Conditions: Inflammation and Pain Associated With Ocular Surgery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 325
Healthy volunteers: no

Brief summary:
The efficacy and safety of SDN-037 twice daily will be evaluated and compared with vehicle for the treatment of inflammation and pain associated with ocular surgery.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: SDN-037 intervention 2: Placebo
Intervention descriptions: intervention 1: twice daily intervention 2: twice daily

Protocol document:
Prot_000.pdf: 
 
CLR_16_31 
  
Version 01/Amendment  02, 02 Aug 2019 
 
 
 
CLINICAL DEVELOPMENT OF 
 
 
Clinical Trial Protocol: CLR_16_31 
 
 
Protocol Title: 
 
 
 
 
Protocol Number 
Version No. 
Amendment No. 
Date  
Study Phase: 
A Randomized, Double-Masked, Parallel Group, Multicenter, Study To 
Evaluate Efficacy And Safety of SPARC’s SDN-037 Twice Daily 
Compared With Vehicle For The Treatment Of Inflammation And Pain 
Associated With Ocular Surgery. 
 
CLR_16_31  
01 
Amendment 02 
 02 Aug 2019 
3 
Investigational Product Name: 
 
IND Number: 
 
Indication: 
Inflammation and pain associated with ocular surgery 
 
Investigators: 
Multi-center 
 
Sponsor: 
Sun Pharma Advanced Research Company, Ltd. (SPARC) 
17 B Mahal Industrial Estate, 
Mahakali Caves Rd Andheri (E), 
Mumbai - 400 093 
India 


 
CLR_16_31 
  
Version 01/Amendment  02, 02 Aug 2019 
 
 
 
 
 
 
 
 
 
SPONSOR  APPROVAL SIGNATURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
3 
 
 
 
 
 
 
 
 
Sponsor’s Medical Expert for the Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
4 
 
 
 
1.0 SYNOPSIS 
 
Title of the Study 
A Randomized, Double-Masked, Parallel Group, Multicenter, 
Study To Evaluate Efficacy And Safety of SPARC’s SDN - 
037 Twice Daily Compared With Vehicle For The Treatment 
Of Inflammation And Pain Associated With Ocular Surgery. 
Protocol Number 
CLR_16_31 
Investigational Product: 
 
Study Phase: 
3 
Primary Objective(s): 
To evaluate the efficacy and safety of topical administration of 
 compared with 
 when dosed 
 post cataract surgery. 
Secondary Objective(s): 
N/A 
Overall Study Design 
Structure 
Multi-center, double-masked, parallel group, randomization. 
Duration: 
Total duration: 
 
Vehicle: 
Vehicle of 
 
Estimated Duration of Trial 
Approximately 
 
Dosage/Dose Regimen/ 
Instillation/Application/Use: 
1 drop of either: 
 
 
 
 
 
 
 
 
 
 
Summary of Visit 
 


 
CLR_16_31 
 
Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
5 
 
 
 
 
 
 
 
 
 
Study Population 
Characteristics: 
Subjects  of all ages  with inflammation and pain associated 
with cataract surgery 
Number of Subjects: 
 
 
Condition/Disease: 
Inflammation and pain associated with ocular surgery. 
Inclusion Criteria: 
Following criteria during screening visit: 
1. 
Be male or female, of all ages  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
      
   
 
 
 
5. 
 
Able to self-instill the IP or have a caregiver available 
to instill all doses of the IP, as instructed.  
6.        Females of childbearing potential must not be pregnant 
(as confirmed by a negative urine pregnancy test 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
6 
 
 
 
7.      Be able and willing to follow study instructions and 
complete all required visits. 
Exclusion Criteria: 
1. 
Any known  allergy or hypersensitivity to 
difluprednate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 
An acute ocular infection (bacterial, viral or fungal) or 
active ocular inflammation in the study eye 
 
 
 
 
 
 
 
 
 
 
 
 
11. 
Any active corneal pathology noted in the study eye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation Criteria : 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects 
with an anterior chamber cell (ACC) grade of 0 at Day 15
 
 
Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the proportion of 
subjects who achieve a pain score of 0 
 
  at day 15 
 
 
Safety Measures: 
 
 
 
Efficacy Analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
8 
 
 
 
 
 
 
 
 
 
 
Safety Analyses: 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
9 
 
 
 
 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
12 
 
 
LIST OF ABBREVIATIONS 
 
ACC 
Anterior Chamber Cell 
ACF 
Anterior Chamber Flare 
AE 
Adverse Event 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice a day (bis in die) 
BSCVA 
Best-Spectacle Corrected Visual Acuity 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
eCRF 
electronic Case Report Form 
ETDRS 
Early Treatment Diabetic  Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IOL 
Intra Ocular Lens 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
mITT 
Modified Intent-To-Treat 
LAR 
Legally Acceptable Representative 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary of Regulatory Affairs 


 
CLR_16_31 
 
 Version 01 /Amendment  02, 
02 Aug 2019 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
13 
 
 
MRHD 
Maximum Recommended Human Dose 
NDA 
New Drug Application 
NOAEL 
No Observed Adverse Effect Level 
OPD 
(in-)Office Physician Dispensing 
PP 
Per Protocol 
PT 
Preferred Term 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SPARC 
Sun Pharma Advanced Research Company, Ltd. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
VAS 
Visual analog scale 
WHO-DD 
World Health Organisation Drug Dictionary 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
2.0 BACKGROUND INFORMATION 
 
Surgical technique in all fields of ophthalmology has evolved considerably over the years, from the 
transition to clear corneal incisions by anterior segment surgeons to the adoption of small-gauge 
minimally invasive pars plana vitrectomies by vitreoretinal specialists. Despite such technical advances, 
however, surgical manipulation of anterior segment structures triggers the release of arachidonic acid 
from cell membranes, leading to the production of prostaglandins and leukotrienes. These inflammatory 
mediators, in turn, lead to cellular reaction and protein leakage. Untreated inflammation can lead to 
complications such as pain/discomfort, photophobia, corneal edema, synechiae, glaucoma, and cystoid 
macular edema.
 
 
In the immediate postoperative period, topical corticosteroids are employed to suppress the production 
of inflammatory mediators. By inhibiting the release of arachidonic acid from cell membrane 
phospholipids, corticosteroids prevent the formation of both leukotrienes and prostaglandins, disrupting 
the inflammatory cascade
 These agents are continued until the anterior chamber (AC) reaction has 
resolved and the blood–aqueous barrier has been reestablished.  
 
In June 2008, difluprednate ophthalmic emulsion 0.05% (Durezol™; Sirion Therapeutics, Tampa, FL) 
was approved by the US Food and Drug Administration (FDA) for the treatment of inflammation and 
pain associated with ocular surgery. 
 
Sun Pharma Advanced Research Company Ltd. (SPARC) has developed a novel topical ophthalmic 
formulation of 
 
 for the treatment of 
inflammation and pain associated with ocular surgery. SPARC intends to develop the ophthalmic 
 product at a 
 dose 
 and with a 
 frequency, 
 
 compared to
 
 
2.1 
Summary of Findings from Nonclinical Studies 
 
Safety and efficacy of Durezol 
 were extensively and 
adequately evaluated in nonclinical studies as described in Prescribing Information and Product 
Monograph  The pharmacology studies in animal models of uveitis demonstrated that 
 
 was effective in a dose-dependent manner. SPARC plans to seek approval of 
 for the same indications as those for Durezol, and thus 
use Durezol as the reference listed drug (RLD). To support development of the novel ophthalmic 
formulation of 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
15 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
2.1.1 
Pharmacology 
 
 
 
 
 
 
 
 
 
 
 
In the 
 model, 
 significantly 
reduced total clinical score, total cell count and total protein levels in aqueous humor compared to the 
disease control. 
 administration of 
 
demonstrated comparable, significant effects on all these measurements, whereas 
 
 only had a significant effect on reducing total clinical 
score, but not on total cell count or total protein levels in aqueous humor. 
In the 
 model, 
 
 treatment demonstrated comparable efficacy as 
 ocular 
instillation. Both treatments significantly reduced total clinical score, total cell count and total protein 
levels in aqueous humor. 
 dosed at a 
dose of 
had 
no significant effect on these measurements as compared to 
. 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
2.1.2 
Pharmacokinetics: 
 
Pharmacokinetic profile of Durezol, 0.05% w/v, is well established by ocular route. The systemic 
absorption of ocular administered difluprednate is very small. During the 7 days ocular instillation studies 
in rabbits of 0.05% 3H-difluprednate, the Cmax in the plasma was not more than 10 ng/g dry weight. 
Difluprednate is rapidly metabolized by deacetylation (at 21- position) in the rabbit eye tissues to the 
metabolite 6 alpha-9-difluoroprednisolone 17- butyrate, active metabolite (DFB), which is in turn 
converted to 17-debutylated DFB , a breakdown product of DFB. Single-dose and multiple-dose studies 
of difluprednate in rabbits demonstrate that difluprednate is rapidly metabolized and distributed to the 
main ocular target tissues that are affected by inflammation (iris, ciliary body, choroids, and aqueous 
humor in the anterior chamber), difluprednate does not accumulate in the blood, and difluprednate seems 
to have a low affinity for melanin, which indicates that difluprednate should work effectively in patients 
regardless of their race and eye color (i.e., differing levels of melanin in the eye, brown eyes having 
higher levels of melanin than blue eyes). Single-dose studies also showed 99.5% of difluprednate and its 
metabolites were cumulatively excreted via the feces and urine, and after repeated doses, difluprednate 
levels increased without affecting the Cmax, with clearance from most ocular tissues within 168 hours
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
2.1.3 
Toxicology 
 
 
 
. The NOAELs in the 
 were 
 
. Neither deaths nor serious toxicological findings were noted in the 
studies. Many changes at higher doses were those generally observed in glucocorticoid (GC) treated 
animals. Ocular 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
administration of
 for up to 
 
 
 
 difluprednate and difluprednate metabolites were 
negative. Reproductive toxicity tests were performed with difluprednate in rats and rabbits. Fetal death 
and malformations such as cleft palate (commonly associated with high-dose administration of GCs) were 
observed during the organogenesis in rabbits. The effects of difluprednate on rat fetuses were weak; fetal 
death and/or malformed fetuses were not found. Long-term studies have not been conducted to evaluate 
the carcinogenic potential of difluprednate. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
18 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
same ratio of dosing frequency of the reference drug and the test drug as in the clinical situation. 
Repeated ocular administration of difluprednate resulted in adverse findings including significant 
alteration in organ weights and histopathological changes in organs like liver and thymus accompanied by 
clinical pathology changes in the study. The systemic NOAEL was not obtained. However, based on 
minimal/less incidence of local effect, the local (ocular) NOAEL was obtained at 
 of 
. No marked drug 
accumulation in systemic exposure was observed following repeated dosing for 30 days. No significant 
difference was observed in the toxicokinetic profiles of 
 
. 
 
 
 
 
2.2 
Summary of the Known and Potential Risks and Benefits to Human Subjects 
 
Difluprednate was approved in US as Durezol® in 2008 in the form of difluprednate ophthalmic emulsion 
0.05%. Difluprednate is used for the treatment of inflammation and pain associated with ocular surgery. 
 
Class warnings for corticosteroids such as difluprednate are well known and state that prolonged use may 
result in glaucoma with damage of optic nerve, defect in visual acuity and field of vision, posterior 
subcapsular cataract formation. It is recommended that if corticosteroids are used for 10 days or longer, 
IOP should be routinely monitored. Prolonged use may also suppress the host response and thus increase 
the hazard of secondary ocular infections. Use of corticosteroids after cataract surgery may delay healing 
and increase the incidence of bleb formation. In diseases causing thinning of the cornea or sclera, 
perforations have been known to occur with the use of topical corticosteroids.  Use of difluprednate is 
also contraindicated in epithelial herpes simplex, and other viral diseases of the cornea and conjunctiva 
and fungal disease of ocular structures. 
 
According to Durezol package insert, ocular adverse reactions occurring in 5-15% of subjects in clinical 
studies with Durezol included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, 
posterior capsule opacification, anterior chamber cells, anterior chamber flare, conjunctival edema, and 
blepharitis. Other ocular adverse reactions occurring in 1-5% of subjects included reduced visual acuity, 
punctate keratitis, eye inflammation, and iritis. Ocular adverse reactions occurring in < 1% of subjects 
included application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye pruritis, 
eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, sclera 
hyperemia, and uveitis
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
19 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
2.3 
Summary of Clinical Data 
 
There have been no specific clinical studies conducted with SPARC’s 
 
 
 
2.4 
Compliance Statement for Study Conduct in Accordance with Protocol, GCP and Applicable 
Regulatory Requirements 
 
The study protocol, amendments to the protocol (if applicable), IB, subject recruitment procedures (e.g. 
advertisements) and the subject’s information and informed consent form and assent forms(as applicable)  
as well as consent  and assent (as applicable) form updates (if applicable) will be submitted to the IRB, 
which is constituted according to local law to obtain approval before initiation of the study and as 
applicable thereafter. 
 
The study will only be initiated after receipt of the approval from the IRB. The investigator will report 
promptly to the IRB new information that may adversely affect the safety of the subjects or the conduct of 
the study. 
 
The investigator will carry out the protocol in conformity with Good Clinical Practice (GCP) described in 
Guideline E6 of the ICH and applicable regulatory requirements. Before admission into the study, the 
written informed consent form and assent form(as applicable) must be personally signed and dated by the 
subject and /or guardian and by the investigator or designee who conducted the informed consent 
discussion. 
 
In obtaining and documenting informed consent and assent (as applicable) the investigator must comply 
with the applicable regulatory requirement(s), and must adhere to GCP. The investigator must inform the 
subject of all pertinent aspects of the study including the written information approved/favorably 
assessed by the IRB. 
 
3.0 STUDY OBJECTIVES 
 
To evaluate the efficacy and safety of topical administration of 
 
compared with 
 dose in the 
surgery followed by 
. 
 
4.0 OVERALL STUDY DESIGN 
 
This study is a phase 3, randomized, multicenter, double-masked, vehicle-controlled, parallel-group 
clinical study. Subjects   of all ages  scheduled to undergo uncomplicated unilateral cataract surgery and 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
who meet all study entry criteria will be enrolled. 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
Prior to enrollment, the study will be discussed with prospective subjects and/or  
LAR/parent/gaurdian  and those who are willing to enter the study will be asked to give written 
informed consent. 
 
Once informed consent and assent (as applicable)  has been obtained, the subjects and/or 
LAR/parent/gaurdian  will be questioned regarding their medical history to determine whether or not they 
are in satisfactory health to enter the study and to determine if they meet the specific entry criteria. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Measures taken to avoid bias 
 
4.1.1 
Subject number 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
4.1.2 
 
 
 
 
 
4.1.3 
 
 
 
 
 
 
. 
 
 
 
 
4.2.1 
Inclusion Criteria 
 
Inclusion criteria during the screening visit are: 
 
1. 
Be male or female, of all ages  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 
Able to self-instill the IP or have a caregiver available to instill all doses of the IP, as instructed. 
6. 
Females of childbearing potential must not be pregnant (as confirmed by a negative urine pregnancy 
test 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
7. Be able and willing to follow study instructions and complete all required visits. 
 
 
4.2.2 
Exclusion Criteria 
 
1. 
Any known allergy or hypersensitivity to difluprednate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 
An acute ocular infection (bacterial, viral or fungal) or active ocular inflammation in the study 
eye. 
 
 
 
 
 
 
 
 
 
11. 
Any active corneal pathology noted in the study eye. 
 
 
 
 
 
14. 
Currently suffering from alcohol and/or drug abuse. 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
     
 
 to exclude subject based on clinical 
judgment, even if other eligibility criteria are    satisfied. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
4.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.0 STUDY PARAMETERS 
 
5.1 
Efficacy Measures 
 
5.1.1 
Primary Efficacy Variable(s) 
 
The primary efficacy endpoint is the proportion of subjects with an anterior chamber cell (ACC) grade of 
0 at Day 15
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
5.1.2 
Secondary Efficacy Variable(s) 
 
The key secondary efficacy endpoints are the proportion of subjects who achieve a pain score of 0 
 
 at day 15( 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0 STUDY MATERIALS 
 
6.1 
Study Treatment(s) 
 
6.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
27 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.3 
Study medication labeling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
28 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
  
 
 
  
                           
 
 
 
6.1.4 
 
 
The IP is to only be prescribed by the principal investigator or his/her delegated sub investigator(s), and is 
to only be used in accordance with this protocol. The IP must only be distributed to subjects properly 
qualified under this protocol to receive IP. 
 
The investigator must keep an accurate accounting of the IP received from the supplier. IP accountability 
includes the amount of IP dispensed to the subjects, amount of IP returned by the subjects, and the 
amount returned or disposed upon the completion of the study. 
 
6.1.5 
Return or Disposal of Investigational Product 
 
All used study drugs will be returned to the sponsor or their designee or destroyed at the study site. The 
return or disposal of study drug will be specified in writing. 
 
7.0 STUDY METHODS AND PROCEDURES 
 
7.1 
Subject Entry Procedures 
 
7.1.1 
Overview 
 
Subjects as defined by the criteria in
, will be considered for entry into this study. 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
29 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
7.1.2 
Informed Consent and Assent (as applicable) 
 
Prior to a subject’s participation in the study (i.e, changes in a subject’s medical treatment and/or study 
specific procedures), the study will be discussed with the subject and/or LARparent/guardian. Subjects 
wishing to participate the study must give written informed consent and assent form (as applicable) using 
an informed consent form (ICF) and assent form(as applicable) The ICF form and the assent form must be 
the most recent version that has received approval/favorable review by a properly constituted Institutional 
Review Board. 
 
7.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
31 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
32 
 
CLR_16_31 
 
Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
33 
 
CLR_16_31 
 
Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3.1.7 
Unscheduled Visits 
 
Additional exams may be scheduled as necessary to ensure the safety and well-being of subjects who 
experience adverse effects during the course of the study. Any additional examinations during the study 
will be fully documented in the source documents and on Unscheduled Visit eCRFs. 
 
7.4 
Compliance with Protocol 
 
Site personal shall contact subjects/ caregivers at least once between the visits during the treatment period 
via phone or email and remind them to instill IP and to complete the pain and dosing diary. A call log has 
to be completed by study personnel after the call. 
 
The specifications of the log will include 
 
1. Date & Time of call 
 
2. Site Staff able to make contact (Y/N) 
 
3. If Yes, Point of Contact 
 
4. A very short description of call 
 
Subjects who are inappropriately enrolled will be discontinued from the study. The reason for such 
discontinuation will be recorded as “protocol violation” in the source document and on the appropriate 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
35 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
page in the eCRF. Notification of such protocol violations will be sent to IRB. Subjects will be provided 
with a pain and dosing diary to document their assigned dosing regimen. Subject compliance with dosing 
will be assured by in-office review of the pain and dosing diary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.5 
Study Duration 
 
 
 
 
  
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
7.6 
Monitoring and Quality Assurance 
 
During the course of the study CRO monitor, or designee, will make routine site visits to review protocol 
compliance, assess study drug accountability, and ensure the study is being conducted according to the 
pertinent regulatory requirements. The review of the subjects’ medical records will be performed in a 
manner that adequately maintains subject confidentiality. Further details of the study monitoring will be 
outlined in a monitoring plan. 
 
Regulatory authorities of domestic and foreign agencies, quality assurance and or its designees may carry 
out on-site inspections and/or audits which may include source data checks.  Therefore direct access to 
the original source data will be required for inspections and/or audits. All inspections and audits will be 
carried out giving consideration to data protection as well as subject confidentiality to the extent that 
local, state, and federal laws apply. 
 
8.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.1 
Definitions 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
37 
 
CLR_16_31 
 
Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
38 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship to study drug, to be 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
39 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
TERM 
DEFINITION 
CLARIFICATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
40 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
Assessment of Expectedness 
 
The most recent version of IB for 
 will be used for assessing 
expectedness of SAE for the subjects who have received 
 
 
Definition of the adverse event reporting period 
 
The AE/ SAE reporting period for safety surveillance begins when the subject sign’s ICF and/or assent 
form continues till end of study visit or early termination visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
41 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3 
Procedures for Reporting Serious Adverse Events (SAE) and Suspected Unexpected Serious 
Adverse Reaction (SUSAR) 
Serious Adverse Events 
 
All SAEs must be reported according to ICH GCP or local regulations, applying the regulation with the 
stricter requirements. The report will contain as much available information concerning the SAE to enable 
the Sponsor’s safety physician/ CRO to file a report, which satisfies regulatory reporting requirements. 
The SAE report will be notified by Investigator within 24-hours of his/ her awareness to the Sponsor’s 
safety physician/CRO. These timelines apply to initial reports of SAEs and to all follow-up reports. 
 
All AEs/SAEs will be recorded on the AE Report Form and SAE report form in the eCRF 
and source documents. 
The following minimum information must be included in the SAE form: 
• 
Name, address and telephone number of the reporting Investigator 
• 
IP details 
• 
Subject identification number, initials, sex and date of birth 
• 
Description of the SAE, measures taken and outcome 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
42 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
In the case of fatal or life-threatening events, please also immediately telephone the Sponsor’s safety 
physician/CRO. 
 
Additional follow-up information should be completed on an SAE follow-up form with a copy sent to the 
Sponsor’s safety physician/CRO. 
 
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone. In these 
cases, a written report must be sent immediately thereafter by e-mail to the Sponsor’s safety 
physician/CRO. 
 
Relevant pages from the eCRF may be provided in parallel (e.g., medical history, concomitant drugs). 
Additional documents may be provided by the Investigator, if available (e.g., laboratory results, hospital 
report, autopsy report). In all cases, the information provided on the SAE Report Form must be consistent 
with the data about the event recorded in the eCRF. 
 
The Investigator must respond to any request for follow-up information (e.g., additional information, 
outcome, final evaluation, other records where needed) or to any question the Sponsor’s safety 
physician/CRO may have on the AE. This is necessary to ensure prompt assessment of the event by the 
Sponsor’s safety physician to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations. 
 
Requests for follow-up will usually be made via the responsible Sponsor’s safety physician/CRO. 
 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs): 
 
The applicable Regulatory Authorities shall be initially notified by Sponsor Safety Physician/ CRO of any 
SUSAR, no later than 15 calendar days from the “date learned” of the event. The applicable Regulatory 
Authorities will be initially notified as per regulation within 7 calendar days of any fatal or life- 
threatening SUSAR. If the safety report submitted within 7 calendar days is complete, an additional 
submission within 15 days from day 0 is not required. 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.5 
Follow-Up 
 
The Investigator should take all appropriate measures to ensure the safety of the subjects, including 
referral to a specialist if indicated. The Investigator should follow up on the outcome of any AE till end of 
study visit/ early termination visit. All SAEs will be followed until the event has resolved or stabilized as 
per medical judgement of the investigator. 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
44 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
Any AE/ SAE brought to the attention of the Investigator post end of study visit/ early termination visit 
requires notification to Sponsor and other stakeholders if it is considered related to study drug. 
 
Any AE unresolved at the time of end of study/ early termination visit requires detailed evaluation and 
will be followed for outcome as per medical judgment of the investigator. 
 
8.6 
PREGNANCY 
 
A pregnancy test will be performed at screening and at visits specified in the protocol. Females of 
childbearing potential must not be pregnant or lactating (as confirmed by a negative urine pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.0 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 
 
 
 
9.1.1 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the proportion of subjects with an ACC grade of 0 at Day 15 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
45 
 
CLR_16_31 
 
Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.2 
Key Secondary Efficacy Endpoint 
 
The key secondary efficacy endpoint is the proportion of subjects who achieve a pain score of 0 
 
 at Day 15 
 
 
 
9.1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.4 
Analysis Populations 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
46 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.5 
Baseline Variables 
 
Age in years ( 7  to < 65, ≥ 65) 
 
• 
Sex (male, female) 
 
• 
Ethnicity (hispanic, nonhispanic) 
 
• 
Race (white, black, other) 
 
9.2 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
47 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
49 
 
CLR_16_31 
 
Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
9.3 
Methods of Analysis 
 
9.3.1 
General Approach 
 
The final analysis will be conducted when all subjects have either completed the 
 visit or 
have otherwise 
. At that time, the database will be cleaned, processed, and 
locked. At this stage the study will be unblinded. Efficacy and safety endpoints will be analyzed based on 
this locked database. 
 
Summary statistics for categorical variables will include frequency and percentage. For continuous 
variables, number of subjects with non-missing value (n), mean, median, standard deviation (SD), 
minimum (min), and maximum (max) will be reported. 
 
Subject disposition, demographics and baseline characteristics will be summarized.
 
 
 
 
 
 
 
 
   
 
 
 
 
 
All summaries and analyses will be presented by treatment group. 
 
Any deviations from the original statistical plan will be described in the final report. 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
9.3.2 
Efficacy Analysis 
 
9.3.2.1 
Analysis of Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the proportion of subjects with an ACC grade of 0 at Day 15. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
51 
 
CLR_16_31 
 
Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 model. 
 
 
 
 
 
9.3.3 
 
 
 
 
 
 
 
 
 
9.3.3.1.1 
 
 
 
 
 
 
 
. 
 
 
 
9.3.3.1.2 Incidence of TEAEs 
 
A summary of TEAEs will be presented by SOC and PT by treatment group. If a subject reports the same 
PT multiple times, then 
 As with the PT, if a subject 
reports multiple AEs within the same SOC, 
 
 
 
9.3.3.1.3 Severity of TEAEs 
A summary of TEAEs by SOC, PT, and severity will be presented by treatment group. Severity will be 
graded by the investigator as “Mild,” “Moderate,” or “Severe.”
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
52 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
9.3.3.1.4 Relationship of Treatment-Emergent Adverse Events to the IP 
 
A summary of TEAEs by SOC, PT, and relationship to the IP will be presented by treatment group. The 
relationships indicate the investigator’s assessment of whether or not the event was caused by the IP. The 
possible relationships are “Not Related,” “Possibly Related,” and “Related.” 
 
 
 
 
 
 
 
 
9.3.3.1.5 Serious Adverse Events 
 
Serious adverse events (SAEs) will be listed by subject; SAEs will be summarized by event and treatment 
group. 
 
9.3.3.1.6 Adverse Events Leading to Study Drug Withdrawal 
 
All AEs leading to study withdrawal or study drug withdrawal will be listed and may be summarized if 
appropriate. 
 
9.3.3.2 
 
 
 
 
 
 
 
 
 
 
 
9.3.3.2.2 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
53 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
54 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
9.3.3.2.3 
 
 
 
 
 
 
 
 
 
9.3.3.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.4 
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
55 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
56 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.0 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL CONSIDERATIONS AND 
ADMINISTRATIVE ISSUES 
 
This study will be conducted in compliance with the protocol, current Good Clinical Practices, including 
the International Conference on Harmonization (ICH) Guidelines, and in general, consistent with the 
Declaration of Helsinki. In addition, all applicable local, state, and federal requirements relevant to the 
use of IPs in the countries involved will be adhered to. 
 
10.1 Protection of Human Subjects 
 
10.1.1 Subject Informed Consent and Assent(as applicable) 
 
Informed consent and assent (as applicable) must take place before any study specific procedures are 
initiated. Signed and dated written informed consent and assent(as applicable) must be obtained from each 
subject prior to enrollment into the study. 
 
All informed consent forms and assent forms(as applicable)  must be approved for use by the sponsor 
and receive approval/favorable opinion from an IRB/IEC prior to their use.  If the consent form and 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
assent form requires revision (eg, due to a protocol 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
amendment or significant new safety information), it is the investigator’s responsibility to ensure that the 
amended informed consent form and assent form(as applicable) is reviewed and approved by CRO prior 
to submission to the governing IRB/IEC and that it is read, signed and dated by all subjects subsequently 
enrolled in the study as well as those currently enrolled in the study. 
 
If informed consent and assent (as applicable) is taken under special circumstances (oral informed 
consent), then the procedures to be followed must be determined by CRO and/or study sponsor and 
provided in writing by CRO and/or study sponsor prior to the consent process. 
 
10.1.2 Institutional Review Board Approval 
 
This study is to be conducted in accordance with Institutional Review Board regulations. 
 
 
 
Only current IRB/ERC approved version of the ICF/Assent form will be used. 
 
10.2 Ethical Conduct of the Study 
 
This study will be conducted in accordance with the ethical principles that originated with the Declaration 
of Helsinki. 
 
10.3 Subject Confidentiality 
 
All personal study subject data collected and processed for the purposes of this study should be 
maintained by the investigator and his/her staff with adequate precautions as to ensure that the 
confidentiality of the data in accordance with local, state, and federal laws and regulations. 
 
Monitors, auditors and other authorized representatives of CRO, the sponsor, the IRB/IEC approving this 
study, the Food and Drug Administration (FDA), the Department of Health and Human Services, other 
domestic government agencies, and other foreign regulatory agencies will be granted direct access to the 
study subject’s original medical and study records for verification of the data and/or clinical trial 
procedures. Access to this information will be permitted to the aforementioned individuals to the extent 
permitted by law. 
 
A report of the results of this study may be published or sent to the appropriate health authorities in any 
country in which the IP may ultimately be marketed, but the subject’s identity will not be disclosed in 
these documents. 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
59 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
10.4 Documentation 
 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
investigator’s study subject files, as well as the results of diagnostic tests performed. The investigator’s 
copy of the electronic case report forms (eCRFs) serves as the investigator’s record of a subject’s study- 
related data. 
 
10.4.1 Retention of Documentation 
 
All study related correspondence, subject records, consent forms, record of the distribution and use of all 
IPs and copies of eCRFs should be maintained on file for at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region; or until at least two years have elapsed since the formal discontinuation of 
clinical development of the IP. These documents will be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained. 
 
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping study records, custody must be transferred to a person who will accept the responsibility. The 
sponsor must be notified in writing of the name and address of the new custodian. 
 
10.5 Recording of Data on Source Documents and Electronic Case Reports Forms (eCRFs) 
 
The investigator is responsible for ensuring that study data is completely and accurately recorded on each 
subject’s eCRF, source document, and all study-related material. All study data should also be 
attributable, legible, contemporaneous, and original. Prior to the start of the study a signature and 
delegation list will be completed showing the signatures and hand written initials of all who are 
authorized to entry data or make corrections in the documents. Recorded datum should only be corrected 
in a manner that does not obliterate, destroy, or render illegible the previous entry (eg, by drawing a 
single line through the incorrect entry and writing the revision next to the corrected data). An individual 
who has corrected a data entry should make clear who made the correction when and why along with 
justification, by adding to the correction his/her initials as well as the date of the correction. 
 
10.6 Handling of Biological Specimens 
 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
60 
 
CLR_16_31 
 
Version 01 /Amendment 02 
,02 Jul  2019 
 
 
 
 
10.7 Publications 
 
Authorship and manuscript composition will reflect cooperation among all parties involved in the study. 
Authorship will be established before writing the manuscript. The study sponsor will have the final 
decision regarding the manuscript and publication. 
 
 
 
11.0 REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Aug 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Aug 2019 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Aug 2019 
 
 
 
 
 
 
12.2 Examination Procedures, Tests, Equipment, and Techniques 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Tests (If Applicable) 
 
Standard dipstick-based urine pregnancy tests will be administered to subjects that are of child bearing 
potential to assess pregnancy status as outlined in the 
. Child bearing potential is 
defined as any female who has had her first menses, not had a hysterectomy or bilateral tubal ligation, and 
has not been post-menopausal for at least 12 consecutive months. Pregnancy is not to be considered an 
AE, but it is an important medical event that must be followed up as described in 
 
 
Blood Pressure (mmHg) 
 
Systolic and diastolic blood pressure should be measured in the same arm each time using a 
sphygmomanometer with the subjects who have been in a resting state (seated upright) at least 5 minutes. 
Blood pressure will be recorded in mm Hg. 
 
 
 
 must be assessed using an 
 
 chart and as indicated in the study flowchart in 
 The procedure used will be 
consistent with the recommendations provided for using the 
. 
 should be 
evaluated at the 
 in the study (ie, 
). 
 
testing should be done with 
 correction. 
 
A 
 will be considered 
 significant, 
and may indicate an 
 


Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
64 
 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Aug 2019 
 
 
 
 
 
Equipment 
 
 If smaller reproduction 
 eg, from 
Prevent Blindness) wall charts are used, the subject viewing distance should be 
 (or as 
specified by the manufacturer). In ALL cases, for purposes of standardizing the testing conditions during 
the study, all sites must use only the 'R' charts, and the right eye should be tested first. For reflectance 
(wall) charts, the chart should be placed frontally and well-illuminated. 
 
 
 
The chart should be at a comfortable viewing angle. The right eye should be tested first. The subject 
should attempt to read each letter, line-by-line, left to right, beginning with line 1 at the top of the chart. 
The subject should be told that the chart has letters only, no numbers. If the subject reads a number, he or 
she should be reminded that the chart contains no numbers, and the examiner should then request a letter 
in lieu of the number. The subject should be asked to read slowly, so as to achieve the best identification 
of each letter. He/she is not to proceed to the next letter until he/she has given a definite response. 
 
If the subject changes a response (eg, 'that was a "C" not an "O"') before he has read aloud the next letter, 
then the change must be accepted. If the subject changes a response having read the next letter, then the 
change is not to be accepted. The examiner should never point to the chart or to specific letters on the 
chart during the test. 
 
A maximum effort should be made to identify each letter on the chart. When the subject says he or she 
cannot read a letter, he or she should be encouraged to guess. If the subject identifies a letter as one of two 
letters, he or she should be asked to choose one letter and, if necessary, to guess. When it becomes 
evident that no further meaningful readings can be made, despite encouragement to read or guess, the 
examiner should stop the test for that eye. However, all letters on the last line should be attempted as 
letter difficulties vary and the last may be the only one read correctly. The number of letters missed or 
read incorrectly should be noted. 
 
 
 
 
 
. 


 
CLR_16_31 
 
 Version 01 /Amendment 02 
,02 Aug 2019 
Company Ltd. 
 
 
 
 
 
 
 
 
 
 
For Example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 line. 
 
 
 
 
 
 
 
 
 
 
 
 
In order to provide standardized and well-controlled assessments of visual acuity during the study, all 
visual acuity assessments at a single site must be consistently done using the same lighting conditions and 
same correction if possible during the entire study. If the same correction cannot be used (ie, a subject 
forgets his glasses), the reason for the change in correction should be documented. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sun Pharma Advanced Research 
Confidential 
60 


Company Ltd. 
 
CLR_16_31 
 
 Version 01 /Amendment 01 
5 Dec 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The investigator or study staff will also be asked to record the time these 2 measurements were obtained. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sun Pharma Adva 
61 


 
CLR_16_31 
 
Version 01 /Amendment 01 
5 Dec 2018 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
62 
 
 
 
 
 
 
 
 
 
In addition to the 
, subjects will be asked to assess their pain via a diary at home 
 to each dose, 
and for 
 after the 
dose, until the 
 
 
For this the following pain assessment criteria where 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
In addition to the above, dosing information shall be completed by the patient/caregiver in the pain ans 
dosing diary along with any information related to the adverse events noted. Detailed diary completion 
instructions will be provided to all subjects. If necessary, a caregiver may transcribe the subject’s pain 
assessment on to the diary for subjects who are unable to write. In this case, study staff must review the 
diary with the subject and ensure the subject agrees with the recorded Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLR_16_31 
 
 Version 01 /Amendment 01 
5 Dec 2018 
Sun Pharma Advanced Research 
Company Ltd. 
Confidential 
63 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 
02,02 Aug 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.3 Protocol Amendment Summary  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 
02,02 Aug 2019 
 
 
 
 
 
12.4 Investigator’s Signature 
 
Protocol Title: 
A Randomized, Double-Masked, Parallel Group, Multicenter, Study 
To Evaluate Efficacy And Safety of SPARC’s SDN -037 Twice 
Daily Compared With Vehicle For The Treatment Of Inflammation 
And Pain Associated With Ocular Surgery. 
Protocol Number: 
CLR_16_31 
Version No. Date 
01  
Amendment No. Date 
 02, 02 Aug 2019 
 
 
 
 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, good 
clinical practices and all applicable laws and regulations. I agree to maintain all information supplied by 
CRO and the sponsor in confidence and, when this information is submitted to an Institutional Review 
Board (IRB), Ethical Review Committee (ERC) or another group, it will be submitted with a designation 
that the material is confidential. 
 
I have read this protocol in its entirety, including the above statement, and I agree to all aspects. 
 
 
 


 
 
 
 
 
CLR_16_31 
 
 Version 01 /Amendment 
02,02 Aug 2019 
 
 
 
 
 


 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
 
 
 
Initial U.S. Approval: 2008 
 
----------------------------INDICATIONS AND USAGE-------------------------- 
DUREZOL® is a topical corticosteroid that is indicated for: 
• The treatment of inflammation and pain associated with ocular surgery 
(1.1) 
• The treatment of endogenous anterior uveitis (1.2) 
 
----------------------DOSAGE AND ADMINISTRATION------------------------ 
• For the treatment of inflammation and pain associated with ocular surgery 
instill one drop into the conjunctival sac of the affected eye 4 times daily 
beginning 24 hours after surgery and continuing throughout the first 2 
weeks of the postoperative period, followed by 2 times daily for a week 
and then a taper based on the response. (2.1) 
• For the treatment of endogenous anterior uveitis, instill one drop into the 
conjunctival sac of the affected eye 4 times daily for 14 days followed by 
tapering as clinically indicated. (2.2) 
 
---------------------DOSAGE FORMS AND STRENGTHS--------------------- 
DUREZOL contains 0.05% difluprednate, as a sterile preserved ophthalmic 
emulsion for topical ophthalmic use only. (3) 
 
-------------------------------CONTRAINDICATIONS----------------------------- 
DUREZOL, as with other ophthalmic corticosteroids, is contraindicated in 
most active viral diseases of the cornea and conjunctiva including epithelial 
herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also 
in mycobacterial infection of the eye and fungal diseases of ocular structures. 
(4) 
 
-----------------------WARNINGS AND PRECAUTIONS----------------------- 
• Intraocular pressure (IOP) increase: Prolonged use of corticosteroids 
may result in glaucoma with damage to the optic nerve, defects in visual 
acuity and fields of vision. If this product is used for 10 days or longer, IOP 
should be monitored. (5.1) 
• Cataracts: Use of corticosteroids may result in posterior subcapsular 
cataract formation. (5.2) 
• Delayed healing: The use of steroids after cataract surgery may delay 
healing and increase the incidence of bleb formation. In those diseases 
causing thinning of the cornea or sclera, perforations have been known to 
occur with the use of topical steroids. The initial prescription and renewal 
of the medication order beyond 28 days should be made by a physician 
only after examination of the patient with the aid of magnification such as 
slit lamp biomicroscopy and, where appropriate, fluorescein staining. (5.3) 
• Bacterial infections: Prolonged use of corticosteroids may suppress the 
host response and thus increase the hazard of secondary ocular infections. 
In acute purulent conditions, steroids may mask infection or enhance 
existing infection. If signs and symptoms fail to improve after 2 days, the 
patient should be reevaluated. (5.4) 
• Viral infections: Employment of a corticosteroid medication in the 
treatment of patients with a history of herpes simplex requires great 
caution. Use of ocular steroids may prolong the course and may exacerbate 
the severity of many viral infections of the eye (including herpes simplex). 
(5.5) 
• Fungal infections: Fungal infections of the cornea are particularly prone to 
develop coincidentally with long-term local steroid application. Fungus 
invasion must be considered in any persistent corneal ulceration where a 
steroid has been used or is in use. (5.6) 
 
-----------------------------------ADVERSE REACTIONS-------------------------- 
To report SUSPECTED ADVERSE REACTIONS, contact Alcon 
Laboratories, Inc. at 1-800-757-9195 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch. 
See 17 for PATIENT COUNSELING INFORMATION. 
Revised: 4/2017 
 
 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
1.1 
Ocular Surgery 
1.2 
Endogenous Anterior Uveitis 
2 
DOSAGE AND ADMINISTRATION 
2.1 
Ocular Surgery 
2.2 
Endogenous Anterior Uveitis 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Intraocular pressure (IOP) Increase 
5.2 
Cataracts 
5.3 
Delayed Healing 
5.4 
Bacterial Infections 
5.5 
Viral Infections 
5.6 
Fungal Infections 
5.7 
Topical Ophthalmic Use Only 
5.8 
Contact Lens Wear 
6 
ADVERSE REACTIONS 
6.1 
Ocular Surgery 
6.2 
Endogenous Anterior Uveitis 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy Teratogenic Effects 
8.3 
Nursing Mothers 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
12.3 
Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, and Impairment of Fertility 
13.2 
Animal Toxicology and/or Pharmacology 
14 
CLINICAL STUDIES 
14.1 
Ocular Surgery 
14.2 
Endogenous Anterior Uveitis 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
 
*Sections or subsections omitted from the full prescribing information are not 
listed. 
 
 
 


 
FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
1.1 
Ocular Surgery 
DUREZOL® (difluprednate ophthalmic emulsion) 0.05%, a topical corticosteroid, is indicated for the treatment of 
inflammation and pain associated with ocular surgery. 
1.2 
Endogenous Anterior Uveitis 
DUREZOL is also indicated for the treatment of endogenous anterior uveitis. 
 
2 
DOSAGE AND ADMINISTRATION 
2.1 
Ocular Surgery 
Instill one drop into the conjunctival sac of the affected eye 4 times daily beginning 24 hours after surgery and continuing 
throughout the first 2 weeks of the postoperative period, followed by 2 times daily for a week and then a taper based on 
the response. 
2.2 
Endogenous Anterior Uveitis 
Instill one drop into the conjunctival sac of the affected eye 4 times daily for 14 days followed by tapering as clinically 
indicated. 
 
3 
DOSAGE FORMS AND STRENGTHS 
DUREZOL contains 0.05% difluprednate as a sterile preserved emulsion for topical ophthalmic administration. 
 
4 
CONTRAINDICATIONS 
The use of DUREZOL, as with other ophthalmic corticosteroids, is contraindicated in most active viral diseases of the 
cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also 
in mycobacterial infection of the eye and fungal disease of ocular structures. 
 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Intraocular pressure (IOP) Increase 
Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields 
of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, 
IOP should be monitored. 
5.2 
Cataracts 
Use of corticosteroids may result in posterior subcapsular cataract formation. 
5.3 
Delayed Healing 
The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those 
diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. 
The initial prescription and renewal of the medication order beyond 28 days should be made by a physician only after 
examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, 
fluorescein staining. 
5.4 
Bacterial Infections 
Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular 
infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms 
fail to improve after 2 days, the patient should be reevaluated. 
5.5 
Viral Infections 
Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great 
caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye 
(including herpes simplex). 


 
5.6 
Fungal Infections 
Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. 
Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal 
culture should be taken when appropriate. 
5.7 
Topical Ophthalmic Use Only 
DUREZOL is not indicated for intraocular administration. 
5.8 
Contact Lens Wear 
DUREZOL should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of 
DUREZOL. The preservative in DUREZOL may be absorbed by soft contact lenses. Lenses may be reinserted after 10 
minutes following administration of DUREZOL. 
 
6 
ADVERSE REACTIONS 
The following serious reactions are found elsewhere in the labeling: 
• 
Elevated IOP [see Warnings and Precautions (5.1)] 
• 
Posterior subcapsular cataract formation [see Warnings and Precautions (5.2)] 
• 
Secondary ocular infection [see Warnings and Precautions (5.4)] 
• 
Perforation of the globe [see Warnings and Precautions (5.3)] 
6.1 
Ocular Surgery 
Ocular adverse reactions occurring in 5% to 15% of subjects in clinical studies with DUREZOL included corneal edema, 
ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber cells, anterior 
chamber flare, conjunctival edema, and blepharitis. Other ocular adverse reactions occurring in 1% to 5% of subjects 
included reduced visual acuity, punctate keratitis, eye inflammation, and iritis. Ocular adverse reactions occurring in less 
than 1% of subjects included application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye 
pruritis, eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, sclera hyperemia, 
and uveitis. Most of these reactions may have been the consequence of the surgical procedure. 
6.2 
Endogenous Anterior Uveitis 
A total of 200 subjects participated in the clinical trials for endogenous anterior uveitis, of which 106 were exposed to 
DUREZOL. The most common adverse reactions of those exposed to DUREZOL occurring in 5% to 10% of subjects 
included blurred vision, eye irritation, eye pain, headache, increased IOP, iritis, limbal and conjunctival hyperemia, 
punctate keratitis, and uveitis. Adverse reactions occurring in 2% to 5% of subjects included anterior chamber flare, 
corneal edema, dry eye, iridocyclitis, photophobia, and reduced visual acuity. 
 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy Teratogenic Effects 
Pregnancy Category C 
Difluprednate has been shown to be embryotoxic (decrease in embryonic body weight and a delay in embryonic 
ossification) and teratogenic (cleft palate and skeletal anomalies) when administered subcutaneously to rabbits during 
organogenesis at a dose of 1-10 mcg/kg/day. The no-observed-effect-level (NOEL) for these effects was 1 mcg/kg/day, 
and 10 mcg/kg/day was considered to be a teratogenic dose that was concurrently found in the toxic dose range for fetuses 
and pregnant females. Treatment of rats with 10 mcg/kg/day subcutaneously during organogenesis did not result in any 
reproductive toxicity, nor was it maternally toxic. At 100 mcg/kg/day after subcutaneous administration in rats, there was 
a decrease in fetal weights and delay in ossification, and effects on weight gain in the pregnant females. It is difficult to 
extrapolate these doses of difluprednate to maximum daily human doses of DUREZOL, since DUREZOL is administered 
topically with minimal systemic absorption, and difluprednate blood levels were not measured in the reproductive animal 
studies. However, since use of difluprednate during human pregnancy has not been evaluated and cannot rule out the 
possibility of harm, DUREZOL should be used during pregnancy only if the potential benefit justifies the potential risk to 
the embryo or fetus. 


 
8.3 
Nursing Mothers 
It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption 
to produce detectable quantities in breast milk. Systemically administered corticosteroids appear in human milk and could 
suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be 
exercised when DUREZOL is administered to a nursing woman. 
8.4 
Pediatric Use 
DUREZOL was evaluated in a 3-month, multicenter, double-masked trial in 79 pediatric patients (39 DUREZOL; 40 
prednisolone acetate) 0 to 3 years of age for the treatment of inflammation following cataract surgery. A similar safety 
profile was observed in pediatric patients comparing DUREZOL to prednisolone acetate ophthalmic suspension, 1%. 
8.5 
Geriatric Use 
No overall differences in safety or effectiveness have been observed between elderly and younger patients. 
 
11 
DESCRIPTION 
DUREZOL (difluprednate ophthalmic emulsion) 0.05% is a sterile, topical anti-inflammatory corticosteroid for 
ophthalmic use. The chemical name is 6α,9difluoro-11β,17,21-trihydroxypregna-1,4- diene-3,20-dione 21-acetate 17- 
butyrate (CAS number 23674-86-4). Difluprednate is represented by the following structural formula: 
Difluprednate has a molecular weight of 508.56, and the empirical formula is C27H34F2O7. 
Each mL of DUREZOL contains: ACTIVE: difluprednate 0.5 mg (0.05%); INACTIVE: boric acid, castor oil, glycerin, 
polysorbate 80, water for injection, sodium acetate, edetate disodium, sodium hydroxide (to adjust the pH to 5.2 to 5.8). 
The emulsion is essentially isotonic with a tonicity of 304 to 411 mOsm/kg. PRESERVATIVE: sorbic acid 0.1%. 
 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
Corticosteroids inhibit the inflammatory response to a variety of inciting agents and may delay or slow healing. They 
inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, 
deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for 
the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of 
phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the 
biosynthesis of potent mediators of inflammation such as prostaglandins and leukotreines by inhibiting the release of their 
common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. 
Difluprednate is structurally similar to other corticosteroids. 
12.4.1 12.3 Pharmacokinetics 
Difluprednate undergoes deacetylation in vivo to 6α, 9-difluoroprednisolone 17-butyrate (DFB), an active metabolite of 
difluprednate. 
Clinical pharmacokinetic studies of difluprednate after repeat ocular instillation of 2 drops of difluprednate (0.01% or 
0.05%) four times per day for 7 days showed that DFB levels in blood were below the quantification limit (50 ng/mL) at 


 
all time points for all subjects, indicating the systemic absorption of difluprednate after ocular instillation of DUREZOL is 
limited. 
 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, and Impairment of Fertility 
Difluprednate was not genotoxic in vitro in the Ames test, and in cultured mammalian cells CHL/IU (a fibroblastic cell 
line derived from the lungs of newborn female Chinese hamsters). An in vivo micronucleus test of difluprednate in mice 
was also negative. Treatment of male and female rats with subcutaneous difluprednate up to 10 mcg/kg/day prior to and 
during mating did not impair fertility in either gender. Long-term studies have not been conducted to evaluate the 
carcinogenic potential of difluprednate. 
13.2 
Animal Toxicology and/or Pharmacology 
In multiple studies performed in rodents and non-rodents, subchronic and chronic toxicity tests of difluprednate showed 
systemic effects such as suppression of body weight gain; a decrease in lymphocyte count; atrophy of the lymphatic 
glands and adrenal gland; and for local effects, thinning of the skin; all of which were due to the pharmacologic action of 
the molecule and are well known glucocorticosteroid effects. Most, if not all of these effects were reversible after drug 
withdrawal. The NOEL for the subchronic and chronic toxicity tests were consistent between species and ranged from 1- 
1.25 mcg/kg/day. 
 
14 
CLINICAL STUDIES 
14.1 
Ocular Surgery 
Clinical efficacy was evaluated in 2 randomized, double-masked, placebo-controlled trials in which subjects with an 
anterior chamber cell grade greater than or equal to "2" (a cell count of 11 or higher) after cataract surgery were assigned 
to DUREZOL or placebo (vehicle) following surgery. One drop of DUREZOL or vehicle was self-instilled either 2 times 
per day or 4 times per day for 14 days, beginning the day after surgery. The presence of complete clearing (a cell count of 
0) was assessed 3, 8 and 15 days post surgery using a slit lamp binocular microscope. In the intent-to-treat analyses of 
both studies, a significant benefit was seen in the 4 times per day DUREZOL-treated group in ocular inflammation, at 
Days 8 and 15, and reduction of pain, at Days 3, 8 and 15, when compared with placebo. The consolidated clinical trial 
results are provided below. 
Figure 1 
Percent of Subjects With Anterior Chamber Cells Clearing (Cell Count = 0) 


 
Figure 2 
Percent of Subjects Who Were Pain Free 
14.2 
Endogenous Anterior Uveitis 
Clinical efficacy was evaluated in two randomized, double masked active controlled trials in which patients who 
presented with endogenous anterior uveitis were treated with either DUREZOL 4 times daily or prednisolone acetate 
ophthalmic suspension, 1%, 8 times daily for 14 days. Both studies demonstrated that DUREZOL was equally effective as 
prednisolone acetate ophthalmic suspension, 1% in treating subjects with endogenous anterior uveitis. The results are 
found in Table 1 below. 
12.4.2 
Table 1: Mean Change from Baseline in Anterior Chamber Cell Grade* 
 
Study 1 time 
point 
DUREZOL 
N=57 
Prednisolone Acetate 
N=53 
Difference† 
(95% CI) 
Baseline 
2.6 
2.5 
0.0  (-0.22, 0.28) 
Day 3 
-1.0 
-1.0 
-0.1  (-0.35, 0.25) 
Day 7 
-1.6 
-1.5 
-0.0  (-0.31, 0.25) 
Day 14 
-2.0 
-1.8 
-0.2  (-0.46, 0.10) 
Day 21 
-2.2 
-1.9 
-0.3  (-0.53, 0.01) 
Day 28 
-2.2 
-2.1 
-0.1  (-0.37, 0.18) 
Day 35 
-2.1 
-2.0 
-0.1  (-0.39, 0.20) 
Day 42 
-2.1 
-2.1 
0.0  (-0.27, 0.34) 
Study 2 time 
point 
DUREZOL 
N=50 
Prednisolone Acetate 
N=40 
Difference† 
(95% CI) 
Baseline 
2.4 
2.4 
0.0  (-0.21, 0.29) 
Day 3 
-0.9 
-0.9 
-0.0  (-0.34, 0.25) 
Day 7 
-1.7 
-1.6 
-0.1  (-0.35, 0.21) 


 
Day 14 
-1.9 
-1.8 
-0.1  (-0.34, 0.20) 
Day 21 
-2.0 
-2.0 
0.0  (-0.25, 0.28) 
Day 28 
-2.0 
-2.0 
0.0  (-0.21, 0.26) 
Day 35 
-2.1 
-2.0 
-0.1  (-0.32, 0.16) 
Day 42 
-2.0 
-1.9 
-0.1  (-0.36, 0.24) 
*with 5 grades: 0 = 0 cells; 1 = 1 to 10 cells; 2 = 11 to 20 cells; 3 = 21 to 50 
cells; and 4 = greater than 50 cells 
†adjusted for baseline AC cell grade and study center and based on ITT dataset with 
LOCF for missing data 
CI = confidence interval 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
DUREZOL (difluprednate ophthalmic emulsion) 0.05% is a sterile, aqueous topical ophthalmic emulsion supplied in an 
opaque plastic bottle with a controlled drop tip and a pink cap in the following sizes: 
5 mL in a 8 mL bottle………………………………………………………………..NDC 0065-9240-07 
12.4.3 Storage and Handling 
Store at 15°C to 25°C (59°F to 77°F). Do not freeze. Protect from light. When not in use, keep the bottles in the protective 
carton. 
 
13.0 PATIENT COUNSELING INFORMATION 
13.1 Risk of Contamination 
This product is sterile when packaged. Advise patients not to allow the dropper tip to touch any surface, as this may 
contaminate the emulsion. 
Use of the same bottle for both eyes is not recommended with topical eye drops that are used in association with surgery. 
13.1.1.1 Risk of Secondary Infection 
If pain develops, or if redness, itching, or inflammation becomes aggravated, advise patients to consult a physician. 
13.1.1.2 Contact Lens Wear 
DUREZOL should not be instilled while wearing contact lenses. Advise patients to remove contact lenses prior to 
instillation of DUREZOL. The preservative in DUREZOL may be absorbed by soft contact lenses. Lenses may be 
reinserted after 10 minutes following administration of DUREZOL. 
 
 
 
 
 
 
 
 





SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 1 of 34 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Double-Masked, Parallel Group, Multicenter, Study to Evaluate Efficacy and 
Safety of SPARC’s SDN-037 Twice Daily Compared with Vehicle for The Treatment of 
Inflammation and Pain Associated with Ocular Surgery. 
 
Protocol No. 
 
: CLR_16_31 
Protocol Version 
: Version 01 Amendment 03 
Protocol Date   
: 22JAN2020  
Plan Version No. 
: 1 
Plan Version Date 
: 17SEP2020 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 2 of 34 
 
SIGNATURE PAGE 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 3 of 34 
 
   
 
 
STATISTICAL ANALYSIS PLAN DETAILS 
 
 
TRIAL FULL TITLE 
A Randomized, Double-Masked, Parallel Group, Multicenter, 
Study to Evaluate Efficacy and Safety of SPARC’s SDN-037 
Twice Daily Compared with Vehicle for The Treatment of 
Inflammation and Pain Associated with Ocular Surgery 
CT IDENTIFIER 
NCT03426267 
SAP VERSION 
1 
SAP VERSION DATE 
17SEP2020 
 
 
TRIAL CHIEF 
INVESTIGATOR 
MULTI-CENTER 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 5 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 6 of 34 
 
2 ABBREVIATIONS AND DEFINITIONS 
 
ACC 
Anterior Chamber Cell 
ACF 
Anterior Chamber Flare 
AE 
Adverse Event 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice a day (bis in die) 
BSCVA 
Best-Spectacle Corrected Visual Acuity 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
eCRF 
electronic Case Report Form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IOL 
Intra Ocular Lens 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
mITT 
Modified Intent-To-Treat 
LAR 
Legally Acceptable Representative 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of 
Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
OPD 
(in-)Office Physician Dispensing 
PP 
Per Protocol 
PT 
Preferred Term 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 7 of 34 
 
SPARC 
Sun Pharma Advanced Research Company, 
Ltd. 
SUSAR 
Suspected Unexpected Serious Adverse 
Reaction 
TEAE 
Treatment-Emergent Adverse Event 
VAS 
Visual Analog Scale 
WHO-DD 
World Health Organization Drug Dictionary 
w/v 
Weight/Volume 
 
3 SUMMARY OF LIST OF CHANGES FROM PROTOCOL 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 8 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 9 of 34 
 
4 INTRODUCTION 
4.1 
Preface 
Sun Pharma Advanced Research Company Ltd. (SPARC) has developed a novel topical ophthalmic 
formulation of difluprednate as a 
 for the treatment of 
inflammation and pain associated with ocular surgery. SPARC intends to develop the ophthalmic 
difluprednate product at a 
 dose 
 and with a 
, 
 
 
4.2 
Purpose of the analyses 
These analyses will assess the efficacy and safety of topical administration of 
 
 
 
5 STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Study Objectives 
To evaluate the efficacy and safety of topical administration of 
 
 dose 
after surgery followed by 
.  
5.2 
Endpoints 
Efficacy: 
• The primary efficacy endpoint is the proportion of subjects with an ACC grade of 0 at Day 15 
 
  
• The key secondary efficacy endpoint is the proportion of subjects who achieve a pain score of 0 
 
 at Day 15. 
 
 
  
 
  
 
 
  
 
  
 
  
 
 
 
 
6 STUDY METHODS 
6.1 General Study Design and Plan 
• 
This study is a phase 3, randomized, multicenter, double-masked, vehicle-controlled, parallel-
group clinical study. 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 10 of 34 
 
• 
Type of control: 
 
 
 
 
• 
Level and method of blinding: 
 
 
 
 
 
• 
Method of treatment assignment: Subjects who qualify via inclusion and exclusion criteria 
will be 
assigned to study treatment groups 
. 
• 
  
 
 
 
 
 
  
• 
 
 
 
• 
 
. 
 
 
 
6.2 Inclusion-Exclusion Criteria and General Study Population 
• INCLUSION CRITERIA 
1. Be male or female, of 18 years of age or older 
 
 
 
 
 
 
 
5. Able to self-instill the IP or have a caregiver available to instill all doses of the IP, as instructed. 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 11 of 34 
 
6. Females of childbearing potential must not be pregnant (as confirmed by a negative urine 
pregnancy test 
 
 
 
 
 
 
 
 
 
7. Be able and willing to follow study instructions and complete all required visits 
 
• EXCLUSION CRITERIA 
1. Any known allergy or hypersensitivity to difluprednate therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. Any active corneal pathology noted in the study eye 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 12 of 34 
 
 
14. Currently suffering from alcohol and/or drug abuse 
 
 
 
 
  
  
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 13 of 34 
 
 
 
 
 
 
 
6.4 Study Termination  
The study may be stopped at any time by the sponsor, the investigator and/or the IRB with 
appropriate notification. 
  
If the study is prematurely terminated or suspended for any reason, the 
investigator/institution should promptly inform the subjects, should assure appropriate 
therapy and follow-up for the subjects, and, where required by the applicable regulatory 
requirement(s), should inform the regulatory authority(ies). 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 14 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 15 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 16 of 34 
 
 
 
 
 
  
  
  
  
  
 
  
 
  
 
  
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 17 of 34 
 
 
 
 
 
 
  
  
  
  
  
 
  
  
 
  
 
 
 
 
  
 
  
  
 
  
  
 
  
  
 
  
 
 
 
 
  
  
  
 
  
  
 
  
  
 
  
 
 
 
 
  
  
  
 
  


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 18 of 34 
 
  
 
  
  
 
  
 
 
 
 
  
  
  
  
  
 
  
  
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 19 of 34 
 
 
 
 
 
 
   
   
   
 
 
 
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
  
  
 
  
 
 
 
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
 
  
 
  
  
 
 
  
 
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 20 of 34 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 21 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 22 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 23 of 34 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 24 of 34 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
10 EFFICACY ANALYSIS 
 
10.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of subjects with an ACC grade of 0 at Day 15 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 25 of 34 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 26 of 34 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 27 of 34 
 
 
 
 
 
11.5 Relationship of Treatment-Emergent Adverse Events to the IP 
A summary of TEAEs by SOC, PT, and relationship to the IP will be presented by treatment group. The 
relationships indicate the investigator’s assessment of whether or not the event was caused by the IP. 
The possible relationships are “Unrelated”, “Unlikely”, “Possibly”, “Probably”, and “Certainly”.
 
 
 
 
 
 
 
11.6 Serious Adverse Events 
Serious adverse events (SAEs) will be listed by subject; SAEs will be summarized by event and treatment 
group. 
11.7 Adverse Events Leading to Study Drug Withdrawal 
All AEs leading to study withdrawal or study drug withdrawal will be listed and summarized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 28 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 REPORTING CONVENTIONS 
Summary tables and listings (e.g., post text tables and individual subject data listings are prepared 
according to ICH Guideline E3) include a header, showing Protocol Number, Status, and sponsor; 
and a “footer” providing explanatory notes that indicate as a minimum: 
• SAS program name and data file source 
• Date of data extraction 
• Date of output generation 
Post text tables also include reference(s) to the subject data listing(s) that supports the summary 
data. The data extraction date links the output to the archived database that is locked to ensure 
the replication of the results. 
Post text tables will be organized with respect to treatment groups for safety and efficacy. The 
order of presentation will be chronological for visits. A total column will appear as the last column, 
as applicable. The summary tables clearly indicate the number of subjects to which the data apply 
and unknown or not performed are distinguished from missing data. 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 29 of 34 
 
Summary tables for medications and medical conditions are coded according the WHO Drug 
Dictionary and MedDRA respectively. Adverse event preferred terms and body/organ systems are 
coded using the MedDRA dictionary. The MedDRA dictionary can be used, as well, in the coding of 
signs and symptoms, medical history, physical examination abnormalities, and clinical diagnoses. 
Supportive individual subject data listings, at a minimum, are sorted and presented by subject ID 
and treatment. Listings also include visit number, visit date, and days relative to the initiation of 
treatment. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 30 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 31 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 32 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 33 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
SAP V1 for Clinical Trial Protocol: CLR_16_31 
 
                            Date of Version 17SEP2020 
    Page 34 of 34