Study of SAR421869 in Participants With Retinitis Pigmentosa Associated With Usher Syndrome Type 1B

A Phase I/IIA Dose Escalation Safety Study of Subretinally Injected SAR421869, Administered to Patients With Retinitis Pigmentosa Associated With Usher Syndrome Type 1B

To evaluate the safety and tolerability of ascending doses of subretinal injections of SAR421869 in participants with Usher syndrome type 1B.

To evaluate for possible biological activity of SAR421869.

Study Overview

• Status: Terminated
• Conditions: Retinitis Pigmentosa; Usher Syndrome
• Intervention / Treatment: Drug: SAR421869

Detailed Description

Following screening procedures, the gene transfer agent were injected once only under the retina by an opthalmic surgeon under anesthesia. Participants then had regular follow-up visits where general health examinations, blood tests and ophthalmic examinations including best corrected visual acuity, slit lamp examination, intraocular pressure, fundoscopy, autofluorescence, optical coherence tomography, perimetry and electroretinogram were undertaken.

At the end of the study, the participants were invited to enter in an open-label safety study for long-term follow-up visits (at least once every six months) including ophthalmological examinations and recording of adverse events (AEs) were continued for 5 years; then the Investigator followed the participants by telephone for a subsequent 10 years at a minimum interval of once a year to monitor delayed AEs.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 75012
    • Investigational Site Number 250001
• United States
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Investigational Site Number 840001

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Clinical and molecular diagnosis of Retinitis Pigmentosa associated with Usher Syndrome type 1B, caused by at least one pathogenic myosin 7a gene (MYO7A) mutation on both alleles, confirmed by direct sequencing and co-segregation analysis within the participant's family.
• Suitable verbal/auditory and/or tactile sign language communication (in the opinion of the investigator) as to allow written informed consent to be obtained.
• Women of childbearing potential had a negative pregnancy test at screening and at baseline, and agree to use an effective form of contraception such as the contraceptive pill or intra uterine device for at least three months following SAR421869 administration, or be surgically sterile or postmenopausal, with the last menstrual period being over two years prior to enrolment.
• Males of reproductive potential agreed with their partner to use two forms of contraception, including one barrier method for at least three months following SAR421869 administration if their partner was of childbearing capacity, or must be surgically sterile.
• Participants agreed to not donate blood, organs, tissues or cells for at least three months following SAR421869 administration.

Exclusion Criteria:

• Presence of significant ocular abnormalities in the study eye that in the opinion of the investigator would preclude the planned surgery, effective safety follow-up, or interfere with the interpretation of study outcome measures (e.g., glaucoma, corneal or significant lens opacities, pre-existing uveitis, intraocular infection, choroidal neovascularization).
• Any pre-existing factor or past history of eye disease in children that might predispose to an increased risk of surgical complications in the study eye (e.g., trauma, previous surgery, uveitis, congenital, developmental or structural abnormalities).
• Concomitant systemic diseases including those in which the disease itself, or the treatment for the disease, can alter ocular function (e.g., malignancies, diabetes, juvenile rheumatoid arthritis or sickle cell disease).
• Any contraindication to pupil dilation in either eye.
• Contraindications to use of anesthesia (local or general, as appropriate).
• Treatment with intravitreal, subtenon, or periocular steroid within 4 months of the screening visit.
• Any known allergy to any component of the delivery vehicle or diagnostic agents used during the study (e.g., fluorescein, dilation drops), or medications planned for use during the peri-operative period, particularly topical, injected or systemic corticosteroids.
• Life-threatening illness.
• Alcohol or other substance abuse.
• History of malignancy within a five year period or have had a positive cancer screening test within a one year period of the screening visit.
• Laboratory test abnormalities or abnormalities in electrocardiogram or chest X-ray, that in the opinion of the principal investigator, are clinically significant and would make the participant unsuitable for participation in the study.
• Intercurrent illness or infection 28 days prior to SAR421869 administration.
• Concurrent anti-retroviral therapy that would inactivate the investigational agent.
• Current treatment with immunosuppressant therapies.
• 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.
• Men or women who did not agree to use barrier contraception as specified in the inclusion criteria.
• Pregnant or breastfeeding women.
• History of any investigational agent within 28 days prior to SAR421869 administration.
• Participation in a prior gene transfer therapy study.
• Enrolment in any other clinical study, for any condition, including those relating to Usher syndrome Type 1B, throughout the duration of the SAR421869 study.
• Current or anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the four weeks prior to surgery.
• Past medical history of HIV, or hepatitis A, B or C.
• Inability to comply with the study protocol.
• Any ocular surgery including laser and cataract surgery with intraocular lens implantation, aphakia or prior vitrectomy, in the study eye within 6 months of screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAR421869 (Cohort 1); Starting dose of SAR421869 given through one subretinal injection.	Drug: SAR421869; Formulation: Sterile suspension for intraocular injection, 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; Other Names: UshStat®
Experimental: SAR421869 (Cohort 2); Escalating dose of SAR421869 given through one subretinal injection.	Drug: SAR421869; Formulation: Sterile suspension for intraocular injection, 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; Other Names: UshStat®
Experimental: SAR421869 (Cohort 3); Escalating dose of SAR421869 given through one subretinal injection.	Drug: SAR421869; Formulation: Sterile suspension for intraocular injection, 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; Other Names: UshStat®
Experimental: SAR421869 (Cohort 4); Maximum tolerated dose (MTD) of SAR421869 given through one subretinal injection.	Drug: SAR421869; Formulation: Sterile suspension for intraocular injection, 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; Other Names: UshStat®
Experimental: SAR421869 (Cohort 5); MTD of SAR421869 given through one subretinal injection.	Drug: SAR421869; Formulation: Sterile suspension for intraocular injection, 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; Other Names: UshStat®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	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 IMP. The TEAEs were defined as any event that started or increased in severity after the participant received IMP, including abnormal laboratory results, electrocardiogram, etc.	From Baseline to Week 48
Percentage of Participants With TEAEs by Severity	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 IMP. The TEAEs were defined as any event that started or increased in severity after the participant received IMP, including abnormal laboratory results, electrocardiogram, etc. 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).	From Baseline to Week 48

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Principal Investigator: Richard Weleber, MD, Casey Eye Institute, Portland, Oregon; Principal Investigator: Jose-Alain Sahel, MD, PhD, Hopital Nationale des Quinze-Vingt, Paris France

Publications and helpful links

General Publications

• Zallocchi M, Binley K, Lad Y, Ellis S, Widdowson P, Iqball S, Scripps V, Kelleher M, Loader J, Miskin J, Peng YW, Wang WM, Cheung L, Delimont D, Mitrophanous KA, Cosgrove D. EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat. PLoS One. 2014 Apr 4;9(4):e94272. doi: 10.1371/journal.pone.0094272. eCollection 2014.

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2012
• Primary Completion (Actual): August 16, 2019
• Study Completion (Actual): August 16, 2019

Study Registration Dates

• First Submitted: January 4, 2012
• First Submitted That Met QC Criteria: January 5, 2012
• First Posted (Estimate): January 6, 2012

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: March 30, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Usher Syndrome Retinitis Pigmentosa; Usher Syndrome associated Retinitis Pigmentosa
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Disease; Congenital Abnormalities; Retinal Degeneration; Retinal Diseases; Genetic Diseases, Inborn; Otorhinolaryngologic Diseases; Ear Diseases; Eye Diseases, Hereditary; Retinal Dystrophies; Sensation Disorders; Abnormalities, Multiple; Hearing Disorders; Vision Disorders; Deaf-Blind Disorders; Hearing Loss, Sensorineural; Blindness; Hearing Loss; Deafness; Syndrome; Retinitis; Retinitis Pigmentosa; Usher Syndromes
• Other Study ID Numbers: TDU13600; US1/001/10 (Other Identifier: Oxford Biomedica)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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