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Clinical Trial Results:
A PHASE III, MULTICENTRE, RANDOMISED, INVESTIGATOR-MASKED, CROSSOVER, COMPARATIVE, NON-INFERIORITY TRIAL EVALUATING THE EFFICACY AND TOLERABILITY OF GENERIC LATANOPROST 0.05 MG/ML EYE DROPS SOLUTION (POLPHARMA S.A.) COMPARED TO XALATAN® (LATANOPROST 0.005 % OPHTHALMIC SOLUTION, PFIZER) IN PATIENTS WITH OCULAR HYPERTENSION OR PRIMARY OPEN ANGLE GLAUCOMA.

Summary
EudraCT number	2018-001727-39
Trial protocol	HU
Global end of trial date	30 Jun 2021

Results information
Results version number	v1(current)
This version publication date	11 Jan 2022
First version publication date	11 Jan 2022
Other versions
Summary report(s)	Summary of CSR, V2, dated 15 Jul 2021 POP03_Synopsis_Protocol_Final_V01.1

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

POP03

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Polpharma S.A. (Zaklady Farmaceutyczne Polpharma S.A.)

Sponsor organisation address

Peplinska 19, Starogard Gdanski, Poland, 83-200

Public contact

Eva Szucs, Appletree CIG-AG, +36 702450085, e.szucs@appletree-cig.com

Scientific contact

Eva Szucs, Appletree CIG-AG, +36 702450085, e.szucs@appletree-cig.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Jun 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Mar 2020

Global end of trial reached?

Yes

Global end of trial date

30 Jun 2021

Was the trial ended prematurely?

Main objective of the trial

PRIMARY OBJECTIVE The primary objective of this study is to evaluate the efficacy and tolerability of Latanoprost Polpharma (test product) in lowering of IOP when compared to the originator Xalatan® (reference product).

Protection of trial subjects

Safety and ocular tolerance of the test product was assessed by evaluating vital signs (blood pressure and heart rate), the ocular comfort level, conjunctival hyperemia, and other side effects (Adverse Events) of the test product in comparison to the reference product. The following study procedures and assessments were carried out according to established clinical practice: Dilated fundus examination, Slit lamp examination, Visual field testing, Visual acuity determination, Gonioscopy, Pachymetry. Patients were instructed to complete the daily medication diary card, indicating the time of dosing of each daily dose as well as any adverse experiences that may have occurred. Urine pregnancy tests are performed at the screening visit, at the Day 1 visits of both treatment periods, and at the final visit. Women of childbearing potential were only eligible for the study either if using an acceptable method of birth control for at least 28 days prior to the first dose and through the study or being heterosexually inactive (abstinent).

Background therapy

Ongoing systemic therapies at study start were allowed to continue as long as the treatment regimen remained unchanged and the treatment was not expected to have an impact on IOP. Topical ocular treatment with lubricant eye drops (artificial tears) was allowed throughout the study.

Evidence for comparator

The comparator in this trial is the medicinal product Xalatan ®, 50 micrograms/mL Eye drops, solution. 1 mL Eye drops solution contains 50 micrograms of latanoprost. One drop contains approximately 1.5 micrograms latanoprost. Excipients with known effect - Benzalkonium chloride 0.2 mg/mL is included as a preservative. The test product was a preservative-free generic version of Xalatan, and based on current regulations the present non-inferiority therapeutic equivalence study had to include the originator drug as reference (comparator).

Actual start date of recruitment

07 Jan 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Russian Federation: 16

Country: Number of subjects enrolled

Hungary: 33

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Hungary: Site 01 - First Patient First Visit (FPFV): 7 Jan 2019, Last Patient Last Visit (LPLV): 4 Mar 2020; Site 02 - FPFV: 11 Feb 2019, LPLV: 25 Jun 2019; Site 03 - FPFV: 18 Jan 2019, LPLV: 4 Mar 2020; Russia: Site 04 - FPFV: 17 May 2019, LPLV: 11 Mar 2020; Site 05 - FPFV: 8 Apr 2019, LPLV: 20 Feb 2020

Screening details

Main Inclusion Criterion - Ocular hypertension or primary open angle glaucoma in both eyes: mean diurnal IOP measured at -12, -8, –4, 0 hours pre-treatment on Day 1 must be higher than or equal to 22 mmHg, and lower than or equal to 34 mmHg (naïve or untreated, i.e., after washout of 28 days). 53 patients were screened in total in all five sites.

Number of subjects started

Number of subjects completed

Period 1 title

Washout

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The non-masked primary packaging required investigator masking (Latanoprost Polpharma - in a HDPE bottle closed with a pump eye dropper, Xalatan® - in a dropper container of polyethylene with a screw cap). The site ensured that an independent professional not otherwise involved in the conduct of the study or not involved in the assessments or observations of the patients dispensed and collected the IPs (“unmasked site staff”). The subjects received drops with equal trial labels blinding IPs.

all subjects

Arm description

All subjects enrolled before randomization

Arm type

washout phase

Investigational medicinal product name

no IMP

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution

Routes of administration

Ocular use

Dosage and administration details

no topical ocular drugs a were allowed other than artificial tears

Number of subjects in period 1	all subjects
Started	49
Completed	49

Period 2 title

Cross-over

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Data analyst, Carer, Assessor, Subject

Blinding implementation details

Investigators and assessorr masking was ensured

Are arms mutually exclusive

Test

Arm description

Latanoprost Polpharma: latanoprost 0.05 mg/ml, preservative free

Arm type

Experimental

Investigational medicinal product name

Latanoprost Polpharma

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops

Routes of administration

Ocular use

Dosage and administration details

1 drop / day in the evening

Reference

Arm description

Xalatan (R) Pfizer

Arm type

Active comparator

Investigational medicinal product name

Xalatan (R)

Investigational medicinal product code

Other name

Pharmaceutical forms

Eye drops, solution

Routes of administration

Ocular use

Dosage and administration details

1 drop / day in the evening

Number of subjects in period 2	Test	Reference
Started	49	49
Completed	47	47
Not completed	2	2
Physician decision	1	1
Protocol deviation	1	1

Baseline characteristics

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Reporting group title

Washout

Reporting group description

all subjects enrolled

Reporting group values	Washout	Total
Number of subjects	49	49
Age categorical
Men and women 18-75 years old who can sign and date an Informed Consent.
Units: Subjects
from 18-84 years	49	49
Age continuous
All subjects, 18-75 years of age
Units: years
arithmetic mean (standard deviation)	64.2 ( 9.8 )	-
Gender categorical
all subjects enrolled
Units: Subjects
Female	35	35
Male	14	14

Subject analysis set title

all subjects enrolled

Subject analysis set type

Per protocol

Subject analysis set description

all subjects enrolled

Subject analysis set title

Subject analysis set type

Per protocol

Subject analysis set description

all patients without major protocol deviation

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

all patients which completed at least 1 treatment period

Subject analysis sets values	all subjects enrolled	PP	ITT
Number of subjects	49	44	47
Age categorical
Men and women 18-75 years old who can sign and date an Informed Consent.
Units: Subjects
from 18-84 years	49	44	47
Age continuous
All subjects, 18-75 years of age
Units: years
arithmetic mean (standard deviation)	64.2 ( 9.8 )	( )	( )
Gender categorical
all subjects enrolled
Units: Subjects
Female	35	32	34
Male	14	12	13

End points

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Reporting group title

all subjects

Reporting group description

All subjects enrolled before randomization

Reporting group title

Test

Reporting group description

Latanoprost Polpharma: latanoprost 0.05 mg/ml, preservative free

Reporting group title

Reference

Reporting group description

Xalatan (R) Pfizer

Subject analysis set title

all subjects enrolled

Subject analysis set type

Per protocol

Subject analysis set description

all subjects enrolled

Subject analysis set title

Subject analysis set type

Per protocol

Subject analysis set description

all patients without major protocol deviation

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

all patients which completed at least 1 treatment period

Primary: reduction in mean diurnal IOP

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End point title

reduction in mean diurnal IOP

End point description

The secondary endpoint was the reduction of the mean diurnal IOP between Day 1 (baseline) and Day 29. The mean diurnal IOP was calculated as the average of the measurements performed at 12, 8, 4 and 0 hours before treatment on Day 1 and at 12, 16, 20 and 24 hours after treatment the previous day on Day 29. In the ITT analysis (n=47), the reduction was 7.29 + 2.53 mmHg or 7.43 + 2.78 mm Hg after treatment with test or reference product, respectively. The fact that in both periods a marked IOP lowering effect was observed, which was even slightly superior to the one reported in literature demonstrates that the patient population under investigation was well responsive to the treatment.

End point type

Primary

End point timeframe

Day 0 versus day 29

End point values	Test	Reference	PP
Number of subjects analysed	44	44	44
Units: mm Hg
arithmetic mean (standard deviation)	7.04 ( 2.14 )	7.17 ( 2.11 )	7.17 ( 2.11 )

non-inferiority analyses

Comparison groups

Test v Reference

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≤ 0.025

Method

Linear Mixed Model

Parameter type

Mean difference (net)

Point estimate

0.024

Confidence interval

level

95%

sides

2-sided

lower limit

-0.457

upper limit

0.504

Variability estimate

Standard error of the mean

Dispersion value

0.238

Secondary: reduction in man diurnal IOP

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End point title

reduction in man diurnal IOP

End point description

End point type

Secondary

End point timeframe

Day 0 versus day 29

End point values	Test	Reference	ITT
Number of subjects analysed	47	47	47
Units: mm Hg
arithmetic mean (standard deviation)	7.29 ( 2.53 )	7.43 ( 2.78 )	7.43 ( 2.78 )

non-inferiority analysis

Statistical analysis description

non- inferiority analysis

Comparison groups

Test v Reference

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

≤ 0.025

Method

Linear Mixed Model

Parameter type

Mean difference (net)

Point estimate

-0.021

Confidence interval

level

95%

sides

2-sided

lower limit

-0.467

upper limit

0.434

Variability estimate

Standard error of the mean

Dispersion value

0.226

Adverse events

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Timeframe for reporting adverse events

The AEs were reported and recorded by PIs within 5 days at the latest.

Adverse event reporting additional description

AEs were collected in clinical trial database and periodically reviewed by the study monitors on behalf of the sponsor. They were reported without exception in the clinical trial report.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

All enrolled patients

Reporting group description

Adverse events (AEs) and serious adverse events (SAEs) were reported from Visit 0 to Visit 8 using the AE form. The assessment of AEs included the type of AE (systemic/ocular), intensity, frequency, action taken, association with study medication, seriousness (SAE) and outcome. AEs were coded according to MedDRA (EN V 23.0). 118 AEs were reported - 65 ocular, 53 systemic (Table 15). AEs which occurred during the interim wash-out were associated with period I, as a causal relation to the test product administered in period I cannot be excluded. This explains partially the higher number of adverse events associated with period I. During the treatment with test product, 67 AEs were reported (37 ocular and 30 systemic), and during the treatment with reference product 51 adverse events were reported (28 ocular, 23 systemic; Table 15). In period I, 82 AEs were reported (43 ocular, 39 systemic), and in treatment period II, 36 AEs were reported (22 ocular, 14 systemic; Table 16).

Serious adverse events	All enrolled patients
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 49 (0.00%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	All enrolled patients
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 49 (65.31%)
Vascular disorders
Migraine
subjects affected / exposed	1 / 49 (2.04%)
occurrences all number	6
Nervous system disorders
Headache
subjects affected / exposed	4 / 49 (8.16%)
occurrences all number	28
Eye disorders
eye pain
subjects affected / exposed	25 / 49 (51.02%)
occurrences all number	65
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 49 (4.08%)
occurrences all number	3

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
01 Mar 2020	Because of the COVID-19 pandemic situation starting mid of March 2020, the study procedures had to be adapted. Due to specific request by the authorities in Hungary, the last monitoring visits and the close-out visits in this country had to be performed remotely, for which specific guidance documents were issued. Further site 04 in Moscow could, due to this situation, not be included in the first evaluation (CSR V1.0) as it was at the time under full quarantine and not accessible to the investigator, his staff or monitors. As a consequence, the respective study data could not be fully monitored and were thus not fit for inclusion in the former analysis. Importantly, the required number of 42 evaluable patients had also been reached without consideration of the 6 patients studied at this site. Therefore, the change had no impact on the validity of the Clinical Study Report V1.0. As mentioned in the Clinical Study Report V 1.0, the present report is the follow-up version of report V 1.0 , including the fully monitored and analysed data from site 04. In modification of the protocol, not only the non-inferiority of the test product when compared to the reference product with respect to the differences in mean diurnal IOP was determined, also the non-inferiority of the test product when compared to the reference product with respect to the difference for each measurement time point at baseline (-12, -8, -4 and 0 hours before treatment) and Day 29 (12, 16, 20 and 24 hours after treatment the previous day) was determined. This modification was reflected in the statistical analysis plan. The change was introduced as after finalizing of the clinical study protocol, it became apparent that increasingly authorities in Europe and overseas requested this data set for non-inferiority assessment of IOP lowering agents. The change has no impact on the validity of the study and its outcomes. On the contrary it even augments its validity.	01 May 2021

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Due to COVID-19, site 04 in Moscow was not included in the first evaluation (CSR V1.0) as it was at the time under full quarantine. The data of site 04 is included in the final CSR V2.0.

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Primary: reduction in mean diurnal IOP

Primary: reduction in mean diurnal IOP

Secondary: reduction in man diurnal IOP

Secondary: reduction in man diurnal IOP

Adverse events

Adverse events

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