Long–term Analysis of DImethyl fumarate, to slow the Growth of Areas of Geographic Atrophy

Phase 2

Not yet recruiting

Conditions: Macular degeneration

Registration Number: 2024-510741-33-00

Lead Sponsor: Assistance Publique Hopitaux De Paris

Brief Summary: Compare the efficacy at month 12, on the rate of change in Geographic Atrophy area, of twice-daily oral Dimethyl Fumarate (120mg x2 the 1st week, 240mg x2 for 51 weeks thereafter), versus standard of care, in patients with Geographic Atrophy resulting from the dry form of AMD

Detailed Description: Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world. Approximately 80% of patients with AMD suffer from the dry form of the disease also called geographic atrophy (GA) which is characterized by the progressive loss of photoreceptors and RPE that are essential to the visual cycle. There is currently no therapy to cure GA. This represent a major health problem with millions patients worldwide.

GA is a complex multifactorial disease influenced by: aging, environmental factors, genetic predispositions, oxidative stress and inflammation. Oxidative stress is the major environmental risk factor of developing AMD. Whereas inflammation, is now, recognized as one of the main player in AMD pathophysiology. Therefore, antioxidant and immunosuppressive therapies are susceptible to be beneficial in humans for patients with GA.

Dimethyl Fumarate activates the NRF2 pathway, which is the major transcription factor regulating anti-oxidative enzymes production. Dimethyl Fumarate commercialized under the name TECFIDERA® by BIOGEN is an effective antioxidant and immunosuppressive drug, used to treat patients with Multiple Sclerosis (MS), an autoimmune disease of the Central Nervous System leading to progressive disability. This new therapeutic agent may be easily repurposed to treat GA patients and could reduce or slow photoreceptors and RPE degeneration and the associated vision loss.

In this randomized, open labelled trial we will evaluate the safety and efficacy of TECFIDERA®, in two groups of patients (treated vs. untreated) with GA. This is the first time this strategy, based on evidences that oxidative stress and inflammation are central in GA physiopathology, will be tested in patients with dry AMD.

Recruitment & Eligibility

Status: Authorised, recruitment pending

Sex: Not specified

Target Recruitment: 60

Inclusion Criteria

Age 55 years of age to 85 years old at the moment of inclusion

Participant must understand and sign the protocol's informed consent document

Participant must have central or non-central geographic atrophy (GA) in at least one eye. GA should be at least 0.75 disk areas (DA) in size but no more than 8 disk areas (DA); approximately 2.54 mm2 is 1 DA

Participant must have a steady fixation in the study eye in the foveal or parafoveal area and media clear enough for good quality photographs

Participant must have visual acuity between 20/20 and 20/200 in the affected eye

No suggestive sign of progressive multifocal leukoencephalopathy on brain MR Imaging within 3 months of Dimethyl Fumaratetreatment Initiation (Only the patients randomized in the Dimethyl FumarateGroup will have to go through the MR Imaging)

Male participants with female partners capable of conceiving children will be required to use contraception (condom) during the study and for four months after their last experimental treatment caps

No documented history of heart disease, absence of family history of sudden death, and QTc duration within normal value (<480ms)

Participants must be affiliated to a social security scheme

Exclusion Criteria

Participant is in another interventional investigational study < 3 months before inclusion

Participant is on chronic (more than 3 months) immunosuppressive medication administered via ocular or systemic route(s) or is immunosuppressed

Participant is on ocular or systemic medications known to be toxic to the lens, retina or optic nerve

Participant with a history of malignancy that would compromise the 2-year study survival

Participant with a history of ocular herpes simplex virus (HSV)

Contra-indications or known hyper-sensibility to Dimethyl Fumarate or experimental treatment excipients

Severe active gastrointestinal disease

Contra-indications to an MRI using gadolinium such as pace maker, cardiac valve non IRM compatible, cochlear implant or any metallic implant non IRM compatible

Any contraindications to gadolinium including pregnancy, previous allergic reaction, severe kidney disease

Any contraindications to aspirin

Any screening laboratory value (hematology, serum chemistry or urinalysis) 3 times above normal values or that in the opinion of the Investigator is clinically significant and not suitable for study participation

Participant is unable to comply with study procedures or follow-up visits

Lymphopenia: below normal laboratory values at inclusion

Severe impairment of a vital organ including severe liver and renal impairment

Previous organ allograft

Patients taking the following non-authorized treatment 3 months prior enrolment: other fumaric acid derivatives (topical (ocular) or systemic), immuno-modulators via ocular or systemic routes (including interferons, sirolimus, chronic use of glucocorticoids), cytotoxic treatments and live attenuated vaccines.(NB: During the experimental treatment period and 3 months thereafter the concomitant use of non-authorized treatment cited above is not allowed in patients randomized in the Dimethyl Fumarate group)

Patients taking the following non-authorized treatment 3 months prior enrolment: nephrotoxic treatment (aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs (via ocular or systemic routes) or lithium). (NB: During the experimental treatment period and 3 months thereafter the concomitant use of non-authorized nephrotoxic treatment cited above is not allowed in patients randomized in the Dimethyl Fumarate group)

Any 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)

History of cancer (other than a non-melanoma skin cancer) diagnosed within the past five years that could be worsened by immunosuppression(In case of history of cancer the risk of immunosuppression must be determined by a specific oncology consultation prior to enrollment.)

Ocular or peri-ocular inflammation or infection in either eye

Presence of active or inactive toxoplasmosis in any or both eye(s)

Presence of active or latent tuberculosis infection

Participant has evidence of ocular disease other than GA in either eye that may confound the outcome of the study (e.g., glaucoma, diabetic retinopathy with 10 or more hemorrhages or micro-aneurysms, uveitis, pseudo-vitelliform macular degeneration, exudative macular degeneration, moderate/severe myopia)

Female participants of childbearing potential (those who are not post-menopausal or surgically sterile). Postmenopausal state is 12 months of amenorrhea + high level of FSH if required

Persons under curatorship or guardianship

Participant with antecedent of neo-vascular AMD

Participant has received treatment for exudative AMD, such as macular laser, photodynamic therapy (PDT) or anti-vascular endothelial growthfactor (anti-VEGF) therapy intra-vitreal (IVT) injection or of any agent (e.g., triamcinolone) in the study eye within the last four months prior to study enrollment. Vitamin supplementation for AMD is not considered an exclusionary criterion

Participant has had a vitrectomy on the study eye

Participant is expected to need ocular surgery during the course of the trial

Participant has undergone lens removal in the last three months or Yttrium Aluminium Garnet (YAG) laser capsulotomy within the last month

Participant is on chemotherapy

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Rate of Change in Area of Geographic Atrophy (GA), based on masked, digital grading as measured on Fundus Auto-fluorescence ((FAF) Imaging Using a Confocal Scanning Ophthalmoscope by an External Reading Center at 12, Months compared to value at Baseline Day 1		Rate of Change in Area of Geographic Atrophy (GA), based on masked, digital grading as measured on Fundus Auto-fluorescence ((FAF) Imaging Using a Confocal Scanning Ophthalmoscope by an External Reading Center at 12, Months compared to value at Baseline Day 1

Secondary Outcome Measures

Name	Time	Method
Incidence and severity of ocular and systemic treatment-related adverse events as assessed by CTCAE v4.0".	24 months

Trial Locations

Locations (11): Clinique Mathilde
🇫🇷
Rouen, France
Retina
🇫🇷
Saint-Cyr-Sur-Loire, France
Centre Hospitalier Intercommunal Creteil
🇫🇷
Creteil, France
Centre Hospitalier Universitaire De Poitiers
🇫🇷
Poitiers, France
Centre Hospitalier Universitaire De Nantes
🇫🇷
Nantes, France
Centre Hospitalier Universitaire De Dijon
🇫🇷
Dijon, France
Hopital Fondation Adolphe De Rothschild
🇫🇷
Paris, France
Theorie Etudes Organisation Recherche En Retine Medicale S.A.R.L.
🇫🇷
Paris, France
Hospices Civils De Lyon
🇫🇷
Lyon Cedex 04, France
Centre Monticelli Paradis D Ophtalmologie
🇫🇷
Marseille, France
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Clinique Mathilde
🇫🇷Rouen, France
Joël UZZAN
Site contact
0232810822
ophtalmo@ussan.net