven to 
be effective in patients with rosacea, particularly for the papulopustular phenotype. In addition, the 
anti-inflammatory capacity of certain antibiotics such as tetracyclines, doxycycline and minocycline, 
have been shown to reduce inflammatory mediators associated with rosacea. Systemic and topical 
metronidazole, systemic tetracyclines and macrolides and others have been used for moderate-to-
severe forms of disease, although slow-release 40mg doxycycline (a member of the tetracyclines 
family) is the only systemic antibiotic approved for this indication. However, since long-term 
treatment is needed in more severe patients, up to several months, the risk of adverse events and 
antibiotic resistance is high. at least at higher dosages. Potential other side effects of the antibiotics 
used in rosacea are summarized in a Cochrane review and include esophagitis, colitis, facial 
melasma (hard-to-treat), for example (van Zuuren 2015). 
Rosacea can be triggered by several factors including heat, hot/spicy food, chemicals, UV radiation, 
exercise, and bacteria and/or microbial products (Holmes and Steinhoff., 2017, Steinhoff 2013, 
Yamasaki 2007). In addition, it has been suggested that quantitative changes of the small intestinal 


 
 
 
 
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microflora, such as small intestinal bacterial overgrowth (SIBO) may also trigger rosacea (Parodi et 
al. 2008, Weinstock and Steinhoff 2013, Drago et al. 2016).  
SIBO is a heterogeneous syndrome and a quantitative change of the gut microbiota characterized 
by an increased number of the bacteria normally populating the small bowel. SIBO can be assessed 
using lactulose hydrogen/methane (H2/CH4) breath test (L-BT) or glucose hydrogen/methane 
(H2/CH4) breath test (G-BT).   
L-BT is a well-established non-invasive, office-based test for assessing malabsorption/fermentation 
of carbohydrates in the small intestine as a consequence of local overgrowth of bacteria. An 
increased number of intestinal bacteria results in increased carbohydrate fermentation in the gut, 
leading to the increased production of H2 (and/or CH4), eventually released with the expiratory 
breath. Breath testing consists of timed and standardized measurement of exhaled H2 and CH4 after 
the ingestion of a solution of water and lactulose. Although, classically, lactulose breath testing has 
been performed using a 4-hour collection time (Gasbarrini et al., 2009), a recent consensus (Rezaie 
et al., 2017) and the American College of Gastroenterology (ACG) clinical guideline (Pimentel et al., 
2020) suggest that a 2-hour procedure is sufficient to detect a significant abnormal colonization of 
the small intestine. Lactulose breath test is usually performed by collecting breath samples every 15 
minutes for 120 minutes (Rezaie et al., 2017). Current guidance (Rezaie et al., 2017, Pimentel et al. 
2020) recommend a rise of >20 ppm of H2 and/or >10 ppm of CH4 by 90 minutes as diagnostic for 
SIBO. However, a threshold of >10 ppm of H2 has also been used in clinical studies and associated 
with rosacea (Parodi et al., 2008), suggesting that also lower degrees of quantitative microbiota 
changes, with a rise of H2-producing bacteria may trigger rosacea, although not entirely meeting the 
current operational definition of small intestinal bacterial overgrowth. However, this need to be 
determined. 
A recent meta-analysis on the sensitivity and specificity of L-BT and G-BT has been recently 
published (Losurdo et al. 2020). This metanalysis included 4 studies performed with L-BT meeting 
the pre-specified inclusion criteria. The results showed that the pooled sensitivity of L-BT was 42.0% 
and pooled specificity was 70.6%. Slightly better results were obtained with G-BT (sensitivity 54% 
and specificity 82%).  
Rifaximin 
Rifaximin is a semi-syntetic Rifamycin-derivate with a large antimicrobial spectrum covering gram-
positive and gram-negative bacteria as well as aerobes and anaerobes (e.g. Clostridium and 
Bacteroides). Rifaximin is a member of the rifamycin class and, like the other components of the 
group, it inhibits the RNA-synthesis binding to the beta-subunit of the DNA-dependent RNA enzyme 
of bacteria.  
Rifaximin is an original molecule discovered and patented by Alfa Wassermann S.p.A. (a Company 
currently merged into Alfasigma S.p.A.) in 1980; it was first registered in Italy in 1985 as 200 mg 
tablets and 2 g/100 mL granules for oral suspension (60 mL bottle) and marketed in 1987.  
Rifaximin is currently approved in 68 countries and marketed, under several trade names, for the 
treatment of bacterial intestinal infections (200-400 mg every 6-8 hours) and for the treatment of 
hepatic encephalopathy (HE) (400 mg). In 2015, Rifaximin 550 mg three times daily was approved 
by the Food and Drug Administration agency (FDA) for treating IBS with diarrhea (IBS-D) in adults. 
The approval of rifaximin in the IBS-D setting is based on the existing understanding that one 
possible underlying cause of IBS is perturbation of the microbiome.  


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  2 7 | 9 4 
 
S y st e mi c e x p o s ur e of Rif a xi mi n f oll o wi n g or al a d mi ni str ati o n i s mi ni m al i n all p o p ul ati o n s st u di e d a n d 
it s  a cti o n  i s  m ai nl y  f o c u s e d  o n  t h e  i nt e sti n al  tr a ct.  B ei n g  virt u all y  n o n- a b s or b e d,  Rif a xi mi n  
bi o a v ail a bilit y  wit hi n  t h e  g a str oi nt e sti n al  tr a ct  i s  r at h er  hi g h,  wit h  i ntr al u mi n al  a n d  f a e c al  dr u g  
c o n c e ntr ati o n s  l ar g el y  e x c e e di n g  t h e  mi ni m al  i n hi bit or y  c o n c e ntr ati o n  v al u e s  o b s er v e d  i n  vitr o  
a g ai n st a wi d e r a n g e of p at h o g e ni c or g a ni s m. 
Rif a xi mi n i n r o s a c e a  
Pr eli mi n ar y  e vi d e n c e  s h o w s  t h at  Rif a xi mi n  m a y  h a v e  a  b e n efi ci al  eff e ct  i n  p ati e nt s  wit h  
p a p ul o p u st ul ar r o s a c e a.   
I n  a n o p e n-l a b el st u d y b y P ar o di a n d c oll a b or at or s ( P ar o di et al., 2 0 0 8), 5 2 p ati e nt s wit h r o s a c e a 
a n d eit h er p o siti v e L- B T or gl u c o s e br e at h t e st w er e r a n d o mi z e d t o r e c ei v e Rif a xi mi n 4 0 0 m g e v er y 
8 h o ur s ( 1 2 0 0 m g d ail y) ( n = 3 2) or pl a c e b o ( n = 2 0) f or 1 0 d a y s.  P ati e nt s tr e at e d wit h pl a c e b o w er e 
s u b s e q u e ntl y s wit c h e d t o Rif a xi mi n t h er a p y.  P ati e nt s u n d er w e nt a s e c o n d L- B T or gl u c o s e br e at h 
t e st a m o nt h aft er st o p pi n g t h er a p y t o a s s e s s t h e n or m ali z ati o n of t h e i nt e sti n al mi cr o bi ot a.  At t h e 
s a m e ti m e, p arti ci p a nt s u n d er w e n t a d er m at ol o gi c vi sit t o a s s e s s t h e o ut c o m e.  I n t h e Rif a xi mi n-
tr e at e d ar m, er a di c ati o n of t h e mi cr o bi ot a alt er ati o n w a s a c hi e v e d i n 2 8 of 3 2 p ati e nt s ( 8 7. 5 %) a n d 
w a s a s s o ci at e d wit h a c o m pl et e r e s ol uti o n of r o s a c e a i nfl a m m at or y l e si o n s i n 2 0 of t h e 2 8 er a di c at e d 
p ati e nt s ( 7 1. 4 %).  Si g nifi c a nt i m pr o v e m e nt of r o s a c e a w a s o b s er v e d i n 6 o ut of t h e 2 8 p ati e nt s 
( 2 1. 4 %).  Ei g ht e e n of 2 0 p ati e nt s tr e at e d wit h pl a c e b o ( 9 0 %) di d n ot s h o w a n y i m pr o v e m e nt a n d 2 
( 1 0 %) w or s e n e d ( P < 0. 0 0 1). T h e 2 0 pl a c e b o-tr e at e d p ati e nt s w er e s u b s e q u e ntl y s wit c h e d t o rif a xi mi n 
a n d 1 7 of t h e m h a d t h eir i nt e sti n al c o n diti o n er a di c at e d. I n t hi s gr o u p, a r e s ol uti o n of t h e i nfl a m m at or y 
c ut a n e o u s l e si o n s o c c urr e d i n 1 5 of t h e 1 7 of t h e l att er p ati e nt s a n d a r el e v a nt i m pr o v e m e nt i n t h e 2 
r e m ai ni n g c a s e s.  O v er all, aft er a 1 0- d a y c o ur s e of Rif a xi mi n, er a di c ati o n of t h e mi cr o bi ot a alt er ati o n 
w a s o b s er v e d i n 4 5 of 5 2 ( 8 6. 5 % ) p ati e nt s. Of t h o s e, 3 5 ( 7 8 %) a chi e v e d c o m pl et e cl e ar a n c e of t h e 
r o s a c e a i nfl a m m at or y l e si o n s a n d 8 ( 1 7. 7 %) w er e s ub st a nti all y i m pr o v e d. Aft er Rif a xi mi n tr e at m e nt, 
1 3 of 1 6 p ati e nt s wit h n e g ati v e br e at h di d n o t s h o w a n y m e a ni n gf ul i m pr o v e m e nt of r o s a c e a. 
A st u d y, p erf or m e d b y t h e s a m e r e s e ar c h gr o u p ( D r a g o et al., 2 0 1 6), s h o w e d t h at a p pr o xi m at el y 
6 5 % of t h e p ati e nt s a c hi e vi n g cli ni c al r e mi s si o n w er e still i n r e mi s si o n t hr e e y e ar s l at er.  
I n a n ot h er cli ni c al st u d y b y W ei n st o c k et al. ( W ei n st o c k a n d St ei n h off, 2 0 1 3), 2 8 of 3 2 p ati e nt s wit h 
r o s a c e a a n d s m all i nt e sti n al b a ct eri al o v er gr o wt h, d efi n e d u si n g L- B T, w er e tr e at e d wit h Rif a xi mi n.  
Of t h e m, 4 6 % s h o w e d cl e ar e d or m ar k e dl y i m pr o v e d r o s a c e a, 2 5 % r e p ort e d m o d er at el y i m pr o v e d 
r o s a c e a, a n d 1 1 % s h o w e d mil dl y i m pr o v e d r o s a c e a. All 4 p ati e nt s wit h o c ul ar r o s a c e a a n d SI B O 
r e p ort e d m ar k e d i m pr o v e m e nt. R o s a c e a w a s u n c h a n g e d i n 1 8 % of p ati e nt s. 
A n ot h er st u d y b y Gr a vi n a et al. ( Gr a vi n a et al., 2 0 1 5) f o u n d a n o n- si g nifi c a nt b e n efit of Rif a xi mi n 
( o d d s r ati o = 6. 9, 9 5 % c o nfi d e n c e i nt er v al = 0. 3 t o 1 3 6. 2), b ut t h e s a m pl e si z e w a s pr o b a bl y t o o s m all 
( N = 9) t o i nf er a n y c o n cl u si o n.     
C CI


 
 
 
 
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Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o nfi d e nti al                                                    P a g.  2 8 | 9 4 
 
T hi s b o d y of e vi d e n c e pr o vi d e s a r ati o n al e a n d a n i niti al pr o of of c o n c e pt f or t h e u s e of Rif a xi mi n i n 
t h e tr e at m e nt of r o s a c e a. 
Rif a xi mi n- EI R 
A n o v el, n ot y et m ar k et e d, d el a y e d r el e a s e f or m ul ati o n of Rif a xi mi n, Rif a xi mi n D el a y e d- R el e a s e  
( Rif a xi mi n- EI R) 2 5 0 m g t a bl et, will b e u s e d i n t hi s st u d y. Rif a xi mi n D el a y e d- R el e a s e  ( Rif a xi mi n- EI R) 
i s a p at e nt e d t e c h n ol o g y b y w hi c h a mi cr o gr a n ul ati o n of Rif a xi mi n i s c o at e d wit h a g a str o-r e si st a nt 
p ol y m er i n s ol u bl e at p H l o w er t h a n 5, i n or d er t o d el a y t h e r el e a s e of Rif a xi mi n. Rif a xi mi n- EI R h a s 
b e e n f or m ul at e d t o b y- p a s s t h e st o m a c h a n d o pti mi z e t h e eff e ct of t h e a cti v e pri n ci pl e i nt o t h e 
i nt e sti n e; t h e i nt e nt of t h e f or m ul ati o n i s i n f a ct t o pr o vi d e a m or e u nif or m c o v er a g e of t h e a cti v e dr u g 
i n t h e i nt e sti n al l u m e n a n d t o m a xi mi z e c o nt a ct wit h t h e i nt e sti n al m u c o s a. 
A  Rif a xi mi n- EI R  f or m ul ati o n  wit h  a  hi g h er  d o s e  ( 4 0 0  m g  t a bl et)  i s  c urr e ntl y  i n v e sti g at e d  i n  a  
E ur o p e a n p h a s e II tri al i n s u bj e ct s wit h m o d er at e-t o- s e v er e p a p ul o p u st ul ar r o s a c e a. I n t hi s tri al t h e 
i n v e sti g at e d d ail y d o s e s ar e 8 0 0 m g ( 4 0 0 m g BI D) a n d 1 6 0 0 m g ( 8 0 0 m g BI D).  
H o w e v er, a l o w er d o s e of Rif a xi mi n- EI R, l o w er t h a n t h o s e i n v e sti g at e d i n t h e o n g oi n g E ur o p e a n 
p h a s e II tri al (i. e. Rif a xi mi n- EI R 2 5 0 m g TI D), i s pl a n n e d t o b e m o v e d f or w ar d i n t hi s i n di c ati o n (i. e. 
p ati e nt s wit h p a p ul o p u st ul ar r o s a c e a). H o w e v er,  t h e eff e ct of t hi s l o w er d o s e, p arti c ul arl y w h e n 
a d mi ni st er e d  TI D,  h a s  n ot  y et  b e e n  a s s e s s e d.  M or e o v er,  t h e  bi o a v ail a bilit y  of  Rif a xi mi n- EI R  i n  
p ati e nt s s uff eri n g fr o m p a p ul o p u st ul ar r o s a c e a h a s n e v er b e e n i n v e sti g at e d.  
P h ar m a c o ki n eti c pr ofil e of Rif a xi mi n- EI R 
P h ar m a c o ki n eti c d at a f or Rif a xi mi n D el a y e d- R el e a s e ( Rif a xi mi n- EI R) h a v e b e e n c oll e ct e d i n h e alt h y 
v ol u nt e er s a n d p ati e nt s wit h Cr o h n’ s Di s e a s e.  
C CI
C CI


 
 
 
 
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Overall, the pharmacokinetic profile of Rifaximin-EIR is similar to that of the marketed form of 
Rifaximin, which has been extensively assessed in studies of healthy volunteers and patients with 
gastrointestinal diseases (Crohn’s disease, ulcerative colitis, pouchitis, IBS), after single and multiple 
oral doses.  
 
 
 


 
 
 
 
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5 
STUDY OBJECTIVES AND PURPOSE 
The effect of the 250 mg tablets formulation of Rifaximin-EIR, particularly when used at low dosages 
and administered three times daily (i.e. 750 mg daily, 250 mg t.i.d.), has not yet been assessed for 
the treatment of subjects with papulopustular rosacea. Moreover, the bioavailability of Rifaximin-EIR 
at doses of 750 mg or 1500 mg daily (i.e. 750 mg daily, 250 mg t.i.d. or 1500 mg daily, 500 mg t.i.d., 
respectively) in subjects with papulopustular rosacea is not known. 
  
This study is therefore aimed at: 
1) evaluating the safety and the efficacy of two different doses of Rifaximin-EIR 250 mg tablets 
(250 mg t.i.d. and 500 mg t.i.d.), administered for 30 days in subjects with moderate-to-severe 
papulopustular rosacea;  
2) evaluating the pharmacokinetics of these two doses of Rifaximin-EIR in a sub-group of 
subjects.  
 
Data collected with this study will provide key information to be used in the development of Rifaximin-
EIR 250mg tablet in rosacea. 
 
 
5.1 
Co-primary efficacy endpoint 
The following co-primary efficacy endpoints will be clinically assessed by the Investigator: 
1) Absolute change from baseline in number of rosacea inflammatory lesions (papules and 
pustules) at the end of treatment (Day 30) AND 
2) Percent of subjects showing treatment success, defined as an IGA score of 0 (clear) or 1 
(almost clear) with at least a 2-grade improvement from baseline at the end of treatment (Day 
30). 
Investigator’s Global Assessment (IGA) score 
Grade 
Description 
Amount and size of inflammatory lesions present 
0 
Clear 
None 
1 
Almost Clear 
Very few, small papules /pustules 
2 
Mild 
Few small papules/pustules 
3 
Moderate 
Several small or large papules/pustules 
4 
Severe 
Numerous small and/or large papules/pustules 
 
5.2 
Secondary endpoints 
Secondary efficacy endpoints: 
1) Mean change from Baseline (V2) in number of inflammatory lesions (papules and pustules) 
at V4. 
2) Percent of participants showing treatment success (i.e. IGA score of 0 or 1) at V3, V4. 
3) Percent of participants with IGA score of 0 (clear) at V3, V4.   
4) Change from Baseline (V2) in the following rosacea additional features at V3, V4. 


 
 
 
 
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x 
Pain, burning/stinging and itching (measured using a 0-10 cm Visual Analogue Scale 
(VAS),  
x 
telangiectasia (absent=0, mild=1, moderate=2, severe=3),  
x 
ocular manifestations (absent=0, mild=1, moderate=2, severe=3),  
x 
phymatous changes (absent=0, mild=1, moderate=2, severe=3).   
5) Change from Baseline in facial non-transient erythema at V3, V4 (absent=0, mild=1, 
moderate=2, severe=3).  
6) Change from baseline in abdominal pain score at V3, V4. 
7) Change from baseline in abdominal distension score at V3, V4. 
8) Change from baseline in bowel habit satisfaction score at V3, V4. 
9) Change from baseline in global severity of abdominal symptoms score at V3, V4. 
10) Percent of participants showing treatment success according to a Modified IGA scale 
excluding rosacea inflammatory lesions but including erythema (i.e. score of 0 or 1) at V3, 
V4. 
11) Percent of participant showing treatment success according to a Modified IGA scale including 
erythema and inflammatory lesions at V3 and V4. 
 
Pharmacokinetic assessments (PK sub-study only): 
12) Pharmacokinetics of the single dose (i.e. at Day 1 after the first dose administration) and 
the repeated doses (i.e. at Day 30 after the last dose). 
 
 
 


 
 
 
 
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6. 
OVERALL STUDY DESIGN AND PLAN 
This is a randomized, double-blind, placebo controlled, phase IIa clinical trial. 
As described in Section 16.1 (Determination of Sample Size), two hundred one (201) eligible 
subjects are planned to participate in the main study while a subgroup of minimum 18 and maximum 
36 subjects are planned to participate in the PK sub-study. A maximum of 12 (minimum 6) subjects 
per arm is established for the PK sub-study.  
At randomization visit (V2, Day 1), subjects will be 1:1:1 randomized to receiving any of the two daily 
doses of active treatment or placebo. TID doses of the assigned treatment will be administered from 
Day 1 to Day 29. On Day 30 (V3) just the first daily dose will be administered, and PK assessed.  
Patients will be stratified at randomization based on their L-BT status (negative vs. positive) and PK 
sub-study participation (yes or not). A negative L-BT is defined as a test showing an increase ≤10 
ppm of H2 by 90 minutes compared to time 0.  
 
The primary endpoint will be evaluated at end of treatment (V3, Day 30).   
Subjects participating in the PK sub-study at V3 (Day 30) will stay overnight to complete the PK 
assessments.   
Venous blood samples for PK analysis will be collected on: 
x 
Day 1: Pre1st dose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dosing. 
x 
Day 30 (V3): Pre dose (single dose in the morning), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 22, 
24, 30 hours post dosing. Blood sampling will continue until Day 31 as appropriate.  
 
Details on the procedures performed with the different recruitment options are described in Section 
11 (Study Procedures). 
 
Participants will be enrolled at approximately 40 US Centers in USA.  
 
 
 


 
 
 
 
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7. 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL 
GROUPS 
This study is a double-blind, placebo-controlled, randomized clinical trial.  
In the present phase IIa trial, the use of placebo is considered appropriate to test the effect size of 
two dosages of Rifaximin-EIR in patients with moderate-to-severe papulopustular rosacea. While 
not always the use of placebo is ethically acceptable, in this specific trial the use a placebo arm is 
deemed ethically acceptable according to the art. 33. Of the Declaration of Helsinki and the 
EMEA/17424/01. In fact, withholding/postponing the use of an established intervention for rosacea 
of approximately one month does not “entail any additional risks of any irreversible harm to the 
participant”.  
Participants in the placebo arm, the 33% of the study sample, might be exposed to a temporary 
discomfort in terms of a lack of improvement or even a slight worsening of the symptoms.  
Although, preliminary evidence shows that Rifaximin may be beneficial particularly in patients with 
rosacea and quantitative microbiota changes, considering the methodological limits of L-BT testing 
and that the role of microbiota quantitative and qualitative composition in the pathogenesis of 
rosacea has not yet been fully clarified, according to the FDA recommendation, patients with 
negative L-BT will also be enrolled. In fact, it cannot be excluded that the benefit of Rifaximin in 
patients with rosacea could be mediated by the effect of the drug on factors different from or just 
associated with SIBO. 
In any case, patients can decide to withdraw from the clinical study at any time with no penalties.  
Similarly, the Investigator can decide to withdraw the patient in his/her best interest, at any time, to 
pursue alternate treatments or no treatment at all. 
 
 
 


 
 
 
 
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8. 
BENEFIT-RISK EVALUATION 
Pharmacological and efficacy studies with Rifaximin (see Investigator’s Brochure) have shown that 
the benefits of Rifaximin include: 
x 
The negligible absorption of Rifaximin (less than 1%) means it has an excellent safety profile 
and can be administered at high doses for long period time. 
x 
No potential for either inhibition or induction of human hepatic cytochrome P450 at expected 
clinical plasma concentrations. 
x 
No drug-drug interactions with oral contraceptives at expected clinical plasma concentrations. 
x 
Rifaximin can be administered with or without food. 
x 
A large antimicrobial spectrum covering most gram-positive and -negative bacteria, including 
aerobes and anaerobes and therefore good activity against the microflora normally present in 
both the small intestine and in the colon. 
x 
Rifaximin is widely used in gastroenterology (i.e. Traveller’s diarrhoea, Hepatic Encephalopathy 
and Irritable Bowel Syndrome with diarrhoea IBS-D). 
x 
Bioavailability studies with Rifaximin-EIR 1200 mg (3 x 400 mg tablet) administered TID for 7 
days showed that absorption is negligible in subjects with Crohn’s Disease (CD). Absorption is 
negligible also in subjects with IBS receiving Rifaximin 550 mg TID for 14 days. 
x 
Rifaximin works by decreasing the triggers of immune activation as well as enteric inflammatory 
response, rifaximin may reduce the uncontrolled immune response to enteric bacteria. 
x 
Based on the available evidence summarized in a recent meta-analysis on 32 clinical trials 
through March 2015, Rifaximin is effective and safe in eradicating SIBO and resolving symptoms 
(overall success with an intention-to-treat: 70.8%) (Gatta, 2017). According to Gatta and 
colleagues, SIBO eradication rates increase linearly with increasing Rifaximin dose, in the 600-
to-1600 mg daily dose range. With regards to safety data, in the above-mentioned meta-analysis 
the 4.6% of SIBO patients treated with Rifaximin reported AEs, but only the 0.47% of them had 
to discontinue the therapy. 
x Data from randomized clinical studies, evaluating the efficacy of Rifaximin 200 mg TID (1200 
md/day) in rosacea patient’s positive for SIBO, demonstrated that eradication of SIBO induced 
an almost complete regression of cutaneous lesions among patients achieving glucose breath 
test negativity after treatment (Parodi, 2008) (Weinstock, 2013).  
 
The safety of Rifaximin evaluated in clinical trial and during post-marketing surveillance indicates 
that Rifaximin is extremely safe. In details: 
x 
The safety of Rifaximin-EIR has been evaluated in 6 studies, 3 Phase II studies involving 379 
patients with mild to moderate Crohn’s disease, 1 PK study on 18 healthy volunteers and 2 PK 
studies on 30 patients with active Crohn’s disease. The safety analysis has shown a favourable 
safety profile of Rifaximin-EIR in the treatment of mild to moderate active Crohn’s disease. 
x 
The safety of Rifaximin (200 mg or 550 mg formulations) has been extensively established in 
approximately 7000 subjects enrolled in clinical studies (IBS-D: 4020 subjects; Hepatic 
Encephalopathy: 697; Traveller’s Diarrhoea: 1527; healthy volunteers: 221) and of Rifaximin 
600 – 1800 mg in approximately 125 patients (receiving rifaximin 1100 mg/day for 2 years),  
x 
Post-marketing experience confirmed that Rifaximin is extremely safe. 
  
Overall, in clinical trials (including those investigating Rifaximin-EIR), nearly all adverse reactions 
recorded were uncommon (<1%). The most frequently reported adverse events were related to 


 
 
 
 
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gastrointestinal, nervous, skin and general disorders, in addition to those revealed by laboratory 
findings. 
The incidence of adverse events in people treated with rifaximin was comparable to or lower than 
that in the placebo-treated patients, as one would be expected from a non-absorbable antibiotic. In 
some of the cases, gastrointestinal adverse events recorded during clinical studies were also 
symptoms of the intestinal disease to be treated with the investigational drug. 
In addition to those identified during clinical trials, further potential risks may include: 
x 
Cases of Clostridium Difficile Associated Diarrhoea (CDAD) have been reported with Rifaximin 
use, ranging in severity from mild diarrhoea to fatal colitis. The potential association of Rifaximin 
treatment with CDAD and Pseudomembranous Colitis (PMC) cannot be ruled out.  
x 
Allergic reactions have also been reported during post-approval use. Systemic absorption of 
Rifaximin is approximately 0.4% of the orally administered dose; however, even these very low 
quantities are sufficient to trigger an allergic reaction, particularly in hypersensitive subjects. 
Therefore, serious unpredictable reactions such as anaphylactic shock or severe skin reactions 
may occur. 
x 
Cases of both increases and decreases in International Normalised Ratio (INR) with a temporal 
association with Rifaximin administration were reported in patients maintained on warfarin and 
Rifaximin with a temporal association with rifaximin administration. Therefore, closer INR 
monitoring and/or dose adjustment of warfarin is required around the time of Rifaximin 
administration. 
x 
In healthy subjects, clinical drug interaction studies demonstrated that rifaximin did not 
significantly affect the pharmacokinetics of CYP3A4 substrates, however, in hepatic impaired 
patients it cannot be excluded that Rifaximin may decrease the exposure of concomitant 
CYP3A4 substrates administered (e.g. antiepileptics, antiarrhythmics), due to the higher 
systemic exposure with respect to healthy subjects.  
x 
In healthy subjects, co-administration of a single dose of cyclosporine (600 mg), a potent P-
glycoprotein inhibitor, with a single dose of Rifaximin (550 mg) resulted in 83-fold and 124-fold 
increases in Rifaximin mean Cmax and AUC∞. The clinical significance of this increase in systemic 
exposure is unknown. 
x 
There is no experience regarding administration of Rifaximin to subjects affected by an 
undiagnosed systemic bacterial infection potentially treatable with rifampicin.  
 
Experts have agreed that the systemic absorption of Rifaximin is too low to select resistant strains, 
and in fact, two recent surveys carried out in Italy, where Rifaximin has been widely used since 1987, 
found no evidence of development of resistance by M. tuberculosis or N. meningitides. Therefore, 
the clinically relevant selection of cross-resistant M. tuberculosis or N. meningitides is considered 
not probable.  
 
In summary, the properties of Rifaximin, including its broad range of activity against bacteria, the 
supposed immunomodulatory activity, its low systemic availability, the excellent safety profile, the 
clinical efficacy shown in Proof of Concept studies in the treatment of rosacea, support a positive 
risk/benefit ratio.  
 
 
 


 
 
 
 
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9. 
SELECTION OF STUDY POPULATION 
9.1 
Number of Participants 
As described in Section 16.1 (Determination of Sample Size),two hundred one (201) eligible subjects 
are planned to be enrolled in the main study while a subgroup of 18-36 (a minimum of 6 and a 
maximum of 12 subjects per arm) are planned to participate in the PK sub-study.  
At the randomization visit (V2), subjects will be 1:1:1 randomized to receiving any of the two daily 
doses of active treatment or placebo. TID doses of the assigned treatment will be administered from 
Day 1 to Day 30. On day 30 (V3) just the first daily dose will be administered, and PK assessed (for 
the PK sub-study only). 
Patients will be stratified at randomization based on their L-BT status (negative vs. positive) and PK 
sub-study participation (yes or not). 
Duration of the study:  
x 
overall (including all parts of the study) approximately 14 months from sites activation;  
x 
study period for a single subject: approximately 3 months (time interval for screening, 
treatment and follow-up). 
 
9.2 
Inclusion Criteria 
All the following criteria must be met both at the Screening and Randomization visits unless 
otherwise specified. 
1. Men and women aged 18 years or older at screening (V1) 
2. Female participants are eligible if they are: 
of non-childbearing potential, i.e.: i) post-menopausal (at least 2 years without spontaneous 
menses), or ii) surgically sterile (bilateral tubal occlusion, or hysterectomy), or iii) ablation of 
both ovaries),  
or  
of childbearing potential with a negative pregnancy test result at screening and randomization 
and agreeing to use a highly effective method of contraception (i.e. with failure rate of less 
than 1% per year) until 72 hours after taking the last study treatment dose.  
Note 1. Based on Clinical Trial Facilitation Group recommendations, highly effective methods of 
contraception are the following:  
x 
intrauterine device (IUD);  
x 
intrauterine hormone-releasing systems (IUS) or;  
x 
combined hormonal contraceptives (i.e. estrogen and progestogen) in oral, intravaginal or 
transdermal form, with inhibition of ovulation as primary mode of action or; 
x 
progestogen-only hormonal contraceptives in oral, injectable or implantable form, with 
inhibition of ovulation as primary mode of action or;  
x 
absolute and continuous sexual abstinence from Day 1 included (first day of treatment) until 
72 hours after taking the last study treatment dose. 
Note 2. In each case of delayed menstrual period (over one month between menstruations), female 
participants of child-bearing potential will be strongly recommended a confirmation of absence of 
pregnancy. This recommendation applies also to women of child-bearing potential with infrequent or 
irregular menstrual cycles.  


 
 
 
 
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3. Presence of rosacea, papulopustular phenotype, defined as papules and/or nodules, with or 
without pustules of rosacea, without comedones, plus: centrofacial persistent erythema or 
phyma or transient episodic facial erythema (flushing) or facial telangiectasia (excluding peri-
alar regions) or major ocular rosacea features (i.e. lid margin telangiectasia, interpalpebral 
conjunctival injection, spade-shaped infiltrates in the cornea, scleritis and sclerokeratitis). 
4. Presence of ≥11 and ≤70 facial papules and/or pustules. 
5. Moderate (Grade 3) or severe (Grade 4) rosacea based on Investigator’s Global Assessment 
(IGA) based on Investigator’s judgement.     
6. Patients accepting to provide and legally capable of providing free and informed consent to 
all procedures included in the protocol (including facial skin photography). 
 
9.3 
Exclusion Criteria 
None of the following criteria must be met both at the Screening visit and at the Randomization visit 
(Day 1) unless otherwise specified: 
1. Granulomatous rosacea or rosacea fulminans.  
2. Erythematoteleangectatic, phymatous or ocular rosacea only. Patients with these subtypes 
associated with papulopustular rosacea can be enrolled.  
3. Rosacea with IGA grade ≤2 based on Investigator’s judgment.  
4. Anticipated need for proctoscopy or colonoscopy within two weeks after lactulose breath test. 
Note 3: Subjects undergoing unanticipated proctoscopy or colonoscopy within two weeks from 
lactulose breath test should have a thorough bowel cleansing with a non-fermentable solution. 
5. Subjects requiring a low galactose diet. 
6. Hypersensitivity or intolerance to lactulose or any excipient of the lactulose preparation to be 
used for L-BT. 
7. History of inflammatory bowel disease (Crohn’s disease or ulcerative colitis) or other 
conditions characterized by severe intestinal ulcers.  
8. History of coeliac disease. 
9. Patients with intestinal obstruction or partial intestinal obstruction. 
10. Presence of diarrhoea associated with fever and/or blood in the stool.  
11. Severe kidney impairment (i.e. estimated glomerular filtration rate <30 ml/min). 
12. Severe hepatic impairment (i.e. Child-Pugh B or C).  
13. Cancer or any cancer-related treatment within 5 years prior to screening (excluding non-
melanoma skin-cancer).  
14. History of alcohol or drug abuse within a year prior to screening, based on Investigator’s 
judgement. 
15. Facial skin conditions that can interfere with reliable assessment of rosacea throughout the 
study (e.g. facial hair, tattoos, other facial adornments, keloids, hypertrophic scarring, recent 
facial surgery, excessive sun exposure including use of tanning beds)   
16. Any other significant health condition (e.g. cardiovascular, respiratory, renal, hepatic, 
neurologic, psychiatric, hematologic, oncologic, immune etc.) or non-health condition that in 
the investigator’s judgement may: 
iv) jeopardize the patient’s safe participation in the trial or 
v) make unlikely the patient’s completion of the study or  
vi) make unlikely the patient’s compliance with the study procedures (e.g. highly 
anticipated need of non-permitted treatments, terminal illness, etc.). 


 
 
 
 
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17. History of hypersensitivity to rifaximin, rifamycin-derivatives, any of the rifaximin-EIR or 
placebo excipients. 
18. Treatment with biologic immunomodulatory and/or immunosuppressive drugs (e.g. anti-TNF 
drugs) within 6 months prior to randomization.  
19. Treatment with non-biologic immunomodulatory and/or immunosuppressive drugs (e.g. 
cyclosporine, methotrexate etc.) within 30 days prior to randomization.  
20. Treatment with warfarin (or other coumarins) within 14 days prior to randomization.  
21. Treatment with niacin within 30 days prior to randomization.   
22. Topical facial or systemic antibiotics within 30 days before randomization; 
23. Treatment with neomycin or other low-absorbable oral antibiotics (such as marketed 
rifaximin) within 90 days before randomization. 
24. Topical facial, inhaled or systemic corticosteroids within 30 days prior to randomization.  
25. Topical facial retinoids within 30 days before randomization. 
26. Systemic retinoids within 6 months before randomization. 
27. Any other topical or systemic treatment for rosacea within 30 days before randomization 
(including also laser and pulsed light, etc.). 
28. Over-the-counter intestinal or topical skin probiotics (functional food is allowed), within 30 
days before randomization. 
29. Any experimental treatment within 6 months prior to randomization. 
30. Current swab-positive or suspected (under investigation) Covid-19 infection;  
or fever and one or more of the following respiratory disease signs or symptoms: cough, 
sputum production, shortness of breath within the last 14 days;  
or contact with people with Covid-19 infection within the last 14 days.  
31. Women who are pregnant, breast-feeding or planning a pregnancy during the trial period. 
32. Subjects who are investigational site staff members and their family members, site staff 
members otherwise supervised by the investigator, or patients who are Alfasigma’s 
employees. 
 
9.4 
Premature Discontinuation from the Study per Subject 
The subject has the right to withdraw from the study at any time without providing any reason. 
Participants may be withdrawn at any time when any of the following conditions occur: 
x 
adverse events; when during the observation period adverse events occur that, in the 
Investigator’s or the patient’s opinion, are of such a nature or severity to recommend 
treatment withdrawal; 
x 
failure to comply with major requirements of the protocol (e.g. inclusion error or evidence of 
non-compliance with exclusion/inclusion criteria arisen during the study, subject misses study 
visits or/and is not compliant with key study procedures); 
x 
explicit withdrawn of patient’s consent to participate or failure to report to study visits; 
x 
patient’s loss to follow-up; 
x 
Investigator’s opinion; the Investigator may choose to withdraw a subject from the study if, in 
the investigator’s opinion, continuing the participation in the study for any reason would 
compromise the safety or well-being of the participant; 
x 
other reasons, different from the ones previously specified. 
Reason and date of patient’s withdrawal must be recorded in the Patient’s Clinical Chart and the e-


 
 
 
 
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CRF. 
The study may be terminated prematurely if: 
x 
the Sponsor feel that the number and/or severity of AEs justify discontinuation of the study; 
x 
the Sponsor considers the applied doses of the study drug to be no longer relevant; 
x 
data not known before becoming available and raise concern about the safety of the study 
drug so that continuation would pose potential risks to the subjects. 
Premature termination of the study should be mutually agreed upon by the Coordinating Investigator 
and the Sponsor and must be documented. However, study results must be reported according to 
the requirements outlined in this protocol as far as applicable. 
The data of subjects who are withdrawn will be considered for evaluation both for efficacy, PK and 
safety. 
Subjects who discontinue treatment due to SAE will be followed up until the event resolves or 
stabilises. 
Subjects withdrawn from the study will not be replaced. 
 
 
 


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  4 0 | 9 4 
 
1 0.
 T R E A T M E N T S
 
1 0. 1
 Tr e at m e nt s
 
t o
 
b e
 
A d mi ni st er e d
 
Eli gi bl e s u bj e ct s will b e all o c at e d i n a bli n d e d f a s hi o n t o o n e of t h e t hr e e tr e at m e nt gr o u p s, a c c or di n g 
t o a c o m p ut er- g e n er at e d r a n d o mi s ati o n li st. 
  
Gr o u p A: t w o t a bl et s of Rif a xi mi n- EI R 2 5 0 m g f or m ul ati o n t.i. d. ( 1 5 0 0 m g d ail y) f or 2 9 d a y s; 
o n D a y 3 0 s u bj e ct s will r e c ei v e t w o t a bl et s of Rif a xi mi n- EI R 2 5 0 m g i n si n gl e a d mi ni str ati o n 
( 5 0 0 m g d ail y). 
  
Gr o u p B: o n e t a bl et of Rif a xi mi n- EI R 2 5 0 m g f or mul ati o n t.i. d.  ( 7 5 0 m g d ail y) + o n e t a bl et of 
pl a c e b o t.i. d. f or 2 9 d a y s; o n D a y 3 0 s u bj e ct s will r e c ei v e o n e t a bl et of Rif a xi mi n- EI R 2 5 0 m g 
a n d o n e t a bl et of pl a c e b o i n si n gl e  a d mi ni str ati o n ( 2 5 0 m g d ail y). 
  
Gr o u p C: t w o t a bl et s of pl a c e b o t.i. d. f or 2 9 d a y s; o n D a y 3 0 s u bj e ct s will r e c ei v e t w o t a bl et s 
of pl a c e b o i n si n gl e a d mi ni str ati o n. 
T h e I n v e sti g at or at e a c h st u d y sit e will b e r e s p o n si bl e f or t h e h a n dli n g a n d st or a g e of t h e st u d y 
m at eri al (i n a c c or d a n c e wit h t h e S p o n s or’ s i n di c ati o n s).  
I m p ort a nt n ot e: I n v e sti g ati o n al pr o d u ct s ar e o nl y all o w e d t o b e a d mi ni st er e d t o s u bj e ct s s el e ct e d 
f or t hi s cli ni c al tri al a c c or di n g t o t h e st u d y pr ot o c ol.  
 
1 0. 2
 I n v e sti g ati o n al
 
Pr o d u ct s
 
1 0. 2. 1
 T e st
 
pr e p ar ati o n
 
Rif a xi mi n- EI R will b e s u p pli e d a s t a bl et s c o nt ai ni n g 2 5 0 m g of a cti v e i n gr e di e nt. 
 
O n e Rif a xi mi n −EI R 2 5 0 m g t a bl et ( Rif a xi mi n D el a y e d- R el e a s e t a bl et) c o nt ai n s: 
A cti v e i n gr e di e nt: rif a xi mi n 2 5 0 m g. 
 
 
.  
 
O n e pl a c e b o t a bl et c o nt ai n s: 
A cti v e i n gr e di e nt: n o n e. 
 
 
 
 
1 0. 2. 2  
L a b elli n g a n d P a c k a gi n g 
T e st dr u g a n d m at c h e d pl a c e b o b ul k m a n uf a ct uri n g will b e p erf or m e d i n Gl att Air T e c h ni q u e s I n c 2 0 
S p e ar R o a d, R a m s e y, N J 0 7 4 4 6 U S.  
All cli ni c al m at eri al will b e p a c k a g e d i n 9 5-t a bl et s b ottl e s. I n v e sti g ati o n al dr u g will b e pr o vi d e d i n 
b o x e s (“ P ati e nt’ s kit s”) i n cl u di n g t h e n u m b er of b ottl e s r e q uir e d f or a 3 0- d a y s tr e at m e nt p eri o d.  
E a c h p ati e nt kit will c o nt ai n t w o b ottl e s c h ar a ct eri z e d b y l a b el s of t w o diff er e nt c ol o ur s ( w hit e a n d 
y ell o w).  B ottl e s  wit h  l a b el s  of  diff er e nt  c ol o ur s  ( w hit e  a n d  y ell o w)  c a n  c o nt ai n  eit h er  t a bl et s  of  
Rif a xi mi n- EI R 2 5 0 m g or t a bl et s of pl a c e b o d e p e n d i n g o n t h e tr e at m e nt ar m. E a c h p ati e nt kit will 
c o nt ai n t w o b ottl e s ( o n e w hit e-l a b ell e d b ottl e a n d o n e y ell o w -l a b ell e d b ottl e) t o b e utili s e d f or t h e 2 9 
C CI
C CI


 
 
 
 
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days of t.i.d. treatment plus one single dose to be administered on Day 30. 
Glatt Air Techniques Inc., 20 Spear Road, Ramsey, NJ 07446 US will be responsible for the IMP 
release  
10.2.3 
Storage, Dispensing, Use and Disposal of the compound during and at the end of 
the study 
An adequate amount of Patient’s kits will be initially supplied to each study centre. According to the 
actual rate of recruitment of the centre, additional supplies will be performed. 
All investigational products must be kept in a locked place with restricted access and maintained 
under controlled temperature conditions at ≤ 25°C. Do not refrigerate. 
At visits V2, each eligible subject will receive a patient’s kit containing two “treatment bottles”, 
covering the treatment necessary for 30 days of study. Treatments will be assigned according to the 
randomization procedure.  
At visits V3, each patient will return to the Investigator all the unused and partially used 
investigational product and bottles contained in the treatment box assigned for the treatment.  
The Investigator must not supply the investigational product to people other than the enrolled 
subjects or the authorized study personnel in charge of distribute it. 
Under no circumstances, without written authorisation from the Sponsor, the Investigator is allowed 
to supply the study drug to other study centres (or Investigators working for other centres involved 
in the study). Similarly, the Investigator is not allowed to or will not instruct people to use or handle 
the investigational drug in a way different from that described in this protocol. 
The investigational products should be stored safely and properly, and they must not be used after 
the expiry date. 
The investigational products will be self-administered by the patient, following instruction provided 
by the Investigator or personnel authorised by the Investigator.  
The final accountability records will reconcile shipment records with those of used and returned 
investigational product. Any discrepancy will be accounted for. All unused investigational products 
will be returned or destroyed locally, based on the local regulation, but return and destruction will not 
occur until authorised by the Sponsor. 
 
10.3 
Method of Assigning Subjects to Treatment Groups / Randomisation 
A unique subject’s identification number will be assigned to all subjects consenting to be enrolled in 
the study obtained concatenating the center number with the screening number.  
A subject who fails to meet the protocol eligibility criteria will be identified as screening failure; his/her 
identification number will not be reallocated. 
Randomisation will occur at visit V2 after all baseline procedures have been performed and eligibility 
for the study has been confirmed. 
Participants will be randomised, on a 1:1:1 basis, to Rifaximin-EIR 250 mg three times a day (750 
mg daily) for 29 consecutive days and Rifaximin-EIR 250 mg single dose on Day 30, Rifaximin-EIR 
500 mg three times a day (1500 mg daily) for 29 consecutive days and Rifaximin-EIR 500 mg single 
dose on Day 30, or placebo for 30 consecutive days. 
Blocks will be used to assure treatment balance. 


 
 
 
 
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Patients will be stratified at randomization based on their L-BT status (negative vs. positive) and PK 
sub-study participation (yes or not). 
 
Randomization will occur throughout an IWR system integrated into the e-CRF.  
At V2, the randomization system will assign an individual Patient’s kit number based on a pre-defined 
randomisation list. 
The enrolment will be competitive.  
Decoding of randomization in case of emergency is described in chapter 11.4. 
The subjects will be offered participation to the PK sub-study. If they agree, they will be randomized 
according to the relevant stratum maintaining treatment balance among groups; otherwise, they will 
enter the main study. 
 
10.4 
Selection of Doses in the Study 
Based on the available evidence summarized in a recent meta-analysis, Rifaximin seems to be 
effective and safe for the treatment of intestinal dysbiosis (Gatta et al., 2017), a condition 
hypothesized triggering rosacea, showing a dose-response relationship in the dose-range between 
800 and 1600 mg per day (Gatta, 2017). 
Rifaximin-EIR 250 mg tablet will be tested in this study. Its peculiar formulation may allow a t.i.d.  
administration. Therefore, in the current study, we aim to test the minimum (750 mg daily) and 
maximum (1500 mg daily) doses that have been shown to act at pathophysiological level (e.g. SIBO 
eradication).  
In agreement with the published studies, the duration of treatment in this study will be 29 days for 
both the Rifaximin-EIR 1500 mg/daily and 750 mg/daily dosages plus Rifaximin-EIR 500mg or 
Rifaximin-EIR mg 250 mg single dose on Day 30, respectively. 
  
10.5 
Selection and Timing of Dose for each Patient 
The experimental treatment should be taken three times a day approximately 8 hours apart, in the 
morning, in the afternoon and in the evening, with a small amount of water, with or without food. 
Treatment bottles will be characterized by labels of two different colours, white and yellow.  
The participant will be instructed to start the study drug intake from the morning of V2 (Day 1), 
immediately after randomization and preferably early in the morning (around 8:00 AM), taking one 
tablet from the bottle with white label and one tablet from the bottle with yellow label, as well as one 
tablet from the bottle of white label and one tablet from the bottle of yellow label in the afternoon 
(around 4:00 PM) as well as one tablet from the bottle of white label and one tablet from the bottle 
of yellow label late in the evening (around 12:00 PM).  
Bottles with labels of different colours can contain either Rifaximin-EIR 250 mg or placebo depending 
on the assigned treatment arm.     
For the subjects included in the PK sub-study the first drug intake must be performed at the 
investigational site in occasion of the randomization visit (V2, Day 1), immediately after the first blood 
drawing (for PK analysis) and preferably early in the morning (around 8:00 AM). Also, at V3 (Day 30) 
subjects participating in the PK sub-study will stay overnight at the centre to complete the PK 
procedures.   


 
 
 
 
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10.6 
Blinding 
Blinding is intended to limit the occurrence of conscious and unconscious bias in the conduct and 
interpretation of a clinical trial arising from the influence which the knowledge of treatment may have 
on the recruitment and allocation of subjects, their subsequent care, the attitudes of subjects to the 
treatments, the assessment of end-points, the handling of withdrawals, the exclusion of data from 
analysis, and so on. 
In accordance with the double-blind design, both the Investigator and the patient will be unaware of 
the treatment being dispensed in each case. The placebo will be indistinguishable from the active 
substance, i.e. will have the same weight, appearance, colour, smell and flavour. 
Only in case of an emergency, when knowledge of the study medication is essential for the patient’s 
safety, the Investigator may unblind a patient’s treatment assignment (see section 11.4 “Decoding 
of randomisation in case of emergency”).  
 
10.7 
Treatment Compliance 
The investigational product will be provided to patients by the Investigator, who will thus monitor 
compliance at each visit. 
To monitor treatment compliance, patients will be asked to bring back the two bottles provided at the 
randomization visit (V2), including all unused tablets.  
The investigational drug supplies, the unused returned investigational drug will be duly recorded in 
the drug accountability forms, as source documents, by the authorized study centre personnel and 
then reported in the e-CRFs. Any discrepancy must be clearly documented. 
A level of compliance >80% during the treatment period will be considered satisfactory. 
 
10.8 
Prior and Concomitant Therapy 
Prohibited Treatment 
Initiation of beta-blocker treatment is not allowed from the screening visit (V1) to the end of follow-
up (Day 60; V4) included. Patients already on chronic treatment with beta-blockers at the screening 
visit can be enrolled in the study.  
Initiation of any oestroprogestinic or progestogen contraceptive or oestroprogestinic or progestogen 
replacement therapy is not allowed from V1 to V4 included. Patients already treated with 
oestroprogestinic or progestogen contraceptives or oestroprogestinic or progestogen replacement 
therapy before V1 can be enrolled in the study.   
 
The following medication will not be permitted from V1 to V4 included:  
x 
Biologic or non-biologic immunomodulatory or immunosuppressive drugs; warfarin (or other 
coumarins); niacin; topical facial or systemic antibiotic treatments; neomycin or any other 
low-absorbable oral antibiotics (such as marketed rifaximin); topical facial, inhaled or 
systemic corticosteroids; topical and systemic retinoids; any other topical or systemic 
treatment for rosacea (including also laser and pulsed light, etc.). 
x 
Any cancer-related treatment.  
x 
“Over the counter” formulations including intestinal and topical skin probiotics. 


 
 
 
 
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x 
Any other experimental treatment  
 
Concomitant Permitted Treatments 
All other medications for concomitant chronic conditions are allowed and should be maintained 
constant throughout the whole study. 
 
 
 


 
 
 
 
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11. 
STUDY PROCEDURES 
11.1 
Visit Schedule 
Social Media recruitment path only 
 
Social Media and On-site recruitment paths 
 
Screening 
Period 
Baseline/ 
Randomization 
Visit 
End of 
Treatment 
Visit 
End of 
Study Visit 
Early 
Termination 
Visit 
Unscheduled 
visit 
 
V1 
V2 
V3 
V4 
ETV 
UV 
Days 
-30 to -1 
1 
30 (±1) 
60 (±3) 
From 1 to 60 
From 1 to 60 
Written informed consent 
X 
 
 
 
 
 
Demographics collection 
and health-related 
behaviour assessment 
X 
 
 
 
 
 
Relevant rosacea-
associated medical history 
X 
 
 
 
 
 
Relevant non-rosacea-
associated medical history 
X 
 
 
 
 
 
Previous and Concomitant 
medications 
X 
X 
X 
X 
X 
X 
Adverse events collection 
X 
X 
X 
X 
X 
X 
Vital signs (heart rate, 
blood pressure, body 
temperature) 
X 
X 
X 
X 
X 
X 
Weight, Height* and BMI 
 
X 
X 
 
X 
 
Complete Physical 
Examination 
X 
X 
X 
X 
X 
X 
 
Remote Data Recording 
(via study website) 
Central Reader 
Validation 
Phone contact for 
scheduling clinic visit 
Visits 
V0 
 
 
Days 
 
Within 2 working 
days from V0 
Within 1 week after C. 
Reader validation  
Online pre-screening consent  
X 
 
 
Contact details, demographics, health 
related behaviour 
X 
 
 
Medical and surgery history questionnaire 
X 
 
 
Concomitant medications questionnaire 
X 
 
 
Face images upload 
X 
 
 
Preliminary compliance with 
inclusion/exclusion criteria 
 
X 
X 
Study description to the subject 
 
 
X 
Decision recording 
 
 
X 
Appointment set-up 
 
 
X 


 
 
 
 
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Rosacea-associated facial 
inflammatory lesion count 
(papules and pustules)  
X 
X 
X 
X 
X 
X4 
Five-points Investigator’s 
Global Assessment (IGA) 
of Rosacea Severity 
X 
X 
X 
X 
X 
X4 
Evaluation of erythema, 
telangiectasia, ocular 
manifestations and 
phymatous changes    
X 
X 
X 
X 
X 
X4 
Visual Analogue Scale 
(VAS) for pain, 
burning/stinging and 
itching  
X 
X 
X 
X 
X 
X4 
Abdominal symptoms 
questionnaire (IBS-SSS)1 
 
 
 
 
 
 
Dermatology Life Quality 
Index Questionnaire1 
 
 
 
 
 
 
Clinical chemistry, 
haematology, urinalysis  
X 
 
X 
X 
X 
X4 
Contraception 
recommendations and/or 
adherence^ 
 
X 
 
 
 
 
Serum pregnancy test^ 
X 
 
 
 
 
 
Urine pregnancy test^ 
 
X 
X 
X 
X 
X4 
Lactulose Breath test 
X 
 
X 
 
X 
X4 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Blood sampling for PK 
analysis^^ 
 
X2 
X3 
 
 
 
Overnight stay^^ 
 
 
X 
 
 
 
Drug dispensing 
 
X 
 
 
 
 
Drug accountability 
 
 
X 
 
X 
 
 
*Height will be recorded at V1 only;   ^Women of child-bearing potential only;  
^^ Only in subjects participating in the PK sub-study; 
1To be collected every 10 days, starting from V2 up to V4, and recording patient’s responses through an 
electronic diary (ePRO). 
2Sampling to be performed right before and after the first morning dose of Rifaximin-EIR at V2 (Day 1) at the 
following time points: immediately pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dosing.  
3Sampling to be performed right before and after the morning dose of Rifaximin-EIR on day 30 at the following 
time points: immediately pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6 and 8, 12, 22, 24, 30 hours post-dosing (single 
dose at Day 30). The sampling started at V3 (Day 30) and will end after overnight stay, as appropriate. 
4If judged necessary by the Investigator  
 
 


 
 
 
 
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11.2 
Study Evaluations/Procedures 
Procedures for Social Media recruitment path 
Specific advertisements targeted to rosacea subjects posted in selected social media will re-direct 
subjects interested in participating to a dedicated study website. 
 
11.2.1. Remote data recording (visit V0)  
In a dedicated study website, a prospective participant will be asked to:  
x 
review a concise study description; 
x 
provide online pre-screening consent;  
x 
provide contact details;  
x 
provide demographics (e.g. age, gender, ethnicity, educational level, profession, etc.); 
x 
provide data on health-related behaviour (e.g. smoking, alcohol consumption);  
x 
complete an online medical history and concomitant medication questionnaire;  
x 
upload either three pictures of their face (one frontal and two lateral [right and left side] 
photos) or a short video of the face.  
 
11.2.2 Central Reader Validation 
This task will be performed no later than 2 working days after V0. A Central reader (expert 
dermatologist) will: 
x 
check preliminary compliance with inclusion/exclusion criteria based on the 
o review of personal and clinical data (including medical history, concomitant 
medications etc.) posted on the website,   
o review of patient’s images downloaded on the website,   
x 
address all the suitable pre-screened candidates to the closest investigational site for 
scheduling the remote screening. The Study Navigator may assist with referring the 
candidates to the closest investigational site after the central reader confirms the candidates’ 
preliminary eligibility.  
 
11.2.3 Phone Contact with the Subject 
This task will be performed no later than 1 week after the candidate validation has been occurred.  
The investigational team will call the prospective participant and in case the subject accepts to move 
forward, a clinic visit will be scheduled. If the site considers also to perform the lactulose breath test 
(L-BT) at the clinic in this occasion, detailed patient’s instruction on L-BT preparation will be provided. 
In case the subject does not accept to move forward, the investigational site will record the reason 
for refusing participation. 
 
Procedures for On-site recruitment path 
Subjects presenting at the Investigational Site with moderate or severe papulopustular rosacea will 
be informed about the possibility to participate in the trial and if they are interested the Investigator 
will provide further information on the study and, if the subject is interested to participate, will 
schedule the Screening visit at the Investigational site (V1, see below). 
 
 
Common procedures for both Social Media and On-site recruitment paths 


 
 
 
 
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11.2.4 Screening Visit (V1, from Day -30 to Day -1)  
The following procedures will be performed during the screening period: 
1. 
Informed consent process and signature of the informed consent form (ICF). For subjects 
participating in the PK sub-study, the “PK-specific” consent signature should also be 
collected; 
2. 
Demographics collection (age, sex, race) and health-related behaviour assessment 
(smoking habit, alcohol consumption, alcohol or drug abuse); 
3. 
Relevant rosacea-associated medical history collection (including but not limited to family 
history for rosacea, age of onset etc.);  
4. 
Relevant non-rosacea-associated medical history collection (attention will be paid to those 
medical conditions included in the exclusion criteria;  
5. 
Record of previous and concomitant medications (attention will be paid to drug-associated 
exclusion criteria and prohibited treatments);  
6. 
Vital signs recording (heart rate, blood pressure, body temperature); 
7. 
Complete physical examination (including also measurement of height); 
8. 
Rosacea-associated facial skin inflammatory lesion count (i.e. papules and pustules); 
9. 
Five-points Investigator’s Global Assessment (IGA) of Rosacea Severity; 
10. Other rosacea-associated lesions assessment (i.e. facial erythema, facial telangiectasia, 
ocular manifestations, phymatous changes); 
11. Visual analogue scale (VAS) for pain, burning/stinging and itching; 
12. Blood collection and performance of the following laboratory tests (to be performed as close 
as possible to the randomisation visit [V2]):  
x 
haematological tests (haematocrit, haemoglobin, red blood cell count, white blood cell 
count with differential count, platelet count) 
x 
clinical chemistry tests (glycaemia, total cholesterol, triglycerides, serum creatinine, 
urea (or BUN), sodium, potassium, chloride, AST, ALT, Gamma-GT, alkaline 
phosphatase, total and fractioned bilirubin, erythrocyte sedimentation rate)  
x 
if not provided by the local laboratory, estimation of glomerular filtration rate 
x 
C-reactive protein 
9. 
Urinalysis (specific gravity, pH, protein, glucose, ketones, haemoglobin, nitrite [if available], 
bilirubin, urobilinogen, and microscopic examination [if available]); 
10. Serum pregnancy tests (women of child-bearing potential only); 
11. Lactulose Breath Test (L-BT): L-BT can be performed either at the study centre under 
Investigator’s supervision or directly by the subject at subject’s home. In both cases, the test 
has to be performed within 14 days before the randomization visit (V2);  
12. Check of inclusion and exclusion criteria; 
13. Schedule Randomization visit (V2, if eligible); 
14. Start Adverse Events collection. 
 
11.2.5 Randomization Visit (V2, Day 1) 


 
 
 
 
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The following procedures will be performed at the randomization visit: 
Procedures for all eligible patients:  
1. 
Concomitant medications recording (change from the previous visit, attention will be paid 
to prohibited treatments); 
2. 
Vital signs recording (heart rate, blood pressure, body temperature); 
3. 
Complete physical examination (including also weight and BMI); 
4. 
Urine pregnancy tests (women of child-bearing potential only);  
5. 
Contraception recommendations and/or adherence (women of child-bearing potential only); 
6. 
Rosacea-associated facial skin inflammatory lesion count (i.e. papules and pustules); 
7. 
Five-points Investigator’s Global Assessment (IGA) of Rosacea Severity; 
8. 
Other rosacea-associated lesions assessment (i.e. facial erythema, facial telangiectasia, 
ocular manifestations, phymatous changes); 
9. 
Visual analogue scale (VAS) for pain, burning/stinging and itching; 
10. Confirmation of inclusion and exclusion criteria; 
11. Randomization (if still eligible); 
12. Instruct the subject on how to complete the electronic Patient Reported Outcome (ePRO), 
which encompasses the abdominal symptoms questionnaire (IBS-SSS) and Dermatology 
Life Quality Index questionnaire (DLQI). 
13. Start of recording IBS-SSS related answers to be collected every 10 days through ePRO up 
to visit V4; 
14. Start of recording DLQI related answers to be collected every 10 days through ePRO up to 
visit V4; 
15. Treatment dispensing (if subject has been randomised);  
16. Adverse Events collection. 
 
Additional procedures for eligible patients participating also in the PK sub-study  
17. Collection of blood samples for PK analysis; 
18. On-site administration of the first investigational drug dose (it must be performed early in the 
morning after the baseline blood drawing). 
 
11.2.6 End of Treatment Visit (V3, Day 30+1) 
The following procedures will be performed at End of Treatment visit: 
Procedures for all randomized patients:  
1. Concomitant medications recording (change from the previous visit); 
2. Vital signs recording (heart rate, blood pressure, body temperature); 
3. Complete physical examination (including also weight and BMI); 
4. Urine pregnancy tests (women of child-bearing potential only);  
5. Rosacea-associated facial skin inflammatory lesion count (i.e. papules and pustules); 
6. Five-points Investigator’s Global Assessment (IGA) of Rosacea Severity; 
7. Other rosacea-associated lesions assessment (i.e. facial erythema, facial telangiectasia, 
ocular manifestations, phymatous changes); 


 
 
 
 
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8. Visual analogue scale (VAS) for pain, burning/stinging and itching; 
9. Blood collection and performance of the following laboratory tests:  
x 
haematological tests (haematocrit, haemoglobin, red blood cell count, white blood cell 
count with differential count, platelet count) 
x 
clinical chemistry tests (glycaemia, total cholesterol, triglycerides, serum creatinine, 
urea (or BUN), sodium, potassium, chloride, AST, ALT, Gamma-GT, alkaline 
phosphatase, total and fractioned bilirubin, erythrocyte sedimentation rate)  
x 
if not provided by the local laboratory, estimation of glomerular filtration rate 
x 
C-reactive protein 
x 
Urinalysis (specific gravity, pH, protein, glucose, ketones, haemoglobin, nitrite [if 
available], bilirubin, urobilinogen, and microscopic examination [if available]); 
10. Check subject’s recording of IBS-SSS and DLQI questionnaires via ePRO (to be ended on 
visit V4); 
11. Lactulose Breath Test (L-BT): L-BT can be performed either at the study centre under 
Investigator’s supervision or directly by the subject at subject’s home. In the latter case, the 
test has to be performed within 3 days after the V4 visit;  
12. Adverse Events collection; 
13. Study drug accountability. 
 
Additional procedures for randomized patients participating also in the PK sub-study  
14. Collection of blood samples for PK analysis; 
15. Administration of the last investigational drug dose (it must be performed early in the morning 
after the baseline blood drawing); 
16. Overnight stay (discharge on Day 31 after the last blood drawing). 
 
11.2.7 End of Study Visit (V4, Day 60+3) 
The following procedures will be performed at the V4 visit: 
1. Concomitant medications recording (change from the previous visit); 
2. Vital signs recording (heart rate, blood pressure, body temperature); 
3. Complete physical examination; 
4. Urine pregnancy tests (women of child-bearing potential only);  
5. Rosacea-associated facial skin inflammatory lesion count (i.e. papules and pustules); 
6. Five-points Investigator’s Global Assessment (IGA) of Rosacea Severity; 
7. Other rosacea-associated lesions assessment (i.e. facial erythema, facial telangiectasia, 
ocular manifestations, phymatous changes); 
8. Visual analogue scale (VAS) for pain, burning/stinging and itching;  
9. Blood collection and performance of the following laboratory tests:  
x 
haematological tests (haematocrit, haemoglobin, red blood cell count, white blood cell 
count with differential count, platelet count) 
x 
clinical chemistry tests (glycaemia, total cholesterol, triglycerides, serum creatinine, 
urea (or BUN), sodium, potassium, chloride, AST, ALT, Gamma-GT, alkaline 
phosphatase, total and fractioned bilirubin, erythrocyte sedimentation rate)  


 
 
 
 
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x 
if not provided by the local laboratory, estimation of glomerular filtration rate 
x 
C-reactive protein 
x 
Urinalysis (specific gravity, pH, protein, glucose, ketones, haemoglobin, nitrite [if 
available], bilirubin, urobilinogen, and microscopic examination [if available]); 
10. Check subject’s recording of IBS-SSS and DLQI questionnaires via ePRO; 
11. Last recording of IBS-SSS and DLQI questionnaires through ePRO; 
12. Adverse Events collection; 
13. End of study. 
 
11.2.8 Early Termination Visit (ETV, from Day 1 to Day 60) 
The following procedures will be performed at the ETV visit: 
1. Concomitant medications recording (change from the previous visit); 
2. Vital signs recording (heart rate, blood pressure, body temperature); 
3. Complete physical examination (including also weight and BMI); 
4. Urine pregnancy tests (women of child-bearing potential only);  
5. Rosacea-associated facial skin inflammatory lesion count (i.e. papules and pustules); 
6. Five-points Investigator’s Global Assessment (IGA) of Rosacea Severity; 
7. Other rosacea-associated lesions assessment (i.e. facial erythema, facial telangiectasia, 
ocular manifestations, phymatous changes); 
8. Visual analogue scale (VAS); 
9. Blood collection and performance of the following laboratory tests:  
x 
haematological tests (haematocrit, haemoglobin, red blood cell count, white blood cell 
count with differential count, platelet count) 
x 
clinical chemistry tests (glycaemia, total cholesterol, triglycerides, serum creatinine, 
urea (or BUN), sodium, potassium, chloride, AST, ALT, Gamma-GT, alkaline 
phosphatase, total and fractioned bilirubin, erythrocyte sedimentation rate)  
x 
if not provided by the local laboratory, estimation of glomerular filtration rate 
x 
C-reactive protein 
x 
Urinalysis (specific gravity, pH, protein, glucose, ketones, haemoglobin, nitrite [if 
available], bilirubin, urobilinogen, and microscopic examination [if available]); 
10. Recording of IBS-SSS and DLQI questionnaires via ePRO; 
11. Lactulose Breath Test (L-BT): L-BT can be performed either at the study centre under 
Investigator’s supervision or directly by the subject at subject’s home. In the latter case, the 
test has to be performed within 3 days after the ETV visit; 
12. Adverse Events collection. 
 
11.2.9 Unscheduled Visit (UV, from Day 1 to Day 60) 
The following procedures will be performed at the UV visit: 
1. Concomitant medications recording; 
2. Vital signs recording (heart rate, blood pressure, body temperature); 
3. Complete physical examination; 


 
 
 
 
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4. Urine pregnancy tests (women of child-bearing potential only), if judged necessary by the 
Investigator;  
5. Rosacea-associated facial skin inflammatory lesion count (i.e. papules and pustules), if 
judged necessary by the Investigator; 
6. Five-points Investigator’s Global Assessment (IGA) of Rosacea Severity), if judged 
necessary by the Investigator; 
7. Other rosacea-associated lesions assessment (i.e. facial erythema, facial telangiectasia, 
ocular manifestations, phymatous changes), if judged necessary by the Investigator; 
8. Visual analogue scale (VAS), if judged necessary by the Investigator; 
9. Blood collection and performance of the following laboratory tests, if judged necessary by 
the Investigator:  
x 
haematological tests (haematocrit, haemoglobin, red blood cell count, white blood cell 
count with differential count, platelet count) 
x 
clinical chemistry tests (glycaemia, total cholesterol, triglycerides, serum creatinine, 
urea (or BUN), sodium, potassium, chloride, AST, ALT, Gamma-GT, alkaline 
phosphatase, total and fractioned bilirubin, erythrocyte sedimentation rate)  
x 
if not provided by the local laboratory, estimation of glomerular filtration rate 
x 
C-reactive protein 
x 
Urinalysis (specific gravity, pH, protein, glucose, ketones, haemoglobin, nitrite [if 
available], bilirubin, urobilinogen, and microscopic examination [if available]); 
10. Lactulose Breath Test (L-BT), if judged necessary by the Investigator; 
11. Adverse Events collection. 
 
 
11.3 
Laboratory Tests 
During the study period, it can be estimated that a total volume of approximately 132 ml of blood for 
each patient will be drawn. 
 
Haematology, chemical chemistry 
The standard procedures to perform laboratory analyses will be followed, and the usual amount of 
blood necessary to carry out the tests will be taken. The following tests will be analysed by the local 
clinical laboratory, unless otherwise indicated.  
x 
Approximately 20 ml of blood will be drawn three times (at V1, V3 and V4 visits, for total of 
60 ml) during the study period to perform standard laboratory tests (haematology and 
standard chemistry): 
o Laboratory tests (haematocrit, haemoglobin, red blood cell count, white blood cell count 
with differential count, platelet count, glycaemia, total cholesterol, triglycerides, serum 
creatinine, urea (or BUN), sodium, potassium, chloride, AST, ALT, Gamma-GT, alkaline 
phosphatase, total and fractioned bilirubin, erythrocyte sedimentation rate and C reactive 
protein) will be performed at the screening visit (V1), at the end of treatment visit (V3) 
and at the end of the study (V4) to assess systemic tolerability.  
Glomerular Filtration Rate will be estimated at the screening visit only for enrolment 
purposes.  


 
 
 
 
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o At the screening visits, other 5 ml of blood (approximately) will be collected to perform a 
serum pregnancy test (serum human chorionic gonadotropin assay). 
 
PK assessment  
Only for those subjects participating in the PK sub-study, additional 132 ml of blood will be drawn 
during the study for the following pharmacokinetic evaluations:  
x 
At randomization (V2, Day 1), sampling will be performed before and after the first morning 
dose of Rifaximin-EIR at the following time points: immediately pre-dose and at 0.5, 1, 1.5, 
2, 3, 4, 6, 8 hours post-dosing.  
x 
At the end of treatment (V3, Day 30), sampling will be performed right before and after the 
morning dose of Rifaximin-EIR at the following time points: immediately pre-dose and at 0.5, 
1, 1.5, 2, 3, 4, 6 and 8, 12, 22, 24, and 30 hours post-single dose at day 11 (the sampling 
started at V3 will end after overnight stay, as appropriate). 
PK samples handling procedures 
The whole process of blood sampling, processing and storage of plasma samples collected from the 
subjects participating in the PK sub-study is detailed below. 
Blood tube 
A 6 mL Vacutainer tube (or equivalent) containing Na-Heparin 
as anticoagulant 
 
Blood handling and 
processing  
Draw about 6 mL blood into the tube (the first 0.5 mL of blood 
withdrawn via cannula will be discarded), invert tube gently to 
mix and place immediately in ice/water bath. Centrifuge at 4°C 
at 1500g for 10 min within 1h from collection. 
Plasma aliquot 
volumes 
 
Aliquot plasma evenly into two (2) polypropylene cryovial 
tubes. One aliquot should be retained at the site. 
Plasma storage 
conditions 
Store at below -65°C until transfer and ship on dry ice. 
Samples will be analyzed within 185 days from the date of collection. 
 
Urinalysis  
Urinalysis (visual examination (specific gravity, pH, protein, glucose, ketones, haemoglobin, nitrite [if 
available], bilirubin, urobilinogen, microscopic examination [if available]) will be performed at the 
screening visit (V1), at the end of treatment visit (V3) and at the end of follow-up visit (V4) to assess 
systemic tolerability.  
Urine pregnancy test will be performed on the sample of urines collected at V2, V3 and V4.  
 
 
Lactulose breath test 
Lactulose Breath Test (L-BT) is a non-invasive test for assessing malabsorption/fermentation of 
carbohydrates in the small intestine as consequence of SIBO. Overgrowth of colonic bacteria results 
in increased carbohydrate fermentation in the gut, leading to a production of hydrogen (H2) and 
methane (CH4), eventually released with the expiratory breath. Breath testing consists of times and 
standardised measurement of exhaled H2 and CH4 after the ingestion of a solution of water and 
lactulose. Although classical L-BT has been performed using a 4-hour collection time (Gasbarrini et 


 
 
 
 
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al. 2009), a recent consensus suggests that a 2-hour procedure is sufficient to detect a significant 
small intestine colonization (Rezaie et al. 2017). 
During the screening period (V1), L-BT will be performed to all subject recruited for participating to 
the clinical study within the last 2-weeks before randomization (V2). Lactulose breath test will be also 
repeated at the end of treatment (V3) or at the Early Termination Visit (if applicable) within 3 days 
from the Visit. 
L-BT can be performed either at the study center or directly by the subject at home. All study subjects 
will be advised to follow dietary restrictions and life-style habits required for the test performance (i.e. 
avoid complex carbohydrate rich diets one day before the test, 12-hours as fasting period, smoking 
and physical exercise were not allowed 2-hours before and during the test, etc.). 
Study investigators will be instructed on how to accurately inform subjects to perform L-BT.  
In summary, a first breath sample will be collected to evaluate the basal breath of H2 level (in ppm) 
after a 12-hours of fasting. Thereafter, subjects will be asked to drink a 10-grams of lactulose 
solution. Subsequently, levels of breath H2 and CH4 will be estimated every 15-20 minutes for a total 
duration of 120 minutes.  
After timely delivery, H2 and CH4 levels will be determined by a centralised laboratory (Quintron). 
11.3.1 
Handling of Biological Samples  
Blood and urine sample for hematology, chemical chemistry, and urinalysis will be handled according 
to a centralized laboratory procedure. Breath samples for centralized L-BT will be handled according 
to directions provided in a separate “Centralized Laboratory Test Manual”. Detailed instructions for 
managing blood samples for PK analysis will be also provided in a separate “PK Laboratory Manual”. 
 
11.4 
Decoding of randomisation in case of emergency 
The overall randomization code will be broken by the Sponsor at the study end, once all final clinical 
data have been entered onto the database and all data queries have been resolved.  
During the study, ONLY the Sponsor’s Pharmacovigilance (PV) may unblind, and ONLY for safety 
reasons upon PV Clinical Safety Unit Manager and EU-QPPV decision or for regulatory purposes 
(when SUSAR has to be submitted to RAs and ECs). 
Only in the case of an emergency safety issue, the Investigator may unblind a subject’s treatment 
assignment, when knowledge of the study medication is essential for the clinical management or 
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After the emergency blind-breaking, the Investigator must notify the unblind, as soon as possible, to 
the PV Clinical Safety Unit Manager without share the treatment information to other people involved 
in the study (see contact details in the “Emergency Instructions” chapter at the beginning of the 
protocol). In addition, the Investigator will record the date and reason for revealing the blinded 
treatment assignment for that subject in the appropriate data collection tool. 
As a rule, the Investigator can break the blind using the online tool embedded in the eCRF system.  
The blindness should be maintained for persons responsible for the ongoing conduct of the study 
(such as management, monitors, sub-investigators); if not the subject must be withdrawn from the 
study and procedures accompanying withdrawal are to be performed. In cases where there are 
ethical reasons for the patient to remain in the study, the Investigator must obtain specific approval 
from the Sponsor for the subject to continue in the study. 
 
11.5 
Subject Diary 
Diary data will be collected and reviewed throughout the course of the study through an electronic 
Patient Reported Outcome (ePRO) from the randomization visit until the end of the follow up period 
(30 days after last dose). The subjects will fill the diary information regarding gastrointestinal 
symptoms (IBS-SSS questionnaire) and dermatologic quality of life (DLQI questionnaire) every ten 
days from V2 to V4 (included). 
This e-PRO will be integrated in the electronic data capture system utilized for the collection of all 
the other study data. The clinical site staff will review periodically the e-PRO data collected and in 
case of missing data will be responsible for reminding the subject about appropriate completion. The 
diary data collected during the different study periods will be also revised by the clinicians in occasion 
of each scheduled study visit.  
 
 
 


 
 
 
 
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12. 
EFFICACY AND SAFETY ASSESSMENTS 
12.1 
Assessment of efficacy 
Rifaximin-EIR has currently being investigated in a phase 2 trial in subjects with rosacea and positive 
L-BT at daily doses of 800mg (400 mg b.i.d.) and 1600mg (800 mg b.i.d.). A lower dose of Rifaximin-
EIR, lower than those investigated in this ongoing trial (i.e. 250 mg t.i.d., overall 750mg daily), is 
planned to be moved forward in this indication. However, the effect on rosacea lesions of this lower 
dose, particularly when administered t.i.d., has not yet been assessed. Moreover, known the 
bioavailability of Rifaximin-EIR in patients with papulopustular rosacea has not been investigated.  
This study is therefore aimed at: 
1) exploring the safety and efficacy of two doses of oral Rifaximin-EIR (750 mg/day and 1500 
mg/day) versus placebo in adult subjects with moderate-to-severe papulopustular rosacea, 
and  
2) in a sub-group of subjects, evaluating the PK of two doses of Rifaximin-EIR 250 mg tablet 
(250 mg t.i.d. [750 mg/daily] and 500 mg t.i.d. [1500 mg/daily])  
administered t.i.d. for 29 consecutive days and one last morning dose on Day 30.  
Data collected with this study will provide key information to be used in the development of Rifaximin-
EIR in rosacea. 
12.1.1 
Primary Efficacy Endpoint 
Co-primary efficacy endpoint: 
The following co-primary efficacy endpoints will be clinically assessed by the Investigator: 
1) Absolute change from baseline in number of rosacea inflammatory lesions (papules and 
pustules) at the end of treatment (V3, Day 30) AND 
2) Percent of subjects showing treatment success, defined as an IGA score of 0 (clear) or 1 
(almost clear) with at least a 2-grade improvement from baseline (V2) at the end of treatment 
(V3, Day 30). 
Investigator’s Global Assessment (IGA) score 
Grade 
Description 
Amount and size of inflammatory lesions present 
0 
Clear 
None 
1 
Almost Clear 
Very few, small papules /pustules 
2 
Mild 
Few small papules/pustules 
3 
Moderate 
Several small or large papules/pustules 
4 
Severe 
Numerous small and/or large papules/pustules 
 
12.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints: 
1) Mean change from Baseline (V2) in number of inflammatory lesions (papules and pustules) 
at V4; 
2) Percent of participants showing treatment success (i.e. IGA score of 0 or 1) at V3 and V4; 


 
 
 
 
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3) Percent of participants with IGA score of 0 (clear) at V3 and V4;   
4) Change from Baseline (V2) in the following rosacea additional features at V3 and V4: 
x 
pain, burning/ stinging and itching (measured using a 0-10 cm Visual Analogue Scale 
(VAS)),  
x 
telangiectasia (absent=0, mild=1, moderate=2, severe=3),  
x 
ocular manifestations (absent=0, mild=1, moderate=2, severe=3),  
x 
phymatous changes (absent=0, mild=1, moderate=2, severe=3).   
5) Change from Baseline in facial non-transient erythema at V3 and V4 (absent=0, mild=1, 
moderate=2, severe=3);  
6) Change from baseline in abdominal pain score at V3, V4; 
7) Change from baseline in abdominal distension score at V3, V4; 
8) Change from baseline in bowel habit satisfaction score at V3, V4; 
9) Change from baseline in global severity of abdominal symptoms score at V3, V4. 
10) Percent of participants showing treatment success according to a modified IGA scale 
excluding papules/pustules but including erythema (i.e. score of 0 or 1) at V3 and V4. 
11) Percent of participant showing treatment success according to a Modified IGA scale 
including erythema and papules/pustules at V3 and V4. 
 
Pharmacokinetic assessments (PK sub-study only): 
12) Pharmacokinetics of the single dose (i.e. at Day 1 after the first dose administration) and 
the repeated doses (i.e. at Day 30 after the last dose) of Rifaximin-EIR 250 mg.  
 
Clinical assessment of rosacea lesions 
 
At each study visits (from V1 to V4 [or ETV]) the Investigators will perform a clinical assessment of 
the rosacea facial skin lesions. The following evaluation will be performed:  
x 
Number of papules and pustules;  
x 
Presence and severity of erythema (absent=0, mild=1, moderate=2, severe=3); 
x 
Presence and severity of telangiectasia (absent=0, mild=1, moderate=2, severe=3);  
x 
Presence and severity of ocular manifestations (absent=0, mild=1, moderate=2, severe=3);  
x 
Presence and severity of phymatous changes (absent=0, mild=1, moderate=2, severe=3).   
The assessment will be performed in 3 areas of the face and reported in the Rosacea Patient Lesion 
Assessment form (see Appendix 4).    
Patients will be asked by the Investigators to perform a “Pain, Burning or stinging and itching” self-
evaluation at each study visits (from V1 to V4 [or ETV]) using a 0-10 cm Visual Analogue Scale VAS) 
(see Appendix 5). 
Investigators will also be required to provide a global assessment using the Investigator 
Investigator’s Global Assessment (IGA) of Rosacea Severity (see Appendix 1) as well as Modified 
IGA scales (see Appendices 2 and 3) to be reported in the Rosacea Patient Lesion Assessment form 
(Appendix 4).  
In order to standardize assessment, Investigators will be instructed on how to perform the evaluation 
and visual aids with photographs of different lesion severity will be provided.   


 
 
 
 
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Five-point Investigator’s Global Assessment (IGA) Scale 
The Investigator’s Global Assessment (IGA) scoring system utilized in the study is a re-formatting of 
a Standardized Grading System used for grading of rosacea severity. The Standardized Grading 
System provides a widely used basic framework for disease quantification (see Appendix 1). 
Visual Analogue Scale (VAS) 
A Visual Analogue Scale is a psychometric measuring tool meant to document the characteristics of 
a symptom severity in individual patients and is used to obtain a statistically measurable 
classification of symptom severity. In the present study, a 10 cm VAS (a straight 10 cm horizontal 
line where the left-hand side end represents the presence of “no pain, stinging/burning or itching” 
and the right-hand side end represents the “worst pain, stinging/ burning or itching ever 
experienced”) will be used to document the presence/severity of pain, burning/stinging or itching in 
participants with rosacea. Patients will be instructed to mark on the line the point that they feel 
represents their perception of their current state. The measure (in cm and millimetres) of the distance 
between the left-hand side end and the patient’s mark will be the measure of the symptom (see 
Appendix 5).   
Irritable Bowel Syndrome - Symptom Severity Scale (IBS-SSS)  
IBS-SSS is the most frequently used severity measure for evaluating IBS severity. Items relate to 
pain, bowel dysfunction and overall well-being. This is a composite score of abdominal pain, number 
of days with abdominal pain, bloating/distension, satisfaction with bowel habits, and IBS-related 
quality of life (QoL). The IBS-SSS questionnaire consists of 5 questions referred ‘‘to the last ten 
days’’ (see Appendix 6).  
Dermatology Quality of Life Index (10-item DLQI) 
The Dermatology Life Quality Index (DLQI) represents a valuable method for measuring the impact 
of skin disease on patients’ lives. The DLQI consists of 10 questions concerning symptoms and 
feelings, daily activities, leisure, work, and school, personal relationships and treatment. Each 
question is answered by a tick box: ‘‘not at all’’, ‘‘a little’’, ‘‘a lot’’ or ‘‘very much’’. Each question is 
scored from 0 to 3 and the scores summed, giving a range from 0 (no impairment of life quality) to 
30 (maximum impairment). All the questions are referred ‘‘to the last week’’. The DLQI was designed 
to be used in adults over the age of 18 years. Information belonging from DLQI can enhance the 
quality of care provided (see Appendix 7). 
 
12.2 Assessment of safety 
Safety will be evaluated by collecting the following parameters: 
x 
Complete Physical Examination including height, weight, BMI;  
x 
Vital signs (including heart rate, blood pressure, and body temperature);  
x 
Routine laboratory parameters (haematology, coagulation, biochemistry, urinalysis, serum 
and urine pregnancy tests);  
x 
Adverse events (AEs);  


 
 
 
 
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x 
Withdraw of subjects from study due to adverse events.    
Accurate monitoring of adverse events will be performed by each Investigator by questioning the 
patient, at each visit during treatment, and on the final assessment visit.  
  
12.3 Appropriateness of Measurements 
Systolic and diastolic blood pressure will be measured at rest in a seated position. Blood pressure 
should be measured by the auscultation method using a mercury sphygmomanometer; however, the 
use of an automatic sphygmomanometer is also permitted. The same assessment method will be 
maintained throughout the study. 
Heart rate will be measured at rest in a seated position using the pulse at the wrist assessed for one 
minute. The same assessment method will be maintained throughout the study. 
Body temperature will be measured at rest, at oral, axillary, or auditory canal level, according to local 
procedures. The same assessment method will be maintained throughout the study. 
Body weight (in kilograms) will be measured using local procedures. The same assessment method 
will be maintained throughout the study.   
 
 


 
 
 
 
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13. 
PHARMACODYNAMIC ENDPOINTS 
Not assessed.  
 
14. 
PHARMACOKINETIC ENDPOINTS 
Pharmacokinetic of the new formulation of Rifaximin-EIR (250 mg tablets) has been included in the 
secondary endpoints. In particular, the PK of the two groups receiving repeated doses of Rifaximin-
EIR (250 mg t.i.d. and 500 mg t.i.d., respectively) after the initial administration (Day 1) and at the 
end of treatment (Day 30) will be assessed. 
 
14.1 
Pharmacokinetics blood sampling 
Venous blood samples (about 6 mL each) will be collected from the subjects by a trained member 
of the clinical team. Consent will be collected from the subjects for use of these samples for the 
purposes of the proposed study. Samples will be processed to isolate plasma and PK analysis will 
be carried out on plasma samples. 
Plasma samples will be sent for laboratory testing in linked anonymised form (subject number only). 
Venous blood samples (heparin) will be withdrawn via an indwelling cannula or by venepuncture. 
For all subject randomized in the three PK sub-groups, approximately 22 venous blood samples for 
PK analysis will be collected over the course of the study according to the following scheme: 
x 
Day 1 (V2): Pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dosing (first dose in the morning) 
x 
Day 30 (V3): Pre dose (single dose in the morning), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 22, 
24, 30 hours post dosing (blood sampling will continue at Day 31 as appropriate).The exact 
time of PK sampling collection must be recorded in the CRF. 
 
The acceptable deviations from the nominal blood sampling times are as follows: 
x 
Day 1 only: The pre-dose samples will be taken ≤1 h before dosing; 
x 
0 to 1 h post-dose samples will be taken within ± 2 min of the nominal post-dose sampling 
time 1.5 to 8 h post-dose on Day 1 and 1.5 to 12 h post-dose on Day 30 samples will be 
taken within ± 10 min of the nominal post-dose sampling time; 
x 
22 to 30 h post-dose samples will be taken within ± 30 min of the nominal post-dose sampling 
time.  
 
Procedures for processing and shipping PK samples are summarised will be described in detail the 
PK sample processing manual. 
Bioanalysis for the quantification of rifaximin in plasma samples will be carried out by using a 
validated HPLC-MS/MS method. Bioanalysis will be performed by a bioanalytical laboratory 
(Pyxant). 
 
14.2 
Pharmacokinetics parameters 
The pharmacokinetics of rifaximin after the repeated administration of Rifaximin-EIR at two different 
dose levels (250 mg t.i.d. and 500 mg t.i.d.) will be assessed after the first and last dosing (Day 1 
and Day 30) as secondary study endpoint. 
The PK analysis will be done for all randomized subjects who received at least one dose of the study 
drug and had a suitable PK profile. Both continuous and categorical variables will be used.  


 
 
 
 
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Pharmacokinetic analysis of the plasma concentration-time data for rifaximin will be performed using 
appropriate non-compartmental techniques to obtain estimates of the PK parameters presented 
below, where appropriate and possible. 
 
Parameter  
Day  
Definition  
Tmax  
1 & 30  
Time of maximum observed concentration  
Cmax  
1 & 30  
Maximum observed concentration  
AUC0-tau  
1 & 30  
Area under the curve for the defined interval between doses 
(tau)  
AUC0-∞  
30 
Area under the curve from time 0 extrapolated to infinity  
AUC0-last  
30 
Area under the curve from time 0 to the time of last measurable 
concentration  
t1/2  
30 
Terminal elimination half-life  
Lambda-z  
30 
First order rate constant associated with the terminal (log-
linear) portion of the curve  
AR Cmax  
30 
Accumulation Ratio based on Day 30 Cmax /Day1 Cmax  
AR AUC0-tau 
30 
Accumulation Ratio based on Day 30 AUC0-tau/Day1 AUC0-tau 
 
Further details of the PK data analysis will be included in the Statistical and Analysis Plan (SAP). 
 
 
 


 
 
 
 
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15. 
SAFETY ASPECTS 
15.1 
Adverse Events 
15.1.1 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial patient 
administered a medicinal product which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational product. 
 
An AE does include any: 
• Exacerbation of pre-existing illness. 
• Increase in frequency or intensity of a pre-existing episodic event or condition. 
• Condition detected or diagnosed after study drug administration even though it may have 
been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at baseline that worsen following the 
start of the study. 
• Symptoms associated with disease not previously reported by the patient. 
 
An AE does not include a/an: 
x 
Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an AE. 
x 
Planned medical or surgical procedures. 
x 
Pre-existing diseases or conditions present or detected at the start of the study that do not 
worsen. 
x 
Situations where an untoward medical occurrence has not occurred (e.g. hospitalization for 
cosmetic elective surgery, social and/or convenience admissions). 
x 
The disease or disorder being studied, or sign or symptom associated with the disease or 
disorder unless more severe than expected for the patient condition. 
x 
Overdose of other study drug or concurrent medication without signs or symptoms. 
x 
Symptoms associated with the disease that are consistent with the patient usual clinical 
course unless the symptom(s) meet(s) the criteria for “serious” except for what detailed in 
chapter. 15.1.3.  
15.1.2 
Definition of Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence in a patient or clinical trial patient 
administered a medicinal product which does not necessarily have a causal relationship with this 
treatment. A serious adverse event can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an investigational product, whether or not related to the investigational product and results in: 
➢ death; 
➢ is life-threatening; 
➢ requires in-patient hospitalisation or the prolongation of existing hospitalisation; 
➢ results in persistent or significant disability/incapacity; 


 
 
 
 
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➢ is an important medical event that may not be immediately life-threatening or result in 
hospitalisation or death, but may jeopardise the subject, or may require intervention to 
prevent one of the occurrences listed above; 
➢ is a congenital anomaly/birth defect. 
 
The term life-threatening refers to an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it had been 
more severe. 
Examples of important medical events which could be reported as serious are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalisation; or development of drug dependency or drug abuse. 
An unexpected adverse event is an AE whose nature, severity or outcome is not consistent with 
the information given into the Reference Safety Information (RSI). Reference documents in this study 
is the Investigator's Brochure. 
Expected serious adverse reactions should be considered always unexpected if: 
➢ have an unexpected outcome (e.g. a fatal outcome); 
➢ have an increase in the rate of occurrence, which is judged to be clinically important. 
Expectedness evaluation is performed by the Sponsor based on Reference Safety Information (RSI). 
15.1.3 
Protocol-Specified Serious Adverse Events  
In the population under study, there are no SAEs that are anticipated to occur independent of drug 
exposure and therefore should not be reported as SAEs. 
Hospitalisation for treatment planned prior to randomisation and hospitalisation for elective 
treatment of a pre-existing condition will not be considered as SAEs. 
Pregnancy 
Although pregnancy is a strict exclusion criteria and acceptance of methods to prevent pregnancy is 
an eligibility criterion, unexpected cases of pregnancy could occur during the study. 
Female patients will be instructed to notify the Investigator in case they become pregnant. 
If a pregnancy occurs during the course of the study, any treatment will be stopped and the 
Investigator shall notify, regardless whether a SAE is present or not, the Sponsor or whoever 
assumes the tasks delegated by the sponsor within 24 hours of knowing about the event. 
The report shall be made using a specific “In Pregnancy/In Utero Exposure” form, for the notification 
of pregnancy, which must be sent by email or fax to the same contact who receives the SAE 
notifications. 
In case of an onset of SAE or an unfavorable outcome occurs (abortion, abnormalities in the fetus, 
early termination of pregnancy) a SAE form also must be filled-in by the Investigator and immediately 
sent to the Sponsor. 
Also, a follow-up of the pregnancy, until the childbirth, will be performed to document its outcome 
and the state of health of the newborn.  
If the pregnancy outcome meets the SAE criteria or if the newborn presents a serious event, the 
procedures for reporting a SAE will be followed. 
 


 
 
 
 
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15.1.4 
Change of Laboratory Parameters 
Whether a change of parameters in the safety laboratory investigations (i.e. haematocrit, liver 
enzymes etc.) is observed and the parameter shifts from normal to a clinically significant abnormal 
value, or a basal abnormal value worsens during treatment with the investigational drug respect pre-
treatment value, can also represent an adverse event.  
If the change is clinically significant, when evaluating such changes, variation from the normal range, 
the extent of deviation from normal and time taken to return to normal after discontinuing treatment, 
should be taken into consideration. 
If there are pathological values at the end of the treatment phase which were not present before, 
further clinical or laboratory investigations must be performed until the values return to normal or, a 
plausible explanation is found for the pathological laboratory value (e.g. concomitant disease). 
The Investigator will decide if a change in laboratory parameter is clinically relevant and therefore 
represents or not an adverse event (serious/not serious) according to the above criteria and the 
clinical state of the subject. 
 
15.1.5  
Classification and Coding of the Causal Relationship and Severity 
The Investigator must assign, for each event, the causal relationship with study treatment 
according to the following categories: 
 
[0 = Not related / No Reasonable possibility]: to be used for an AE/SAE which is not suspected to 
be related to the study treatment. 
[1 = Related/Reasonable possibility] to be used for an AE/SAE which is suspected to be related 
to the study treatment. The definition implies a reasonable possibility of a causal relationship 
between the event and the study treatment. This means that there are facts (evidence) or 
arguments to suggest a causal relationship. 
 
Moreover, Investigators must assign the possible grade of Severity to the observed AEs using 
Common 
Terminology 
Criteria 
for 
Adverse 
Event 
(CTC-AE) 
V5.0 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Ref
erence_5x7.pdf ), as follows: 
 
• Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
• Moderate: minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental ADL (Activities of Daily Living). 
• Severe: or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL (Activities of Daily 
Living). 
• Life-threatening consequences: urgent intervention indicated. 
• Death. 
 
Categories “Severe”, “Life-threatening” and “Death” will be considered as seriousness criteria per 
se. 
 
Outcome: “recovered”, “recovered with sequelae”, “not yet recovered”, “death”, “unknown/lost to 
follow up”. 


 
 
 
 
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C o nfi d e nti al                                                    P a g.  6 5 | 9 4 
 
 
1 5. 1. 6  
D o c u m e nt ati o n of A d v er s e E v e nt s 
All A E s o c c urri n g d uri n g t h e st u d y,  aft er p ati e nt si g n at ur e of t h e i nf or m e d c o n s e nt ( wit h t h e e x c e pti o n 
d e s cri b e d i n c h a pt er s 1 5. 1. 1. a n d 1 5. 1. 3., e v e nt s r e c or d e d i n a p pr o pri at e e- C R F p a g e s), m u st b e 
a s s e s s e d a n d d o c u m e nt e d b y t h e i n v e sti g at or o n t h e A E p a g e s of t h e s u bj e ct s’  e- C R F. If t h e y m e et 
t h e crit eri a f or “ s eri o u s” r e q uir e al s o t h e c om pl eti o n of a S A E R e p ort F or m t h at m u st b e i m m e di at el y 
( wit hi n m a xi m u m 2 4 h o ur s) r e p ort e d t o t h e S p o n s or ( s e cti o n 1 5. 1. 7). 
T h e I n v e sti g at or will al w a y s pr o vi d e hi s/ h er a s s e s s m e nt of c a u s alit y at t h e ti m e of t h e i niti al r e p ort. 
E a c h A E will b e a s s e s s e d a n d d o c u m e nt e d b y t h e i n v e sti g at or a c c or di n g t o t h e f oll o wi n g c at e g ori e s: 
• St u d y pr ot o c ol n u m b er. 
St u d y C e ntr e n u m b er. 
P ati e nt i d e ntifi c ati o n n u m b er. 
D e s cri pti o n of t h e si g n a n d s y m pt o m/ e v e nt. 
S e v erit y a s pr e vi o u sl y d efi n e d i n S e cti o n 1 5. 1. 5. 
D ur ati o n: R e c or d t h e o n s et a n d r e s ol uti o n ti m e a n d d at e s of t h e e v e nt. 
A cti o n t a k e n. 
C a u s alit y t o st u d y tr e at m e nt/i n di vi d u al c o m p o n e nt: a s pr e vi o u sl y d efi n e d i n s e cti o n 1 5. 1. 5. 
O ut c o m e 
S eri o u s n e s s. 
All A E s r e p ort e d d uri n g t h e st u d y m u st b e f oll o w e d- u p b y t h e I n v e sti g at or u ntil t h e e v e nt r e s ol v e s, 
st a bili s e s or t h e p ati e nt i s l o st t o f oll o w- u p ( s e e s e c. 1 5. 1. 9.). 
A E s still pr e s e nt at t h e e n d of t h e st u d y p eri o d a n d f or t h e s u b s e q u e nt 3 0 d a y s m u st b e f oll o w e d 
u ntil t h e fi n al o ut c o m e i s d et er mi n e d. 
A n A E t h at i s i niti all y r e p ort e d a s n o n- s eri o u s a n d l at er m e et s t h e crit eri a f or a S A E, it m u st b e 
r e p ort e d a s a S A E a s s o o n a s t h e i nf or m ati o n r e g ar di n g t h e pr e s e n c e of o n e or m or e s eri o u s n e s s 
crit eri a b e c o m e k n o w n t o t h e I n v e sti g at or. 
 
T h e I n v e sti g at or i s r e s p o n si bl e t o e n s ur e t h at t h e f oll o w- u p i n cl u d e s a n y s u p pl e m e nt al i n v e sti g ati o n s 
a s m a y b e i n di c at e d t o el u ci d at e a s c o m pl et el y a s pr a cti c al, t h e n at ur e a n d/ or c a u s alit y of t h e A E. 
T hi s m a y i n cl u d e a d diti o n al l a b or at or y t e st s or i n v e sti g ati o n s, hi st o p at h ol o gi c al e x a mi n ati o n s, or  
c o n s ult ati o n wit h ot h er h e alt h c ar e pr of e s si o n al s. 
T h e S p o n s or m a y r e q u e st t h e I n v e sti g at or t o p erf or m or arr a n g e f or t h e c o n d u ct of s u p pl e m e nt al 
m e a s ur e m e nt s a n d/ or e v al u ati o n s.  
 
1 5. 1. 7  
Pr o m pt R e p orti n g of S A E t o t h e S p o n s or  
A n y S A E o c c urri n g d uri n g t h e st u d y, w h et h er r el at e d t o t h e i n v e sti g ati o n al pr o d u ct or n ot, m u st b e 
r e p ort e d i m m e di at el y (i. e., wit hi n 2 4 h o ur s) t o Alf a si g m a P V Cli ni c al S af et y. 
 
T h e S A E f or m m u st b e f a x e d or m ail e d u si n g t h e f oll o wi n g c o nt a ct d et ail s: 
E- m ail: 
 
or 
F a x: 
 
P P D
P P D


 
 
 
 
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One “SAE form” should be used for each SAE. However, if at the time of initial reporting, multiple 
SAEs are present that are temporally and/or clinically related, they may be reported on the same 
“SAE form” preferably as a diagnosis. 
The SAE form must be completed as thoroughly as possible with all available details of the event, 
signed by the Investigator (or appropriately qualified designee), and reported immediately to the 
Sponsor, within 24 hours from first awareness of the event. 
If the Investigator does not have all information regarding an SAE, he/she will not wait to receive 
additional information before compiling the SAE form and notifying the event to the Sponsor, 
although the following minimal information is required: 
¾ Study Protocol number 
¾ Study Centre number 
¾ Patient identification number 
¾ Sex, and age 
¾ Investigational product(s) 
¾ Description of the adverse event 
¾ Causal relationship by the investigator.  
¾ Name, affiliation, telephone and fax number of the reporting Investigator 
 
The additional information as soon as available will be recorded in a separate SAE form completed 
in every part that will be sent as a follow-up report. 
 
The Investigator will always provide his/her assessment of causality at the time of the initial report. 
If follow-up obtained subsequently, lead the investigator to change the assessment of causality, the 
SAE form may be appropriately amended, signed and dated, and resubmitted to the Sponsor as 
follow up report. 
If a patient dies during participation in the study or during a recognized follow-up period, the 
Investigator should send to the Sponsor, together with SAE Form, any other available post-mortem 
information, including autopsy and histopathology. 
In accordance with local Independent Ethics Committee (IEC) requirements, the Investigator might 
have to notify to IEC also any SAEs. 
 
15.1.8 
Reportable events 
Reportable events are those serious adverse events that are causally related to the study drug, and 
that are both serious and unexpected (SUSAR). Such events are subject to expedited reporting to 
regulatory authorities and they must be reported within the timelines foreseen by the relevant rules 
by the Sponsor or a suitably qualified designee. 
The Sponsor is responsible for reporting SUSAR to the relevant regulatory authorities in the time 
frames and methodology applicable according to local Law and Regulations. 
 
15.1.9 
Post study AEs and SAEs 
Serious and non-serious AEs will be recorded, after patient signature of informed consent, from the 
Screening visit (V1) to the End of study visit (V5) or Early termination visit, regardless of whether the 
participant is on treatment. 
SAEs will be recorded and reported as appropriate and followed-up until resolution or the patient is 
lost to follow up. Non-serious AEs will be recorded as appropriate and followed-up until End of Study 


 
 
 
 
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visit (V5, ESV) or Early Termination Visit (ETV) with event’s outcome reporting. 
SAEs will be recorded and reported as appropriate and followed-up until Resolution, Chronicity or 
the patient is lost to follow up. 
SAEs still present at the end of the study period and for the subsequent 30 days, must be followed 
until a final outcome is determined or the patient is lost to follow up. 
A post-study AE/SAE is defined as any event that occurs outside the AE/SAE detection period as 
defined previously. 
Investigators are not obliged to actively seek AEs or SAEs after study termination. However, if the 
Investigator learns of any SAE, including death, at any time after a subject has been discharged from 
the study, and he/she considers the event reasonably related to the Investigational Product, the 
Investigator will promptly notify the Sponsor, according to the process explained at section 15.1.7. 
 
15.2 
Warnings and Precautions 
Rifaximin is a safe and well tolerated drug as demonstrated by Clinical Studies and years of post-
marketed experiences in registered indications. Due to its pharmacodynamics and pharmacokinetics 
characteristics, life-threatening, serious AEs are not expected. 
 
Patients should be informed that despite the negligible absorption of the drug (less than 1%), like all 
rifamycin derivatives, rifaximin may cause a reddish discolouration of the urine. 
Clostridium Difficile associated diarrhoea (CDAD) has been reported with use of nearly all 
antibacterial agents, including rifaximin. The potential association of rifaximin treatment with CDAD 
and pseudomembranous colitis (PMC) cannot be ruled out. 
 
 
 


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  6 8 | 9 4 
 
1 6.  
S T A TI S TI C A L P L A N A N D D E T E R MI N A TI O N O F S A M P L E SI Z E 
T h e f oll o wi n g d e s cri b e s t h e st ati sti c al a n al y si s a s it i s at t h e ti m e of pl a n ni n g t h e tri al. A d et ail e d 
St ati sti c al A n al y si s Pl a n ( S A P) will b e i s s u e d aft er t h e st u d y st art s. 
S A S s oft w ar e ( V. 9. 3 or s u b s e q u e nt) will b e u s e d f or all st ati sti c al a n al y s e s. 
T h e pri m ar y o bj e cti v e of t h e st u d y i s t o e v al u at e  t h e eff e ct of Rif a xi mi n D el a y e d- R el e a s e 5 0 0 m g 
t.i. d. or Rif a xi mi n- EI R 2 5 0 m g t.i. d. v s pl a c e b o i n t er m s of  
o   a b s ol ut e c h a n g e fr o m b a s eli n e i n n u m b er of r o s a c e a l e si o n s ( p a p ul e s a n d p u st ul e s) at t h e e n d 
of tr e at m e nt ( V 3, D a y 3 0), a n d  
o   r at e of s u bj e ct s s h o wi n g tr e at m e nt s u c c e s s d efi n e d a s a n I G A s c or e of 0 ( cl e ar) or 1 ( al m o st 
cl e ar) wit h at l e a st a 2- gr a d e i m pr o v e m e nt fr o m b a s eli n e, at t h e e n d of tr e at m e nt ( V 3, D a y 3 0). 
D u e t o t h e Pr o of of C o n c e pt p ur p o s e of t hi s tri al, n o al p h a-l e v el a dj u st m e nt f or m ulti pli cit y will b e 
a p pli e d.  
A u ni q u e r a n d o mi z ati o n li st will b e cr e at e d. T h e r a n d o mi z ati o n li st will b e str atifi e d b y L- B T st at u s 
( n e g ati v e v s p o siti v e) a nd b y P K s u b- st u d y p arti ci p ati o n ( y e s or n ot). 
1 6. 1  
D et er mi n ati o n of S a m pl e Si z e 
T h e s a m pl e si z e e sti m ati o n i s b a s e d o n t h e c o- pri m ar y effi c a c y e n d p oi nt s, i. e. m e a n c h a n g e fr o m 
b a s eli n e i n n u m b er of i nfl a m m at or y l e si o n s a n d p er c e nt of p ati e nt s s h o wi n g tr e at m e nt s u c c e s s. 
 
 
 
 
 
 
 
 
 
 
B a s e d o n t h e s e a s s u m pti o n s, 5 1 p ati e nt s w er e t o b e e nr oll e d i n e a c h tr e at m e nt ar m a s s h o w n i n t h e 
t a bl e s b el o w. 
C CI
C CI


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  6 9 | 9 4 
 
T h e t ot al s a m pl e si z e ( 1 5 3) w a s a dj u st e d t o 1 7 1 p a ti e nt s ( 5 7 i n e a c h tr e at m e nt gr o u p) c o n si d eri n g 
a n e x p e ct e d dr o p o ut r at e of a b o ut 1 0 % ( u si n g Fr e e d m a n’ s f or m ul a ( C o ntr ol Cli n Tri al s, 1 9 9 0): n’ = 
1 0 0* n/( 1 0 0- x), w h er e x i s t h e e x p e ct e d dr o p o ut r at e). 
T h e i niti all y pl a n n e d s a m pl e si z e h a s b e e n i n cr e a s e d t o a t ot al of 2 0 1 p ati e nt s ( 6 7 i n e a c h tr e at m e nt 
gr o u p) t o miti g at e t h e i m p a ct o n t h e st ati sti c al p o w er of t h e tr e at m e nt kit mi s all o c ati o n t h at o c c urr e d 
f or 1 5 p ati e nt s o ut of t h e i niti al 3 0 p ati e nt s r a n d o mi z e d. A c a p of 3 3 s u bj e ct s p er ar m h a vi n g a 
n e g ati v e L- B T r e s ult at s cr e e ni n g (i. e., a t e st s h o wi n g a n i n cr e a s e ≤1 0 p p m of H 2  b y 9 0 mi n ut e s 
c o m p ar e d t o ti m e 0) i s e st a bli s h e d. 
S a m pl e si z e f or t h e s u b- st u d y o n P K i s n ot b a s e d o n f or m al st ati sti c al a s s u m pti o n s. A c a p of 1 2 
s u bj e ct s p er ar m i s e st a bli s h e d. T hi s i s c o n si d er e d a g o o d v al u e f or t hi s ki n d of st u d y. I n a n y c a s e, 
i n or d er t o h a v e a n a d e q u at e s a m pl e si z e, it i s a d vi s a bl e t o h a v e at l e a st 6 s u bj e ct s p er ar m. 
1 6. 2  
D efi niti o n of St u d y P o p ul ati o n s 
St u d y p o p ul ati o n s d efi niti o n s ar e pr o vi d e d b el o w. T h e n u m b er s of s u bj e ct s i n e a c h p o p ul ati o n a n d 
r e a s o n s f or e x cl u si o n will t h e s u m m ari z e d. 
All d e ci si o n s o n p o p ul ati o n s will b e t a k e n d uri n g a Bli n d D at a R e vi e w M e eti n g a n d will b e d et ail e d i n 
t h e r el e v a nt d o c u m e nt s. 
1 6. 2. 1
 S cr e e n e d
 
P o p ul ati o n
 
S cr e e n e d  P o p ul ati o n  i s  d efi n e d  a s  all  s u bj e ct s  e nr oll e d  i nt o  a  s cr e e ni n g  p h a s e  aft er  i nf or m e d  
c o n s e nt. A s cr e e n f ail ur e i s d efi n e d a s a s u bj e ct w h o h a s n ot b e e n r a n d o mi z e d t o tr e at m e nt. D at a 
fr o m s cr e e n f ail ur e s will o nl y b e li st e d a s i n di c at e d. 
1 6. 2. 2
 S af et y
 
P o p ul ati o n
 
All s af et y a n d t ol er a bilit y a n al y s e s will b e c arri e d- o ut i n t h e S af et y A n al y si s S et ( S A F), c o n si sti n g of 
all r a n d o mi z e d s u bj e ct s h a vi n g r e c ei v e d at  l e a st o n c e t h e i n v e sti g ati o n al tr e at m e nt. 
A n al y si s o n t h e S A F will b e p erf or m e d a c c or di n g t o t h e a ct u al tr e at m e nt r e c ei v e d. 
1 6. 2. 3  
F ull A n al y si s S et ( F A S) 
T h e  pri m ar y  effi c a c y  a n al y si s  p o p ul ati o n  will  b e  t h e  F ull  A n al y si s  S et  ( F A S),  d efi n e d  a s  all  
r a n d o mi s e d p ati e nt s h a vi n g t a k e n at l e a st o n e d o s e of t h e i n v e sti g ati o n al tr e at m e nt. 
T o miti g at e t h e i m p a ct of t h e tr e at m e nt kit mi s all o c ati o n s, t h e pri m ar y st ati sti c al a n al y si s o n t h e F A S 
will b e p erf or m e d a c c or di n g t o t h e a ct u al tr e at m e nt r e c ei v e d ( n ot a c c or di n g t o t h e “r a n d o mi z e d” 
tr e at m e nt, a s p er I T T pri n ci pl e). 
1 6. 2. 4
 M o difi e d
 
F ull
 
A n al y si s
 
S et
 
( m F A S)
 
M o difi e d F ull A n al y si s S et ( m F A S) i s d efi n e d a s all p a ti e nt s i n t h e F A S e x cl u di n g t h e i niti al 3 0 p ati e nt s 
r a n d o mi z e d.  
T h e a n al y si s o n t h e m F A S will b e p erf or m e d a c c or di n g t o t h e “r a n d o mi z e d” tr e at m e nt.  
1 6. 2. 5  
P er Pr ot o c ol S et ( P P S) 
P er Pr ot o c ol S et ( P P S) i s d efi n e d a s all s u bj e ct s i n  t h e F A S w h o f ulfil t h e st u d y pr ot o c ol r e q uir e m e nt s 
wit h n o m aj or d e vi ati o n s t h at m a y aff e ct st u d y r e s ult s. 
C CI


 
 
 
 
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Analysis on the PPS will be performed according to the actual treatment received. Patients 
randomized to a wrong stratification factor level will not be excluded from the PPS and will be 
analysed according to the actual stratum (not the randomized one). 
The analyses of the efficacy endpoints will be performed on the FAS and the PPS. Results on the 
FAS will be considered primary. Results on the PPS population will be used as supportive. 
16.2.6 
PK Set 
The PK analysis set will include all randomized subjects who received at least one dose of Rifaximin 
and had a suitable PK profile. 
16.2.7 
Disposition 
The number of subjects screened, randomized, treated and completing the trial (and reason for not 
completing) will be presented in frequency tables by treatment group. 
The number of subjects in each analysis population (SAF, FAS, mFAS and PPS) will be summarized 
by treatment group. 
All major protocol violations will be presented as a frequency table by treatment group. 
 
16.2.8 
Demographic and Other Baseline Variables 
Baseline values are the last recorded values collected prior to treatment initiation. 
Subject demographics, medical history and disease characteristics, previous and concomitant 
medications, and others baseline characteristics measured before randomization will be summarized 
descriptively by treatment group on the FAS. Selected summaries will be provided by treatment 
group and stratification factor (details to be provided prospectively in the SAP). 
If the PPS comprises less than 80% of the FAS, selected baseline data will be also summarized on 
the PPS.  
 
Concomitant diseases at baseline and relevant previous diseases will be coded using the latest 
available version of Medical Dictionary for Regulatory Activities (MedDRA).  
 
Relevant previous and concomitant treatments will be coded using the latest available version of the 
World Health Organization dictionary of medical codes (WHO).  
 
16.3 
Statistical and Analytical Plans 
The statistical analyses will be performed at the end of the study, when the data base has been 
cleaned and locked. 
The primary statistical analysis on the FAS will be performed according to the actual treatment 
received. 
In addition, two sensitivity analyses will be implemented for the primary analysis: 
x 
The first by analyzing the FAS according to the “randomized treatment”, as originally planned 
x 
The second on the mFAS according to the “randomized treatment”. 
 
16.3.1 
Primary Efficacy Endpoints and Statistical Model of Analysis 


 
 
 
 
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The co-primary efficacy endpoints, clinically assessed by the Investigator, are the absolute change 
from baseline in number of rosacea inflammatory lesions (papules and pustules) at the end of 
treatment AND the percent of subjects showing treatment success, defined as an IGA score of 0 
(clear) or 1 (almost clear) with at least a 2-grade improvement from baseline at the end of treatment. 
The first co-primary efficacy endpoint (i.e.: mean change from Baseline [V2] in number of 
inflammatory lesions at Day 30 [V3]) will be analysed by means of an Analysis of Covariance 
(ANCOVA) model, with change from Baseline to Day 30 as dependent variable, treatment group and 
stratification factor as explicative factors, and baseline number of inflammatory lesions as covariate. 
The adjusted mean differences will be presented with 95% CIs and p-values. 
The second co-primary efficacy endpoint (i.e.: percent of patients showing treatment success) will 
be analysed by means of a stratified Cochran Mantel-Haenszel (CMH) chi square test. The Breslow-
Day test for stratified tables will be applied. A two-sided 95% CI for difference in success rate 
between the treatment groups (each active group vs placebo) will also be computed. 
All statistical tests will be conducted at the two-sided α = 0.05 significance level. Due to the 
explorative purposes of this trial, no adjustment of significance level for multiplicity will be applied. 
16.3.2 
Secondary Endpoints and Statistical Model of Analysis  
16.3.2.1 
Secondary Efficacy Endpoints and Statistical Model of Analysis 
Exploratory secondary endpoints are the following: 
1) Mean change from Baseline (V2) in number of inflammatory lesions (papules and pustules) at 
V4. 
2) Percent of participants showing treatment success (i.e. IGA score of 0 or 1) at V3, V4. 
3) Percent of participants with IGA score of 0 (clear) at V3, V4.   
4) Change from Baseline (V2) in the following rosacea additional features at V3, V4: 
x 
pain, burning/stinging and itching (measured using a 0-10 cm Visual Analogue Scale (VAS))  
x 
telangiectasia (absent=0, mild=1, moderate=2, severe=3)  
x 
ocular manifestations (absent=0, mild=1, moderate=2, severe=3),  
x 
phymatous changes (absent=0, mild=1, moderate=2, severe=3).   
5) Change from Baseline in facial non-transient erythema at V3, V4 (absent=0, mild=1, moderate=2, 
severe=3).  
6) Change from baseline in abdominal pain score at V3, V4. 
7) Change from baseline in abdominal distension score at V3, V4. 
8) Change from baseline in bowel habit satisfaction score at V3, V4. 
9) Change from baseline in global severity of abdominal symptoms score at V3, V4. 
10) Percent of participants showing treatment success according to Modified IGA scale excluding 
papules/pustules but including erythema (i.e. score of 0 or 1) at V3, V4. 
11) Percent of participant showing treatment success according to a Modified IGA scale including 
erythema and papules/pustules at V3 and V4. 


 
 
 
 
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The change from baseline to the relevant visit in secondary endpoints 1 and from 4 to 9 will be 
analyzed by means of an Analysis of Covariance (ANCOVA) Model, with change from Baseline to 
the relevant visit for the current endpoint as dependent variable, treatment group and stratification 
factor  as explicative factors and baseline value of the current endpoint as covariate. The adjusted 
mean differences will be presented with 95% CIs and p-values. 
The secondary endpoints expressed as percentages (endpoints 2, 3, 10 and 11) will be analyzed by 
means of a two-sided Cochran Mantel-Haenszel Chi-square test stratified by L-BT status. The 
Breslow-Day test for stratified tables will be applied. A two-sided 95% CI for difference of success 
rate between the treatment groups (each active group vs placebo) will also be computed. 
Considering the explorative nature of the secondary endpoints, all the inferential results obtained on 
them will be descriptively interpreted. 
16.3.2.2 
Pharmacokinetics Methods and Statistical Data Analysis  
Individual plasma concentrations and collection times will be listed by subject for all subjects 
including those excluded from the PK analysis due to non-completion. 
Summaries of concentration data will include mean, standard deviation and coefficient of variation 
by dose day at each scheduled collection time, by dose. Mean concentration–time profiles will be 
presented graphically, with concentration shown on linear and logarithmic scales. 
Pharmacokinetic parameters will be calculated for all subjects who belong to the pharmacokinetic 
population (see paragraph 16.2.5), using standard non-compartmental methods as described in 
paragraph 14.2. 
No value of derived parameters such as Lambda-z, t1/2, AUC0-∞ will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. All times used in the 
calculation of pharmacokinetic parameters will be the actual elapsed time from treatment 
administration, with the exception of pre-dose data which will be given the nominal time of 0.00 
hours. Determination of PK parameters will be performed using appropriate software.  
Pharmacokinetics parameters will be summarised by descriptive statistics by dose day, study 
groups, gender and overall. 
16.3.3 
Safety Laboratory Statistical Analysis 
All safety measures will be descriptively summarized by treatment group in the SAF population.  
Where appropriate, the reported laboratory values and the corresponding reference ranges will be 
converted into SI units. 
For laboratory data and vital signs, the numeric values and corresponding changes from baseline 
will be summarized using descriptive statistics (number of subjects, mean, standard deviation, 
minimum, median, maximum) by parameter and visit.  
In addition, laboratory values will be classified as normal/high/low based on the reference range. 
Abnormal values will also be classified as clinically significant (CS) abnormalities and non-clinically 
significant (non-CS) abnormalities. This classification will be summarized by means of shift tables 
from baseline to post-baseline assessments. 
16.3.4 
Statistical Analysis of Adverse Events 
Adverse events will be presented for the Safety Analysis Set (SAF), by treatment group. 


 
 
 
 
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All adverse events will be assigned to a Preferred Term (PT) and will be classified by Primary SOC 
according to the latest MedDRA version. 
Any adverse event which started at or after the first administration of study treatment will be 
considered as Treatment Emergent Adverse Event (TEAE). If the start date is missing for an AE, 
the AE will be considered to be treatment emergent. 
Adverse events will be reported on a per-patient basis. This means that even if a patient reported 
the same event repeatedly, the event will be counted only once. 
TEAEs relationship to study medications will be investigated with frequency tables. Missing 
classifications concerning study drug relationship will also be considered as treatment-related. 
The following tables will be presented: 
1. Overview of AEs and TEAEs showing the number of AEs and TEAEs and the number of 
patients with any AEs and TEAEs, treatment-related TEAEs, serious TEAEs, treatment-
related serious TEAEs and TEAEs leading to study withdrawal; 
2. Summary of TEAEs by Primary SOC and PT; 
3. Summary of Related TEAEs by Primary SOC and PT; 
4. Summary of TEAEs by Primary SOC, PT and maximum Severity; 
5. Summary of Serious TEAEs by Primary SOC and PT; 
6. Summary of Related and Serious TEAEs by Primary SOC and PT; 
7. Summary of Serious TEAEs by Primary SOC, PT and maximum Severity; 
8. Summary of TEAEs causing early discontinuation of the study treatment by Primary SO 
and PT. 
No inferential statistical tests will be applied to compare the treatment arms in terms of incidence of 
adverse events. 
Adverse events occurred before the first administration of study treatment will only be listed. 
16.3.5 
Statistical Analysis of Lactulose Breath Test Results 
Results relevant to the lactulose breath test (Positive/Negative SIBO) will be summarized by 
treatment group, stratification factor and visit by means of frequency tables (counts and 
percentages). 
16.3.6       Statistical Analysis of Vital Signs and Body Weight 
Vital signs will be summarised by treatment group and visit using descriptive statistics. 
Changes from Baseline to the relevant visits will be summarised by treatment group using descriptive 
statistics. 
Also, body weight will be summarised by treatment group and visit using descriptive statistics. 
 
16.3.7      Statistical Analysis of Physical Examination 
Physical examination (signs and symptoms) will be summarized by Body System, treatment group 
and visit by means of descriptive summaries (counts and percentages). 
 
16.3.8     Handling of Missing and Incomplete Data 


 
 
 
 
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Summary statistics will generally be reported based upon observed data. Should a determination of 
treatment period (on treatment, pre-treatment) be required for adverse events or Lactulose 
medication but the corresponding date is missing, or is a partial date, the event/medication will be 
considered on treatment unless the portions of the date that are available indicate this is not possible. 
With reference to the statistical analyses performed on the FAS, the last observation carried forward 
(LOCF) strategy will be employed for dealing with any missing continuous data for the relevant 
primary and secondary endpoints. For categorical data (i.e. Success/Failure) missing data will be 
considered as Failures, unless differently specified in the SAP.  
With reference to other categorical variables, the number of patients with missing data will be 
presented under the “unknown” category. Missing values will be included in the denominator count 
when computing percentages, unless otherwise specified in the SAP. 
When other continuous data will be summarized, only the non-missing values will be evaluated for 
computing summary statistics. 
Missing data in safety variables will not be replaced. 
 
16.4 
Additionally Planned Statistical Analyses 
16.4.1 
Interim Analyses and Data Monitoring Committee 
No interim analysis or assignment of a data monitoring committee is planned. 
16.4.2 
Multicentre study 
Considering that the number of subjects per center will be low, the center will not be considered as 
an explicative factor in the statistical analyses. 
16.4.3 
Examination of Subgroups 
There are no pre-defined sub-groups in this study. However, there is one sub-study on PK data. 
 
 
 


 
 
 
 
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17. 
DOCUMENTATION, RECORD ACCESS AND ARCHIVING 
17.1 
Documentation of Essential Documents/Supplements at Study Centre 
during the Trial 
An “Investigator Study File” will be established at the study centre at the beginning of the trial. The 
investigator/institution must maintain the trial documents as specified in the Guideline for Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 (R2) - EMA/CHMP/ICH/135/1995) and the 
applicable regulatory requirement(s).  
17.2 
Screening/Enrollment Log  
The date of screening of all subjects fulfilling the inclusion requirements before any study related 
action is taken will be documented on the “Screening/Enrolment Log”. 
The Investigator will document that the subject satisfies the inclusion and exclusion criteria, and 
therefore if the subject is enrolled or is screening failure. 
The screening list must not permit the identification of subjects. The original list will be handed to the 
sponsor, and a copy will be archived in the "Investigator's Study File"  
With this list the investigator documents the relationship between the general patient population in 
the specific indication and the study population.  
17.3 
Documentation of Subjects’ Participation 
The investigator must record all subject identification data (full name, initials, date of birth, screening 
number, randomisation number, hospital admission-number and date of admission [if relevant], 
study termination date) for all subjects who have given informed consent - whether the subject has 
received any investigational product(s) or not - in the "Confidential Subject Identification List". The 
subject identification list must allow the definite identification of subjects who take part in this study. 
The subject identification list is kept by the investigator in his “Investigator Study File” and archived 
according to the requirements of the applicable national/international regulations, in particular in 
accordance with art. 32 of the EU Regulation 2016/679. 
17.4 
Data Protection 
Personal data are securely stored to prevent unauthorized access, disclosure, dissemination, 
alteration or loss of information and unauthorized personal data processing. Access to personal 
information is restricted so that only personnel who are required to access personal data as part of 
their job role can do so. All personnel who access personal information are bound by a duty of 
confidentiality. 
Technical arrangements surrounding the electronic storage and use of data are as follows: 
x 
Computers storing electronic personal data are protected by antivirus software and the 
network on which computers are linked are protected by industry grade firewalls; 
x 
Off-site personnel can only access networked computers through a virtual private network; 
x 
All data are stored on password protected computers. 
 
Organisational arrangements are as follows: 
x 
All buildings are secured by key-card access; 
x 
Manual files of personal data are stored within locked cabinets that can only be accessed by 
authorized personnel; 
x 
Data security and/or confidentiality provisions are utilized in agreements with third parties; 
x 
Documented Back-up and disaster recovery procedures are in place; 


 
 
 
 
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x 
Internal audit and compliance functions provide regulatory oversight. 
 
The personal data of patients will be pseudonymized in that they will only include health status, 
patients code and demographics (age, gender and ethnicity) and cannot be linked back to the 
individual by the recipient. The sponsor and the clinical center shall be the independent data 
controller in respect of the personal data of the study subjects collected in connection with the study 
and shall act in accordance with the relevant data protection laws in relation to the collection and 
processing of those personal data. The study subjects’ pseudonymized personal data shall be 
collected and processed for the purposes of the study and may also be added to research databases 
and used in the future by the sponsor and its affiliates for certain additional clinical research, for 
product regulation and safety reporting purposes and for ensuring compliance with legal 
requirements. The study subjects’ pseudonymized personal data may be processed for such 
purposes by other parties including: the sponsor’s affiliates and licensing partners, its business 
partners, regulatory agencies and other health authorities, and ECs. Additionally, the CRO personnel 
are contractually bound by a duty of confidentiality obligation through a data processing agreement 
and the standard contractual clauses if it comes from extra EU. 
 
17.5. Personal Data Breach 
The Clinical Centre and the CRO have a comprehensive process to identify, assess, resolve and 
report any potential data security breaches. All staff are trained by Sponsor or delegate to identify 
potential data security breaches. Potential personal data breaches are handled by appropriately 
trained personnel according to Sponsor/CRO SOPs. Each incident and violation of personal data 
must be communicated to the Sponsor within 48 hours at the latest and, in any case, without undue 
delay after becoming aware of a personal data breach.  
 
Notification must contain at least the following information: 
¾ a description of the nature of the personal data breach including the following elements: 
x the categories and the approximate number of data subjects involved;  
x the categories and the approximate number of personal data involved; 
x the data breach impact level; 
x the safety measures implemented; 
x the name and contact details of the Data Protection Officer or other contact point from 
which further information may be obtained; 
x the name of the Data Protection Officer or appropriate privacy office of any sub-
responsible parties involved in the processing that can be contact for further information. 
¾ a description of the measures adopted and/or the measures that intends to adopt to remedy 
the personal data breach, including, where it is appropriate, measures to mitigate the possible 
negative consequences; 
¾ a description of the probable consequences of the personal data breach; 
¾ any further information necessary to notify the competent control Authority of the breach. 
 
If it is not possible to provide all this information simultaneously, the information may be 
communicated at a later moment, without undue delay. 
Every party shall be obliged to notify any case of personal data breach, regardless of its degree of 
severity.  Any assessment of the seriousness of a possible personal data breach is assessed 


 
 
 
 
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exclusively by the sponsor. 
17.6 
Source Documents 
Source documents consist of inpatient hospital charts, clinic notes, outpatient records, original test 
results, laboratory data, worksheets, drug accountability records, consent forms, patient’s diaries, 
etc. Source documents must be available for review and inspection during on-site monitoring of the 
study by the Sponsor, its designees, IRB/IEC, and/or appropriate regulatory authorities. 
 
17.7 
Subjects' Records 
If subjects’ files are in electronic format, the system used must be compliant with the minimum 
requirements of the “Computerised system used in clinical trials” regulation.  
If the above-mentioned minimum requirements are not fulfilled, the Investigator must print-out, sign 
and date the patient’s data that will become the source documents The Investigator must assure in 
writing that the data on the print-outs are identical to the electronic data and are complete. These 
print-out must to be archived in the Investigator’s Study File. No e-CRF print-out will serve as source 
documentation. 
All data collected from screened subjects will be verified against the source documents.  
This will include all entries in subjects’ e-CRF and all laboratory data. Data documented in the e-
CRF at the baseline visit, during treatment and in the follow-up period will be verifiable through the 
original source documents (i.e. patient’s notes, laboratory records). 
It is the Investigator’s responsibility to ensure all relevant data are entered in the patient’s medical 
file, for example medical history/concomitant diseases, date of study enrolment, visit dates, results 
of examinations and AEs. 
The Investigator(s)/Institution(s) will permit study-related monitoring, audits, IRB/IEC reviews, and 
regulatory inspections, and provide direct access to source data/documents.  
17.8 
Case Report Forms 
An electronic CRF (e-CRF) is used to record clinical trial data and is an integral part of the trial and 
subsequent reports. They must reflect patient’s status at each phase during the course of the trial.  
All information requested on the eCRF should be entered. If one is not available or is not applicable, 
this must be indicated. 
The Investigator must ensure the accuracy, the completeness and the consistency of the data 
entered in the e-CRF. A User Manual with detailed instructions about e-CRF filling in will be provided 
to each Investigator and a specific training will be performed. 
Subjects must not to be identified on the e-CRF by name, but by subject’s identification number. The 
e-CRF is specifically designed to record the data required by this protocol. They must be kept up-to-
date so that they always reflect the latest observations on the subjects enrolled in the study; the e-
CRF should be filled in immediately after the conclusion of each subject’s visit, preferably within 24 
hours but no later than five working days after the visit. 


 
 
 
 
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The principal investigator will electronically sign and date each e-CRF attesting to his/her 
responsibility for the quality of all data included therein, and that the data represented a complete 
and accurate record of each subject's participation in the study. 
The eCRFs system will foresee an audit trail allowing the tracking of all the changes and corrections 
performed to the eCRFs, with the indication of date and author of entry and of correction. 
17.9 
Data Management 
The contract research organization (CRO) Data Management will identify and implement the most 
effective data acquisition and management strategy for the clinical trial protocol and deliver datasets 
which support the protocol objectives. Subject’s data will be entered into a defined eCRFs and then 
combined with data provided by other sources (e.g. Central Labs, ePRO etc).  Clinical data 
management will be performed in accordance with CRO standards and data cleaning procedures 
with the objective of removing errors and inconsistencies in the data, which would otherwise impact 
on the analysis and reporting objectives, or the credibility of the Clinical Study Report. Adverse 
events and concomitant medications terms will be coded using validated dictionaries such as 
MedDRA and WHO-Drug. 
This study will conform to SDTM standards and ADaM and will be fully CDISC compliant adhering 
to the latest CDISC standards including all associated documentation to aid review such as the study 
data reviewers guide, the analysis data reviewers guide, metadata and Define.xml for both SDTM 
and ADaM. 
17.10 
Database Processing 
Clinical data will be captured using a study specific eCRF using a validated and Code of Federal 
Regulations (CFR) Part 11 compliant Electronic Data Capture (EDC) system. Sites will receive 
training and have access to the study specific eCRF completion guidelines. 
All eCRFs should be completed by designated trained site staff and reviewed, electronically signed 
and dated by the Investigator. 
Pre-defined data validation checks will be run within the eCRF as the data are entered and submitted 
by authorised site staff.  The resulting data queries will be reviewed by the clinical site and resolved.   
An electronic audit trail of all changes made to the eCRF will be kept within the EDC system. This 
audit trail identified the user making the change and date and time of change. 
At the end of the study, each site will receive their subject’s data in an electronic readable format 
(i.e., PDF format) burned on an adequate media (e.g., CD or DVD). The site will receive a PDF file 
for each enrolled subject; the file will contain the patient’s data and its audit trail. Data files will be 
archived with the site study records 
 
17.11 
Archiving Requirements for Sponsor and Investigator 
Essential documents (as defined in the Guideline for Good Clinical practice E6 (R2) 
EMA/CHMP/ICH/135/1995) must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents must be retained for a longer 
period however if required by the applicable regulatory requirement(s) or if required by Alfasigma 
S.p.A. 


 
 
 
 
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The subject identification list must be retained according to the requirements of the applicable 
national/international regulations after the completion, or discontinuation, of the study. 
Alfasigma S.p.A will notify the Investigator(s)/Institution(s) in writing when the trial related records 
are no longer needed. 
If an investigator moves, withdraws from a trial or retires, the responsibility for maintaining the 
records may be transferred to another investigator who accepts this responsibility. Notice of this 
transfer must be given to and agreed upon by Alfasigma S.p.A. 
 


 
 
 
 
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18 
PROJECT MANAGEMENT 
18.1 
Investigator Information and Training 
The Investigators and essential support staff will be trained by the Sponsor or its designee with 
regards to the International Council on Harmonization (ICH) GCPs and all aspects of protocol 
application and study management. It is the responsibility of the Investigator to train ancillary study 
staff and to document such training. 
18.2 
Quality Assurance and Quality Control 
The sponsor will implement and maintain quality assurance and quality control systems with written 
Standard Operating Procedures (SOPs) in accordance with the Guidelines for Good Clinical Practice 
E6 (R2) (EMA/CHMP/ICH/135/1995).  
 
18.2.1 Audit and Supervision of the Study 
At its own discretion the Sponsor or its designee may conduct a quality assurance audit of this study. 
If such an audit occurs, the Investigator agrees to allow the auditor direct access to all relevant 
documents and to allocate his/her time and his/her staff to the auditor to discuss findings on any 
relevant issue. In the event that on-site auditing visits cannot occur, alternative measures (e.g.: 
remote audits) may be considered, as allowed by local regulations and according to the relevant 
SOPs. 
An independent representative for quality assurance will ensure quality by auditing the conformity of 
protocol, monitoring data handling and archiving (trial master file) with the Guidelines for Good 
Clinical Practice E6 (R2) (EMA/CHPMP/ICH/135/19-95), national drug law(s) and SOP(s).  
In addition, regulatory agencies may conduct a regulatory inspection of this study. If such an 
inspection occurs, the Investigator agrees to allow the inspector direct access to all relevant 
documents and to allocate his time and his staff to the inspector to discuss findings and any relevant 
issue. Inspections may be performed by regulatory authorities. 
18.2.2 
Monitoring 
The Sponsor may engage a Contract Research Organization (CRO) to monitor the study, according 
to the Sponsor’s or the CRO’s SOPs. Monitors from this agency have the same rights and 
responsibilities as monitors of the sponsor. 
This study will be monitored by the Sponsor or its designee, in accordance with ICH GCPs Topic E6 
guideline "Note for Guidance on Good Clinical practice". By signing this protocol, the Investigator agrees 
to periodic, on-site monitoring of all appropriate study documentation. 
The monitors will establish contact between the investigator and the sponsor. 
The monitors will evaluate the competence of each study centre and inform the sponsor of any 
problems relating to the facilities and technical staff. During the study the monitors will check that 
informed consent was obtained from all subjects, that the data are recorded correctly and completely, 
the Investigator providing direct access to source data/documents for data verification, and that the 
investigator complies with the protocol (and any amendments), GCPs, and all applicable regulatory 
requirements. 
The clinical monitor will check whether the envelopes have been opened during the monitoring visits. 


 
 
 
 
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In case of restrictions to on-site monitoring visits due to SARS-CoV2 pandemic, remote monitoring 
activities will be implemented in order to remotely check the correspondence of the data inputted in 
the e-CRF throughout the sharing of Pseudonymized copy of the source data, protecting the 
subjects’ privacy. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring, assessment of 
the impact of the envisaged processing operations on the protection of personal data), methods, 
responsibilities and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
18.3 
Trial steering committee 
No trial steering committee has been planned for this study. 
18.4 
Data monitoring committee 
No data monitoring committee has been planned for this study. 
18.5 
Amendments to the Protocol 
Modifications of the signed protocol are only possible by protocol amendments with the agreement of 
all responsible persons.  
 
The investigator should not implement any deviation from, or changes to the protocol without agreement 
by Alfasigma S.p.A. and prior review and documented approval/favourable opinion from the IRB/IEC of 
an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when 
the change(s) involves only logistical or administrative aspects of the trial. 
 
Protocol amendments must be submitted to the appropriate regulatory authorities. 
Alfasigma S.p.A. and the Investigator/Institution must have approval/favourable opinion from the 
IRB/IEC for any amendment to the protocol. 
Any protocol amendment must be distributed to those who received the original protocol and be 
appended to it. 
18.6 
Closure or Discontinuation of Study and Site 
Upon completion of the study, the following activities, when applicable, must be conducted by the 
monitor in conjunction with the Investigator, as appropriate: 
x 
Return of all study data to the Sponsor or its designee 
x 
Data clarifications and/or resolutions 
x 
Accounting, reconciliation, and final disposition of used and unused study drug 
x 
Review of site study records for completeness. 
18.7 
Premature Discontinuation of the Study in a Trial Site 
The study site can be discontinued at the request of the Sponsor, the Investigator, or regulatory 
authorities. 
Conditions that may warrant discontinuation of the study site include, but are not limited to 
the following: 
x 
The centre cannot include an adequate number of subjects within the planned time. 


 
 
 
 
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x 
Serious and/or persistent non-compliance with the protocol. 
x 
Careless or premeditated false documentation in the CRFs. 
x 
Inadequate co-operation with the Sponsor. 
x 
Non-compliance with GCP, SOPs or regulatory requirements. 
x 
The investigator asks to discontinue the trial. 
x 
The submission of knowingly false information from the research facility to regulatory 
authorities 
 
If the trial is prematurely terminated or suspended for any reason, the subjects will be informed 
promptly, appropriate therapy and follow-up will be assured and where required the relevant 
regulatory authorities will be informed. The IRB/IEC will be promptly informed and provided with a 
detailed written explanation. 
18.8 
Premature Discontinuation of the Whole Study 
If the trial is prematurely ended or suspended, Alfasigma S.p.A. will promptly inform the 
Investigators/Institutions, and the regulatory authorities with appropriate justifications. A written 
explanation will be promptly sent to the IRB/IEC by Alfasigma S.p.A. or the Investigator/Institution, 
as specified in the regulatory requirements. 
18.9 
Insurance for Subjects 
Alfasigma S.p.A will arrange insurance for all study subjects. The following guidelines must be taken 
into account:  
x Any serious adverse event which may be correlated or not to investigational product or diagnostic 
procedures during the trial must be reported to the sponsor or the CRO immediately. 
x The insurance company is entitled to ask all doctors involved in the treatment of a subject, other 
insurance companies and the national insurance for information which might help to clarify the 
cause of injury. Before enrolment in the study a subject must be informed of insurance against 
trial-related injuries and who to contact for compensation. 
 
The terms of the insurance will be included in the Investigator’s Study File.  
18.10 
Disclosure of all Information and Results 
By signing the study protocol, the investigator agrees to keep confidential all information and results 
concerning the study and the investigational product, until the data are published. 
18.11 
Publication policy 
The Sponsor declare its intent to publish the results of the study, after completion of the regulatory 
Report. 
The personal data especially sensitive data regarding the clinical trial, will be only dissemination in 
strictly anonymous form. 
The Sponsor will work with the protocol development team and will identify a lead author for the 
manuscript development. The authors for the manuscript will be determined by the amount of effort 
and participation each Investigator contributes towards the study design, the study conduct, as well 
as the analysis of study results. 
All of the parties agree to provide the other with the text sufficiently in advance to allow examination, 


 
 
 
 
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prior to submission to a scientific journal. 
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed, as required, to other clinical Investigators, and regulatory authorities.  
18.12 
Ownership 
All data and records provided by the Sponsor or generated during the study (other than a subject’s 
medical records) and all inventions discovered in the course of conducting the study are the property 
of the Sponsor. If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed than contract’s ownership provisions shall apply rather 
than this statement. 
 
18.13 
Contracts, Finances 
In addition to the protocol trial-related duties, functions and financial aspects must be specified in a 
separate contract between Alfasigma S.p.A., the investigator and any other parties involved in the 
clinical trial. 
 
 
 


 
 
 
 
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19. 
REPORTING 
After completion of the study an "integrated" full report will be prepared (according to the ICH 
Harmonised Tripartite Guideline Topic E3 “Structure and Content of Clinical Study Reports.  
 
 
 


 
 
 
 
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20. 
REFERENCE LIST 
 
Buddenkotte M and Steinhoff M. Recent advances in understanding and managing rosacea. FI000 
Research 2018. 
 
Campieri M, Gionchetti P, Hackett AM (Inst. of Gastroenterology, University of Bologna, Italy): 
Rifaximin pharmacokinetic study after oral administration in patients with Crohn’s disease. (Study 
NORMIX 01.95), 1999. 
 
 
Drago F, De Col E, Agnoletti AF, Schiavetti I, Savarino V, Rebora A, et al. 2016. The role of small 
intestinal bacterial overgrowth in rosacea: A 3-year follow-up. J Am Acad Dermatol 75: e113-e5. 
 
Gallo RL, Granstein RD, Kang S, et al. Standard classification and pathophysiology of rosacea: The 
2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018; 78: 
148-155. 
 
Gether L, Overgaard L.K., Egeberg A, Thyssen J.P. Incidence and prevalence of rosacea: a 
systematic review and meta-analysis. BJD. 2018; 179:282-289. 
 
Gatta L, Scarpignato C. Systematic review with meta-analysis: rifaximin is effective and safe for the 
treatment of small intestine bacterial overgrowth. Aliment Pharmacol Ther. 2017; 45:604–16. 
 
Gionchetti P, Rizzello F, Ferrieri A, et al. Rifaximin in patients with moderate or severe ulcerative 
colitis refractory to steroid-treatment: a double-blind placebo-controlled trial. Dig Dis Sci. 1999a; 
44:1220-1221. 
 
Gionchetti P, Rizzello F, Venturi A, et al.: Antibiotic combination therapy in patients with chronic, 
treatment-resistant pouchitis. Aliment Pharmacol Ther. 1999b; 13: 713-718. 
 
Gravina A, Federico A, Ruocco E, Lo Schiavo A, Masarone M, Tuccillo C, et al. Helicobacter pylori 
infection but not small intestinal bacterial overgrowth may play a pathogenic role in rosacea. United 
European Gastroenterol J. 2015; Feb.3(1):17-24. 
 
Holmes AD, Steinhoff M. Integrative concepts of rosacea pathophysiology, clinical presentation and 
new therapeutics. Exp Dermatol. 2017. 26: 659-667. 
 
Lazaridou E, Giannopoulou C, Fotiadou C, Vakirlis E, Trigoni A, Ioannides D. The Potential Role of 
Microorganisms in the Development of Rosacea. J Dtsch Dermatol Ges. 2011; 9: 21-5. 
Parodi A, Paolino S, Greco A, Drago F, Mansi C, Rebora A, et al. 2008. Small intestinal bacterial 
overgrowth in rosacea: Clinical effectiveness of its eradication. Clin Gastroenterol Hepatol 6:759-64. 
 
Losurdo G, Leandro G, Ierardi E, Perri L, Barone M, Principi M, Di Leo A. Breath Tests for the Non-
invasive Diagnosis of Small Intestinal Bacterial Overgrowth: A Systematic Review With Meta-
analysis. J Neurogastroenterol Motil, 2020; 26:16-28. 
 
Ponziani FR, Scaldaferri F, Petito V, et al. Rifaximin treatment increases lactobacillus abundance in 
patients with different gastrointestinal and liver diseases. UEG Journal 2015; 3(5S): A138. 
 
Rizzello F, Gionchetti P, Venturi A, Ferretti M, Peruzzo S, Raspanti X. Rifaximin systemic absorption 
in patients with ulcerative colitis. Eur J Clin Pharmacol. 1998; 54: 91-93 
 
Simren and Stotzer. Use and abuse of hydrogen breath test. Gut. 2006; Mar; 55(3):297-303 
 


 
 
 
 
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Steinhoff M, Buddenkotte J, Aubert J, Sulk M, Novak P, Schwab VD, et al. Clinical, cellular, and 
molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011; 15: 2-
11. 
 
Steinhoff M, Schauber J, Leyden JJ. New Insights into Rosacea Pathophysiology: A Review of 
Recent Findings. J Am Acad Dermatol. 2013; 69: S15-26. 
 
Tan J, Almeida LM, Bewley A, Cribier B, Dlova NC, Gallo R, Kautz G, Mannis M, Oon HH, 
Rajagopalan M, Steinhoff M, Thiboutot D, Troielli P, Webster G, Wu Y, van Zuuren EJ, Schaller M. 
Updating the diagnosis, classification and assessment of rosacea: recommendations from the global 
ROSacea COnsensus (ROSCO) panel. Br J Dermatol. 2017 Feb;176(2):431-438. 
 
van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. Interventions for rosacea. 
Cochrane Database Syst Rev. 2015; Apr 28;2015(4). 
 
Weinstock LB, Steinhoff M. 2013. Rosacea and small intestinal bacterial overgrowth: Prevalence 
and response to rifaximin. J Am Acad Dermatol 68:875-6. 
 
Wilkin J, Dahl M, Detmer M, Drake L, Liang MH, Odom R and Powell F. Standard grading system 
for Rosacea: Report of The National Rosacea Society Expert Committee on the Classification and 
Staging of Rosacea. J Am Acad Dermatol. 2004; 50: 907-12. 
 
Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A et al. Increased serine protease 
activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007; 13: 975-80 
 
 


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  8 7 | 9 4 
 
2 1.   A p p e n di c e s 
 
C CI


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o nfi d e nti al                                                    P a g.  8 8 | 9 4 
 
C CI


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o nfi d e nti al                                                    P a g.  8 9 | 9 4 
 
C CI


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o nfi d e nti al                                                    P a g.  9 0 | 9 4 
 
C CI


St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
C o nfi d e nti al                                                    P a g. 9 1 | 9 4
C CI


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
C o nfi d e nti al                                                    P a g.  9 2 | 9 4 
 
C CI


 
 
 
 
St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1 
 
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o nfi d e nti al                                                    P a g.  9 3 | 9 4 
 
C CI


St u d y c o d e: R E- R O S 2 0 0 2- 2 0 2 1
Fi n al V er si o n 2. 0 2 5 M ar c h 2 0 2 2
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
C o nfi d e nti al                                                    P a g. 9 4 | 9 4
C CI


C ertifi c at e Of C o m pl eti o n
E n v el o p e I d: 
St at u s: C o m pl et e d
S u bj e ct: Pl e a s e D o c u Si g n: R E- R O S 2 0 0 2- 2 0 2 1 St u d y _ Pr ot o c ol _ Fi n al _ V er si o n _ 2. 0 of 2 5 M ar 2 0 2 2 ( cl e a n). d o c x
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 9 4
Si g n at ur e s: 7
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 3
I niti al s: 0
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: Di s a bl e d
Ti m e Z o n e: ( U T C + 0 1: 0 0) A m st er d a m, B erli n, B er n, R o m e, St o c k h ol m, Vi e n n a
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             2 9- 0 3- 2 0 2 2 | 1 7: 4 6
H ol d er: 
            
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
R & D Q A O p er ati o n s P o m e zi a
Alf a si g m a S. p. A.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 2 9- 0 3- 2 0 2 2 | 1 7: 5 6
Vi e w e d: 2 9- 0 3- 2 0 2 2 | 1 7: 5 7 
Si g n e d: 2 9- 0 3- 2 0 2 2 | 1 7: 5 8
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
Alf a si g m a S. p. A.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 2 9- 0 3- 2 0 2 2 | 1 7: 5 6
Vi e w e d: 3 0- 0 3- 2 0 2 2 | 1 7: 0 4 
Si g n e d: 3 0- 0 3- 2 0 2 2 | 1 7: 0 4
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI
P P D


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
Alf a si g m a S p A ( G x P)
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   A p pr o v o il d o c u m e nt o
S e nt: 2 9- 0 3- 2 0 2 2 | 1 7: 5 6
Vi e w e d: 2 9- 0 3- 2 0 2 2 | 1 8: 4 3 
Si g n e d: 2 9- 0 3- 2 0 2 2 | 1 8: 4 4
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
H e a d of Cli ni c al O p er ati o n s
Alf a si g m a S. p. A.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 2 9- 0 3- 2 0 2 2 | 1 7: 5 6
Vi e w e d: 3 0- 0 3- 2 0 2 2 | 1 1: 0 0 
Si g n e d: 3 0- 0 3- 2 0 2 2 | 1 1: 0 0
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
E arl y Cli ni c al D e v el o p m e nt H e a d
Alf a si g m a S. p. A.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 2 9- 0 3- 2 0 2 2 | 1 7: 5 6
Vi e w e d: 2 9- 0 3- 2 0 2 2 | 1 9: 0 5 
Si g n e d: 2 9- 0 3- 2 0 2 2 | 1 9: 0 5
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
Alf a si g m a S. p. A.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 2 9- 0 3- 2 0 2 2 | 1 7: 5 6
Vi e w e d: 2 9- 0 3- 2 0 2 2 | 1 8: 0 6 
Si g n e d: 2 9- 0 3- 2 0 2 2 | 1 8: 0 6
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
Alf a si g m a S. p. A.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   A p pr o v o il d o c u m e nt o
S e nt: 2 9- 0 3- 2 0 2 2 | 1 7: 5 6
Vi e w e d: 3 0- 0 3- 2 0 2 2 | 1 0: 0 4 
Si g n e d: 3 0- 0 3- 2 0 2 2 | 1 0: 0 4
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
2 9- 0 3- 2 0 2 2 | 1 7: 5 6
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
3 0- 0 3- 2 0 2 2 | 1 0: 0 4
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
3 0- 0 3- 2 0 2 2 | 1 0: 0 4
C o m pl et e d
S e c urit y C h e c k e d
3 0- 0 3- 2 0 2 2 | 1 7: 0 4
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s
P P D
P P D
P P D
P P D

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E L E C T R O NI C R E C O R D A N D SI G N A T U R E DI S C L O S U R E   
Fr o m ti me t o ti me, Bi orasi, L L C ( we, us or C o m pa n y) ma y be re q uire d b y la w t o pr o vi de t o y o u 
certai n writte n n otices or discl os ures. Descri be d bel o w are t he ter ms a n d c o n diti o ns f or pr o vi di n g 
t o y o u s uc h n otices a n d discl os ures electr o ni call y t hr o u g h t h e D oc u Si g n s yste m. Please rea d t he 
i nf or mati o n bel o w caref ull y a n d t h or o u g hl y, a n d if y o u ca n access t his i nf or mati o n electr o nicall y 
t o y o ur satisf acti o n a n d a gree t o t his Electr o nic Rec or d a n d Si g nat ure Disc l os ure ( E R S D), pleas e 
c o nfir m y o ur a gree m e nt b y sel ecti n g t h e c hec k- b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d 
si g nat ur es’ bef ore clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yste m.  
 
Getti n g p a per c o pies   
At a n y ti me, y o u ma y re q uest fr o m us a pa p er c o p y of a n y rec or d pr o vi d e d or ma de a v aila ble 
electr o nic all y t o y o u b y us. Y o u will ha ve t he a bilit y t o d o w nl oa d a n d pri nt d oc u me nts we se n d 
t o y o u t hr o u g h t he D o c u Si g n s yste m d uri n g a n d i m me diatel y after t he si g ni n g sessi o n a n d, if y o u 
elect t o create a D oc u Si g n acc o u nt, y o u ma y acce ss t he d oc u me nts f or a li mite d peri o d of ti me 
( us uall y 3 0 d a ys) after s u c h d oc u me nts are first se nt t o y o u. After s uc h ti me, if y o u wis h f or us t o 
se n d y o u p a per c o pies of a n y s u c h d oc u me nts fro m o ur office t o y o u, y o u will be c har ge d a 
$ 0. 0 0 per- pa ge fee. Y o u ma y re q uest deli ver y of s uc h pa per c o pies fr o m us b y f oll o wi n g t he 
pr oce d ure descri be d bel o w. 
 
Wit h dr a wi n g y o ur c o nse nt   
If y o u deci d e t o recei ve n otices a n d discl os ures fr o m us electr o nicall y, y o u ma y at a n y ti me 
c ha n ge y o ur mi n d a n d t ell us t hat t hereafter y o u wa nt t o recei v e re q uir e d n otices a n d discl os ures 
o nl y i n pa per f or mat. H o w y o u m ust i nf or m us of y o ur decisi o n t o recei ve f ut ure n otices a n d 
discl os ure i n pa per f or mat a n d wit h dra w y o ur c o ns e nt t o recei v e n otices a n d discl os ures 
electr o nicall y is des cri be d bel o w. 
 
C o nse q ue nces of c h a n gi n g y o ur mi n d   
If y o u ele ct t o recei ve re q uire d n otices a n d discl os ures o nl y i n p a per f or mat, it will sl o w t he 
s pee d at w hic h we ca n c o m plete certai n ste ps i n tra nsacti o ns wit h y o u a n d deli veri n g s er vices t o 
y o u beca use we will nee d first t o se n d t he re q uir e d n otices or discl os ures t o y o u i n pa per f or mat, 
a n d t he n wait u ntil we recei ve bac k fr o m y o u y o ur ac k n o wle d g m e nt of y o ur recei pt of s uc h 
pa per n otices or discl os ures. F urt her, y o u will n o l o n ger be a bl e t o use t he D oc u Si g n s yste m t o 
recei v e re q uir e d n otices a n d c o nse nts electr o nicall y fr o m us or t o si g n electr o nicall y d o c u me nts 
fr o m us. 
 
All n otices a n d discl os ures will be se nt t o y o u electr o nic all y   
P P D


U nless y o u tell us ot her wise i n acc or da nce wit h t he pr oce d ures des cri be d h erei n, we will pr o vi de 
electr o nicall y t o y o u t hr o u g h t he D o c u Si g n s yste m all re q uire d n otices, discl os ures, 
a ut h orizati o ns, ac k n o wle d ge m e nts, a n d ot her d oc u me n ts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u d uri n g t he c o urse of o ur relati o ns hi p wit h y o u. T o re d u ce t he c ha n ce of y o u 
i na d verte ntl y n ot recei vi n g a n y n otice or discl os ure, we prefer t o pr o vi de all of t he re q uire d 
n otices a n d discl os ures t o y o u b y t he s a me met h o d a n d t o t he sa me a d dress t hat y o u ha v e gi ve n 
us. T h us, y o u ca n recei ve all t he discl os ures a n d n otices electr o nicall y or i n pa per f or mat t hr o u g h 
t he pa per mail deli ver y s yste m. If y o u d o n ot a gree wit h t his pr ocess, pleas e let us k n o w as 
descri be d b el o w. Please als o see t he pa ra gra p h i m me diatel y a b o ve t hat des cri bes t he 
c o nse q ue nces of y o ur ele cti n g n ot t o recei ve deli ver y of t he n otices a n d dis cl os ures 
electr o nicall y fr o m us. 
 
H o w t o c o nt act Bi or asi, L L C:   
Y o u ma y c o ntact us t o let us k n o w of y o ur c ha n ges as t o h o w we ma y c o nt act y o u electr o nicall y, 
t o re q uest pa per c o pies of cert ai n i nf or mati o n fro m us, a n d t o wit h dra w y o ur pri or c o nse nt t o 
recei v e n otices a n d discl os ures electr o nicall y as f oll o ws: 
T o c o ntact us b y e mail se n d messa ges t o: 
 
 
T o a d vise Bi or asi, L L C of y o ur ne w e m ail a d dress   
T o let us k n o w of a c h a n ge i n y o ur e mail a d dress w here we s h o ul d se n d n otices a n d discl os ures 
electr o nicall y t o y o u, y o u m ust se n d a n e mail messa ge t o us at 
 a n d i n t he 
b o d y of s u c h re q u est y o u m ust state: y o ur pre vi o us e mail a d dress, y o ur ne w e mail a d dress.  We 
d o n ot re q uire a n y ot h er i nf or mati o n fr o m y o u t o c ha n ge y o ur e m ail a d dress.  
If y o u create d a D oc u Si g n acc o u nt, y o u ma y u p d ate it wit h y o ur ne w e mail a d dress t hr o u g h y o ur 
acc o u nt pr efere nces.  
 
T o re q uest p a per c o pies fr o m Bi or asi, L L C   
T o re q uest deli ver y fr o m us of pa per c o pies of t he n otices a n d discl os ures pre vi o usl y pr o vi de d 
b y us t o y o u ele ctr o nicall y, y o u m ust se n d us a n e mail t o 
 a n d i n t he b o d y 
of s uc h re q u est y o u m ust state y o ur e mail a d dress, f ull na me, maili n g a d dress, a n d tele p h o ne 
n u m ber. We will bill y o u f or a n y fees at t hat ti me, if a n y. 
 
T o wit h dr a w y o ur c o nse nt wit h Bi or asi, L L C   
T o i nf or m us t hat y o u n o l o n ger wis h t o recei ve f ut ure n otices a n d discl os ur es i n electr o nic 
f or mat y o u ma y: 
P P D
P P D
P P D


i. decli ne t o si g n a d o c u me nt fr o m wit hi n y o ur si g ni n g sessi o n, a n d o n t he s u bse q ue nt pa ge, 
select t he c h ec k- b o x i n dicati n g y o u wis h t o wit h dra w y o ur c o ns e nt, or y o u ma y; 
ii. se n d us a n e mail t o 
 a n d i n t he b o d y of s uc h re q u est y o u m ust state 
y o ur e mail, f ull na me, m aili n g a d dress, a n d te le p h o ne n u m ber. We d o n ot nee d a n y ot her 
i nf or mati o n fr o m y o u t o wit h dra w c o nse nt..  T h e c o nse q ue nces of y o ur wit h dra wi n g c o nse nt f or 
o nli ne d oc u me nts will be t hat tra nsacti o ns ma y ta ke a l o n ger ti me t o pr o cess.. 
 
Re q uire d h ar d w are a n d s oft w are   
T he mi ni m u m s yste m re q uire me nts f or usi n g t he D oc u Si g n s yste m ma y c h a n ge o ver ti me. T h e 
c urre nt s yste m r e q uire me nts are f o u n d h ere: htt ps://s u p p ort. d oc usi g n.c o m/ g ui des/si g ner- g ui de-
si g ni n g-s yste m-re q uire m e nts.  
 
Ac k n o wle d gi n g y o ur access a n d c o nse nt t o recei ve a n d si g n d oc u me nts electr o nic all y   
T o c o nfir m t o us t hat y o u ca n access t his i nf or mati o n electr o nicall y, w hi c h will be si milar t o 
ot her electr o nic n otices a n d discl os ures t hat we wi ll pr o vi de t o y o u, pleas e c o nfir m t hat y o u ha ve 
rea d t his E R S D, a n d (i) t hat y o u are a ble t o pri nt o n pa per or electr o ni call y sa v e t his E R S D f or 
y o ur f ut ure refere n ce a n d access; or (ii) t hat y o u are a ble t o e mail t his E R S D t o a n e mail a d dress 
w here y o u will be a ble t o pri nt o n pa per or s a ve it f or y o ur f ut ur e refere nce a n d access. F urt her, 
if y o u c o nse nt t o recei vi n g n otices a n d discl os ures e x cl usi vel y i n electr o nic f or mat as des cri be d 
herei n, t he n sel ect t he c h ec k- b o x ne xt t o ‘I a gree t o use electr o ni c rec or ds a n d si g nat ur es’ bef ore 
clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yst e m.  
B y sele cti n g t he c hec k- b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ur es’, y o u c o nfir m 
t hat: 
 
Y o u ca n access a n d rea d t his Electr o nic Rec or d a n d Si g nat ure Discl os ure; a n d 
 
Y o u ca n pri nt o n pa per t his Electr o nic Rec or d a n d Si g nat ure Discl os ure, or sa ve or se n d 
t his Electr o nic Rec or d a n d Discl os ure t o a l ocati o n w here y o u ca n pri nt it, f or f ut ure 
refere nce a n d access; a n d 
 
U ntil or u nless y o u n otif y Bi orasi, L L C as des cri be d a b o ve, y o u c o nse nt t o recei v e 
e x cl usi vel y t hr o u g h ele ctr o nic mea ns all n otices, discl os ures, a ut h orizati o ns, 
ac k n o wle d ge me nts, a n d ot her d oc u me nts t hat  are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u b y Bi orasi, L L C d uri n g t he c o urse of y o ur relati o ns hi p wit h Bi orasi, 
L L C. 
P P D