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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01367444
Recruitment Status : Terminated (Study stopped not for safety reasons. Due to review of clinical development plans and priorities, Sponsor decided to stop development of the product.)
First Posted : June 7, 2011
Results First Posted : June 5, 2020
Last Update Posted : June 5, 2020
Sponsor:
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE June 3, 2011
First Posted Date  ICMJE June 7, 2011
Results First Submitted Date  ICMJE May 19, 2020
Results First Posted Date  ICMJE June 5, 2020
Last Update Posted Date June 5, 2020
Actual Study Start Date  ICMJE June 8, 2011
Actual Primary Completion Date August 16, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 19, 2020)
  • 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.
  • 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).
Original Primary Outcome Measures  ICMJE
 (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
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (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  ICMJE Phase I/IIA Study of SAR422459 in Participants With Stargardt's Macular Degeneration
Official Title  ICMJE 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 participants with Stargardt's Macular Degeneration (SMD).

Secondary Objective:

To evaluate for possible biological activity of SAR422459.

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

Study Arms  ICMJE
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 26, 2019)
27
Original Estimated Enrollment  ICMJE
 (submitted: June 6, 2011)
28
Actual Study Completion Date  ICMJE August 16, 2019
Actual Primary Completion Date August 16, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01367444
Other Study ID Numbers  ICMJE TDU13583
SG1/001/10
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to participant 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. Participant 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://www.clinicalstudydatarequest.com/
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Sanofi
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP