Conditions: Safety Tolerability Ocular Surface Ocular Comfort
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: yes

Brief summary:
Clinical phase I, controlled, non comparative, open, single center study evaluating the safety and tolerability of ophthalmic solution PRO-172 when applied on the ocular surface of healthy volunteers.

Detailed description:

Arms:
arm 1: PRO-172 Ophthalmic Solution QID (four times per day). Single arm.

Interventions: intervention 1: Bepotastine Besilate
Intervention descriptions: intervention 1: Bepotastine Besilate 1.5% QID (quater in die) for 7 days

Protocol document:
Prot_000.pdf: 
SOPH172-0919/I
Title:  Phase  I  clinical  study  to  evaluate  the  safety  and  tolerability  of  the  PRO-172  
ophthalmic  solution,  developed  by  Laboratorios  Sophia,  SA  de  CV,  on  the  ocular  
surface  of  clinically  healthy  subjects.
Protocol  for  the  study:
Indication:  Allergic  conjunctivitis
Phase  of  the  study:  I
Version:  2.0
Clinical  Practices  and  in  compliance  with  ICH  guidelines  and  current  local  legislation  Study  information
Generic  name:  Bepotastine  1.5%
Protocol  information
Distinctive  name:  PRO-172
Information  on  the  molecule  under  study
Version  date:  Nov  11,  2019
This  protocol  has  been  carried  out  in  accordance  with  the  principles  of  the  Declaration  of  Helsinki  and  
will  be  carried  out  in  accordance  with  the  Good
Sponsor:  Sophia  Laboratories,  SA  de  CV
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Changelog
1.  Page  57,  first  paragraph.  The  CIOMS  reference  has  been  updated  from  2002  to  2016.
2.  Page  60,  third  paragraph.  The  paragraph  is  deleted:  In  the  event  that  a  subject  is  illiterate,
acceptance  will  be  with  your  fingerprint,  and  in  the  event  that  the  subject  is  not  able  to  grant  a
adequate  written  informed  consent,  a  representative  of  the  subject  “legally
Version  2.0
November  11,  2019
Study  No:  SOPH172-0919/I
Sophia  Laboratories,  SA  de  CV
“authorized”  may  provide  such  consent  by  the  subject  in  accordance  with  the  laws  and
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applicable  regulations.
Changes  from  version  1.0,  dated  September  23,  2019,  to  version  2.0,  dated  November  11,  2019
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Page  intentionally  left  blank
Version  2.0
November  11,  2019
Study  No:  SOPH172-0919/I
Sophia  Laboratories,  SA  de  CV
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Content
List  of  abbreviations.......................................................................................................................................12
November  11,  2019
2.1
Study  Schedule..................................................................................................................17
2.2.3  Safety  of  bepotastine ................................................................................................................21
Background  on  the  research.................................................................................................22
2.2
2.4.2  Known  potential  benefits.................................................................................................23
Background  on  bepotastine .......................................................................................................20
2.3.2  From  the  development  phase  of  the  investigational  product................................................................23
2.4
1.1
3  of  73
Contents ...............................................................................................................................................................3
Study  diagram .................................................................................................................................16
2.2.2  Efficacy  of  bepotastine ................................................................................................................21
2.4.1  Known  potential  risks.......................................................................................................23
2.  Introduction  and  Background................................................................................................................18
2.2.4  Summary  of  the  pharmaceutical  development  of  PRO-172 ................................................................22
Problem  statement........................................................................................................................23
Sophia  Laboratories,  SA  de  CV
Signature  Pages.................................................................................................................................................10
2.5
Version  2.0
Researcher  Agreement ................................................................................................................................11
1.3
23
1.  Summary ..................................................................................................................................................13
Theoretical  framework..................................................................................................................................18
2.3.1  About  the  research  question..................................................................................................22
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Risk-benefit  assessment..................................................................................................................23
Changelog ................................................................................................................................................1
Synopsis..............................................................................................................................................13
Study  No:  SOPH172-0919/I
From  the  sponsor.................................................................................................................................................10
1.2
2.2.1  Pharmacology  of  bepotastine................................................................................................20
Study  leaders ......................................................................................................................................8
Content
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4.3
November  11,  2019
3.1
Specific  objectives................................................................................................................................25
Design  Overview .......................................................................................................................26
5.3
Procedure  in  case  of  loss  of  tracking..................................................................................29
Patient  Elimination  and  Substitution  Criteria........................................................................................27
6.  Investigational  Product........................................................................................................................31
5.  Study  population.................................................................................................................................27
2.6
3.3
Scrutiny  errors.................................................................................................................................28
5.6
6.1
6.1.2  Reference  product ...............................................................................................................31
Storage  and  handling  of  investigational  products  at  the  study  center.................32
6.1.1  Investigational  Product..................................................................................................................31
4.  Study  design ....................................................................................................................................26
Primary  objective ................................................................................................................................25
Eligibility  Criteria........................................................................................................................27
Recruitment  and  retention  strategies .......................................................................................28
6.2
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Subject  Identification..................................................................................................................29
4.1
Sophia  Laboratories,  SA  de  CV
Secondary  objectives.......................................................................................................................25
5.1.2  Exclusion  criteria..................................................................................................................27
6.1.3  Dose  of  the  investigational  product ................................................................................................31
5.5
3.4.1  Hypothesis ....................................................................................................................................25
Version  2.0
Justification  of  the  study  design..................................................................................................26
5.2
Concomitant  treatments  and  medications  not  authorized  during  the  study..................................32
Lifestyle  Considerations ..................................................................................................................28
3.2
Justification.......................................................................................................................................24
Expected  duration ................................................................................................................................26
5.7
6.3
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5.4
3.  Objectives  and  hypotheses.......................................................................................................................25
3.4
Study  No:  SOPH172-0919/I
Hypothesis.......................................................................................................................................25
4.2
5.1
Managed  Products .................................................................................................................31
5.1.1  Inclusion  criteria ..................................................................................................................27
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November  11,  2019
7.1
7.4
7.3.3  Definition  of  variables,  methods  and  scales  to  be  used  for  their  measurement ...................................................36
7.5.3  File........................................................................................................................................42
8.1
8.  Evaluation  and  management  of  adverse  events ................................................................................................43
8.4.1  Recording  adverse  events  in  the  electronic  case  report  form................................................45
Data  collection........................................................................................................................41
Definition  of  adverse  event.................................................................................................................43
8.4.3  Procedures  for  a  serious  adverse  event ................................................................................47
6.4
7.3
8.3
8.5
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8.5.1  PNA  Report.........................................................................................................................................51
7.  Methods  and  procedures  of  the  study ....................................................................................................35
7.3.2  Secondary  outcome  variables.......................................................................................................36
7.5.2  Electronic  forms  of  data  collection.......................................................................................42
Researcher  Responsibilities........................................................................................................44
Study  visits  and  activities  program........................................................................................40
7.5.4  Unscheduled  follow-up  visits.......................................................................................42
8.4.2  Monitoring  of  adverse  events.......................................................................................................46
Sophia  Laboratories,  SA  de  CV
Clinical  Study  Registration .................................................................................................................35
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8.4.4  Causality  Assessment .......................................................................................................................48
Version  2.0
6.5
7.4.2  Unscheduled  follow-up  visits.......................................................................................41
Regulation  and  standards  on  adverse  events..................................................................................43
7.2
7.5
8.2
Procedure  for  monitoring  and  measuring  adherence..................................................................33
8.4
Definitions  relevant  to  the  classification  of  adverse  events.................................................................43
Unanticipated  Problems..................................................................................................................51
Strategies  to  improve  adherence..................................................................................................34
7.3.1  Primary  outcome  variables.......................................................................................................36
Study  No:  SOPH172-0919/I
Outcome  variables........................................................................................................................36
7.4.1  Description  of  activities  per  visit.......................................................................................40
7.5.1  Source  documents ....................................................................................................................41
From  the  research  center..................................................................................................................35
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10.1.3
November  11,  2019
10.
9.2.1  Pre-study  audit..................................................................................................................53
Procedure  for  handling  missing  data..................................................................................55
11.
Obtaining................................................................................................................................59
10.2.2
Special  Considerations..................................................................................................60
10.1.5
Monitoring  of  study  centers .....................................................................................................52
10.1.1
11.2  Amendments  to  the  Protocol..................................................................................................................58
11.4.3
11.5
11.6
11.6.1
Conflict  of  interest........................................................................................................................61
Data  interpretation ...............................................................................................................  54
Audit  and  quality  control .................................................................................................................53
Sample  size  calculation .................................................................................................................55
11.4  Informed  consent ................................................................................................................59
11.8  Ancillary  and  post-study  care .......................................................................62
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11.4.1
Deviations  from  the  statistical  analysis  plan..................................................................................55
Sophia  Laboratories,  SA  de  CV
9.2
Justification  of  the  sample  calculation .....................................................................................55
Declaration  of  interests ........................................................................................................62
11.4.2
Statistical  analysis..................................................................................................................................54
Version  2.0
10.1.2
Ethical  Considerations ........................................................................................................................57
11.7  Access  to  information ..................................................................................................................62
11.1  Approval  of  Committees..................................................................................................................57
10.1  Data  Analysis..................................................................................................................................54
9.  Study  monitoring ...............................................................................................................................52
10.1.4
Modifications  to  informed  consent..................................................................................60
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11.3  Early  termination  of  the  study..................................................................................................58
9.1
Statistical  analysis..................................................................................................................54
Study  No:  SOPH172-0919/I
9.2.2  Audit  during  the  study.................................................................................................53
Subjects  included  in  the  analysis..................................................................................................55
10.2
Confidentiality.................................................................................................................................60
10.2.1  Calculated  N ...............................................................................................................................55
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Publication  of  results.................................................................................................................64
Study  No:  SOPH172-0919/I
Version  2.0
13.3
Annexes................................................................................................................................................71
16.1
November  11,  2019
14.
ICO................................................................................................................................................71
Biosecurity  aspects..................................................................................................................................63
Financing  and  Insurance..................................................................................................................65
Oxford  Scale.................................................................................................................................73
12.
14.1  Compensation  to  Study  Participants.......................................................................................65
16.2
Publication  Policy..................................................................................................................................64
14.2  Insurance  for  study  participants ..................................................................................................65
16.3
13.1  Final  Report..................................................................................................................................64
References.......................................................................................................................................66
Efron  Scale .................................................................................................................................73
13.
15.
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13.2  Communication  of  results.................................................................................................................64
16.
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Study  leaders
Guadalajara-Nogales  Km13.5  CP  45010  Zapopan,  Jalisco,  Mexico  Tel  +52(33)  3000  4200
Employees  of  Laboratorios  Sophia,  SA  de  CV  Av.  Paseo  del  Norte  No.  5255,  Col.  Guadalajara  Technology  Park,  Carretera
Table  1.  Study  leaders
¥
¥
Dr.  Oscar  Olvera  Montaño
November  11,  2019
Affiliation
Dr.  Leopoldo  Martín  Baiza  Durán
francisco.garcia@sophia.com.mx
Development
Safety  Pharmacologist
ricardo.llamas@sophia.com.mx
Dr.  Patricia  del  Carmen  Muñoz  Villegas
Team  of
The  administrative  structure  of  the  sponsoring  party,  corresponding  to  Laboratorios  Sophia,  SA  de  CV
Medical  Director
Team  of
Biostatistics
8  of  73
QFB.  Francisco  García  Vélez
Name/Contact
Medical  Editor
Clinical
Clinic
Director  of  the  
study
Sophia  Laboratories,  SA  de  CV
leopoldo.baiza@sophia.com.mx
Dr.  en  C.  Ricardo  Alonso  Llamas  Velázquez
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patricia.munoz@sophia.com.mx
Function
Version  2.0
Clinics
Team  of
Clinical
Medical  Director  
of  the
oscar.olvera@sophia.com.mx
Development
is  shown  in  Table  1.  Those  responsible  for  the  study
study
Study  No:  SOPH172-0919/I
Operations  Manager
Development
Clinical
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Leader  of
project
Medical  
editor/
Medical  Director  of  the  study
Medical  monitor
Clinical  Study  Director
Assistant  of
Clinical  team
logistics
Specialist  in
Clinical  monitor
Startup
Biostatistics
Logistics  Coordinator
Safety  Pharmacologist
Version  2.0
November  11,  2019
Study  No:  SOPH172-0919/I
Sophia  Laboratories,  SA  de  CV
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Figure  1.  Administrative  structure
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From  the  sponsor
Signature  pages
Dr.  Leopoldo  Martín  Baiza  Durán
Medical  Director  of  the  study
QFB.  Francisco  García  Vélez
Director  of  the  study
Version  2.0
November  11,  2019
Study  No:  SOPH172-0919/I
Sophia  Laboratories,  SA  de  CV
Oscar  Olvera  Montaño
Author  of  the  protocol
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Name:
Qualification:
Date
Name:
Qualification:
Signature
Signature
Name:
Signature
Date
Date
Qualification:
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Researcher  Agreement
Study  No:  SOPH172-0919/I
provided  by  the  sponsor,  strictly  in  accordance  with  this  protocol.
Version  2.0
I  understand  that  the  information  that  identifies  me  may  be  used  by  the  sponsor.  Because  the
November  11,  2019
information  contained  in  this  protocol  and  the  Researcher's  Manual  is  confidential,  I  understand  that  it  is
prohibited  from  sharing  it  with  any  third  party,  who  is  not  involved  in  the  approval,  supervision  or
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I  agree  to  conduct  this  clinical  study  according  to  the  design  and  guidelines  of  this  protocol,
conducting  the  study.  I  will  ensure  that  necessary  precautions  are  taken  to  protect  the  information  of
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in  compliance  with  the  provisions  of  this  protocol  and  in  adherence  to  the  accepted  standards  of  Good
loss,  inadvertent  disclosure  or  access  by  unauthorized  third  parties.
Clinical  Practices.
I  agree  to  report  all  information  or  data  in  accordance  with  the  provisions  of  the  protocol,
Sophia  Laboratories,  SA  de  CV
in  particular,  any  adverse  event.  Also,  I  agree  to  handle  clinical  supplies,
Qualification:
Date
Signature
Name:
Geographic  location  (city/state/country)
Name  of  the  center:
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List  of  abbreviations
IC
AVcc
November  11,  2019
Federal  Commission  for  the  Protection  against  Sanitary  Risks
Electronic  Case  Report  Form
RAC
Principal  Investigator
PI
World  Health  Organization
OD
Nonsteroidal  anti-inflammatory  drugs
COFEPRIS
Informed  consent  form
Both  eyes
Research  products
National  Registry  of  Clinical  Trials
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Conjunctival  allergen  challenge
EA
Research  Ethics  Committee
YOU
Confidence  interval
Right  eye
eCRF
Sophia  Laboratories,  SA  de  CV
Intrauterine  device
PNA
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Left  eye
NSAIDs
Version  2.0
FDA
QID
RNEC
CEI
IP
Unanticipated  problems
United  States  Food  and  Drug  Administration
Visual  acuity  with  correction
IUD
Study  No:  SOPH172-0919/I
Adverse  event
FCI
WHO
Four  times  a  day
OU
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1.  Summary
Estimated  duration  of  the  study  (from  the  first  visit  of  the  first  
patient  to  the  preparation  of  the  final  report):
November  11,  2019
September  23,  2019
by  Laboratorios  Sophia,  SA  de  CV  on  the  ocular  surface  of  clinically  healthy  subjects.
Therapeutic  indication:
unexpected  adverse  events  (AEs)  related  to  the  investigational  product.
10%  of  the  study  population  experienced  unexpected  adverse  events  related  to  the  product
Specific  objectives:
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Clinical  development  phase:  I
November  11,  2019
Ocular  Comfort  (OC)
2.0
Phase  I  clinical  study,  to  evaluate  the  safety  and  tolerability  of  the  PRO-172  ophthalmic  solution,  prepared
Main  objective:
H0=  The  PRO-172  ophthalmic  solution  is  safe  and  tolerable  in  its  ophthalmic  application  as  it  presents  in  less
investigation.
Antihistamine
Study  number:
Sophia  Laboratories,  SA  de  CV
SA  de  CV  on  the  ocular  surface  of  clinically  healthy  subjects.
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Creation  date:
Version  2.0
Allergic  conjunctivitis
•  To  evaluate  the  safety  of  PRO-172  ophthalmic  solution  through  the  incidence  of  events
•  To  evaluate  the  tolerability  of  PRO-172  ophthalmic  solution  by  means  of  the  Index  score
Version  date:
5  months
Hypothesis:
Title  of  the  study:
Protocol  version:
Study  No:  SOPH172-0919/I
SOPH172-0919/I
Use:
Goals:
•  Evaluate  the  safety  and  tolerability  of  the  PRO-172  formulation  manufactured  by  Sophia  Laboratories
1.1  Synopsis
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-  Have  corrected  visual  acuity  (CCVA)  of  20/30  or  better  in  both  eyes.
November  11,  2019
-  Healthy  subjects.
Phase  I  clinical  study,  controlled,  non-comparative,  open,  single-center.
-  Be  able  and  willing  to  comply  with  scheduled  visits,  treatment  plan,  and  other  study  procedures.
-  Have  participated  in  clinical  research  studies  90  days  prior  to  inclusion  in  this  study
-  Having  started  using  hormonal  contraceptives  or  IUDs  30  days  prior  to  inclusion  in  the
For  women:  be  pregnant,  breastfeeding,  or  planning  to  become  pregnant  during  the  study  period.
-  Have  a  history  of  any  chronic-degenerative  disease.
-  Have  an  intraocular  pressure  ÿ10  and  ÿ  21  mmHg.
10%  of  the  study  population  experienced  unexpected  adverse  events  related  to  the  product
Inclusion  criteria:
-  Have  previously  participated  in  this  same  study.
-  Present  unresolved  injuries  or  traumas  at  the  time  of  entering  the  study.
-  Have  undergone  non-ophthalmological  surgical  procedures  in  the  last  3  months.
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-  Have  the  capacity  to  voluntarily  grant  signed  informed  consent.
Study  design:
Exclusion  criteria:
-  That  they  cannot  follow  lifestyle  considerations.
present  study.
-
Sophia  Laboratories,  SA  de  CV
Number  of  subjects  (planned  and  analyzed):
-  Being  a  user  of  medications  or  herbal  products,  by  any  other  route  of  administration.
-  Present  inflammatory  or  infectious  disease,  active  at  the  time  of  entering  the  study.
Diagnosis  and  main  inclusion  criteria:
Version  2.0
Women  of  childbearing  potential  must  ensure  continued  use  (started  ÿ  30  days  prior  to  signing  the  ICF)  of  a  hormonal  
contraceptive  method  or  intrauterine  device  (IUD)  during  the  study  period.
-
study.
Selection  criteria:
H1=  PRO-172  ophthalmic  solution  is  not  safe  and  tolerable  for  ophthalmic  application  as  it  presents  in  more  than
-  Have  vital  signs  within  normal  parameters.
-  Have  a  history  of  any  type  of  eye  surgery.
-  Be  a  contact  lens  user  who  cannot  discontinue  use  during  the  study.
investigation.
Be  clinically  healthy.
Number  of  planned  subjects:  22  evaluable  subjects  (both  eyes)
Study  No:  SOPH172-0919/I
-  Be  between  18  and  45  years  old.
-
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-  Be  a  user  of  topical  ophthalmic  products  of  any  kind.
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November  11,  2019
-  Corneal  and  conjunctival  staining  changes  with  fluorescein  (TE:  day  8).
7  days
An  ÿ  ÿ  0.05  will  be  considered  significant.
-  ICO  score  (TE:  day  8).
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-  Incidence  of  chemosis  (TE:  day  8).
-  PRO-172.  Bepotastine  1.5%  Ophthalmic  Solution.  Laboratorios  Sophia,  SA  de  CV  Zapopan,  Jalisco,
Evaluation  criteria:
Dosage:  1  drop  4  times  a  day.
-  Incidence  of  unexpected  AEs  related  to  the  investigational  product.  (Evaluation  Time  [ET]:  days  8  and  10)
Data  will  be  expressed  using  measures  of  central  tendency:  mean  and  standard  deviation  for  quantitative  variables.  Qualitative  
variables  will  be  presented  as  frequencies  and  percentages.  Statistical  analysis  will  be  performed  using  the  Wilcoxon  rank  test  for  
quantitative  variables.  Differences  between  qualitative  variables  will  be  analyzed  using  the  X2  (Chi-square)  test  or  Fisher's  exact  test.
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Secondary  outcome  variables:
Sophia  Laboratories,  SA  de  CV
-
Version  2.0
Subject's  duration  in  the  study:
-  Changes  in  corneal  and  conjunctival  staining  with  lissamine  green  (TE:  day  8).
10  days
-  Conjunctival  hyperemia  changes  (TE:  day  8).
Research  Product  (RP):
Mexico.
Primary  outcome  variables
Duration  of  treatment:
-  Changes  in  Corrected  Visual  Acuity  (CCVA)  (TE:  day  8).
Statistical  methodology
Study  No:  SOPH172-0919/I
-  Route  of  administration:  Ophthalmic.
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final  clinics
Evaluations
Application  
start
N=  
22.
1  
drop  
QID  
OU
from  
PRO-172
Compliance  
with  
all  
criteria
Selection.  
Obtaining  
baseline  
values
Obtaining  
informed  
consent.
1.2  Study  diagram
7  days  of
treatment
VB
VB=baseline  visit,  VF=final  visit.  Evaluation  of  final  outcome  variables.,  Ll  S=safety  call.,  QID=Four  times  a  day,  OU=both  eyes
Version  2.0
November  11,  2019
Study  No:  SOPH172-0919/I
Sophia  Laboratories,  SA  de  CV
In  parentheses  ()  is  the  allowed  window  period.
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D  1
(+1)
LL  S
D  8
VF
(±  1)
D  10
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Obtaining informed consent. 
Compliance with all selection criteria.
Obtaining baseline values.
N = 22
Start of application
of PRO-172 
1 drop QID OU


1.3  Study  schedule
Study  No:  SOPH172-0919/I
November  11,  2019
Version  2.0
Sophia  Laboratories,  SA  de  CV
17  of  73
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X
X
(Staining  and  evaluation  of  conjunctival  
hyperemia  and  chemosis)
X
X
Comprehensive  ophthalmological  evaluation
AVcc
X
X
X
X
LlS
X
X
EA  Assessment
Research  Product  Assignment
X
X
VF
X
Vital  signs
X
Eye  Comfort  Index
Delivery  of  the  PI  and  start  of  intervention
X
X
X
Drug  Evaluation
X
D  1
X
Delivery  of  the  subject's  diary
X
PIO
(PI)
Adherence  assessment
D  10  ±  1
X
Integrity  of  the  ocular  surface
Return/Evaluation  of  the  Subject's  Diary
FCI  Signature
X
Urine  pregnancy  test
Eligibility  criteria
X
X
X
X
VB
Medical  record
Concomitant
X
D  8  A  +1
X
Return  of  PI
Procedures
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2.1  Theoretical  framework
There  are  4  types  of  histamine  receptors:  H1,  H2,  H3  and  H4.  They  all  belong  to  the  family  of  receptors
2.  Introduction  and  Background
due  to  allergic  processes.  [3,  5]  The  binding  of  histamine  to  the  H1  receptor  generates  the  H1R  complex,  which
However,  in  allergic  diseases,  inflammation  is  activated  inappropriately,  which  can  cause
Non-pharmacological  treatment  includes  the  use  of  ocular  lubricants,  physical  aids,  and  hygiene  measures.
Persistent  in  cases  where  symptoms  last  longer  than  4  weeks  and  intermittent  in  cases  where  symptoms  last  shorter  than  4  weeks.
It  can  synergize  with  lipopolysaccharides  and  tumor  necrosis  factor  alpha.  If  this  response  continues,
The  currently  available  treatment  for  allergic  conjunctivitis  can  be  non-pharmacological  and
Thus,  allergic  conjunctivitis  is  an  abnormal  inflammatory  response  of  the  conjunctiva  to  antigens  of  different
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vascular.  This  physiological  response  generates  hyperemia,  itching  and  secretion.  [1,  2]  Despite  the  above,  the
Hyperemia,  tearing,  chemosis,  and  discharge  are  among  the  most  common.  They  differ  in  etiology  and  management
interleukins  (IL-5,  IL-6,  IL-8),  prostaglandins  and  other  inflammatory  cells  (eosinophils  and  lymphocytes).  In  addition,
a  specific  time  of  year,  although  more  precisely  by  the  duration  of  the  same.  It  is  considered
to  this  period.[1]
will  be  released  by  eosinophils,  cytotoxic  proteins  and  cytokines  that  will  perpetuate  inflammation.  [5,  6,
mast  cells  and  basophils  with  activation  of  central  and  peripheral  receptors.  [1,  2]
Sophia  Laboratories,  SA  de  CV
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coupled  to  G  proteins.  [3,  4]  The  H1  receptor  is  the  one  that  has  the  greatest  participation  in  the  immune  response
The  allergic  inflammatory  response  provides  an  acute  defense  mechanism  against  toxins  and  infections.
pharmacological.  The  goal  is  to  reduce  associated  symptoms.  [8,  9]
It  generates  an  increase  in  intracellular  calcium,  smooth  muscle  contraction  and  increased  permeability.
structural  damage  to  the  affected  tissue.[2]
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Allergic  conjunctivitis  is  a  pathology  that  presents  with  symptoms  similar  to  infectious  conjunctivitis:  itching,
Late  responses  appear  to  be  unaffected  by  histamine,  where  cytokines  have  been  implicated,
7]
origin.  It  can  be  classified  as  intermittent  and  persistent  according  to  the  presentation  of  the  picture  in  a
Study  No:  SOPH172-0919/I
pharmacological.  However,  the  common  pathophysiological  mechanism  is  the  release  of  histamine  by  the
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H3
H4
H2
H1
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•  Headache
•  Vascular  permeability
•  Stimulation  of  vagal  afferent  nerves  in  the  airways
Immunomodulator
Pharmacological  treatment  can  be  administered  by  different  routes.  The  main  therapies  used
Modulation  in  neurotransmission
a)  Corticosteroids
•  Bronchodilation
c)  Systemic  antihistamines
e)  Mast  cell  stabilizers
General  function
Use  is  limited  to  severe  or  persistent  cases.  Despite  the  above,  topical  antihistamines  are  the
allergic  conjunctivitis.  [10]
a  42%  prevalence  of  allergic  diseases,  rhinitis,  asthma  and  conjunctivitis  in  the  central  part  of  the  country.
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The  most  effective  treatment  is  corticosteroids,  however,  due  to  their  adverse  effects,
Increases:
•  Bronchoconstriction
Gastric  acid  secretion
Prevents  excessive  bronchoconstriction,
Increases:
are:
Sophia  Laboratories,  SA  de  CV
•  Pain
most  commonly  used  drugs  and  those  with  the  greatest  scientific  evidence  of  their  effectiveness  for  the  treatment  of
b)  Topical  decongestants
In  Mexico  there  is  no  exact  data  on  the  presentation  of  allergic  conjunctivitis,  however,  it  is  estimated
Version  2.0
Acute  allergic  reactions
•  Vascular  permeability
the  itching  is  medium.
•  Headache
•  Tachycardia
Differentiation  of  myeloblasts  and  promyelocytes
Characteristic  function
d)  Topical  antihistamines
This  group  represents  an  absence  from  work  and  school  of  approximately  3  to  12  days.  It  also  means  a
f)  Non-steroidal  anti-inflammatory  drugs
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Receiver
•  Tachycardia
•  Vasodilation
•  Gastric  acid  secretion
•  Mucus  production
Study  No:  SOPH172-0919/I
•  Itching
Table  2.  Function  of  histamine  receptors.
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2.2  Background  on  bepotastine
2.2.1  Pharmacology  of  bepotastine
Bepotastine  besylate  is  a  selective  H1  receptor  antagonist  and  mast  cell  stabilizer  drug,
regulated  to  be  purchased  under  prescription,  unlike  other  OTC  antihistamines.  [19,  20,  21]
Belonging  to  the  antihistamine  family.  It  was  approved  for  the  treatment  of  allergic  conjunctivitis
Version  2.0
The  main  differences  with  other  drugs  in  the  same  class  lie  in  the  frequency  of  dosing,  the
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onset  of  action,  bioavailability  and  low  presence  of  sedative  effects.  [8,  9,  10]
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high  cost  for  health  institutions  and  affects  the  sector  that  suffers  from  it,  since  it  is  estimated  that  between  10-30%
by  the  FDA  in  2009,  in  addition  to  being  authorized  in  other  countries  such  as  Japan  and  Argentina.  In  addition  to  this
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experience,  since  2000,  it  has  been  marketed  in  Japan  for  oral  administration.  [15]
of  the  income  per  person  is  allocated  to  drug  treatment.  [11]
Its  pharmacological  effect  on  allergic  conjunctivitis  is  due  to  several  mechanisms:
1)  Selective  H1  receptor  antagonist .  [21]
In  the  United  States,  15  to  40%  of  the  population  is  affected  by  this  disease.  In  the  United  Kingdom,  it  represents
2)  Mast  cell  stabilizer.  [22]
It  is  a  drug  used  in  the  treatment  of  allergic  responses,  although  it  is  specifically  found
15%  of  general  medicine  consultations  and  an  estimated  annual  cost  of  1  billion  euros.  [12,  13]
3)  Suppression  of  eosinophil  infiltration.[22]
4)  Probable  inhibition  of  IL-5  secretion  by  mononuclear  cells  and  suppression  of  the  leukotriene  B4-dependent  
allergic  response.  [23,  24]
In  2015,  Castillo  et  al.  concluded  that  antihistamines  and  mast  cell  stabilizers  had  the
Sophia  Laboratories,  SA  de  CV
Greater  evidence  regarding  efficacy  in  treating  the  symptoms  of  allergic  conjunctivitis.[14]
approved  for  the  treatment  of  the  signs  and  symptoms  of  allergic  conjunctivitis.[16][17][18]  It  is  found
Available  for  oral  and  topical  ophthalmic  administration.  In  the  countries  where  it  is  marketed,  it  is
Study  No:  SOPH172-0919/I
Figure  2.  Chemical  structure  of  bepotastine  besylate
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H3.
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In  the  studies  conducted  by  Abelson  et  al  and  Macejko  et  al,  it  was  compared  in  an  allergen  challenge  model
Metabolism:  Minimal  metabolism  by  enzymes  of  the  cytochrome  P450  pathway.  In  vitro  studies  have
In  a  study  conducted  by  Bergmann  et  al,  they  conducted  two  clinical  studies,  in  which  they  compared  the  efficacy
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Rapid  and  sustained,  lasting  up  to  8  hours,  itching.  Other  secondary  signs  of  inflammation  were  also  seen
bepotastine  (1%  vs  1.5%),  both  were  effective  in  reducing  pruritus,  however,  although  it  was
pharmacological,  due  to  its  high  selectivity  for  the  H1  receptor  (101  IC50nM)  and  its  low  activity  on  the
Route  of  administration:  topical-ophthalmic.
Elimination:  The  absorbed  fraction  is  eliminated  in  the  urine.  However,  the  vast  majority  appears  to  be  eliminated
Absorption:  Highest  concentrations  appear  after  1-2  hours  of  instillation.  Cmax  was
less  than  2  ng/mL.  It  can  also  be  eliminated  by  P-glycoprotein.  [21]  [25]  [26]  [27]
modest.  [28,  16]
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of  bepotastine  1.5%  vs  placebo  in  a  RAC  model  and  determined  that  bepotastine  significantly  reduces
There  are  several  clinical  studies,  reported  in  the  literature,  that  demonstrate  the  efficacy  of  besilate
Sophia  Laboratories,  SA  de  CV
three  times  lower  than  that  reported  for  oral  administration.
Version  2.0
reversible  by  melanin.
studies  have  been  compared  against  placebo,  Olopatadine  and  the  same  bepotastine,  but  in  1%  concentration.
considerably  decreased.[29]
suggested  a  low  interaction  by  microsomes  CYP3A4,  2C9  and  2C19.
conjunctival  (RAC),  the  efficacy  in  reducing  itching  and  conjunctival  hyperemia  of  two  concentrations  of
Bepotastine  besylate  is  an  antihistamine  with  less  sedation  than  other  members  of  this  class.
Release:  immediate.
via  the  nasolacrimal  route.  After  24  hours  of  the  last  instillation,  plasma  concentrations  are
Distribution:  Protein  binding  of  approximately  55%.  Low  penetration  into  brain  tissue.  Has  affinity
Bepotastine  1.5%,  in  the  treatment  of  symptoms  and  signs  associated  with  allergic  conjunctivitis.  In  these
statistically  significant  decrease  in  conjunctival  hyperemia,  this  was  considered  a  reduction
Study  No:  SOPH172-0919/I
5.1  ±  2.5  ng/mL  for  1%  concentration  and  7.3  ±  1.9  ng/mL  for  1.5%  concentration.  This  Cmax  is
2.2.2  Efficacy  of  bepotastine
2.2.1.1  Pharmacokinetics  in  the  eyeball
2.2.3  Safety  of  bepotastine
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November  11,  2019
PRO-172  has  been  developed  by  Laboratorios  Sophia,  SA  de  CV.  It  has  the  physicochemical  characterization
Regarding  carcinogenicity,  it  has  not  been  reported  after  2  years  of  exposure  in  rats  and  mice.
Allergic  conjunctivitis  is  an  under-diagnosed  disease  because  its  clinical  picture  may
of  adverse  events;  toxicity  variables  were  histopathological  changes  in  the  cornea  and  conjunctiva.
•  Facial  edema  and  pharyngeal  dryness  (1/1153  patients)
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toxicity  in  albino  rabbits  in  New  Zealand,  with  60  days  of  application  of  PRO-172  BID.
the  quality  of  life  and  affects  labor  productivity,  which  has  an  important  effect  on  increasing  the
Ophthalmic  instillation  has  not  generated  histopathological  and  inflammatory  changes  in  preclinical  studies.
•  Drowsiness  (59/4453  patients)
an  application  of  1  drop  twice  a  day  for  6  weeks.  In  addition,  no  changes  in  the  number  were  reported
•  Dry  mouth  (3 /  1153  patients)
Safety  variables  included:  conjunctival  hyperemia,  discharge,  ocular  surface  staining,  and  incidence
occupational  in  patients  with  allergic  conjunctivitis.[30]
172  was  considered  safe  for  ophthalmic  application.
Urticaria  (2/1316  patients)  [21]
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The  most  common  adverse  event  is  dysgeusia.
Version  2.0
It  is  secreted  in  the  breast  milk  of  rats.  However,  this  is  unknown  in  humans.
By  oral  administration  the  main  adverse  events  that  have  been  reported  are:
and  the  accelerated  and  long-term  stability  protocol.  A  preclinical  safety  and
be  confused  with  other  allergic  pathologies.  It  affects  15  -  40%  of  the  American  population.  [12]  Decreases
In  animal  models,  no  respiratory  or  cardiological  adverse  events  have  been  reported  with  the  usual  doses.
cost  for  their  treatment.  In  the  United  Kingdom,  a  decrease  of  2.3  hours  per  week  in  the  workday  was  reported
In  healthy  humans  older  than  3  years,  no  serious  adverse  events  or  deaths  were  reported  following
•  Upper  abdominal  pain  (6/4453  patients)
It  is  categorized  as  C,  because  there  is  evidence  of  teratogenicity  in  animal  models.
•
follow-up  visits  during  the  60  days  and  a  final  visit,  considered  for  the  outcome  variables.
Study  No:  SOPH172-0919/I
endothelial  cells,  intraocular  pressure,  visual  acuity  and  anterior  and  posterior  segment  structures.
2.3  Background  on  the  research
2.2.4  Summary  of  the  pharmaceutical  development  of  PRO-172
2.3.1  About  the  research  question
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2.4.1  Known  potential  risks
2.4  Risk-benefit  assessment
2.3.2  From  the  development  phase  of  the  research  product
2.4.2  Known  potential  benefits
2.5  Problem  statement
November  11,  2019
In  the  treatment  of  allergic  conjunctivitis,  the  use  of  topical  antihistamines  has  proven  to  be  an  option
As  previously  mentioned,  ophthalmic  formulations  of  bepotastine  besilate  are
However,  the  PRO-172  formulation,  developed  by  Laboratorios  Sophia,  SA  de  CV  requires  documentation
Symptoms  associated  with  allergic  conjunctivitis  will  not  be  evaluated.
which  makes  it  a  safe  antihistamine.  Its  main  expected  adverse  effects  are  dysgeusia,  as  well  as  heartburn.
in  different  pharmacological  formulations.
used  concomitantly  with  other  therapies,  that  is  low  cost,  with  a  low  event  rate
and  scientific  evidence  of  its  safety.
The  use  of  anhistamines  in  the  treatment  of  allergic  conjunctivitis  blocks  the  H1  receptor  of  the
of  bepotastine  and  nasal  route  of  bepotastine  nasal  solution.
No  other  risks  are  anticipated  with  ophthalmic  application  of  PRO-172.
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In  this  phase  of  research,  the  known  potential  benefits  of  bepotastine,  such  as  relief  from
its  own  safety  and  tolerability  profile.  No  human  studies  have  been  previously  conducted  with  this
Sophia  Laboratories,  SA  de  CV
used  in  other  countries,  which  has  had  few  adverse  events  reported  and  a  superior  efficacy  profile.
Version  2.0
They  are  commercially  available  in  Japan,  the  USA  and  Argentina,  and  therefore  have  clinical  studies.
Effective  in  relieving  symptoms.  Bepotastine  is  an  antihistamine  whose  efficacy  and  safety  are  known
Bepotastine,  as  an  active  ingredient,  has  a  known  safety  profile,  already  described  in  the  literature,  which
The  ideal  treatment  should  be  in  accordance  with  the  etiology  and  severity,  however,  it  is  important  that  it  can  be
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adverse  effects,  easy  to  access  and  easy  to  use  by  healthcare  teams  and  patients.
In  addition,  there  is  also  evidence  of  its  safety  after  oral  administration  of  tablets.
other  indicated  pharmacological  therapies.[19] .
formulation,  so  the  phase  I  clinical  trial  is  indicated  to  evaluate  said  profile.
transient.
Study  No:  SOPH172-0919/I
histamine,  decreasing  the  presentation  of  symptoms.  Topical  bepotastine  is  a  treatment  option,
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adverse  events  and  pharmacokinetic  and  pharmacodynamic  characteristics.
Bepotastine  besilate  1.5%,  developed  by  Laboratorios  Sophia  SA  de  CV,  seeks  to  be  an  alternative  to
Version  2.0
treatment  for  allergic  conjunctivitis,  based  on  the  experience  of  its  use  in  other  populations.
Laboratorios  Sophia,  SA  de  CV  seeks  to  expand  therapeutic  options  for  symptom  relief
November  11,  2019
However,  according  to  pharmacological  development,  it  is  required  to  document  its  safety  profile  and
associated  with  allergic  conjunctivitis.  PRO-172  is  a  1.5%  bepotastine  ophthalmic  solution  formulation
tolerability.
for  which  we  seek  to  know  its  clinical  safety  and  tolerability  profile.
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The  most  widely  used  pharmacological  therapy  with  the  greatest  scientific  evidence  is  the  receptor  antagonists.
Sophia  Laboratories,  SA  de  CV
histamine  1.  However,  in  this  therapeutic  class  there  are  differences  due  to  their  efficacy,  risk  of
Study  No:  SOPH172-0919/I
2.6  Justification
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3.3  Secondary  objectives
3.4.1  Hypothesis
3.2  Specific  objectives
3.1  Primary  objective
3.4  Hypothesis
(EA)  unexpected  adverse  events  related  to  the  investigational  product.
CV  by  changes  in  corneal  and  conjunctival  fluorescein  staining.
-  To  evaluate  the  tolerability  of  PRO-172  ophthalmic  solution  by  means  of  the  Index  score
Version  2.0
-  To  know  the  safety  of  the  PRO-172  formulation  manufactured  by  Laboratorios  Sophia,  SA  de
10%  of  the  study  population  unexpected  adverse  events  related  to  the  investigational  product.
CV  through  changes  in  conjunctival  hyperemia.
Ocular  Comfort  (OC).
November  11,  2019
H1=  PRO-172  ophthalmic  solution  is  not  safe  and  tolerable  for  ophthalmic  application  as  it  presents  more  than
10%  of  the  study  population  unexpected  adverse  events  related  to  the  investigational  product.
-  To  know  the  safety  of  the  PRO-172  formulation  manufactured  by  Laboratorios  Sophia,  SA  de
-  To  know  the  safety  of  the  PRO-172  formulation  manufactured  by  Laboratorios  Sophia,  SA  de
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CV  by  incidence  of  chemosis.
To  evaluate  the  safety  and  tolerability  of  the  PRO-172  formulation  manufactured  by  Laboratorios  Sophia  SA  de  CV
CV  through  changes  in  Avcc.
-  To  know  the  safety  of  the  PRO-172  formulation  manufactured  by  Laboratorios  Sophia,  SA  de
on  the  ocular  surface  of  clinically  healthy  subjects.
H0=  The  PRO-172  ophthalmic  solution  is  safe  and  tolerable  in  its  ophthalmic  application  as  it  presents  in  less  than
CV  by  changes  in  corneal  and  conjunctival  staining  with  lissamine  green.
-  To  evaluate  the  safety  of  PRO-172  ophthalmic  solution  through  the  incidence  of  adverse  events
Sophia  Laboratories,  SA  de  CV
-  To  know  the  safety  of  the  PRO-172  formulation  manufactured  by  Laboratorios  Sophia,  SA  de
Study  No:  SOPH172-0919/I
3.  Objectives  and  hypotheses
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4.3  Expected  duration
4.1  Design  Overview
4.2  Justification  of  the  study  design
The  objective  of  the  study  is  to  evaluate  safety  and  tolerability,  so  the  intervention  time  is
The  total  average  recruitment  rate  during  the  study  should  be  no  less  than  0.37  subjects  per  day.
short  and  the  required  sample  size  is  smaller  than  that  of  an  efficacy  clinical  trial.  The  presence  of  groups
Version  2.0
The  approximate  duration  of  each  subject  in  the  study  is  10  days.
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parallels  allows  comparison  between  intervention  groups  on  outcome  variables.
Blinding  was  not  considered  for  this  study  due  to  the  characteristics  of  both  products  in
investigation
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Phase  I  clinical  trial,  controlled,  non-comparative,  open,  single-center
It  is  estimated  that  the  total  duration  of  the  study,  from  the  first  visit  of  the  first  patient  to  the  preparation  of  the
The  study  design  (clinical  trial)  is  considered  the  highest  standard  of  quality  in  data  when  it  comes  to
seeks  to  explore  the  effect  of  an  intervention.  The  pharmacological  development  phase  (phase  I)  corresponds  to  the
Sophia  Laboratories,  SA  de  CV
final  report,  be  it  5  months.
The  planned  recruitment  period  is  2  months.  Considering  that  the  proposed  sample  is  22  subjects,
Study  No:  SOPH172-0919/I
4.  Study  design
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5.1.2  Exclusion  criteria
5.2  Criteria  for  eliminating  and  replacing  patients
5.1.1  Inclusion  criteria
5.1  Eligibility  criteria
November  11,  2019
study.
-  Have  corrected  visual  acuity  of  20/30  or  better  in  both  eyes.
-  Have  a  history  of  any  type  of  eye  surgery.
present  study.
-  Being  a  user  of  medications  or  herbal  products,  by  any  other  route  of  administration.
-  Present  inflammatory  or  infectious  disease,  active  at  the  time  of  entering  the  study.
-  Presentation  of  a  serious  adverse  event,  whether  or  not  related  to  the  investigational  product,  which,  in  the  opinion  of  the  PI  and/or  
sponsor,  could  affect  the  patient's  ability  to  safely  continue  study  procedures.
-  Be  a  contact  lens  user  who  cannot  discontinue  use  during  the  study.
-  Be  or  have  an  immediate  family  member  (e.g.,  spouse,  parent/legal  guardian,  sibling,  or  child)  who  is  a  research  site  or  sponsor  
staff  member  directly  involved  in  this  study.
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-  Have  an  intraocular  pressure  ÿ10  and  ÿ  21  mmHg
-  Be  clinically  healthy
-  Be  a  user  of  topical  ophthalmic  products  of  any  kind.
-  Having  started  using  hormonal  contraceptives  or  IUDs  30  days  prior  to  inclusion  in  the
-  Withdrawal  of  the  FCI  letter.
-  Have  a  history  of  any  chronic-degenerative  disease.
-  In  the  case  of  women:  being  pregnant,  breastfeeding  or  planning  to  become  pregnant  within
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-  Be  able  and  willing  to  comply  with  scheduled  visits,  treatment  plan,  and  other  study  procedures
Sophia  Laboratories,  SA  de  CV
Version  2.0
-  Women  of  childbearing  potential  must  ensure  continued  use  (started  ÿ  30  days  prior  to  signing  the  ICF)  of  a  hormonal  contraceptive  
method  or  intrauterine  device  (IUD)  during  the  study  period.
-  Have  participated  in  clinical  research  studies  90  days  prior  to  inclusion  in  this  study
-  Present  unresolved  injuries  or  traumas  at  the  time  of  entering  the  study.
-  Have  vital  signs  within  normal  parameters.
-  Have  previously  participated  in  this  same  study.
-  Have  undergone  non-ophthalmological  surgical  procedures  in  the  last  3  months.
-  That  they  cannot  follow  the  lifestyle  considerations  described  in  section  5.3.
-  Be  between  18  and  45  years  old.
of  the  study  period.
Study  No:  SOPH172-0919/I
-  Have  the  ability  to  voluntarily  grant  signed  informed  consent
5.  Study  population
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November  11,  2019
Details  of  the  counting  failure  (specify  whether  due  to  eligibility  criteria,  which  one,  or  some  other  reason  for  the  failure).
Avoid  direct  exposure  to  fans  (including  air  conditioning  vents)  during  activities  that  involve  vision.  24  hours  before  your  
checkup  visits.
This  is  a  Phase  I  study,  which  is  planned  to  be  conducted  at  one  center.  The  selected  center  will  be  responsible.
Subjects  who  do  not  meet  the  eligibility  criteria  to  participate  in  the  study  due  to  a  factor
A  screening  failure  is  defined  as  those  participants  who  agree  to  participate  in  the  study,
use  the  same  initial  counting  number.
However,  the  subjects  will  be  entitled  to  travel  expenses  for  transportation  and  to  carry  out  their  visits.
-
The  minimum  expected  recruitment  rate  is  0.37  subjects  per  day.
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-  Non-tolerability  or  hypersensitivity  to  any  of  the  investigational  drugs.
-
For  the  study,  participants  may  need  to  modify  some  of  their  lifestyle  activities.
the  publication  of  results  or  to  respond  to  potential  questions  from  regulatory  authorities.
You  will  only  need  to  attend  one  visit  after  the  baseline  visit,  so  retention  problems  are  not  anticipated.
modifiable  specific,  could  participate  again  in  the  scrutiny.  The  subjects  in  this  case  must
giving  their  consent,  but  are  not  assigned  to  a  treatment  group,  that  is,  they  do  not  enter  the
Other  strategies  to  improve  subject  retention  include,  but  are  not  limited  to:
Sophia  Laboratories,  SA  de  CV
-  Refrain  from  smoking.
CONFIDENTIAL
Version  2.0
Avoid  immersing  yourself  in  water  without  eye  protection  (goggles ).
-  Demographic  data.
-
-  Presence  of  serious  adverse  events  during  the  scrutiny.
from  the  recruitment  of  subjects.
-  Non-tolerability  or  hypersensitivity  to  any  of  the  compounds  used  during  the  tests  (fluorescein,  lissamine  green,  tetracaine).
The  duration  of  the  subject's  participation  in  the  study  is  approximately  10  days,  during  which
-  Maintain  your  sleep-wake  cycle  with  which  you  enter  the  study.
The  above  is  necessary  to  comply  with  the  CONSORT  (Consolidated  Standards  of  Reporting  Trials)  guidelines  for
-  Refrain  from  using  electronic  vaporizers.
study.  It  is  necessary  to  report  at  least  the  following  information  on  counting  errors:
Study  No:  SOPH172-0919/I
to  comply  with  the  following:
5.4  Scrutiny  failures
5.3  Lifestyle  considerations
5.5  Recruitment  and  retention  strategies
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5.6  Procedure  in  case  of  loss  of  tracking
5.7  Subject  identification
November  11,  2019
results  obtained.  [31,  32]
submitted  for  approval  by  the  relevant  committees.
If  the  person  has  two  names  or  a  compound  surname,  the  first  letter  will  always  be  used.
to  find  out  the  reason  and  will  try  to  arrange  a  new  appointment  within  the  established  window  period  or  a
a.  Initials:  AMC
A.  Arieh  Daniel  Mercado  Carrizalez
numbers  in  the  following  order  from  left  to  right:
Study  subjects  will  be  identified  by  a  number  and  the  initials  of  their  name.
At  the  screening  stage  (within  the  baseline  visit)  the  participant  number  will  be  assigned  to  you  in  the  form
29  of  73
•  Make  calls  or  send  text  messages  to  remind  yourself  of  appointments  or  activities  to  do.
For  this  protocol,  loss  to  follow-up  is  defined  as  those  subjects  who  were  randomized,  who
•  Offer  flexible  business  hours.
In  the  event  that  the  participating  subject  does  not  attend  his  appointment,  the  research  center  must  make  a  call
first  letter  of  the  first  surname  and  the  first  letter  of  the  second  surname,  obtaining  a  maximum  of  three  letters,  in
a  number  with  which  you  will  be  identified  throughout  the  study.  This  code  will  be  made  up  of  eight
Example:
unscheduled  appointment.  If  an  appointment  cannot  be  made,  the  presence  of  a
•  three  digits  of  the  molecule  under  study  according  to  the  name  given  by  the  sponsor.
Sophia  Laboratories,  SA  de  CV
essential  on  your  visit.
CONFIDENTIAL
Version  2.0
All  materials  to  be  delivered  to  the  subject  or  recruitment  strategies  implemented  by  the  Centers  will  be
A  loss  to  follow-up  <10%  is  not  considered  to  be  a  problem  for  the  validity  of  the  studies.
B.  Juan  De  la  Torre  Orozco
b.  Initials:  JDO
•  Clearly  communicate  the  importance  of  the  study  and  the  benefits  the  population  will  obtain  from  its  results.
consecutive,  using  3  consecutive  digits.  Once  the  subject  has  been  selected,  he  or  she  will  be  assigned
•  Provide  a  printed  calendar  and  ID  card  to  remind  you  of  upcoming  appointments  and  activities,  as  well  as  their  estimated  duration.
At  some  point  they  were  active  subjects  in  the  study,  but  their  final  evaluation  could  not  be  completed.
•  Minimize  subject  waiting  times.
adverse  events  and  reason  for  withdrawal  from  the  study,  as  minimum  data.
The  initials  of  the  study  subject  will  be  obtained  by  starting  with  the  first  letter  of  the  name,  followed  by  the
Study  No:  SOPH172-0919/I
•  Systematic  organization  of  the  study  procedures,  so  that  the  subject  does  not  last  longer  than
Machine Translated by Google


•  two  digits  corresponding  to  the  research  center  number.  •  three  digits  of  the  consecutive  
number  assigned  to  its  inclusion  in  the  research  center.
Example:
Key  to  the  
molecule
Inclusion  
number
Version  2.0
November  11,  2019
Study  No:  SOPH172-0919/I
Sophia  Laboratories,  SA  de  CV
Number  of
01  (Single  center)
30  of  73
172-01-001
center
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6.  Investigational  product
-  Active  ingredients:  Bepotastine  besilate  1.5%.
space  out  applications  as  much  as  possible  during  the  rest  of  the  day.
Sophia  Laboratories,  SA  de  CV
At  this  stage  of  the  study,  it  is  not  essential  to  have  a  comparator.  This  is  because  the  effects
-  Generic  name:  Bepotastine.
Non-comparative  study.
Optimally,  it  is  suggested  to  apply  every  6  hours,  however,  it  is  not  limiting.  On  days  2  to  7,  every
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-  Packaging  description:  White  bottle  made  of  low-density  polyethylene  filled  to  5mL.
For  this  reason,  and  in  order  to  evaluate  a  higher  dosage  in  phase  II,  the  aim  is  to  evaluate  the  safety  of  the
There  must  be  at  least  one  hour  between  each  application.
-  Prepared  by:  Laboratorios  Sophia,  SA  de  CV
which  does  not  justify  using  a  comparator,  the  inclusion  of  a  comparator  would  only  mean  greater
Published  clinical  studies  of  bepotastine  evaluate  efficacy  and  duration  of  action  at  8  hours.  Although
4  hours  is  a  reasonable  spacing  for  subjects'  waking  period.  On  the  basal  day,  one  should  consider
-  Distinctive  name:  PRO-172.
CONFIDENTIAL
-  Pharmaceutical  form:  Ophthalmic  solution.
Side  effects  of  ophthalmic  formulations  containing  bepotastine  have  already  been  described  in  the
One  drop,  both  eyes  (OU),  four  times  a  day,  for  7  days.
application  4  times  a  day.
Study  No:  SOPH172-0919/I
November  11,  2019
-  Solution  description:  clear  solution,  free  of  visible  particles.
exposure  of  healthy  subjects  to  a  drug.
8  hours  is  still  effective  for  controlling  itching,  the  decrease  in  hyperemia  has  been  less.
Version  2.0
-  Presentation:  multi-dose  dropper  bottle,  5  mL.
literature.  On  the  other  hand,  the  primary  objective  is  the  search  for  unexpected  AEs  related  to  the  PI,
6.1.2  Reference  product
6.1.1  Investigational  Product
6.1  Managed  Products
6.1.3  Dose  of  the  investigational  product
6.1.2.1  Justification  of  the  reference  product
6.1.3.1  Justification  of  the  dose
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study
6.2  Storage  and  handling  of  investigational  products  at  the  research  center
6.3  Concomitant  treatments  and  medications  not  authorized  during  the  study
condition  of  the  primary  packaging  (box).  If  it  shows  alterations  or  defects  in  its  integrity  that
Sponsor  reserves  the  right  to  initiate  civil  and  criminal  actions  against  IP  in  case  of  failure  to  comply  with
Sophia  Laboratories,  SA  de  CV
Storage  temperature  should  be  2°C  to  30°C.
expressly  selected  for  this  purpose,  to  the  address  of  the  research  center  in  accordance  with  the  study  plan.
Storage  and  safeguarding  is  the  responsibility  of  the  research  center.  The  medication  must  be
closing  audit.  The  final  delivery  of  material  will  be  made  by  the  principal  investigator  (PI)  or  the  person
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It  will  verify  the  content  (PI)  with  what  is  reported  in  the  document.  In  case  the  document  corresponds  with
a  clear  description  of  the  mechanism  by  which  the  loss  occurred.
Hormonal  contraceptives  in  women  of  childbearing  age.  The  purpose  of  this  restriction  is  to  avoid  interactions
undocumented  material  at  the  end  of  the  study.
November  11,  2019
They  will  be  reviewed  by  the  clinical  monitor  according  to  the  record  in  the  data  logger.
Inside  you  will  need  to  find  the  receipt  acknowledgment  document  and  the  temperature  data  logger .
The  use  of  concomitant  medications  by  any  route  of  administration  will  not  be  permitted  during  the
designated  by  the  latter  for  delivery  of  material  at  the  end  of  the  study.
The  reception  will  be  carried  out  by  the  assigned  staff  of  the  research  team.  They  must  verify  the  good
protected  in  a  secure  area  with  restricted  access.
CONFIDENTIAL
from  your  judgment  could  have  damaged  the  contents  you  must  report  it  to  the  sponsor.  If  the  package  does  not  show
The  research  center  is  required  to  record,  in  the  designated  format,  the  recorded  temperature
Delivery  will  be  made  through  a  courier  service  contracted  by  the  sponsor,
The  content  will  sign  the  receipt  and  send  it  to  the  sponsor.  Otherwise,  the  sponsor  will  be  notified.
Upon  completion  of  the  protocol,  all  study  material  will  be  recovered  by  the  sponsor  as  part  of  the
Study  No:  SOPH172-0919/I
pharmacological  agents  that  could  alter  the  results  of  the  variables  evaluated.
You  must  check  that  the  recorded  temperature  complies  with  the  specifications  for  transport  and  storage.
In  case  of  loss  of  material,  this  must  be  documented  in  the  log  of  entries  and  exits  along  with
intervention  period.  Except  as  specified  for  the  study  procedures  and  the  use  of
Version  2.0
significant  defects  will  proceed  to  open  it.
in  the  data  logger,  every  day  while  the  protocol  is  in  force  and  has  PIs.  Said  data
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6.4  Procedure  for  monitoring  and  measuring  adherence
Sophia  Laboratories,  SA  de  CV
For  over  four  decades,  there  has  been  extensive  research  on  the  proper  way  to  measure  and
Biochemical  measurement  of  the  drug,  or  its  metabolite,  is  one  of  the  methods  that  best  confirms
The  approach  with  multiple  adherence  measurement  procedures  is  recommended.  Because  it  is  not
o  Tropicamide  0.8% /  Phenylephrine  5%
implementation;  they  have  a  high  degree  of  specificity  for  non-adherence,  however,  the  sensitivity  and
(could  have  been  intentionally  shot  or  instilled  outside  the  eye)  and  2.  It  depends  on  the  subject  bringing
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-  Ophthalmic:
The  most  common  procedure  involves  self-reports,  these  include:  patient  interviews,
“pills”  in  ophthalmology  translates  to  the  weight  of  the  bottle.  This  is  a  simple,  inexpensive,  and  noninvasive  method.
There  is  no  ideal  adherence  measurement,  it  is  appropriate  to  use  more  than  one  method  when  attempting  to
taking  into  account  the  following  information:  the  weight  of  the  drop,  the  initial  weight  of  the  container,  the  final  weight  of  the
November  11,  2019
[40]
undetectable;  and  samples  from  other  tissues  involve  more  invasive  methods  that  would  not  be  advisable.  [40]
Reliability  for  adherence  is  low.[40][41]
return  the  medicine.[40][41]
their  strengths  and  weaknesses,  to  more  accurately  capture  adherence  levels.[39]
CONFIDENTIAL
Study  No:  SOPH172-0919/I
quantify  adherence  to  medications,  however  none  has  reached  a  consensus  to  establish
way  the  use  of  the  drug.  However,  in  addition  to  raising  costs  and  being  impractical,  it  is  of  little
or  Tetracaine  0.5%
Self-monitoring  questionnaires  and  diaries.  Their  strengths  are  speed,  flexibility,  low  cost,  and  ease  of  use.
The  main  disadvantages  of  this  method  are:  1.  The  application  of  the  drug  cannot  be  confirmed
packaging  and  the  calculation  of  the  total  applications.  The  following  simplified  formula  will  be  used:
Permitted  medications:
There  are  different  procedures  for  measuring  adherence  to  pharmacological  interventions.
Medication  counting  is  another  way  to  measure  adherence.  Classically  referred  to  as  “medication  count,”
The  evaluation  of  the  adhesion  will  be  favored  by  means  of  the  weight  of  the  bottle  and  will  be  carried  out  as  follows:
Version  2.0
as  the  gold  standard,  both  in  cross-sectional  and  longitudinal  studies.[33][34][35][36][37][38][39]
usefulness  in  the  context  of  ophthalmic  applications,  since  concentrations  at  the  peripheral  level  could  be
achieve  results  that  resemble  reality.  Selecting  two  or  more  methods  allows  them  to  compensate  each  other
Machine Translated by Google


%,  =  $%0)1
%,
Sophia  Laboratories,  SA  de  CV
=  adhesion
Packaging  that  does  not  maintain  its  physical  integrity  will  not  be  considered  for  the  calculation  of  adhesion.
=  Applications  indicated  for  the  intervention
3.  Delivery  of  a  printed  calendar  specifying  the  date  of  the  visit  and  its  activities.
Where:
G
=  Registered  applications
correct  application  of  the  PI.
Where:
=  Adhesion
CONFIDENTIAL
The  research  center  will  designate  a  person  in  charge  of  monitoring  adherence  through  the  diary,  during
4.  Training  in  filling  out  and  reviewing  the  subject's  Diary.
%,  =  weight  of  the  dosage  indicated  for  the  intervention
November  11,  2019
!"  =  (!4)100/!&
Ad
=  number  of  applications  indicated  for  the  intervention
Ai
There  is  no  standardized  parameter  to  define  adequate  adherence,  it  must  be  defined  and  delineated.
2.  Direct  questioning  by  the  IP  regarding  the  application  of  the  PI.
The  content  of  such  messages  must  be  previously  approved  by  the  IEC.
Study  No:  SOPH172-0919/I
%&  =  weight  of  the  container  delivered  to  the  subject  at  the  start
For  cases  where  the  packaging  is  not  returned,  or  it  has  not  retained  its  physical  integrity,  the
!"  =
%0  =  weight  of  a  drop  of  the  intervention,  determined  by  the  research  and  development  department
Ar
1.  The  IP  will  sensitize  the  subject  on  the  importance,  in  order  to  achieve  the  objectives  of  the  study,  of  the
$%&  ÿ  %()100
Ad
by  the  objectives  of  the  particular  research.[40]
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Version  2.0
%( =  weight  of  the  container  returned  by  the  subject
adherence  through  the  subject's  diary,  as  follows:
Visits.  Measuring  adherence  by  weight  will  be  the  sponsor's  responsibility.
5.  If  deemed  necessary,  text  messages  may  be  sent  as  reminders.
6.5  Strategies  to  improve  adherence
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7.  Methods  and  procedures  of  the  study
The  research  center  will  be  responsible  for  forming  a  multidisciplinary  research  team  to
Sophia  Laboratories,  SA  de  CV
must  be  verified  before  carrying  out  any  activity  related  to  the  protocol.  The  above
must  be  filed  in  the  master  file  of  the  study.
center  will  be  an  institution  or  establishment  where  health  research  is  carried  out  that  complies  with  the
Responsibilities.”
amendments,  standard  operating  procedures,  etc.)  and  on  the  ICH  Good  Clinical  Practices,
CONFIDENTIAL
(co-investigator,  sub-investigator,  nurse,  etc.)  or  a  specific  role  of  participation  in  the  study
The  sponsor  must  ensure  that  all  staff  from  the  study  centers  participating  in  the
WHO  primary  records  meet  specific  criteria  for  content,  quality  and
November  11,  2019
Principal  (IP)  is  a  specialist  in  ophthalmology.
functions  in  the  study,  both  at  the  central  level  and  in  the  study  centers,  is  the  responsibility  of  the
start  (inclusion  of  the  first  patient):  National  Registry  of  Clinical  Trials  (RNEC)  of  the  Federal  Commission
current  regulations.
The  competence  and  training  of  all  persons  who  have  direct  participation  in  the  study  activities
before  the  start  of  your  participation  in  the  training.  The  training  must  be  recorded  in  writing  and  those  records
Study  No:  SOPH172-0919/I
Carry  out  the  clinical  study  according  to  the  protocol.  It  is  their  prerogative  to  design  the  organization  and  select
must  be  registered  and  documents  constituting  evidence  of  this  competence  and/or  training  must  be
This  study  will  be  conducted  at  a  research  center  previously  evaluated  by  the  sponsor.  This
(pharmacist,  administrative  assistant,  study  coordinator,  etc.)  must  appear  in  the  “Delegation  of
study,  be  adequately  trained  on  it  (research  protocol,  researcher's  manual,
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Any  person  who  is  assigned,  under  his  or  her  responsibility,  a  part  of  the  study  monitoring
sponsor.
for  the  Protection  against  Health  Risks  (COFEPRIS)  and  in  a  WHO  primary  records  platform.
Version  2.0
of  the  staff  who  will  perform  the  functions.  However,  it  is  the  sponsor's  requirement  that  the  Researcher
be  kept  in  the  master  file  of  the  study.  The  competence  and  training  of  the  personnel  who  have
This  clinical  study  will  be  registered  by  the  sponsor  in  public  clinical  trial  registries  prior  to  its
7.1  From  the  research  center
7.2  Clinical  study  registration
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7.3.2  Secondary  outcome  variables
7.3.3  Definition  of  variables,  methods  and  scales  to  be  used  for  measurement
7.3.1  Primary  outcome  variables
7.3  Outcome  variables
statistics
Score  of  the
November  11,  2019
Method  of
VB,  VF  and  LLS  ÿ2  or  exact
Staining
Wilcoxon
Degrees
Number  of
Wilcoxon
-  Changes  in  corneal  and  conjunctival  staining  with  lissamine  green  (TE:  day  8).
nominal
Snellen  chart
Time  of
Sophia  Laboratories,  SA  de  CV
fluorescein
ÿ2  or  exact
Discreet
NA
-
Variable
ICO
corneal  and
measurement
Fisher's
validity,  accessibility,  unique  identification,  technical  capacity,  and  administration.  The  Registries
AVcc
0
cases  (n)
Discreet
-  Corneal  and  conjunctival  staining  changes  with  fluorescein  (TE:  day  8).
1
36  of  73
Proof
Observation
Study  No:  SOPH172-0919/I
Unit
Fisher's
Counting
VB,  VF
Guy
Secondary  schools
conjunctival
Worth
Discreet
EA
WHO  primary  sources  meet  the  requirements  of  the  International  Committee  of  Medical  Journal  Editors
VB,  VF
Points
-  Conjunctival  hyperemia  changes  (TE:  day  8).
Present/
Incidence  of  unexpected  AEs  related  to  the  investigational  product  (TE  8  and  10).
VB,  VF
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assessment
Absent
Version  2.0
(Symbol)
Ordinal
0
Ranges  of
-  Changes  in  Corrected  Visual  Acuity  (CCVA)  (TE:  day  8).
Primaries
Ranges  of
Categorical
Fraction
(ICMJE).
normal
with
Questionnaire
-  Incidence  of  chemosis  (TE:  day  8).
absent
-  ICO  score  (TE  8).
slit  and  blue  filter
cobalt,  graduation
with  lamp
Direct  observation
Oxford  scale
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cleft,
Oxford
with  lamp
Direct  observation
graduation  scale
Table  3.  Operational  definition  of  variables
Ordinal
VB,  VF
November  11,  2019
Efron.
in  English  Case  Report  Form)  the  AEs  that  the  subjects  of  the  study  may  present  in  addition  to  referring  to  it  in  the
Absent
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Normal/  Very
absent
Variable
annexes;  anterior  segment  and  posterior  segment  that  is  performed  in  a  routine  ophthalmological  examination,  whose
conjunctival
administer  a  PI,  regardless  of  causal  attribution.
Method  of
Sophia  Laboratories,  SA  de  CV
The  IOP  will  be  measured  in  this  evaluation,  with  the  instrument  of  the  IP's  choice,  it  should  be  measured  after  the
conjunctival
Observation
Categorical
Time  of
Degrees
ÿ2  or  exact
medical  record.
ÿ2  or  exact
Proof
VB,  VF
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Light/  Light/
Guy
procedures  are  not  specifically  included  in  the  study  variables.  The  evaluation  of  pole
The  management  of  AEs  will  be  carried  out  as  described  in  the  Adverse  Events  section.
measurement
ÿ2  or  exact
Ordinal
Study  No:  SOPH172-0919/I
with  green  of
evaluation  of  the  stains.  The  result  of  the  assessment  will  be  recorded  in  the  clinical  record.  In  the  eCRF  only
direct.
nominal
assessment
0
Fisher's
For  an  adequate  evaluation  of  the  EA,  in  addition  to  the  directed  questioning,  it  is  necessary  to  carry  out  in  each
Fisher's
Unit
The  variables,  method  and  scales  for  their  measurement  are  described  in  detail  below.  They  are
posterior  may  be  with  direct  or  indirect  ophthalmoscopy,  with  or  without  pharmacological  mydriasis,  at  the  discretion  of  the  IP.
Staining
Moderate/
Worth
The  IP  will  record  in  the  corresponding  section  of  the  electronic  case  report  form  (eCRF).
Fisher's
Normal
Version  2.0
lissamine
Findings  that  are  considered  as  such  by  the  IP  will  be  reported  as  AEs.
Classification  of
Chemosis
statistics
VB,  VF
Present/
Visit  the  Comprehensive  Ophthalmological  Evaluation  which  consists  of:  the  ophthalmological  examination  of  the  eyelids  and
Hyperemia
As  defined  in  section  8.2,  an  AE  is  any  unfavorable  medical  occurrence  in  a  subject  who  is
(Symbol)
in  order  according  to  table  3.
An  evaluation  of  the  fundus  will  be  performed  to  look  for  abnormalities  that  could  alter  the  results  of  the  study.
corneal  and
Severe
normal
7.3.3.1  Adverse  events
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7.3.3.3  Visual  Acuity  with  correction
7.3.3.2  ICO  Score
Snellen  notation  is  described  as  the  distance  at  which  the  test  is  performed,  divided  by  the  distance  to  the
November  11,  2019
The  evaluator  will  give  the  questionnaire  to  the  subject  and  allow  him  to  answer  it  calmly  without  any  kind  of
produce  estimates  on  a  linear  interval  scale  (scores:  0-100).  Similar  to  the  index  for
Visual  acuity  (VA)  is  a  test  of  visual  function.  Spatial  VA  is  the  ability  to  distinguish
lines  that  the  evaluator  points  out,  the  line  of  smallest  letters  that  the  evaluator  can  see  will  be  noted  by  the  evaluator
38  of  73
The  visual  acuity  of  each  eye  will  be  taken,  starting  with  the  right  eye  (RE)  asking  the  subject  to  maintain
minutes  of  arc,  a  letter  6/12  (20/40)  is  equivalent  to  10  minutes,  and  a  letter  6/60  (20/200)  is  equivalent  to  50
Headache,  nasopharyngitis,  dry  eye,  ocular  itching,  nasal  congestion  and  rhinorrhea.[42]
Management  as  AE:  The  ICO  assesses  symptoms,  which  may  or  may  not  be  related  to  an  AE.  The  score
Subsequently,  the  objective  and  subjective  refractive  correction  of  the  subject  will  be  performed.  The  result  of  the
[44]
The  ICO  is  a  questionnaire  designed  to  measure  ocular  surface  irritation  with  Rasch  analysis  for
In  addition,  the  eCRF  will  record  it  as  a  decimal.  By  definition,  the  AVcc  cannot  be  less  than  the  VA.
CONFIDENTIAL
separate  elements  of  an  object  and  identify  them  as  a  whole.  It  is  quantified  as  the  minimum  angle  of
Sophia  Laboratories,  SA  de  CV
Ocular  surface  diseases,  the  Ocular  Comfort  Index  (OCI)  assesses  symptoms.  The  OCI  contains  items
in  a  place  with  adequate  lighting,  natural  or  artificial  and  at  a  distance  of  3m  from  the  subject  to  be  evaluated.
The  questions  have  two  parts,  which  separately  inquire  about  the  frequency  and  severity  of  symptoms.[43]
Version  2.0
separated.
both  eyes  open  and  using  an  occluder  to  cover  the  left  eye  (OS);  the  subject  will  read  aloud  the
as  a  fraction  as  the  AV  of  OD  in  the  clinical  record.  The  OS  is  carried  out  using  the  same  method.
pressure  and/or  coercion,  will  only  assist  you  if  you  have  difficulty  understanding  any  of  the  questions.
According  to  the  available  literature,  the  expected  AEs  for  the  use  of  PI  are:  dysgeusia,  eye  irritation,
which  the  letter  is  equivalent  vertically  to  5  minutes  of  arc.  Thus,  at  6  meters  a  letter  6/6  (20/20)  is  equivalent  to  5
Subjective  refraction  will  be  reported  as  AVcc,  and  will  be  noted  as  a  fraction  in  the  clinical  record  and  on  the  eCRF,
obtained  from  the  ICO  alone,  should  not  be  considered  an  EA.
minutes.  The  Snellen  fraction  can  also  be  expressed  as  a  decimal  (i.e.  20/20  =  1  and  20/40  =  0.5).
Study  No:  SOPH172-0919/I
that  focus  on  the  discomfort  associated  with  ocular  surface  alterations.  Each  of  these
separation  (located  at  the  nodal  point  of  the  eye)  between  two  objects  that  allows  them  to  be  perceived  as  objects
VA  will  be  assessed  at  baseline,  without  refractive  correction,  using  the  Snellen  chart.  It  will  be  placed
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7.3.3.6  Conjunctival  hyperemia
7.3.3.5  Conjunctival  staining  with  lissamine  green
7.3.3.4  Corneal  and  conjunctival  staining  with  fluorescein
7.3.3.7  Chemosis
November  11,  2019
The  PI  will  record  in  the  file  and  the  eCRF  the  grade  awarded  for  fluorescein  staining  of  OD  and  OS
neutral  or  with  the  red-free  filter.  It  will  be  graded  according  to  the  Oxford  scale.  [45]
superiors.
saline  solution  allowing  it  to  sit  on  the  strip  for  5  seconds  to  elute  the  dye.  A  drop  of
Conjunctival  hyperemia  is  defined  as  the  simplest  reaction  of  the  conjunctiva  to  a  stimulus,  it  is  seen
using  the  Efron  scale.  [46]  See  appendix.
39  of  73
respectively.
It  is  defined  as  conjunctival  edema,  the  result  of  an  inflammatory  reaction.  It  is  classified  as  present  or
as  EA.
Management  as  AE:  Corneal  staining  that  is  equal  to  or  greater  than  grade  III  will  be  considered  as  AE.
A  drop  of  topical  anesthetic  will  be  instilled  in  the  conjunctival  fornix,  then  a  drop  will  be  applied.
After  the  fluorescein  examination,  a  drop  of  lissamine  green  will  be  applied  to  the  tip  of  the  strip.
ÿ  1/3  of  the  total  eyelid  opening  or  if  it  exceeds  the  gray  line.  [47]
the  strip  in  the  temporal  fornix,  while  the  patient  looks  up,  without  damaging  the  conjunctiva.  It  can  be
a  red  appearance  secondary  to  vasodilation  of  the  conjunctival  vessels  of  varying  intensity.  It  will  be  graded
CONFIDENTIAL
Sophia  Laboratories,  SA  de  CV
elute  the  dye,  shaking  off  the  excess  at  the  end.  A  small  contact  of  the  strip  with  the  conjunctiva  is  made  in  the
Version  2.0
according  to  the  Oxford  scale.[45]
The  scan  should  be  performed  between  1  and  4  minutes  after  instillation  through  a  density  filter.
Management  as  AE:  Conjunctival  hyperemias  classified  as  grade  3  or  higher  will  be  considered  as  AE.
respectively.
The  PI  will  record  in  the  file  and  the  eCRF  the  grade  awarded  for  fluorescein  staining  of  OD  and  OS
Management  as  AE:  A  decrease  of  more  than  2  lines  on  the  Snellen  chart  should  be  reported  and  managed
absent.  The  evaluator  will  use  a  narrow  beam  of  light  at  60°  and  measure  whether  the  conjunctiva  separates  from  the  sclera  in
Management  as  AE:  Corneal  staining  that  is  equal  to  or  greater  than  grade  III  will  be  considered  as  AE.
Study  No:  SOPH172-0919/I
temporal  fornix,  while  the  patient  looks  up,  without  damaging  the  conjunctiva.  It  will  be  classified  as
ask  the  patient  to  blink  repeatedly  to  avoid  accumulation  in  the  conjunctival  folds.
second  drop  on  the  tip  of  the  fluorescein  strip  allowing  it  to  sit  on  the  strip  for  5  seconds  to
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7.4.1  Description  of  activities  per  visit
7.4  Study  visits  and  activities  program
7.4.1.1  Baseline  Visit
•  Signature  of  the  ICF:  refers  to  the  signing  of  the  written  informed  consent  document.  Without  informed  consent,  none  of  the  study  
procedures  can  be  performed.
Study  No:  SOPH172-0919/I
Version  2.0
Medical  record:  refers  to  the  technical,  clinical,  and  legal  document  that  chronologically  records  the  subject's  health  
conditions,  medical  procedures,  and  other  procedures  performed  on  the  subject.  It  includes  anthropometric  measurements,  
anamnesis,  a  comprehensive  ophthalmological  examination  that  allows  determining  the  patient's  eligibility,  i.e.,  evaluation  of  
both  eyes  and  ocular  adnexa,  slit-lamp  examination  of  the  ocular  surface  and  anterior  segment,  and  fundoscopy.  If  the  
subject  is  taken  from  the  study  center's  established  population  base,  the  existing  medical  record  may  be  used;  only  one  
update  is  required.
•  Ocular  surface  stains:  See  7.3.3.4  and  7.3.3.5
•  Ophthalmological  evaluation:  See  7.3.3.1
November  11,  2019
•  Evaluation  of  concomitant  medications:  refers  to  the  IP  questioning  the  subject,  inquiring  about  the  use  of  medications.
Eligibility  criteria:  refers  to  the  review  by  the  PI,  where  it  is  confirmed  that  the  subject  can  be  included  in  the  study  by  meeting  
the  inclusion  criteria  and  not  meeting  the  exclusion  criteria.
Handling  as  EA:  Your  presence  will  be  considered  as  an  EA.
•  Urine  pregnancy  test:  This  refers  to  a  rapid  pregnancy  test  performed  on  all  women  of  childbearing  age  who  wish  to  enter  the  
study.  By  childbearing  age,  we  mean  women  who  have  experienced  menarche  but  have  not  yet  experienced  menopause.  
Menopause  is  defined  as  12  months  from  the  last  menstrual  period  in  women  over  40  years  of  age,  or  who  have  undergone  
a  hysterectomy  or  bilateral  oophorectomy.  Women  of  childbearing  age  using  contraceptive  methods,  including  bilateral  tubal  
obstruction,  must  undergo  a  pregnancy  test.
•
This  test  will  be  performed  by  the  IP  or  designated  team  member  according  to  the  instructions  on  the  device  provided  by  the  
sponsor.
•  PI  Assignment:  Refers  to  determining  the  intervention  the  patient  will  follow  during  the  study.  Since  this  is  an  open-label  study,  
all  eligible  subjects  will  be  assigned  to  PRO-172.  However,  assignment  is  the  procedure  by  which  the  number  of  a  given  
medication  is  linked  to  the  subject's  identification  number.  This  assignment  will  be  performed  at  the  baseline  visit  (day  1).
•  Vital  signs:  refers  to  heart  rate,  respiratory  rate,  systemic  blood  pressure,  and  temperature.  This  information  must  be  recorded  in  the  
patient's  medical  history  and  progress  notes.  •  ccVA:  See  7.3.3.2
•  Delivery  of  the  PI  and  start  of  intervention:  Refers  to  the  delivery  of  the  PI  to  the  study  patient  by  the  research  center.
The  procedures  are  listed  in  the  order  in  which  they  are  suggested  to  be  performed,  trying  to  maintain  the
•
40  of  73
consistency  of  assessments  and,  as  far  as  possible,  from  the  least  invasive  to  the  most  invasive.
ICO:  See  7.3.3.2
CONFIDENTIAL
Sophia  Laboratories,  SA  de  CV
•
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7.5  Data  collection
7.4.2  Unscheduled  follow-up  visits
7.4.1.2  Final  Visit
7.5.1  Source  documents
November  11,  2019
§
ICO:  See  7.3.3.2
EA  Assessment:  See  7.3.3.1
§
At  the  request  of  the  patient  or  any  other  individual  related  to  the  study,  visits  may  be  carried  out
§
example:  printouts  of  laboratory  results  issued  by  automated  analysis  equipment)  where
Subject  Diary  Assessment:  See  7.5.1.1
Collect  all  relevant  data  on  reported  adverse  events  and,  where  appropriate,  establish
patient.  Examples  of  source  documents  include  medical  records,  clinical  progress  notes,  and  reports.
•  Delivery  of  patient  materials  and  instructions  for  completion:  This  refers  to  the  PI  providing  the  subject  with  the  subject's  diary,  
identification  card,  and  calendar,  improving  adherence.  Staff  assigned  by  the  research  center  will  provide  the  subject  with  prior  
training  on  how  to  complete  the  diary.
§
surgical  records,  etc.
involves  direct  access  to  source  documents.
CONFIDENTIAL
part  of  ethics  and  research  committees,  and  inspections  by  the  health  authority,  this  obligation
Evaluation  of  concomitant  medications:  See  7.5.1.1  above
Comprehensive  ophthalmologic  evaluation:  Ver7.3.3.1
Return  of  PI  and  Subject  Diary:  Refers  to  the  return  by  the  subject  of  the  PI  and  subject  diary  to  the  research  center.
§
§
Source  documents  are  all  written  or  printed  records  derived  from  automated  processes  (for  example,
Sophia  Laboratories,  SA  de  CV
Vital  signs:  See  7.5.1.1  above
41  of  73
information  is  recorded  for  the  first  time  and  becomes  part  of  the  permanent  records  of  the  history  of  the
Version  2.0
§
§
§
§
unscheduled  follow-up  visits  for  reporting  adverse  events.  During  these  visits,  the  following  must  be
•  EA  Assessment:  See  7.3.3.1
laboratory  reports,  office  study  reports,  nursing  notes,  follow-up  notes,
an  appropriate  management  plan.
The  IP  is  obliged  to  accept  the  monitoring  of  information  related  to  the  study,  audits,  review  by
Ocular  surface  stains:  See  7.3.3.4  and  7.3.3.5
Adhesion  assessment:  See  7.5.1.1
Study  No:  SOPH172-0919/I
AVcc:  See  7.3.3.2
§
Urine  Pregnancy  Test:  See  above  7.5.1.1
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7.5.3  File
7.5.2  Electronic  forms  of  data  collection
7.5.4  Unscheduled  follow-up  visits
Study  No:  SOPH172-0919/I
understands  that  all  eCRF  forms  captured  and  submitted  for  data  analysis  are  approved  by  the
Version  2.0
Researcher.
protected  for  at  least  5  years.
November  11,  2019
At  the  request  of  the  patient  or  any  other  individual  related  to  the  study,  visits  may  be  carried  out
The  data  collected  in  this  database  is  anonymous  (it  only  stores  the  number
unscheduled  follow-up  visits  for  reporting  adverse  events.  During  these  visits,  the  following  must  be
All  data  relating  to  the  protocol  will  be  captured  via  an  eCRF  by  team  personnel.
of  the  patient  along  with  other  information  of  interest).  The  program  used  for  the  capture  and  storage
Collect  all  relevant  data  on  reported  adverse  events  and,  where  appropriate,  establish
of  research.  Data  relating  to  the  protocol  should  NOT  be  captured  directly  in  the  eCRF,  but
of  data  covers  the  traceability  requirements  necessary  for  the  execution  of  clinical  studies.  The  data
an  appropriate  management  plan.
which  must  be  transcribed  from  the  corresponding  source  document.  This  procedure  allows  the
collected  will  be  stored  by  the  sponsor  or  designated  clinical  research  organization  for
42  of  73
Carrying  out  monitoring  to  verify  the  information  captured  in  the  eCRF.  It  is  the  responsibility  of  the
This  and  its  storage  will  last  for  10  years.  The  records  of  patient  number  assignment
CONFIDENTIAL
Sophia  Laboratories,  SA  de  CV
researcher  that  the  information  is  transcribed  to  the  eCRF  in  a  correct,  complete  and  timely  manner.
They  will  remain  in  the  participating  institutions  under  the  care  of  the  IP  or  his/her  work  team  and  must  be
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adverse
8.  Event  evaluation  and  management
According  to  the  International  Conference  on  Harmonization  (ICH),  an  adverse  event  (AE)  is  any
Study  No:  SOPH172-0919/I
Version  2.0
adverse  medical  occurrence  in  a  patient  undergoing  clinical  research  who  is  administered  a  product
produce  a  change  in  the  study  treatment  or  concomitant  treatment  or  discontinuation  of  the
study  drug.
November  11,  2019
pharmacist,  regardless  of  causal  attribution.
Common,  non-life-threatening  conditions  require  treatment  and  may  or  may  not  require  discontinuation
of  the  medication;  severe,  those  that  interfere  with  normal  activities  and  require  treatment
Therefore,  an  AE  can  be  any  of  the  following:  any  undesirable  medical  event  that  is
Severity  (serious/not  serious),  also  called  seriousness  (serious/not  serious).  It  is  defined  as  serious  or  grave.
pharmacological  and  discontinuation  of  the  medication.
temporally  related  to  the  use  of  a  medical  product,  whether  or  not  it  is  considered  to  be  related  to
any  event  that:  results  in  death,  threatens  life,  requires  hospitalization  or  prolongs  the
43  of  73
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said  product;  any  new  disease  or  exacerbation  of  an  existing  disease  (worsening
hospitalization,  are  a  cause  of  permanent  or  significant  disability  or  incapacity,  are  a  cause  of  alterations  or
The  registration  and  reporting  of  adverse  events  will  be  carried  out  in  accordance  with  the  guidelines  established  in  the
the  nature,  frequency,  or  severity  of  a  known  condition);  relapse  of  a  medical  condition
malformations  in  the  newborn,  other  medically  important  conditions.
NOM-220-SSA1-2016  which  is  in  accordance  with  the  international  ICH  E6  guidelines.
Intermittent  (e.g.,  headache)  not  present  at  baseline;  some  deterioration  in  a  laboratory  value  or  other
Severity  (mild,  moderate,  or  severe).  Mild  symptoms  are  those  that  occur  with  minimal  symptoms,  not
Sophia  Laboratories,  SA  de  CV
clinical  test  (e.g.,  electrocardiogram  [ECG],  X-ray)  that  is  related  to  the  symptoms  or  that
require  treatment  or  discontinuation  of  the  medication;  moderate,  when  they  interfere  with  activities
8.3  Definitions  relevant  to  the  classification  of  adverse  events
8.1  Regulation  and  standards  on  adverse  events
8.2  Definition  of  adverse  event
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8.4  Researcher  Responsibilities
November  11,  2019
Once  all  possible  information  has  been  obtained  about  the  adverse  event,  it  remains  unclassifiable.
to  the  Hospital  Center  with  the  greatest  resolution  power  with  which  the  research  center  has  an  agreement
and  final  discharge  of  the  EA,  following  the  definitions  determined  in  national  and  international  regulations.  [48]
adverse  event).
If  the  research  subject  debuts  during  his/her  participation  in  the  study  with  any  adverse  event  of
Sophia,  SA  de  CV,  the  report  of  adverse  events  will  be  included  in  compliance  with  national  and  international  regulations.
CONFIDENTIAL
national  and  international  regulations.  In  the  case  of  serious  adverse  events,  the  sponsor  will  be  notified  and
competent  health  for  your  chronic  treatment.  The  follow-up  and  completion  of  your  participation  will  be
the  drug,  there  is  clear  evidence  of  causality,  ie  the  adverse  event  reappears  with  administration
It  is  the  Researcher's  responsibility  to  perform  the  EA  verification  through  questioning,  reviewing  the
There  is  no  direct  evidence  or  it  is  considered  unnecessary  or  dangerous,  ie  the  reaction  disappears  when
such  as  appropriate  medical  and  pharmacological  management;  as  well  as  follow-up  until  resolution  or  outcome
The  attention  of  the  EA  will  be  carried  out  according  to  the  event  attention  diagram  (see  Figure  3.  Attention  of  the
44  of  73
[49]  [50]
In  the  final  report  that  will  be  written  by  the  Clinical  Team  of  the  Department  of  Clinical  Operations  of  Laboratories
Sophia  Laboratories,  SA  de  CV
suggests  that  the  cause  may  be  due  to  another  medication  or  disease;  unlikely  to  be  caused  by  the
Version  2.0
medication;  conditional,  data  are  lacking  to  issue  a  clear  causality;  not  classifiable,  those  for  which
Subjects  will  be  provided  with  relevant  medical  care  either  at  the  research  center  or  will  be  referred
current  international.  [49]  [48]
medical  attention.  The  IP  will  notify  the  sponsor's  clinical  monitor,  according  to  the  times  established  in  the
chronic  course,  such  as  diabetes  or  systemic  arterial  hypertension,  you  will  be  referred  to  a  health  professional.
Causality.  It  is  the  relationship  assigned  between  the  medication  and  the  adverse  event:  certainly  caused  by
as  stipulated  by  the  ICH.
of  the  drug;  probably  caused  by  the  drug,  there  is  a  high  suspicion  of  causality  but
information  recorded  in  the  subject's  diary,  the  relevant  physical  examination,  the  evaluation  of  progress,  as  well  as
Study  No:  SOPH172-0919/I
medication,  there  is  a  clear  explanation  of  the  origin  due  to  the  underlying  disease  or  the  use  of  another
In  the  event  of  an  AE  or  any  event  that  puts  the  health  and  well-being  of  the
will  record  the  corresponding  information  in  the  eCRF  and,  in  turn,  will  inform  the  CEI  and  the  CI.
discontinue  the  medication;  possibly  caused  by  the  medication,  there  is  additional  information  that
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8.4.1  Recording  of  adverse  events  in  the  electronic  case  report  form
November  11,  2019
-  Information  on  diagnosis  and  clinical  management.  If  a  lack  of  therapeutic  response  to  the  PI  and/or
o  Patient  who  died  and  it  is  judged  that  the  drug  may  have  contributed
o  Patient  recovered  without  sequelae
associated  with  the  EA,  RAM  or  SRAM.  As  applicable,  information  concerning
circumstances  that  justify  opening  the  blind  to  determine  whether  the  adverse  event  may  be
as  appropriate  according  to  the  methodological  design  of  the  study,  this  is  relevant  in  the  case  of
route  of  administration,  start  and  end  dates  of  administration  and/or  consumption,  reason  for  the
investigation,
pharmacologically  inert(s),  such  as  vehicles  or  additives,  as  appropriate  for  the  phase
that  the  patient  is  currently  participating  in)  or  it  is  a  medication  that  the  subject  is  currently  undergoing  research
The  EA  registry  considers:
stipulated  by  current  regulations.  Include  the  therapy  used  in  concomitant  medications
CONFIDENTIAL
-  Information  about  the  type  of  AE  to  the  PI  or  the  study  drug,  as  appropriate.
-  Establish  the  outcome  or  resolution  of  the  event:
-  Information  about  the  investigational  product  or  drug  or  the  drug
record  the  data  concerning  the  batch  number,  manufacturing  laboratory,  expiration  date,  dose,
o  Recovered  patient  with  sequelae
generic  name,  distinctive  name  or  code  of  the  PI  and/or  investigational  medicinal  product,
prescription;  depending  on  whether  it  is  an  investigational  product  or  drug  (protocol  in  which
Sophia  Laboratories,  SA  de  CV
o  Date  on  which  the  EA  occurs
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Version  2.0
o  Date  of  resolution  or  outcome,  as  applicable.
o  Patient  who  died  due  to  AE
blinded  studies  or  those  where  placebo  is  used  as  comparators,  since  there  are
investigational  drug,  must  be  reported  as  a  serious  adverse  event  within  the  period
or  Patient  who  died  and  this  was  not  related  to  the  product  or  medication  in  question
attributable  to  the  active  agent,  the  combination  of  active  agents,  or  the  substance(s)
clinical  research  in  which  the  development  of  the  drug  is  located.  It  will  also  be  necessary
-  The  subject's  identification  information  such  as:  code,  age,  sex,  left  eye,  right  eye.
for  the  pharmacological  management  of  the  adverse  event.
Study  No:  SOPH172-0919/I
o  Date  on  which  the  IP  is  informed  of  the  same
or  Patient  not  recovered
Or,  indicate  that  the  consequence  of  the  event  is  unknown.
-  Information  on  important  dates:
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8.4.2  Monitoring  of  adverse  events
Study  No:  SOPH172-0919/I
dose,  if  the  event  changes  in  intensity  or  severity,  persistence  of  the  reaction.  It  is
Version  2.0
It  is  important  to  indicate  whether  in  those  patients  who  are  exposed  again  to  the  PI,  medication  in
previously  narrated,  notwithstanding  the  clinical  context  in  which  said  harmful  phenomenon  occurs
in  the  participants  of  the  clinical  research  protocol,  is  of  special  interest,  so  the
November  11,  2019
investigation  or  medication,  which  had  previously  been  suspended,  the  AE  reappears.
information  about  previous  conditions,  hypersensitivity  or  allergy  phenomena,
consumed  for  the  treatment  of  underlying  concomitant  diseases  or  used  for  the  management  of
-  Information  regarding  concomitant  pharmacotherapy.  Indicate  the  generic  name,  the
previous  surgical  procedures,  laboratory  tests  or  office  examinations  that  have  been  performed
CONFIDENTIAL
any  transient  sign  or  symptom  that  does  not  correspond  to  the  Natural  History  of  the  pathology  that  caused  it
dose,  route  of  administration,  start  and  end  dates  of  use,  as  well  as  the  reason  for  the
performed  on  the  participant,  etc.,  that  the  researcher  deems  appropriate  to  mention  may  do  so.
your  entry  into  the  research  protocol.
prescription  regardless  of  whether  it  is  in  accordance  with  the  prescribing  information  or  technical  data  sheet  or
-  Indicate  the  withdrawal  or  maintenance  of  the  drug,  PI  or  investigational  drug,  as  appropriate.
is  used  outside  of  the  regulations  or  what  has  been  authorized  by  the  local,  national  or  regulatory  entity
The  IP  will  provide  care  and  guidance  for  the  EA  presented  by  the  participant  until  its  outcome,
appropriate.  Indicate  whether  when  withdrawing  the  PI  or  investigational  drug  or  suspected  drug
international.
according  to  what  is  referred  to  in  the  following  section.
Sophia  Laboratories,  SA  de  CV
(if  the  event  is  caused)  the  adverse  event  disappears.  Also  indicate  whether  an  adjustment  is  made  to
-  Information  on  relevant  clinical  history.  The  analysis  of  the  AE  considers  the  information
46  of  73
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Adverse  
Event
Serious  EA
Figure  3.  Adverse  event  care
8.4.3  Procedures  for  a  serious  adverse  event
By  severity:
November  11,  2019
Care  and  
treatment
+  Follow  up  the  EA  until  its  
conclusion
Inform
END
causal  relationship  with  the  PI  or  investigational  drug.  These  harmful  phenomena  may  occur
+  Clinical  Safety  
Pharmacologist
During  the  development  and  conduction  of  this  study,  events  may  occur  in  the  subject  under  investigation.
pharmacovigilance
The  EA  care  process  considers  the  following  stages:
In  1st-3rd  level  hospital
a  local,  national  or  international  regulatory  body.  However,  there  may  be  a  suspicion  that  the  IP  or  the
that  the  clinical  review  is  scheduled,  according  to  the  schedule  of  activities)  or  suddenly,  in  such  a  way
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several  medications  may  occur  during  the  systematic  evaluation  of  participants  (on  days  in
relevant
Registration  and  notification  in  eCRF
+  Inform  the  sponsor  within  24  
hours  of  becoming  aware  of  it
END
that:
Categorization
Sophia  Laboratories,  SA  de  CV
Physical  examination
Notify:
harmful  undesirable  or  adverse  reactions,  of  medical  implication,  which  do  not  necessarily  have  a
EA
Version  2.0
Serious/Not  Serious
outcome
CONFIDENTIAL
+  Unit  of
At  the  research  site
Mild,  moderate  or  severe
during  the  use  of  investigational  medicinal  products  at  doses  authorized  for  use  in  humans,  by
+  Inform  the  CEI
Preparation  of  medical  notes
(if  required)
Study  No:  SOPH172-0919/I
and  evaluation  of  the
By  outcome:
EA  not  serious
investigational  drug  may  cause  any  undesirable  clinical  manifestation.  The  AEs,  ADRs  or  SRAs  to  one  or
Follow  up  the  EA  
until  its
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Study  No:  SOPH172-0919/I
of  Karch  and  Lasagna  modified  by  Naranjo  referred  to  by  Aramendi  I,  as  a  tool  to  facilitate  the
of  the  researcher),  are  of  an  ophthalmic  nature,  however,  there  may  be  systemic  alterations.  Therefore,
Version  2.0
Probabilistic  categorization  of  causality.  In  this  algorithm,  different  items  are  scored,  which,
They  allow  a  value  to  be  assigned  to  the  cause-effect  relationship  between  the  administration  of  the  medication  and  the  reaction
November  11,  2019
1.  The  researcher  must  be  the  first  person  to  whom  the  patient  notifies  that  he  or  she  has  developed  or  presented  with  any  
harmful  clinical  phenomenon  during  his  or  her  participation  in  the  present  study.
The  researcher's  judgment  will  consider  the  withdrawal  of  the  participant  or  his/her  continuation.
adverse.  [51]  See  Table  4.  Karch  and  Lasagna  algorithm  modified  by  Naranjo.
2.  Based  on  clinical  judgment,  the  principal  investigator  will  determine  the  appropriate  course  of  treatment  for  the  adverse  
event/reaction  based  on  the  relevant  physical  examination,  history,  etc.,  as  well  as  the  analysis  of  information  available  
in  the  medical  literature  and  the  information  contained  in  the  investigator's  manual,  Prescribing  Information,  or  the  
comparator  drug's  data  sheet.
Causality  assessment  is  the  methodology  used  to  estimate  the  probability  of  attributing  to  a
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3.  Such  care  may  be  provided  at  the  research  center  or  at  the  hospital  with  the  highest  capacity  for  treatment.  Thus,  if  the  
patient  is  referred  by  the  PI  to  a  hospital,  they  will  receive  care  through  a  referral  system.  The  referral  may  be  through  a  
card  identifying  the  subject  as  a  study  participant  and  linking  them  to  the  pre-established  agreement  with  the  institution,  
or  through  a  referral  medical  note  issued  by  the  PI.  Laboratorios  Sophia,  SA  de  CV,  will  pay  the  costs  for  medical  care  
for  participating  patients  when  the  adverse  event  is  associated  with  or  related  to  the  PI  or  investigational  drug.
drug,  investigational  drug  or  PI,  the  observed  adverse  event.  Consider  categories
CONFIDENTIAL
probabilistic  according  to  the  available  evidence  and  the  quality  of  the  information,  based  on  national  regulations
4.  Taking  into  account  the  clinical  information  collected,  either  during  the  care  provided  at  the  research  center  or  provided  by  
the  treating  physician(s)  at  the  hospital,  the  IP  will  record  the  AE  in  his/her  clinical  note,  noting  the  seriousness,  intensity  
(mild,  moderate,  or  severe),  and  relationship  with  the  product  or  drug  under  investigation.
5.  The  PI  must  migrate  the  relevant  data  to  the  eCRF  and  its  respective  adverse  event  section.  Therefore,  in  cases  of  serious  
adverse  events,  which  must  be  reported  within  24  hours  of  the  PI  becoming  aware  of  them,  the  clinical  monitor  of  the  
study  is  informed  and,  in  turn,  informs  the  Clinical  Team  and  the  UTFLS,  so  that  the  IEC  is  subsequently  informed.  
Regarding  non-serious  adverse  events,  these  will  be  recorded  and  appropriately  addressed,  and  the  corresponding  
regulatory  entity  will  be  informed  about  the  safety  profile  of  the  PI  or  investigational  drug  in  the  final  report  of  the  clinical  
trial.
Sophia  Laboratories,  SA  de  CV
The  recording  of  the  outcome  of  the  EA  depends  substantially  on  the  follow-up  that  the  IP  carries  out  on  the  subject,  since
pharmacovigilance.[48]
The  Pharmacovigilance  and  Technovigilance  Unit  of  Sophia  Laboratories  (UFTLS)  can  use  the  algorithm
Most  harmful  phenomena  are  expected  (see  safety  profile  section  in  the  manual)
8.4.4  Causality  Assessment
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Study  No:  SOPH172-0919/I
relevant.  [52]
c)  The  exposure-effect  pattern,  which  determines  the  relationship  with  the  site  of  appearance,  time,  dose  and
Version  2.0
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November  11,  2019
In  such  a  way  that  the  degree  of  certainty  to  establish  the  PI  or  investigational  drug  (according  to
reversibility  after  suppression.
d)  Biological  plausibility,  which  refers  to  possible  pharmacological  or  pathophysiological  mechanisms
(as  appropriate)  as  the  causal  agent  of  the  harmful  phenomenon  that  occurs  to  the  subject  of  the  clinical  study.
involved  in  the  development  or  presentation  of  the  adverse  event.
It  can  also  be  indicated  directly  by  the  IP  based  on  his  clinical  experience  or  through  the
e)  Experimental  findings,  for  example,  the  appearance  of  anomalous  metabolites  or  high  levels  of
drug  or  the  product  of  its  biotransformation.
voluntary  application  of  the  aforementioned  tool.  However,  it  is  important  that  the
researcher  and  the  UFTLS  take  into  account  the  following  arguments  in  favor  of  the  causal  relationship:
Sophia  Laboratories,  SA  de  CV
a)  Strength  of  association,  which  refers  to  the  number  of  cases  in  relation  to  those  exposed.
f)  Analogy,  which  refers  to  the  experience  acquired  with  other  related  drugs,  adverse  reactions  frequently  
produced  by  the  same  family  of  pharmacological  agents.
g)  Nature  and  characteristics  of  the  data,  i.e.  objectivity,  accuracy  and  validity  of  the  documentation
b)  The  consistency  of  the  data,  that  is,  the  presence  of  a  common  characteristic  or  pattern.
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Table  4.  Karch  and  Lasagna  algorithm  modified  by  Naranjo
Study  No:  SOPH172-0919/I
November  11,  2019
Version  2.0
Sophia  Laboratories,  SA  de  CV
Probabilistic  category  based  on  the  score  obtained
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5.
The  patient  has  had  similar  reactions  to  the  investigational  drug/product  or  medication
5  to  8
0
+1
summation
The  adverse  reaction/adverse  event/suspected  adverse  reaction  to  medication  occurred  after  the
0
The  adverse  event  occurred  when  the  suspected  drug  was  administered
IV
8.
ÿ,9
Yeah
4.
effect  between  the  administration  of  the  investigational  product  and  the  adverse  reaction,  adverse  event,  or  suspected  reaction
3.
+1
+1
0
There  are  alternative  causes  that  can  provoke  this  reaction.
in  research,  in  the  past
The  ADR  may  be  due  to  the  investigational  drug  or  product
+1
0
Score
placebo  administration
10.
2.
The  causal  relationship  is  doubtful
II
No
+2
+1
Adverse  drug  reaction,  adverse  event  or  suspected  adverse  drug  reaction
adverse.
7.
0
1.
-1
9.
III
Adverse  drug  reaction/adverse  event/suspected  adverse  drug  reaction
The  intensity  of  the  adverse  reaction/adverse  event/suspected  adverse  drug  reaction  was
Yo
No.
The  adverse  reaction/adverse  event/suspected  adverse  reaction  to  medication  was  confirmed  with  some
0
+2
6.
There  are  conclusive  previous  reports  on  adverse  drug  reaction,  adverse  event  or
The  ADR  is  likely  due  to  the  investigational  drug  or  product
-1
0
improved  by  discontinuing  or  administering  a  specific  antagonist
The  drug  was  determined  in  blood  or  other  fluids  in  toxic  concentrations
Total  score
+1
+2
+1
1  to  4
higher  with  higher  doses  or  lower  with  lower  doses
The  causal  relationship  is  verified
reappeared  upon  administration  of  the  investigational  drug/product/investigational  drug
Reagent
objective  evidence
Each  reagent  receives  a  defined  score  and  the  final  sum  allows  estimating  the  probabilistic  category  of  the  causal  relationship.
-1
-1
suspected  adverse  reaction  to  medication
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•  Indicative  that  the  research  places  participants  at  increased  risk  of  harm  (including  physical,
PNA.
psychological,  economic  or  social)  than  previously  recognized.
Version  2.0
PNAs  that  are  EAS  must  be  reported  to  the  IEC  and  the  sponsor  within  the  first  24  hours  of
that  the  IP  was  aware  of  this.
November  11,  2019
The  PI  will  be  responsible  for  reporting  PNAs  to  the  sponsor,  the  IC,  and  the  IEC.  The  report  must  contain  the
Unanticipated  problems  (ANP)  consider  those  situations  that  pose  risks  to  the  subjects.
following  information:
Any  other  PNA  will  be  reported  to  the  CEI  and  the  sponsor  within  the  first  5  business  days  after  the
IP  became  aware  of  this.
Participants,  in  general,  any  incident,  experience  or  outcome  that  meets  all  criteria
•  Study  identification:  protocol  title  and  number,  name  of  the  PI  and,  where  applicable,  the  center.
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•  Detailed  description  of  the  event,  incident,  experience  or  result.
following:
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•  Unexpected  in  terms  of  its  nature,  severity,  or  frequency  in  relation  to:  1)  study-related  documents  such  as  the  
investigator's  manual,  study  protocol,  and  informed  consent  form;  and  2)  the  characteristics  of  the  study  population.
Sophia  Laboratories,  SA  de  CV
•  Related  or  possibly  related  to  your  participation  in  the  study  (possibly  related  means  that  there  is  a  reasonable  
possibility  that  the  incident  or  results  were  caused  by  study  procedures).
•  Explanation,  justification  of  the  reasons  why  the  incident  represents  a  PNA.
•  Description  of  changes  to  the  protocol  or  corrective  actions  taken  or  proposed  in  response  to  the
Study  No:  SOPH172-0919/I
8.5  Unanticipated  Problems
8.5.1  PNA  Report
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9.1  Monitoring  of  study  centers
adverse  events  have  been  carried  out  appropriately.  At  this  visit  the  monitor  will  discuss  the  findings  with  the
The  study  sponsor  is  responsible  for  monitoring  the  study.  Monitoring  activities  include:
Monitoring  of  the  research  centers  participating  in  the  study  will  be  carried  out.  For  each  center,
applicable  operating  procedures,  data  filling  has  been  complete  and  timely,  and  that  event  reports
52  of  73
CONFIDENTIAL
November  11,  2019
At  the  follow-up  visit(s),  the  monitor  will  review  the  study  documents  to
in  a  Monitoring  Plan.
documents  needed  to  file,  that  all  biological  samples  have  been  sent  for  analysis,  that  everything
unused  material  has  been  recovered.
discharged  from  monitoring.  During  this  visit,  the  monitor  will  verify  that  the  site  has  all  the
The  monitor  will  verify  that  the  material  to  be  used  during  the  study  has  been  received  and  that  the  personnel  who
Sophia  Laboratories,  SA  de  CV
monitoring  by  study  site,  detection  monitoring,  reporting  and  follow-up  of  adverse  events,
several  follow-up  visits  between  those  two  mandatory  visits.
researcher  and  will  define  the  actions  to  be  carried  out.
Responsibility  for  monitoring  activities  and  ultimate  responsibility  for  monitoring  rests  with  the
confirm  that:  the  research  protocol  has  been  followed,  standard  procedures  have  been  followed
Details  on  monitoring  are  set  out  in  the  corresponding  plan.
Version  2.0
Details  of  the  monitoring  activities  are  specified  in  a  separate  document  from  this  protocol.
comply  with  applicable  regulatory  requirements  and  standard  operating  procedures.
the  study  drug  (used  and  unused)  has  been  recovered  and  shipped  to  the  sponsor,  and  that  all
sponsor.
will  participate  in  the  study  activities  has  been  trained  on  the  study,  will  also  verify  that
The  closing  visit  will  take  place  at  the  end  of  the  study,  once  the  last  participant  from  the  site  has  been
monitoring  to  resolve  discrepancies  in  data  capture,  etc.
The  initial  visit  must  be  carried  out  before  the  inclusion  of  the  first  participant  in  that  center;  in  it,  the
Study  No:  SOPH172-0919/I
but  are  not  limited  to:  general  safety  monitoring,  general  study  quality  monitoring,
At  least  one  initial  visit  and  one  closing  visit  must  be  carried  out,  which  does  not  exclude  the  carrying  out  of  one  or  more
9.  Study  monitoring
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Study  centers  included  in  the  study  will  be  subject  to  a  pre-selection  feasibility  visit.
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from  the  center,  where  it  will  be  verified  that  they  meet  the  minimum  requirements  indicated  by  the  sponsor.
Version  2.0
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November  11,  2019
They  may  take  place  at  any  time  before,  during  or  after  the  conclusion  of  the  study.  If  it  is  carried  out
To  ensure  compliance  with  GCP  and  all  applicable  regulatory  requirements,  Laboratories
any  audit  or  inspection,  the  researcher  and  the  institution  must  agree  to  allow  the
Sophia,  SA  de  CV  may  conduct  quality  assurance  audits.  Regulatory  agencies
auditor/inspector  has  direct  access  to  all  relevant  documents,  and  will  allocate  their  time  and  that  of  their
staff  to  the  auditor/inspector  to  discuss  the  findings  and  any  relevant  issues.  In  the  event  that  the
They  could  also  conduct  a  regulatory  review  of  this  study.
Details  of  the  audit  process  are  set  out  separately  in  an  Audit  Plan.
Sophia  Laboratories,  SA  de  CV
If  the  audit  has  not  been  scheduled  by  the  sponsor,  the  center  must  notify  Laboratorios  Sophia,  SA
of  CV  immediately.
Study  No:  SOPH172-0919/I
9.2.1  Pre-study  audit
9.2  Audit  and  quality  control
9.2.2  Audit  during  the  conduct  of  the  study
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10.1.1  Statistical  analysis
10.1.2  Data  interpretation
Data  analysis
10.1
Study  No:  SOPH172-0919/I
quantitative  variables.  [54]
an  Excel  spreadsheet  (Microsoft®  Office).  The  data  will  then  be  exported  to  the
Version  2.0
The  level  of  difference  to  consider  significance  will  be  an  alpha  (ÿ)  of  0.05  or  less.
The  final  results  report  will  be  displayed  in  tables  or  graphs,  as  appropriate.
The  results  of  the  nominal  and  ordinal  qualitative  variables  will  be  presented  in  frequencies,  proportions  and  
percentages.
November  11,  2019
SPSS  software  platform.  Variables  will  be  categorized  according  to  their  nature.
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Statistical  analysis  to  identify  significant  differences  in  qualitative  variables  will  be  performed  by  creating  2x2  
contingency  tables  and  will  be  carried  out  as  follows:
The  Kolmogorov-Smirnov  test  will  be  performed  to  determine  the  distribution  of  the  results  obtained.  [53]
•  Intra-group  analysis:  Pearson's  Chi-square  (X2)  test  or  Fisher's  exact  test  on  expected  values
The  results  of  the  continuous  quantitative  variables  will  be  presented  in  measures  of  central  tendency:
under  5.
mean,  standard  deviation  and  ranges.
The  level  of  difference  to  consider  significance  will  be  an  alpha  (ÿ)  of  0.05  or  less.
For  adverse  event  reporting,  all  eyes  of  participants  assigned  to  the  intervention  after  the  baseline  visit  will  be  
considered.  Results  will  be  expressed  as  a  percentage  of  subjects.
The  statistical  analysis  will  be  performed  by  staff  of  Laboratorios  Sophia,  SA  de  CV.  The  program  will  be  used
SPSS  statistical  version  19.0  (IBM  Corporation,  Armonk,  NY,  USA).
Sophia  Laboratories,  SA  de  CV
The  statistical  analysis  of  continuous  quantitative  variables  to  find  significant  differences  (p)  will  be  as  follows:
•  Intra-group  analysis:  They  will  be  determined  by  the  Wilcoxon  rank  test,  for  the
Coding  will  be  done  using  consecutive  numbers.  Data  will  be  collected  and  sorted  into
10.  Statistical  analysis
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evaluable  (both  eyes).  If  this  number  is  not  met  due  to  a  loss  of  subjects  greater  than
the  study  population  unexpected  adverse  events  related  to  the  investigational  product.
to  the  20%  contemplated  in  this  protocol  (loss  to  follow-up  or  withdrawal  of  FCI),  the  sponsor  may
Version  2.0
A  multicenter,  double-blind,  randomized,  parallel-group  controlled  clinical  trial  was  conducted.  The  trial  evaluated  the
Efficacy  and  tolerability  of  a  1.5%  bepotastine  besilate  ophthalmic  solution  (n=43)  versus  bepotastine
1.0%  (n=44)  and  placebo  (n=43),  in  130  subjects  in  a  conjunctival  allergen  challenge  (CARC)  model.
November  11,  2019
replace  these  subjects.
The  intervention  consisted  of  the  application  of  3  drops  in  each  eye  of  each  of  the  interventions  (3  minutes
after  RAC),  with  measurements  at  15  minutes,  8  and  16  hours  post  instillation.
The  results  obtained  from  the  replaced  subjects  will  continue  to  be  used  for  the  analysis  of
The  safety  assessment  will  include  in  the  analysis  all  those  subjects  (both  eyes)  who  have  been  exposed
security  and  will  be  part  of  the  ITT.
n=  22  evaluable  subjects  (both  eyes)
at  least  once  a  year  after  the  intervention,  regardless  of  the  visit  at  which  they  were  eliminated  from  the  study  (ITT,
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CONFIDENTIAL
Those  subjects  who  meet  an  adherence  ÿ75%  will  be  included  in  the  statistical  analysis  for
intention-to-treat  population).
Although  there  are  no  references  on  sample  calculation  in  phase  I  studies,  it  was  considered  relevant
perform  it  according  to  the  presence  of  Adverse  Events  (AE)  referred  to  by  Macejko  et  al.,  2010,  [16]  in  a  trial
meet  the  objective  of  the  study,  taken  from  the  weight  of  the  PI.
According  to  the  sample  size  calculation  to  meet  the  objective  of  the  study,  22  subjects  are  required.
Sophia  Laboratories,  SA  de  CV
The  investigational  drug  will  be  considered  safe  and  tolerable  when  present  in  less  than  10%  of
Study  No:  SOPH172-0919/I
10.1.5  Subjects  included  in  the  analysis
10.2.1  Calculated  N
10.1.4  Deviations  from  the  statistical  analysis  plan
10.1.3  Procedure  for  handling  missing  data
10.2
10.2.2  Justification  of  the  sample  calculation
Sample  size  calculation
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A  =  <(1  ÿ  <)  B  C?DE  +  C?DG
Yo
C  =
<  ÿ  <:  ÿ  >  H
1  ÿ  J  =  K(C  ÿ  C?DE)  +  K(ÿC  ÿ  C?DE) ,
9?:  <  ÿ  <:  >  >
9::  <  ÿ  <:  ÿ  >
Study  No:  SOPH172-0919/I
possible  losses.  The  total  sample  size  required  is  22  subjects,  who  will  provide  an  eye  for  the  analysis.
Version  2.0
Where,  ÿ  is  the  non-inferiority  margin  (-10%).
Where;
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The  calculation  to  estimate  the  sample  size  and  power  was  performed  using  the  following  equations.
n  is  the  sample  size,
The  percentage  of  adverse  events  was  30%  for  the  1.5%  bepotastine  group,  47.5%  for  bepotastine
po  is  the  reference  proportion,
CONFIDENTIAL
1%  and  22.5%  for  placebo,  so  a  non-inferiority  margin  of  10%  was  considered  with  the
ÿ  is  the  normal  distribution  function,
formulation  proposed  in  this  protocol  (bepotastine  1.5%).[16]
ÿ  is  the  Type  I  error
The  sample  size  was  calculated  using  the  equation  for  a  proportion,  [55]  considering  a  power  of
ÿ  is  the  Type  II  error,  which  means  that,  1-ÿ  is  the  power,  and
80%  (ÿ),  a  significance  level  of  0.05  (ÿ)  and  a  non-inferiority  margin  (ÿ)  of  10%.
ÿ  is  the  test  margin.
Sophia  Laboratories,  SA  de  CV
According  to  the  previous  calculation,  the  result  is  18  subjects,  this  calculation  was  increased  by  20%  considering
OP(QRP)  S
LDLMDN
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Approval  of  the  committees
11.1
57  of  73
International  Organizations  of  Medical  Sciences  (CIOMS,
the  local,  national  or  international  requirements  applicable  by  regulatory  entities.
Section  III,  published  in  the  Official  Gazette  of  January  6,  19873
November  11,  2019
research:  research  protocol,  informed  consent  letter,  researcher's  manual,
Council  for  Harmonisation  (ICH)  Good  Clinical  Practice  Guidelines.  Ethical  Guidelines
The  study  will  not  be  started  without  having  met  the  local,  national  or  international  regulatory  requirements.
The  study  is  considered  to  be  research  with  greater  than  minimum  risk,  according  to  Regulation
Research  Committees,  and  when  applicable,  by  the  Biosafety  Committee,  corresponding.
current  regulations  of  the  regulatory  authority.
Belmont  Report,  National  Commission  for  the  Protection  of  Biomedical  Research  Subjects  and
This  study  will  be  conducted  in  accordance  with  the  standards  of  the  Declaration  of  Helsinki,  Medical  Association
the  study  and  will  issue  their  approval  or  possible  modifications  for  its  implementation,  these  Committees  must  be
economic  proposal  from  each  of  the  principal  investigators,  duly  signed  and  without  having
Sophia  Laboratories,  SA  de  CV
CONFIDENTIAL
International  Organizations  for  Biomedical  Research  Involving  Human  Subjects  of  the  Council  for
subject  diary  and  patient  material,  as  well  as  other  additionally  requested  documents,  according  to
of  the  General  Health  Law  on  Health  Research,  Title  Two,  Chapter  I,  Article  17,
Version  2.0
of  medicinal  products  for  human  use  of  the  International  Conference  on  Harmonization  (The  International
Research  Committees,  and  when  applicable  to  the  Biosafety  Committee,  the  essential  documentation  of  the  project
relevant  and  without  having  the  corresponding  health  authorization.
Study  No:  SOPH172-0919/I
The  personnel  authorized  by  the  sponsor  will  be  subject  to  evaluation  by  the  Research  Ethics  Committees,
previously  obtained  the  favorable  opinion  and/or  approval  of  the  Research  Ethics  Committees,
2013  World  Cup.  Nuremberg  Code;  Nuremberg  Trials  by  the  International  Tribunal  at  Nuremberg,  1947.
notified  of  any  significant  changes  to  the  protocol.  In  addition  to  the  above,  the
Conduct,  1979.  It  will  be  conducted  in  accordance  with  the  scientific  and  technical  requirements  necessary  for  registration
2016).  The  Research  Ethics  Committee  and  the  Research  Committee  will  evaluate  the  protocol  before  carrying  out
The  study  will  not  be  started  at  the  research  center  if  the  confidentiality  agreements  are  not  in  place  and
11.  Ethical  considerations
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will  show  an  increased  risk  to  participants,  premature  termination  or  suspension  of  the  study,
Research  or  when  applicable,  by  the  Biosecurity  Committee,  (entities  that  issued  the  opinion
participants  in  the  research.  Likewise,  you  must  report  any  situation  or  new  knowledge  that
to  the  study  participants,  the  CI  and  the  IEC,  providing  the  reasons.
Situations  in  which  suspension  or  early  termination  of  the  study  will  be  considered  include,  but  are  not  limited  to:
November  11,  2019
The  principal  investigator  has  the  responsibility  to  communicate  to  the  Research  Ethics  Committee  any
Any  amendment  must  be  approved  by  the  sponsor  and/or  the  principal  investigator,  the  document(s)
sufficiently  reasonable.  Written  notice,  documenting  the  reason  for  the  suspension  or  termination
1.
CONFIDENTIAL
research  subjects,  must  be  approved  by  the  aforementioned  Committees.  It  is  the  responsibility  of  the
study.
Research.  Documents  that  may  be  amended  include:  protocol,  letter  of  consent
document  that  is  part  of  the  research  project  or  protocol,  derived  from  variations  to  the  structure
relevant  regulatory.
reasons  and  the  results  obtained  up  to  that  point.  You  must  also  report  on  the  conclusion
Sophia  Laboratories,  SA  de  CV
limit:
amended,  once  reviewed  and  approved  by  the  Research  Ethics  Committee  and  the  Committee  of
early,  must  be  delivered  by  the  party  executing  the  suspension.  The  IP  must  inform  as  soon  as  possible
amendment  to  the  protocol  that  could  potentially  affect  the  rights,  safety  or  well-being  of
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Version  2.0
activities.
to  the  study  participants.
The  study  may  be  temporarily  suspended  or  terminated  prematurely  if  there  is  a  cause
informed,  researcher's  manual,  patient  documents,  measurement  scales  and  schedule  of
researcher  take  action  in  situations  that  require  immediate  action  to  avoid  unnecessary  harm
of  the  study,  upon  completion  of  the  research  protocol.
methodological,  replacement  of  the  principal  investigator  or  identification  of  risks  in  the  subjects  of
Amendments  that  substantially  modify  the  protocol,  confer  an  additional  or  different  risk  to  the
Study  No:  SOPH172-0919/I
Presence  of  serious  adverse  events  in  more  than  10%  of  participants  in  a  group  of
The  amendment  procedure  will  be  relevant  when  there  is  a  need  to  make  any  changes  to  a
initial  favorable  for  the  realization  of  the  investigation)  will  be  sent  for  authorization  by  the  entity
11.3
11.2
Amendments  to  the  protocol
Early  termination  of  study
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In  case  of  suspension,  the  study  can  be  resumed  once  the  situations  that  have  been  corrected  have  been  resolved.
3.
The  data  obtained  are  not  evaluable  or  are  not  sufficiently  complete.
10.
is  responsible  for  ensuring  that  all  new  versions  of  informed  consent  are  submitted  to  the
approvals  that  apply  (the  same  ones  to  which  the  original  informed  consent  letter  was
The  IP  will  provide  the  potential  participant  with  all  the  information  regarding  the  characteristics  of  the  study,  its
potential  benefits,  risks,  objectives  and  procedures  thereof.
November  11,  2019
8.
Obtaining  new  relevant  security  information.
in  accordance  with  current  applicable  regulations  and  Good  Clinical  Practices.
indicated  in  the  protocol.  For  this  purpose,  the  informed  consent  letter  must  be  signed.
described  in  the  Declaration  of  Helsinki  and  the  ICH  Guideline  for  Good  Clinical  Practice  and  will  be  in
5.
Informed  consent  must  be  obtained  before  any  procedure  is  performed  on  the  subject.
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Sophia  Laboratories,  SA  de  CV
The  Sponsor  determines  it  for  its  convenience  or  eventualities  such  as:  support
Determination  of  futility.
resulted  in  suspension;  as  long  as  this  justification  is  sufficient  for  the  sponsor,  CI,  CEI  and
Lower  recruitment  than  stipulated.
submitted)  and  that  the  most  current  approved  version  is  the  one  presented  to  the  study  subjects.
This  information  will  be  in  a  language  that  the  subject  understands,  and  it  will  be  explained  to  the  subject  that  he  has  the  right
2.
Insufficient  adherence  to  protocol  requirements.
9.
The  FCI  will  be  considered  a  source  document  and  will  be  archived  as  such.  The  principal  investigator  of  the  site
Written  consent  documents  will  incorporate  the  elements  of  informed  consent
compliance  with  all  applicable  laws  and  regulations.
Version  2.0
unacceptable.
7.
The  FCI  contains  complete  and  understandable  information  about  the  study  and  the  investigational  product,
Determination  of  unexpected  risks  to  participants,  which  are  significant  or
6.
regulatory  authorities.
economic,  manufacturing  errors,  etc.
4.
Study  No:  SOPH172-0919/I
to  interrupt  their  participation  in  the  study  at  any  stage,  without  affecting  the  relationship  with  the
The  regulatory  authority  (COFEPRIS)  considered  it  due  to  security  alerts.
Determination  that  the  primary  objective  has  been  achieved.
Informed  consent
11.4
11.4.1  Obtaining
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Such  amendments  may  be  implemented  only  after  obtaining  the  written  approval  of  the
participant;  he  or  she  must  have  sufficient  time  to  analyze  each  and  every  aspect
The  FCI  must  be  signed  in  duplicate  by  all  those  involved,  and  two  witnesses,  one  copy  will  be  filed
approval  before  the  Research  Ethics  Committees,  and  if  applicable  before  the  Competent  Authorities.
All  documents  and  information  provided  to  the  research  center  by  the  sponsor  are
November  11,  2019
study  and  any  doubts  were  clarified.
same  conditions  as  those  described  above,  in  order  to  promptly  communicate  to  this  new
The  researcher  will  keep  the  second  original.
A  re-consent  process  must  be  carried  out  for  each  subject  affected  by  the  amendment  in  the
CONFIDENTIAL
Sophia  Laboratories,  SA  de  CV
obtaining  informed  consent.
document  the  process  of  obtaining  Informed  Consent  through  a  detailed  medical  note,
Research  Ethics  Committee  and  the  Regulatory  Entity  (as  applicable),  with  the  exception  of  one  amendment
informed  consent  in  the  presence  of  two  witnesses  who  may  or  may  not  have  a  relationship  with  the  subject  of  the  study,
strictly  confidential.  The  IP  expressly  agrees  that  the  data  regarding  his  or  her  professional  experience  and
researcher  and/or  his/her  future  assistance.  Informed  consent  will  be  submitted  to  the  prospective
The  IP  must  also  sign  and  date  this  consent.
Any  change  to  the  “FCI”  constitutes  an  amendment  to  this  document  and  must  be  submitted  for  review.
Version  2.0
carried  out  prior  to  any  study  procedure,  which  was  clearly  explained  the  information  of  the
should  be  considered  apart  from  the  procedures  listed  for  informed  consent.
information  contained  in  the  document.  The  subject  will  be  given  a  signed  original  of  the  amendment  and  the
who  will  participate  during  the  informed  consent  process  and  will  sign  guaranteeing  that  the  process  is
The  procedures  that  will  be  performed  during  the  study  do  not  pose  any  additional  risk  that
that  is  required  to  eliminate  an  immediate  danger  to  the  subjects  of  the  study.
Once  the  participant  agrees  to  participate  in  the  study,  he  or  she  must  sign  and  date  the  letter  of
where  the  signed  version,  the  date  on  which  the  document  was  signed  and  how  the  process  was  carried  out  are  specified.
Study  No:  SOPH172-0919/I
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mentioned  above  and  in  case  you  have  any  questions,  these  will  be  clarified  by  the  person  in  charge
in  the  researcher's  folder  and  the  other  will  be  given  to  the  participant.  The  PI  or  delegated  staff  must
Confidentiality
11.5
11.4.3  Modifications  to  informed  consent
11.4.2  Special  considerations
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sponsor  and  the  research  center,  must  be  treated  confidentially.  The  Health  Authority,
use  related  to  your  activities  with  the  sponsor  of  clinical  studies,  in  accordance  with  the  Good
The  researcher  will  not  reveal  any  information  without  the  prior  written  consent  of  Laboratories
of  identification  of  the  subject  under  study.  The  information  collected  in  this  study  will  be  exchanged  between  the
The  independence  of  the  conduct  of  the  study  and  its  results  from  any  current  or  external  influence
perceived  is  critical.  For  this  reason,  any  current  conflict  of  interest  of  any  person  who  exercises  a  role
November  11,  2019
compliance  with  professional  secrecy.
just  as  any  information  taken  from  it  must  not  be  disclosed  to  other  parties  without  authorization  by
publish  the  results  of  the  study,  no  personal  information  of  the  study  subjects  will  be  revealed.
research,  in  no  case  will  they  contain  information  on  the  identification  of  the  study  subjects.  If
The  researcher  will  complete  and  maintain  a  record  of  subject  selection,  as  well  as  the  identification  and  list  of
CONFIDENTIAL
Sophia  Laboratories,  SA  de  CV
The  researcher  agrees  that  he  and  his  team  members  will  use  the  information  only  within  the
of  the  same.  In  the  latter  case,  the  researcher  is  obliged  to  inform  Laboratorios  Sophia,  SA  de  CV  before
The  IEC,  the  IC,  the  sponsor,  the  monitors/auditors  and  third-party  auditors  will  be  the  only  bodies
confidential  information  has  not  been  disclosed  to  the  public  by  the  sponsor.
in  the  design,  conduct,  analysis,  publication,  or  any  other  aspect  of  this  study  will  be  declared.  Furthermore,
clinic,  provided  to  the  sponsor  in  paper  form  and  stored  in  electronic  format,  are  for  the  sole  purpose  of
sponsor's  writing.
All  eCRFs  and  communications  related  to  study  subjects  will  identify  them  only  by  their  number.
Version  2.0
to  obtain  informed  consent  from  subjects  for  the  study.  The  clinical  study  protocol,  at
to  the  auditor  and/or  the  representatives  of  the  Competent  Authorities.  The  information  will  be  treated  giving
The  protection  of  personal  data  will  be  in  accordance  with  the  corresponding  current  regulations.
The  clinical  study  protocol  provided  to  the  researcher  may  be  used  by  the  researcher  and  his  team.
Enrollment  of  each  of  the  subjects  participating  in  the  study.  The  researcher  agrees  to  provide  on-site  access
authorized  to  review  the  study  documentation.  If  publications  arise  from  this  project,
framework  of  this  study,  to  carry  out  the  protocol.  This  agreement  is  mandatory  as  long  as  the  information
to  disclose  the  information  to  these  authorities.
Study  No:  SOPH172-0919/I
61  of  73
Clinical  Practices.
Sophia,  SA  de  CV,  except  to  representatives  of  the  Competent  Authorities,  and  only  upon  request
Conflict  of  interest
11.6
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Once  the  study  is  completed  and  the  adverse  events  are  closed  according  to  section  8,  the  sponsor  does  not
The  final  database  of  the  study  will  be  property  of  Laboratorios  Sophia,  SA  de  CV  and  its  access  will  be
Version  2.0
will  extend  care  to  the  research  subject.
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Those  individuals  who  have  a  perceived  conflict  of  interest  will  be  asked  to  handle  it  in  a  manner
restricted.  The  IP  will  not  have  access  to  this,  except  with  prior  written  authorization  from  the
sponsor.
appropriate  to  their  participation  in  the  study.
The  information  obtained,  which  is  relevant  to  the  safety  of  the  subjects  participating  in  the  study,
CONFIDENTIAL
must  be  shared  immediately  with  the  research  center,  so  that  it  can  in  turn  be  notified  to  the
subjects  of  the  study.
The  IP  undertakes  to  make  a  declaration  of  financial  interests,  as  well  as  conflict  of  interests
prior  to  the  start  of  the  study.
Sophia  Laboratories,  SA  de  CV
Study  No:  SOPH172-0919/I
Access  to  information
Ancillary  and  post-study  care
11.7
11.6.1  Declaration  of  interests
11.8
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Viruses  of  any  kind;  radioactive  material  of  any  kind;  animals  and/or  plant  cells
genetically  modified;  toxic,  hazardous  or  explosive  substances;  any  other  material  that
Version  2.0
puts  at  risk  the  health  or  physical  integrity  of  the  research  center  staff  or  subjects
November  11,  2019
research  or  affect  the  environment.  It  is  also  declared  that  in  this  project  no  further  research  will  be  carried  out
NO  BIOSECURITY  IMPLICATIONS
carry  out  cell,  tissue  or  organ  transplant  procedures,  or  cell  therapy,  nor  will  they  be  used
This  protocol,  entitled:  “Phase  I  clinical  study,  to  evaluate  the  safety  and  tolerability  of
laboratory,  farm,  or  wildlife  animals.
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PRO-172  ophthalmic  solution,  manufactured  by  Laboratorios  Sophia,  SA  de  CV  on  the  ocular  surface  of
clinically  healthy  subjects.”,  and  number:  SOPH172-0919/I  HAS  NO  BIOSECURITY  IMPLICATIONS,
Sophia  Laboratories,  SA  de  CV
since  infectious  biological  material  will  NOT  be  used;  pathogenic  strains  of  bacteria  or  parasites;
CONFIDENTIAL
Study  No:  SOPH172-0919/I
12.  Biosecurity  aspects
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13.2
Publication  of  the  results
Final  report
13.1
13.3
Communication  of  results
November  11,  2019
as  to  its  function  and  retains  exclusive  property  rights  over  the  results  of  the  study,  the
Regardless  of  the  results  of  the  study,  Laboratorios  Sophia,  SA  de  CV,  is  committed
The  assignment  of  authorship  of  publications,  being  the  responsibility  of  the  sponsor,  will  be  the  prerogative  of  this  sponsor.
attempt  to  submit  for  publication  in  any  scientific  journal  or  conference
of  the  information  contained.
results  of  the  study,  the  sponsor  may  delay  its  publication  or  communication  of  the  results  of  the  study.
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The  IP  undertakes  not  to  publish  or  communicate  data  collected  from  the  study,  unless  it  has  the
as  authors.  Authors  have  the  right  to  review  the  manuscript  prior  to  publication,  as  well  as  to
will  also  be  shared  with  the  research  committee  and  the  IEC.  The  IP  will  be  responsible  for  communication
Once  the  statistical  analysis  is  completed,  the  final  report  will  be  written  with  the  results  obtained,  in  charge
Laboratorios  Sophia,  SA  de  CV  will  retain  at  all  times  the  rights  to  the  publication  and  dissemination
obtained  with  this  protocol  must  be  reviewed  by  the  sponsor  before  any
first  15  calendar  days  from  the  date  the  project  is  received.
However,  in  case  the  sponsor  is  in  the  process  of  filing  a  patent  application  on  the
CONFIDENTIAL
The  report  will  be  prepared  following  the  recommendations  of  the  ICH  E3  Step  4  Guide.
Sophia  Laboratories,  SA  de  CV
Version  2.0
Laboratorios  Sophia,  SA  de  CV,  acting  as  the  sponsor  of  the  study,  assumes  full  responsibility
study  until  the  date  of  registration  or  when  it  deems  appropriate.
to  communicate  the  final  report  of  the  study  to  the  principal  investigators  and  COFEPRIS.  These  results
Lastly,  however,  the  express  authorization  of  the  persons  invited  to  participate  must  be  obtained.
which  you  can  use  in  any  way  you  see  fit.
make  comments  and  suggestions  in  this  regard,  such  comments  must  be  submitted  within  the
to  the  research  subjects.
prior  written  agreement  of  Laboratorios  Sophia,  SA  de  CV  Any  manuscript  derived  from  the  data
Study  No:  SOPH172-0919/I
from  the  Clinical  Team  of  the  Clinical  Operations  Department  of  Laboratorios  Sophia,  SA  de  CV  Said
13.Publishing  Policy
Machine Translated by Google


Insurance  for  study  participants
14.2
Compensation  to  study  participants
14.1
informed  consent  letter.
informed  consent  letter.  In  case  of  a  medical  emergency,  the  research  center  must  have
with  personnel,  materials,  equipment  and  procedures  for  immediate  handling.
Version  2.0
65  of  73
November  11,  2019
The  subjects  participating  in  the  study  will  sign  the  informed  consent  letter,  which  specifies  that
Laboratorios  Sophia,  SA  de  CV  agrees  to  pay  for  immediate  treatment  resulting  from  injuries
CONFIDENTIAL
or  diseases  caused  by  the  investigational  products  until  their  resolution,  according  to  the  criteria
doctor.
Subjects  participating  in  the  study  will  not  receive  financial  compensation  for  their  participation  in  the  study.
same.  However,  randomized  subjects  will  receive  financial  support  in  the  form  of  travel  expenses  in  each
scheduled  visit  to  which  they  attend  punctually.  Said  support,  as  well  as  the  amount,  will  be  specified  in  the
Sophia  Laboratories,  SA  de  CV
All  study  participants  will  be  eligible  for  liability  insurance  coverage,
contracted  by  Laboratorios  Sophia,  SA  de  CV  The  information  of  the  contracted  policy  will  be  found  in  the
Study  No:  SOPH172-0919/I
14.  Financing  and  insurance
Machine Translated by Google


[4]  C.  Akdi  and  F.  Simons,  “Histamine  receptors  are  hot  in  immunopharmacology,”  Eur  J  Pharmacol,  vol.  533,
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November  11,  2019
conjunctivitis:  systematic  review  and  meta-analysis  of  efficacy  and  effectiveness,”  Br  J  General  Practice
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CONFIDENTIAL
,
[8]  B.  Bielory,  T.  O'Brien,  and  L.  Bielory,  “Management  of  seasonal  allergic  conjunctivitis:  guide  to  therapy,”
References
[5]  R.  Thurmond,  E.  Gelfand  and  P.  Dunford,  «The  role  of  histamine  H1  and  H4  receptors  in  allergic
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2008.
[9]  C.  Owen,  A.  Shah,  K.  Henshaw,  L.  Smeeth  and  A.  Sheikh,  “Topical  treatments  for  seasonal  allergic
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and  histamine  receptors,"  J  allergy  Clin  Immunol,  vol.  128,  pp.  1153-1162,  2011.
histamine-induced  proinflammatory  cytokine  production  through  inhibition  of  Ca2+-dependent
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69,  pp.  433-449,  2005.
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Study  No:  SOPH172-0919/I
[2]  P.  Barnes,  “Pathophysiology  of  allergic  inflammation,”  Immunological  reviews,  vol.  242,  pp.  31-50,
15.References
Machine Translated by Google


November  11,  2019
Effectivenesses  of  bepotastine  besilate  ophthalmic  solution  for  the  treatment  of  ocular  symptoms  of
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CONFIDENTIAL
Review  of  Cornea  &  Contact  Lenses,  vol.  March,  pp.  18-23,  2016.
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Sophia  Laboratories,  SA  de  CV
p.  S154,  2007.
Version  2.0
conjunctivitis  in  allergic  rhinoconjunctivitis  and  associated  risk  factors  in  rural  UK  children,”  PLos  ONE,
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of  action  of  the  antihistamine  bepotastine  besilate  ophthalmic  solutions  1.0  %  and  1.5  %  in  allergic
Study  No:  SOPH172-0919/I
[12]  K.  Singh  and  L.  Bielory,  “Ocular  allergy:  a  national  epidemiologic  study,”  J  Allergy  Clin  Immunol,  vol.  119,
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allergic  conjunctivitis  in  Oxfordshire,"  Ophthalmic  Epidemiol,  vol.  11,  pp.  17-33,  2004.
1.5%,"  Clinical  Ophthalmology  2014,  vol.  8,  p.  1495–1505,  2014.
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CONFIDENTIAL
Expert  Opinion  Pharmacother,  vol.  14,  no.  18,  pp.  1-17,  2013.
betostaine  besilate,  suppresses  interleukin-5  production  by  human  peripheral  blood  mononuclear
selective  histamine  H1  receptor  antagonist,  suppress  vascular  hyperpermeability  and  eosinophil
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Sophia  Laboratories,  SA  de  CV
Research,  vol.  91,  pp.  85-91,  2010.
Version  2.0
responses  through  the  inhibition  of  the  leukotriene  B4  action  in  mice,"  Eur  J  Pharmacol,  vol.  547,  pp.
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intestinal  absorption  and  brain  penetration  of  antiallergic  agent  bepotastine  besilate,»  Drug
of  Action  of  the  Antihistamine  Bepotastine  Besilate  Ophthalmic  Solutions  1.0%  and  1.5%  in  Allergic
Study  No:  SOPH172-0919/I
recruitment  in  vitro  and  in  vivo  experimental  allergic  conjunctivitis  models,"  Experimental  Eye
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CONFIDENTIAL
[44]  J.  Kanski,  Clinical  Ophthalmology,  Barcelona:  Elsevier,  2009.
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Machine Translated by Google


ICO
16.1
Eye  Comfort  Index
16.Annexes
Version  2.0
November  11,  2019
Study  No:  SOPH172-0919/I
Sophia  Laboratories,  SA  de  CV
71  of  73
CONFIDENTIAL
I  haven't  felt  it
I  haven't  felt  it
I  haven't  felt  it
Identification  card
I  haven't  felt  it
2
5
1
5
6
4
6
3
6
4  In  the  past  week,  how  often  did  your  eyes  feel  tired ?
0
1
5
3
Subject  No.:  172-______-______
0
2
5
0
2
2
3
3
1
Example:
6
/
There  are  no  right  or  wrong  answers.  Don't  spend  too  much  time  on  each  question.
6
4
When  your  eyes  felt  like  they  were  stinging,  how  intense  was  the  sensation  usually?
2
5
4
2
2
0
Directions:
0
3
3
When  your  eyes  felt  gritty,  typically,  how  intense  was  the  sensation?
3
6
In  the  past  week,  how  often  were  your  eyes  red?
1
4
In  the  past  week,  how  often  did  your  eyes  feel  throbbing ?
2
In  the  past  week,  how  often  did  your  eyes  feel  dry ?
/
1
5
0
3
When  your  eyes  felt  dry,  how  severe  was  the  sensation  usually?
0
3
5
0
6
4
In  the  past  week,  how  often  did  your  eyes  feel  gritty ?
This  questionnaire  was  designed  to  rate  the  comfort  of  your  eyes.
Study  No.:  SOPH172-0919-I
1
4
6
4
2
2
5
0
3
1
Date:
4
When  your  eyes  felt  tired,  how  intense  was  the  feeling  usually?
1
4
1
1
5
6
For  each  question,  circle  your  answer.
Subject's  initials:
Sheet  1  of  2
Never
Always
Never
Never
Always
Never
Severe
Never
Always
Always
Severe
Always
Severe
Severe
Machine Translated by Google


2
1
0
6
4
3
When  your  eyes  felt  itchy ,  how  intense  was  the  sensation  usually?
5
3
1
6
In  the  past  week,  how  often  did  your  eyes  feel  sore ?
4
2
When  your  eyes  felt  sore,  how  severe  was  the  sensation  usually?
5
3
In  the  past  week,  how  often  did  your  eyes  feel  itchy ?
5
4
1
6
6
3
2
0
2
1
5
5
6
0
4
0
Never
Always
Severe
Severe
Ocular  Comfort  Index,  translated  from  the  Ocular  Comfort  Index  available  at:  http:// iovs.arvohournals.org
Always
Never
Sheet  2  of  2
Eye  comfort  index
Version  2.0
November  11,  2019
Study  No:  SOPH172-0919/I
Sophia  Laboratories,  SA  de  CV
CONFIDENTIAL
72  of  73
I  haven't  felt  it
I  haven't  felt  it
Machine Translated by Google


Equal  to  or  less  than  panel  C,  greater  
than  B
Equal  to  or  less  than  panel  B,  greater  
than  A
Equal  to  or  less  than  panel  A
Equal  to  or  smaller  than  panel  E,  
larger  than  D
Equal  to  or  less  than  panel  D,  greater  
than  C
Very  mild  1
Light  2
Normal  0
Larger  than  panel  E
Severe  4
Moderate  3
Efron  Scale
16.3
16.2
Oxford  Scale
Study  No:  SOPH172-0919/I
November  11,  2019
Version  2.0
Sophia  Laboratories,  SA  de  CV
73  of  73
CONFIDENTIAL
Machine Translated by Google

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 






 
 
 
 






 
 
 
 
β 
α 
δ 
𝐻0: 𝑝−𝑝0 ≤𝛿
𝐻1: 𝑝−𝑝0 > 𝛿
δ 


 
𝑛= 𝑝(1 −𝑝) (
𝑧1−𝛼+ 𝑧1−𝛽
𝑝−𝑝0 −𝛿)
2
1 −𝛽= 𝜃(𝑧−𝑧1−𝛼) + 𝜃(−𝑧−𝑧1−𝛼) 𝑧=
𝑝−𝑝0−𝛿
√𝑝(1−𝑝)
𝑛
θ 
α 
β 
β 
δ 
 
 
 
• 
• 
 
• 
• 
• 
• 
• 
 
 


• 
• 
• 
• 
• 
• 
•
• 


•
• 


•
• 


• 
• 
• 
• 
α 
•


α 




Ejemplo:
En la semana pasada, ¿qué tan seguido sus ojos estuvieron rojos?
No existen respuestas correctas o incorrectas. No tome demasiado tiempo en cada pregunta.
1
En la semana pasada, ¿qué tan seguido sus ojos se sintieron secos?
Cuando sus ojos se sentían secos, por lo general, ¿qué tan intensa era la sensación?
2
En la semana pasada, ¿qué tan seguido sus ojos se sintieron arenosos ?
Cuando sus ojos se sentían arenosos , por lo general, ¿qué tan intensa era la sensación?
3
En la semana pasada, ¿qué tan seguido sus ojos sintieron punzadas ?
Cuando sus ojos sentían punzadas , por lo general, ¿qué tan intensa era la sensación?
4
En la semana pasada, ¿qué tan seguido sus ojos se sintieron cansados ?
Cuando sus ojos se sentían cansados , por lo general, ¿qué tan intensa era la sensación?
5
6
Nunca
Siempre
Nunca
0
1
2
3
4
6
Siempre
Severo
0
1
2
3
4
5
0
1
2
3
4
5
6
Nunca
Siempre
0
1
2
3
4
5
6
Severo
0
1
2
3
4
5
6
No lo he sentido
Nunca
Siempre
0
1
2
3
4
5
6
Severo
0
1
2
3
4
5
6
No lo he sentido
Nunca
Siempre
0
1
2
3
4
5
6
Severo
0
1
2
3
4
5
6
No lo he sentido
Hoja 1 de 2
No lo he sentido
Statistical Analysis Plan 
SOPH7 72-0919/1 
Bepostatin besylate 1.5% 
l O.O Annexes 
1 0.1 Eye comfort i ndex 
1 
1 
1 
("'------------------------------------------------------------------------------------------------------------------------------------------------------------1 
: 
1 
: 
1 
: 
1 
! 
-~~~~~~~~~ 
1 
: 
1 
L---·- ··-·- ·--·- ·- ·- ·~--.--.- ·--·- ·- ·~--.--.- ·- ·--·- ·- ··-·~--.- ·- ·--·- ··-·- ·--·- ·- ·- ·~--.--.- ·___________..1 
--, 
1 
1 
1 
1 
1 
1 
1 
1 
1 
-- , 
1 
1 
1 
1 
------------------------------------------------------------------------------~ 
76 


5
En la semana pasada, ¿qué tan seguido sus ojos se sintieron adoloridos ?
Cuando sus ojos se sentían adoloridos , por lo general, ¿qué tan intensa era la sensación?
6
En la semana pasada, ¿qué tan seguido sus ojos sintieron comezón ?
Cuando sus ojos sentían comezón , por lo general, ¿qué tan intensa era la sensación?
Nunca
Siempre
0
1
2
3
4
5
6
Severo
0
1
2
3
4
5
6
No lo he sentido
No lo he sentido
Índice de confort ocular
Hoja 2 de 2
Índice de confort ocular, traducido del Ocular Comfort Index disponible en: http://iovs.arvohournals.org
Severo
0
1
2
3
4
5
6
Nunca
Siempre
0
1
2
3
4
5
6
Statistical Analysis Plan 
SOPH7 72-0919/1 
Bepostatin besylate 1.5% 
___ , 
1 
1 
1 
1 
1 
1 
1 
1 
1 
77 


 
 
 
 
 
 
 
Statistical Analysis Plan 
SOPH7 72-0919/1 
Bepostatin besylate 1.5% 
l 0.2 Efron sea le for conjunctival hyperemia 
l 0.3 Oxford Sea le 
PANEL 
Grade 
Criteria 
A <Or> 
o 
Equal to or less than panel A 
B <Or> 
Equal to or less than panel B, greater than A 
e 
11 
Equal to or less than panel C, greater than B 
D 
111 
Equal to or less than panel D, greater than e 
E 
IV 
Equal to or less than panel E, greater than D 
>E 
V 
Greater than panel E 
78