Clinical Trials Register

Summary
EudraCT Number:	2017-001179-21
Sponsor's Protocol Code Number:	11-EI-0263
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:	2017-11-24
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

2017-001179-21

A.3

Full title of the trial

A Pilot Study for the Evaluation of Minocycline as a Microglia Inhibitor in the Treatment of Branch Retinal Vein Occlusions

A.3.1

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

A Pilot Study for the Evaluation of Minocycline in the Treatment of Branch Retinal Vein Occlusions

A.3.2

Name or abbreviated title of the trial where available

MiBRVO

A.4.1

Sponsor's protocol code number

11-EI-0263

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01468831

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	The National Eye Institute
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	The National Eye Institute
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The Emmes Corporation
B.5.2	Functional name of contact point	Eric Hardter
B.5.3	Address:
B.5.3.1	Street Address	401 N. Washington Street, Suite 700
B.5.3.2	Town/ city	Rockville, MD
B.5.3.3	Post code	20850
B.5.3.4	Country	United States
B.5.4	Telephone number	013012511161
B.5.5	Fax number	013012511355
B.5.6	E-mail	ehardter@emmes.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	Information not present in EudraCT
D.2.1.1.1	Trade name	Minocycline
D.2.1.1.2	Name of the Marketing Authorisation holder	Almirall
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Minocycline
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Minocycline Hydrochloride
D.3.9.1	CAS number	13614-98-7
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Branch Retinal Vein Occlusion

E.1.1.1

Medical condition in easily understood language

Branch Retinal Vein Occlusion

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The study objective is to investigate the safety and potential efficacy of minocycline, a microglia inhibitor, in the treatment of Branch Retinal Vein Occlusion.

E.2.2

Secondary objectives of the trial

The secondary objective is to determine the difference between the minocycline and placebo groups, including with the difference between the minocycline and placebo groups in the number of intravitreal bevacizumab injections between 12 and 24 months and baseline, changes in mean macular sensitivity as measured by microperimetry at 3, 6, 12, 18 and 24 months compared to baseline, the mean change in Best Corrected Visual Acuity at 24 months compared to baseline, changes in retinal thickness as measured by Optical Coherence Tomography at 6, 12, 18 and 24 months compared to baseline, number of participants improving ≥ 1 logOCT scale step at 12 and 24 months compared to baseline, as well as changes in fluid leakage in the macula as demonstrated by fluorescein angiography at 12 and 24 months compared to baseline.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Participant Inclusion Criteria:
(1)Participant is 18 years of age or older.
(2)Participant must understand and sign the protocol’s informed consent document.
(3)Female participants of childbearing potential must not be pregnant or breast-feeding and must be willing to undergo urine pregnancy tests throughout the study.
(4)Female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two acceptable methods of contraception throughout the course of the study and for one week after study medication discontinuation (based on the half life of minocycline which is 11-22 hours). Acceptable methods of contraception include: hormonal contraception (i.e., birth control pills*, injected hormones, dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization (hysterectomy or tubal ligation).
*Oral birth control pills must be used with caution as minocycline decreases the effectiveness of some oral contraceptives. Participants already taking oral contraceptives may continue to use them, but must agree to use at least one other method of birth control while on study.
(5)Participants must agree to notify the study investigator or coordinator if any of their doctors initiate a new medication during the course of the study.
(6)Participant must have normal renal function and liver function or have mild abnormalities not above grade 1 as defined by the Common Terminology Criteria for Adverse Events v4.0 (CTCAE).
(7)Participant must agree to minimize exposure to sunlight or artificial UV rays and to wear protective clothing, sunglasses and sunscreen (minimum SPF 15) if s/he must be out in the sun.
(8)Participant has at least one eye that meets the study eye criteria.

Study Eye Inclusion Criteria:
(1)The study eye has a best-corrected ETDRS visual acuity score between 78 and 34 letters (i.e., between 20/32 and 20/200).
(2)The study eye shows evidence of definite retinal thickening due to a BRVO based on clinical examination involving the center of the macula that is not refractory to further therapy as based on the investigator’s clinical judgment. BRVO is defined as an eye that had retinal hemorrhage or other biomicroscopic evidence of RVO (e.g., telangiectatic capillary bed) and a dilated (or previously dilated) venous system in one or two quadrants or less of the retina drained by the affected vein. Hemiretinal vein occlusion (HRVO) is an RVO that involves two altitudinal quadrants. In this study, eyes with a HRVO will be considered a BRVO and are given the same treatment as BRVO eyes.
(3)The study eye has retinal thickness in the central subfield on baseline OCT measurement > 350 microns, as measured by Zeiss Cirrus spectral domain OCT, or an equivalent retinal thickness on a similar OCT machine.
(4)The study eye has media clarity and pupillary dilation sufficient for adequate fundus photographs. Furthermore, the participant must be able to cooperate during the procedure for accurate fundus photographs.

If both eyes of a participant meet the inclusion criteria,the study eye will be determined at the investigator’s discretion.

E.4

Principal exclusion criteria

Participant Exclusion Criteria:
(1)Participant is in another investigational study and actively receiving investigational product for BRVO.
(2)Participant is unable to comply with study procedures or follow-up visits.
(3)Participant has a known hypersensitivity to sodium fluorescein dye.
(4)Participant has a condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control).
(5)Participant has a history of chronic renal failure requiring dialysis or kidney transplant.
(6)Participant has a history of chronic hepatitis or liver failure.
(7)Participant has an allergy or hypersensitivity to minocycline or any drug in the tetracycline family.
(8)Participant is currently taking a tetracycline medication.
(9)Participant is taking any medication that could adversely interact with minocycline such as methoxyflurane.
(10)Participant has a blood pressure of > 180/110 (systolic above 180 OR diastolic above 110).If blood pressure is brought below 180/110 by anti-hypertensive treatment, the participant can become eligible.
(11)Participant is currently being treated with systemic anti-VEGF agents or systemic steroids.
(12)Participant had a cerebral vascular event (CVA) or myocardial infarction (MI) within three months prior to study entry.
(13)Participant has a history of thyroid cancer.

Study Eye Exclusion Criteria:
(1)The study eye has macular edema considered to be due to a cause other than BRVO.
(2)An eye should not be considered eligible if: The macular edema is considered to be related to cataract extraction, or clinical examination and/or OCT suggest that vitreoretinal interface disease (e.g., a taut posterior hyaloid or epiretinal membrane) is the primary cause of the macular edema, or clinical examination, medical history and/or fluorescein angiography suggest that diabetic retinopathy is the primary cause of the edema.
(3)The study eye has a history of a recurrent RVO.
(4)The study eye has a history of RVO present for > 18 months.
(5)A brisk afferent pupillary defect (APD) is present in the study eye.
(6)An ocular condition is present in the study eye such that, in the opinion of the investigator, visual acuity would not improve from resolution of macular edema
(e.g., foveal atrophy, pigmentary changes, dense subfoveal hard exudates, laser scar at fovea, non-retinal condition).
(7)An ocular condition (other than RVO) is present that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc.).
(8)A substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal) is present in the study eye.
(9)The study eye has had panretinal or sectoral scatter photocoagulation (PRP) within four months prior to study entry.
(10)The study eye has had pars plana vitrectomy within six months prior to study entry.
(11)The study eye has undergone major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within three months prior to study entry.
(12)A yttrium aluminum garnet (YAG) capsulotomy has been performed on the study eye within two months prior to study entry.
(13)The study eye has had treatment < 3 months prior to study entry of intravitreal or periocular steroid injections.
(14)The study eye has had treatment < 28 days prior to study entry of intravitreal anti-VEGF agents.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measure is the mean change of BCVA, as measured in ETDRS letters, between the placebo and minocycline groups in the study eye at 12 months compared to baseline.

E.5.1.1

Timepoint(s) of evaluation of this end point

The time point of evaluation of the primary outcome is at the 12 month visit.

E.5.2

Secondary end point(s)

Secondary outcomes include the difference between the minocycline and placebo groups in the:
• Number of bevacizumab injections from baseline to 12 months and from baseline to
24 months,
• Changes in mean macular sensitivity as measured by microperimetry at 3, 6, 12, 18 and 24 months compared to baseline,
• Mean change in the ETDRS BCVA in the study eye at 24 months compared to baseline,
• Changes in retinal thickness as measured by OCT at 6, 12, 18 and 24 months compared to baseline,
• Number of participants improving ≥ 1 logOCT scale step at 12 and 24 months compared to baseline,
• Changes in fluid leakage in the macula as demonstrated by fluorescein angiography at 12 and 24 months compared to baseline.

Also, a decrease of ≥ 1-step on the logOCT scale, where Change in logOCT = log(follow-up thickness/300) – log(baseline thickness/300) is considered clinically significant. A 1-step decrease is equivalent to at least a 20% improvement of central macular thickness and represents greater than twice the variability of retinal thickness measurements (approximately 25-30 microns).

E.5.2.1

Timepoint(s) of evaluation of this end point

The time points of evaluation of the secondary end points are at months 3, 6, 12, 18 and 24.

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

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

This a a pilot, double-masked, randomized, multi-center study

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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)

E.8.2.2

Placebo

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

Yes

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1