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    Summary
    EudraCT Number:2007-005601-22
    Sponsor's Protocol Code Number:poc1doxy
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-11-05
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2007-005601-22
    A.3Full title of the trial
    Proof–of–concept study 1 (POC1):
    Evaluation of effect of doxycycline versus placebo on retinal function and posterior segment neovascularization in patients with severe non-proliferative or early (non-high-risk) proliferative diabetic retinopathy
    A.3.2Name or abbreviated title of the trial where available
    Evaluation of effect of doxycycline on diabetic retinopathy
    A.4.1Sponsor's protocol code numberpoc1doxy
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of Sponsor
    B.1.3.4Country
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Oracea
    D.2.1.1.2Name of the Marketing Authorisation holderCollaGenex
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameOracea
    D.3.2Product code J01AA02
    D.3.4Pharmaceutical form Capsule*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDOXYCYCLINE
    D.3.9.1CAS number 564250
    D.3.9.2Current sponsor codepoc1doxy
    D.3.9.3Other descriptive nameproof of concept
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeantibiotic
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule*
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diabetic retinopathy
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10012689
    E.1.2Term Diabetic retinopathy
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objectives of this proof-of-concept study are to investigate whether doxycycline can 1) slow the deterioration or improve retinal function and 2) induce regression, or slow progression, of diabetic retinopathy.
    E.2.2Secondary objectives of the trial
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria include:

    • age ≥ 18 years
    • diagnosis of type 1 or type 2 diabetes mellitus (defined as current regular use of oral anti-hyperglycemia agents and/or insulin for the treatment of diabetes)
    • able and willing to give informed consent
    • best-corrected ETDRS visual acuity in study eye ≥ 49 letters (20/100)
    • severe non-proliferative diabetic retinopathy (ETDRS level 53E) (19) or retinal and/or optic disk neovascularization >1/2 disc area and less than the “high-risk” characteristics defined by the Diabetic Retinopathy Study (ETDRS level 65) (17), and in whom panretinal photocoagulation is not imminently required in the ophthalmologist’s judgment
    • able to perform reliable visual field and dark adaptation testing
    • central subfield thickness on OCT of ≤ 275 m
    • foveal fixation present in each eye (assessed by fundus photography using an internal fixation pointer or assessed by the investigator)
    • media clarity and pupil dilation sufficient for high-quality fundus photographs and fluorescein angiograms.

    If both eyes meet these criteria, the eye with more extensive and/or more “active” new vessels, as determined by the clinician, will be the study eye (with more active new vessel patches defined as those in which the proportion of blood-filled new vessels to fibrous tissue is greater). If both eyes have the same extent/activity of new vessels based on the clinician’s judgment, then the eye with the worse grade (as determined by the clinician) will be the study eye. If both eyes have the same grade, the eye with the better acuity will be designated the study eye, and if the acuity in both eyes is identical, the right eye will be designated the study eye.
    E.4Principal exclusion criteria
    Ocular exclusion criteria include:

    • high-risk neovascularization in study eye
    • prior panretinal photocoagulation in the study eye
    • focal/grid laser photocoagulation in the macula within the past 15 weeks in the study eye
    • intraocular pressure > 22mmHg by Goldmann Tonomerty
    • history of pars plana vitrectomy in the study eye
    • vitreous or pre-retinal hemorrhage in the study eye
    • systemic or intravitreal anti-VEGF agent to the study eye or the fellow eye within the past 3 months
    • peribulbar steroid injection to the study eye or the fellow eye within the past 6 months
    • intravitreal triamcinolone acetonide to the study eye within the past 4 months;
    • expectation by the investigator that retinal photocoagulation or other treatment for diabetic retinopathy (e.g. focal/grid laser to study eye, intravitreal triamcinolone acetonide to study eye, intravitreal anti-VEGF agent to study or fellow eye, ruboxistaurin or systemic anti-VEGF agent for diabetic macular edema) will be administered in the subsequent 24 months
    • best-corrected ETDRS visual acuity < 49 letters (20/100) in the fellow eye
    • an ocular condition (other than diabetes) is present in the study eye that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g. retinal vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc)
    • anticipated need for cataract surgery in the study eye in the subsequent 24 months
    • history of major ocular surgery (including cataract surgery, scleral buckle, any intraocular surgery, etc) in the study eye within prior 6 months or anticipated within the subsequent 24 months following randomization
    • aphakia in the study eye
    • history of YAG capsulotomy performed in the study eye within 2 months prior to randomization.


    Systemic exclusion criteria include:

    • unstable medical status (e.g. glycemic control, blood pressure, cardiovascular disease) in the opinion of investigator
    • significant renal disease (defined as a serum creatinine > 2.5 mg/dL),
    • systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg
    • pregnancy; for women of child-bearing potential, a urine pregnancy test will be performed.
    • lactating or intending to become pregnant during the study period (at least 24 months)
    • sexually active women of child-bearing potential not actively practicing birth control by using a medically accepted device or therapy (that is, intrauterine device, hormonal contraceptive, or barrier devices) during the study period (at least 24 months); since doxycycline may interfere with the effectiveness of hormonal contraceptives, sexually active women of child-bearing potential who use a hormonal contraceptive will be required to use a second form of contraception to safeguard against contraceptive failure while participating in the study
    • known allergy/intolerance to doxycycline or any ingredient in the study drug or placebo (e.g. hypromellose, iron oxide, methacrylic acid copolymer, polyethylene glycol, polysorbate 80, sugar spheres, talc, titanium dioxide, and triethyl citrate)
    • patients taking phenytoin, barbiturates or carbamazepine, with gastroparesis, with a history of gastrectomy, gastric bypass surgery or otherwise deemed achlorhydric or with a BMI > 30 kg/m2 will also be excluded because of altered doxycycline pharmacokinetics and/or bioavailability
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy outcome measures:

    Efficacy outcomes to be assessed in this proof-of-concept study include:
    • change in dark adaptation (change in the duration of the rod-intercept)
    • change in mean deviation of scotopic full-threshold 24-2 visual fields
    • change in the number of abnormal points (p<5%) on the scotopic full-threshold 24-2 visual fields
    • change in the number of abnormal points (p<5%) in a cluster on the scotopic full-threshold 24-2 visual fields
    • change in mean deviation of photopic Swedish Interactive Threshold Algorithm (SITA) 24-2 visual fields
    • change in the number of abnormal points (p<5%) on the photopic SITA 24-2 visual fields
    • change in the number of abnormal points (p<5%) in a cluster on the photopic SITA 24-2 visual fields
    • change in foveal threshold on the photopic SITA 24-2 visual fields
    • change in frequency doubling perimetry (FDP)
    • change in ETDRS visual acuity
    • development of definite neovascularization in eyes free of neovascularization at baseline
    • increase in area of neovascularization by 50% from baseline in eyes with neovascularization at baseline
    • proportion of patients who receive panretinal photocoagulation during the study period
    • proportion of patients who develop vitreous or preretinal hemorrhage during the study period
    • change in total area of retinal and/or optic disk neovascularization
    • a >1-step progression in ETDRS diabetic retinopathy severity level
    • change in total area of retinal thickening
    • change in central subfield thickness on optical coherence tomography (OCT)
    • change in macular volume on OCT
    • proportion of patients who meet any of the following criteria:
    o develop definite neovascularization in eyes free of neovascularization at baseline
    o demonstrate an increase in area of neovascularization by 50% from baseline in eyes with neovascularization at baseline
    o receive panretinal photocoagulation during the study period
    o develop vitreous or preretinal hemorrhage during the study period
    • change in central retinal artery equivalent (CRAE)
    • change in central retinal vein equivalent (CRVE)
    • change in arteriovenous ratio (AVR = CRAE/CRVE)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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 No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial 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
    Provided in protocol
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-12-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-03-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-06-01
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