Phase I/II Study of SAR422459 in Patients With Stargardt's Macular Degeneration

• ClinicalTrials.gov Identifier: NCT01367444
• Recruitment Status: Terminated
• First Posted: June 7, 2011
• Last Update Posted: September 27, 2019
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: June 3, 2011
• First Posted Date: June 7, 2011
• Last Update Posted Date: September 27, 2019
• Actual Study Start Date: June 8, 2011
• Actual Primary Completion Date: July 2, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 3, 2016)

• Number of patients with treatment emergent adverse events [ Time Frame: at 48 weeks ]
• Change from baseline in ocular safety assessments [ Time Frame: at 48 weeks ]
  Measured as change from baseline in Best Corrected Visual Acuity (BCVA), Slit-lamp, Ophthalmoscopy, Fundus Photography, Intraocular Pressure, Microperimetry, full-field static and kinetic perimetry, OCT and ERG

Original Primary Outcome Measures (submitted: June 6, 2011)

The incidence of adverse events [ Time Frame: 48 weeks ]

The number and percentage of patients with treatment emergent adverse events.

• Change History: Complete list of historical versions of study NCT01367444 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: February 3, 2016)

Delay in retinal degeneration [ Time Frame: at 48 weeks ]

Measured as change from baseline in function relative to untreated contralateral eye on: BCVA, microperimetry, full-field static/kinetic perimetry, OCT and FAF

Original Secondary Outcome Measures (submitted: June 6, 2011)

Delay in retinal degeneration [ Time Frame: 48 weeks ]

Changes from baseline function relative to the contralateral eye utilising retinal analytical techniques.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase I/II Study of SAR422459 in Patients With Stargardt's Macular Degeneration
• Official Title: A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected SAR422459, Administered to Patients With Stargardt's Macular Degeneration

Brief Summary

Primary Objective:

To assess the safety and tolerability of ascending doses of SAR422459 in patients with Stargardt's Macular Degeneration.

Secondary Objective:

To evaluate for possible biological activity of SAR422459.

Detailed Description

The total duration per patient is up to 52 weeks, which includes a 4 week screening period and a 48 weeks study period.

At the end of the study, the patient will be invited to enter in an open-label safety study (LTS13588) and long-term follow-up visits including ophthalmological examinations and recording of adverse events for up to 15 years.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Stargardt's Disease

Intervention

Drug: SAR422459

Pharmaceutical form: sterile solution Route of administration: subretinal injection

Study Arms

• Experimental: SAR422459 (Dose 1)
  Starting dose of SAR422459 given through subretinal injection
  Intervention: Drug: SAR422459
• Experimental: SAR422459 (Dose 2)
  Escalating dose of SAR422459 given through subretinal injection
  Intervention: Drug: SAR422459
• Experimental: SAR422459 (Dose 3)
  Maximum tolerated dose (MTD) of SAR422459 given through subretinal injection
  Intervention: Drug: SAR422459

• Publications *: Davis JL. The Blunt End: Surgical Challenges of Gene Therapy for Inherited Retinal Diseases. Am J Ophthalmol. 2018 Dec;196:xxv-xxix. doi: 10.1016/j.ajo.2018.08.038. Epub 2018 Sep 5. Review.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 26, 2019): 27
• Original Estimated Enrollment (submitted: June 6, 2011): 28
• Actual Study Completion Date: July 2, 2019
• Actual Primary Completion Date: July 2, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Signed and dated written informed consent obtained from the patient and/or the patient's legally acceptable representative.
• Diagnosis of Stargardt's Macular Degeneration (SMD), with at least one pathogenic mutant ABCA4 allele on each chromosome.
• Women of childbearing potential must have a negative pregnancy test at Day -1, and agree to use an effective form of contraception for at least three months, or be surgically sterile or postmenopausal, with the last menstrual period being over two years prior to enrollment.
• Males must agree with their partner to use two forms of contraception for at least three months following SAR422459 administration.
• Patients must agree to not donate blood, organs, tissues or cells for at least three months following SAR422459 administration.
• Patients enrolled in France must be affiliated to or benefit from a social security regimen.

Specific Inclusion Criteria Patient Group A:

• Patients (18 years or older) with advanced Stargardt's Macular Degeneration.
• Visual acuity ≤20/200 in the worst eye.
• Severe cone-rod dysfunction with no detectable or severely abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Patient Group B:

• Patients (18 years or older) with Stargardt's Macular Degeneration.
• Visual Acuity ≤20/200 in the worst eye.
• Abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Patient Group C:

• Patients (18 years or older) with Stargardt's Macular Degeneration.
• Visual acuity ≤20/100 in the worst eye.
• Abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Patient Group D:

• Symptomatic patients (from 6 years to 26 years old) with early or childhood-onset SMD (age at disease onset <18 years) with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed by direct sequencing and co-segregation analysis within the patient's family.
• Visual acuity of ≥20/200 in both eyes at the time of the screening visit.

• Patients are anticipated to experience rapid deterioration in visual function and/or retinal structure as determined by an annual progression rate in at least one of the following parameters occurring in at least one eye (assessments recorded up to 2 years prior to the screening visit date may be considered to document evidence of rapid deterioration):

  • Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters).
  • Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry.
  • Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by >14 dB-sr as assessed by static perimetry.
  • Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate of ≥0.5 mm^2.
  • Enlargement in the area of central macular retinal thinning/photoreceptor loss by ocular coherence tomography at a rate of ≥0.5 mm^2.
• All eligible patients must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform required study procedures as judged and confirmed by the study investigator.

Specific inclusion criteria Patient Group E:

• Symptomatic patients (between 6 years and 17 years old) with early or childhood-onset SMD with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed by direct sequencing and co-segregation analysis within the patient's family.
• Visual acuity of ≥20/100 in both eyes at the time of screening visit.

• Patients are anticipated to experience rapid deterioration in visual function and/or retinal structure as determined by an annual progression rate in at least one of the following parameters occurring in at least one eye (assessments recorded up to 2 years prior to the screening visit date may be considered to document evidence of rapid deterioration):

  • Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters).
  • Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry.
  • Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by >14 dB-sr as assessed by static perimetry.
  • Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate of ≥0.5 mm^2.
  • Enlargement in the area of central macular retinal thinning/photoreceptor loss by ocular coherence tomography at a rate of ≥0.5 mm^2.
• All eligible patients must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform required study procedures as judged and confirmed by the study investigator.

Exclusion Criteria:

• Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints.
• Cataract surgery with intraocular lens implantation within 6 months of enrolment.
• Aphakia or prior vitrectomy in the study eye.
• Concomitant systemic diseases including those in which the disease itself, or the treatment for the disease, can alter ocular function.
• Any intraocular surgery or laser in either eye planned within 6 months of Day 0.
• Any contraindication to pupil dilation in either eye.
• Any known allergy to any component of the delivery vehicle or diagnostic agents used during the study, or medications planned for use in the perioperative period particularly topical, injected or systemic corticosteroids.
• Any injectable intravitreal treatment to the treated eye or intravitreal device in the treated eye within 6 months prior to screening.
• Any periocular injections of corticosteroids to the treated eye within 4 months prior to screening.
• Laboratory test abnormalities or abnormalities in electrocardiogram, chest X-rays that in the opinion of the Principal Investigator would make the patient unsuitable for participation in the study.
• Significant intercurrent illness or infection during the 28 days prior to enrolment.
• Pre-menopausal or non-surgically sterile women who are unwilling to use an effective form of contraception such as the contraceptive pill or intrauterine device.
• Alcohol or other substance abuse.
• Contraindications to use of anesthesia (local or general, as appropriate).
• Concurrent anti-retroviral therapy that would inactivate the investigational agent.
• History of any investigational agent within 28 days prior to SAR422459 administration.
• Participation in a prior ocular gene transfer therapy study.
• Enrolment in any other clinical treatment study throughout the duration of the SAR422459 study.
• Current or anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the four weeks prior to surgery.
• A past medical history of human immunodeficiency virus (HIV) or hepatitis A, B, or C infection.
• Women who are pregnant or are breastfeeding.
• History or signs consistent with unilateral amblyopia (strabismic, anisometropic, or stimulus deprivation).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, United States

Administrative Information

• NCT Number: NCT01367444
• Other Study ID Numbers: TDU13583; SG1/001/10
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Sanofi
• Study Sponsor: Sanofi
• Collaborators: Not Provided

Investigators

• Principal Investigator: Richard Weleber, MD; Oregon Health & Science University, Portland, Oregon
• Principal Investigator: Jose-Alain Sahel, MD. Ph.D; Hopital Nationale des Quinze-Vingt, Paris France

• PRS Account: Sanofi
• Verification Date: September 2019