Clinical Trials Register

Summary
EudraCT Number:	2016-001823-30
Sponsor's Protocol Code Number:	043/SI
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-02-02
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-001823-30

A.3

Full title of the trial

Randomized, Assessor-Masked, Active-Controlled, Phase 3 Study to Evaluate Efficacy, Safety and Tolerability of 0.08% Polyhexamethylene Biguanide (PHMB) Ophthalmic Solution in Comparison with 0.02% PHMB + 0.1% Propamidine Combination Therapy in Subjects Affected by Acanthamoeba keratitis.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy, Safety and Tolerability of 0.08% PHMB eye drops in comparison with 0.02% PHMB + 0.1% Propamidine eye drops in patients with Acanthamoeba keratitis

A.3.2

Name or abbreviated title of the trial where available

ODAK Phase 3 study

A.4.1

Sponsor's protocol code number

043/SI

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

P/134/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	SIFI SpA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	SIFI SpA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PSR Orphan Experts
B.5.2	Functional name of contact point	Jolanda Overweel
B.5.3	Address:
B.5.3.1	Street Address	Antareslaan 41
B.5.3.2	Town/ city	Hoofddorp
B.5.3.3	Post code	2132 JE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31233036900
B.5.5	Fax number	31233036999
B.5.6	E-mail	jolanda.overweel@psr-group.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/498
D.3 Description of the IMP
D.3.1	Product name	Polyhexamethylene biguanide hydrochloride 0.08%
D.3.2	Product code	PHMB 0.08%
D.3.4	Pharmaceutical form	Eye drops, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POLIHEXANIDE
D.3.9.1	CAS number	32289-58-0
D.3.9.2	Current sponsor code	polyhexamethylene biguanide hydrochloride
D.3.9.3	Other descriptive name	PHMB
D.3.9.4	EV Substance Code	SUB09970MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.08
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/498
D.3 Description of the IMP
D.3.1	Product name	Polyhexamethylene biguanide hydrochloride 0.02%
D.3.2	Product code	PHMB 0.02%
D.3.4	Pharmaceutical form	Eye drops, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POLIHEXANIDE
D.3.9.1	CAS number	32289-58-0
D.3.9.2	Current sponsor code	polyhexamethylene biguanide hydrochloride
D.3.9.3	Other descriptive name	PHMB
D.3.9.4	EV Substance Code	SUB09970MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.02
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Brolene
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi
D.2.1.2	Country which granted the Marketing Authorisation	Poland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Brolene
D.3.4	Pharmaceutical form	Eye drops, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Propamidine isetionate 0.1% w/v
D.3.9.1	CAS number	140-63-6
D.3.9.3	Other descriptive name	PROPAMIDINE ISETIONATE
D.3.9.4	EV Substance Code	SUB04079MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Eye drops, solution
D.8.4	Route of administration of the placebo	Ocular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acanthamoeba keratitis

E.1.1.1

Medical condition in easily understood language

Corneal Infection due to Acanthamoeba

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10069408
E.1.2	Term	Acanthamoeba keratitis
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to compare the Clinical Resolution Rate (CRR) at 12 months (CRR_12 ) of 0.08% PHMB + placebo with that of 0.02% PHMB + 0.1% propamidine combination therapy, estimating the difference in CRR_12 together with the surrounding degree of uncertainty, and to test for therapeutic superiority or non-inferiority of 0.08% PHMB monotherapy.

E.2.2

Secondary objectives of the trial

A further aim of this study is to obtain additional safety information on 0.08% PHMB ophthalmic solution.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject must be able and willing to give informed consent.
2. Subject must be a man or woman of any race and ≥12 years of age, inclusive. Subjects <18 years will only be enrolled in selected study sites.
3. Subject must be able to understand and willing to comply with study procedures, restrictions and requirements, as judged by the investigator.
4. Clinical findings consistent with Acanthamoeba keratitis.
5. Confocal microscopy findings consistent with Acanthamoeba keratitis (performed within 7 days prior to study entry or as part of screening procedures).
6. Subjects using the following previous treatments for Acanthamoeba keratitis are eligible for the study: antibiotics, antiviral and antifungal drugs, anti-inflammatory drugs.
7. Females of childbearing potential will be included if they are either sexually inactive (sexually abstinent for 14 days prior to the first study drug dose continuing through 28 days after the last study drug dose, or using highly effective contraceptive (i.e. results in <1% failure rate when used consistently and correctly) methods in this study.
8. Females of childbearing potential agree to remain sexually inactive or to keep the same birth control method for at least 28 days following the last study drug dose.
9. A female of non-childbearing potential must have undergone sterilization procedures at least 6 months prior to the first study drug dose.
10. A non-vasectomized male subject agrees to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study drug and the female partner agrees to comply with inclusion 7 or 9. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male.
11. If male, agrees not to donate sperm from the first study drug dose until 90 days after dosing.

E.4

Principal exclusion criteria

1. Subject with documented history and/or clinical signs of concomitant presence of an ocular infection caused by viruses (herpes simplex virus [HSV]) or fungi.
2. Subject treated with drugs having effects on Acanthamoeba cysts prior to study entry, including biguanides (PHMB, chlorhexidine) and diamidines (propamidine, hexamidine).
3. Subjects requiring systemic immunosuppression for Acanthamoeba associated scleritis.
4. Subjects requiring urgent surgical intervention for advanced Acanthamoeba keratitis in either eye (e.g., for advanced corneal thinning/melting etc.).
5. Subject with known or suspected allergy to biguanides, diamidines or intolerance to any other ingredient of the investigational treatments.
6. Subject affected by immunodeficiency diseases or taking systemic immunosuppressive therapy.
7. Subject with a major systemic disease or other illness that would, in the opinion of the investigator, compromise subject’s safety or interfere with the collection or interpretation of study results.
8. If female, pregnancy, planned pregnancy, or breast-feeding.
9. Subject is participating in another interventional clinical study with an experimental or unapproved/unlicensed therapy or has participated in another interventional clinical study within 4 weeks prior to this study.

E.5 End points

E.5.1

Primary end point(s)

Clinical Response Rate

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

E.5.2

Secondary end point(s)

Secondary efficacy parameters are:
• BCVA
• Corneal scarring as identified by slit lamp examination
• Ulceration severity as identified by slit lamp examination using a 2 grade scoring procedure
• Anterior chamber inflammation as identified by ophthalmoscopy using a 3 grade scoring procedure
• EQ-5D questionnaire
• VFQ25 questionnaire
Secondary safety parameters are:
• Adverse events
• Clinical laboratory tests
• Intraocular pressure (IOP)
• Opthalmoscopy
• Worsening of the corneal epithelial defect and definable inflammatory signs (development of ring abscess and hypopyon) despite >30 days of treatment with the study drug)
• Rate of subjects with a relapse
• Rate of subjects requiring surgery, including amniotic membrane transplants, superficial keratectomy, application of cyanoacrylate glue, therapeutic penetrating, lamellar keratoplasty, cataract surgery, evisceration, or enucleation
• Rate of subjects requiring non-study therapies, e.g., topical steroids and NSAIDs
• Rate of subject discontinuation from study: to permit alteration of anti-amoebic therapy or for other unrelated specified reasons.
• Incidence of secondary complications, such as significant corneal neovascularization, corneal scarring, corneal perforation, scleritis, secondary glaucoma, cataract, retinopathy.

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1