Phase I/IIA Study of SAR422459 in Participants With Stargardt's Macular Degeneration

• ClinicalTrials.gov Identifier: NCT01367444
• Recruitment Status: Terminated
• First Posted: June 7, 2011
• Results First Posted: June 5, 2020
• Last Update Posted: April 14, 2022
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

Primary Objective:

To assess the safety and tolerability of ascending doses of SAR422459 in participants with Stargardt's Macular Degeneration (SMD).

Secondary Objective:

To evaluate for possible biological activity of SAR422459.

Condition or disease	Intervention/treatment	Phase
Stargardt's Disease	Drug: SAR422459	Phase 1; Phase 2

Detailed Description:

The total duration per participant was up to 52 weeks, which included 4 week screening period and 48 weeks study period.

At the end of the study, the participants were invited to enter in an open-label safety study (LTS13588-NCT01736592) for long-term follow-up visits including ophthalmological examinations and recording of adverse events (AEs) for up to 15 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/IIA Dose Escalation Safety Study of Subretinally Injected SAR422459, Administered to Patients With Stargardt's Macular Degeneration
• Actual Study Start Date: June 8, 2011
• Actual Primary Completion Date: August 16, 2019
• Actual Study Completion Date: August 16, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: SAR422459 (Dose 1); Starting dose of SAR422459 given through subretinal injection	Drug: SAR422459; Pharmaceutical form: sterile solution, 100 microliters (μL) aliquots in 0.3 milliliter (mL) type I borosilicate glass 'V' vials with a butyl stopper and aluminum crimp seal. Route of administration: subretinal injection
Experimental: SAR422459 (Dose 2); Escalating dose of SAR422459 given through subretinal injection	Drug: SAR422459; Pharmaceutical form: sterile solution, 100 microliters (μL) aliquots in 0.3 milliliter (mL) type I borosilicate glass 'V' vials with a butyl stopper and aluminum crimp seal. Route of administration: subretinal injection
Experimental: SAR422459 (Dose 3); Maximum tolerated dose (MTD) of SAR422459 given through subretinal injection	Drug: SAR422459; Pharmaceutical form: sterile solution, 100 microliters (μL) aliquots in 0.3 milliliter (mL) type I borosilicate glass 'V' vials with a butyl stopper and aluminum crimp seal. Route of administration: subretinal injection

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From Baseline to Week 48 ]
   An adverse event (AE) was any unfavorable and unintended physical sign, symptom, or laboratory parameter that developed or worsened in severity during the course of the study, whether or not considered related to the investigational product. The TEAEs were defined as any event that started or increased in severity after the participant received investigational medicinal product (IMP), including abnormal laboratory results, electrocardiogram, etc.
2. Percentage of Participants With TEAEs by Severity [ Time Frame: From Baseline to Week 48 ]
   An AE was any unfavorable and unintended physical sign, symptom, or laboratory parameter that developed or worsened in severity during the course of the study, whether or not considered related to the investigational product. For each AE, the severity was categorized as either mild, moderate or severe where 'mild' was defined as discomfort noticed but did not interfere with the participant's daily routines (an annoyance), 'moderate' was defined as some impairment of function, not hazardous to health (uncomfortable or embarrassing), and 'severe' was defined as significant impairment of function, hazardous to health (incapacitating).

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Signed and dated written informed consent obtained from the participant and/or the participant's legally acceptable representative.
• Diagnosis of SMD, with at least one pathogenic mutant ABCA4 allele on each chromosome.
• Women of childbearing potential must had 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.
• Participants must agree to not donate blood, organs, tissues or cells for at least three months following SAR422459 administration.
• Participants enrolled in France must be affiliated to or benefit from a social security regimen.

Specific Inclusion Criteria Participant Group A:

• Participants (18 years or older) with advanced SMD.
• Visual acuity less than or equal to (<=) 20/200 in the worst eye.
• Severe cone-rod dysfunction with no detectable or severely abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Participant Group B:

• Participants (18 years or older) with SMD.
• Visual Acuity <=20/200 in the worst eye.
• Abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Participant Group C:

• Participants (18 years or older) with SMD.
• Visual acuity <=20/100 in the worst eye.
• Abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Participant Group D:

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

• Participants were 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 might be considered to document evidence of rapid deterioration):

  • Loss of >=1 line of Snellen visual acuity (equivalent to 5 early treatment diabetic retinopathy study [ETDRS] letters).
  • Reduction in macular mean sensitivity of >=1.2 decibels (dB) as assessed by microperimetry.
  • Reduction in macular mean sensitivity of >=5 dB or reduction in hill of vision by greater than (>)14 dB-sr as assessed by static perimetry.
  • Enlargement in the area of macular retinal pigment epithelial (RPE) atrophy by fundus autofluorescence at a rate of >=0.5 millimeter square(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 participants 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 Participant Group E:

• Symptomatic participants (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 participant's family.
• Visual acuity of >=20/100 in both eyes at the time of screening visit.

• Participants were 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 were 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 participants demonstrated 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 outcome measures.
• 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 participant 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 were 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 or hepatitis A, B, or C infection.
• Women who were pregnant or were breastfeeding.
• History or signs consistent with unilateral amblyopia (strabismic, anisometropic, or stimulus deprivation).

Contacts and Locations

Locations

United States, Florida

Investigational Site Number 840002

Miami, Florida, United States, 33136

United States, Iowa

Investigational Site Number 840005

Iowa City, Iowa, United States, 52242

United States, Oregon

Investigational Site Number 840001

Portland, Oregon, United States, 97239-3098

United States, Texas

Investigational Site Number 840004

Houston, Texas, United States, 77030

France

Investigational Site Number 250001

Paris, France, 75012

Sponsors and Collaborators

Sanofi

Investigators

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

  Study Documents (Full-Text)

Documents provided by Sanofi:

Study Protocol  [PDF] November 29, 2018

Statistical Analysis Plan  [PDF] September 16, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Parker MA, Choi D, Erker LR, Pennesi ME, Yang P, Chegarnov EN, Steinkamp PN, Schlechter CL, Dhaenens CM, Mohand-Said S, Audo I, Sahel J, Weleber RG, Wilson DJ. Test-Retest Variability of Functional and Structural Parameters in Patients with Stargardt Disease Participating in the SAR422459 Gene Therapy Trial. Transl Vis Sci Technol. 2016 Oct 1;5(5):10. doi: 10.1167/tvst.5.5.10. eCollection 2016 Oct.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01367444
• Other Study ID Numbers: TDU13583; SG1/001/10
• First Posted: June 7, 2011
• Results First Posted: June 5, 2020
• Last Update Posted: April 14, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sanofi:

Stargardt's Disease

Additional relevant MeSH terms:

Macular Degeneration; Stargardt Disease; Retinal Degeneration; Retinal Diseases; Eye Diseases; Eye Diseases, Hereditary; Genetic Diseases, Inborn