A Phase I/IIA Dose Escalation Safety Study of Subretinally Injected SAR421869, Administered to Patients With Retinitis Pigmentosa Associated With Usher Syndrome Type 1B
Overview
- Phase
- Phase 1
- Intervention
- SAR421869
- Conditions
- Usher Syndrome
- Sponsor
- Sanofi
- Enrollment
- 9
- Locations
- 2
- Primary Endpoint
- Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
- Status
- Terminated
- Last Updated
- 4 years ago
Overview
Brief Summary
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.
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.
Investigators
Eligibility Criteria
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.
Arms & Interventions
SAR421869 (Cohort 1)
Starting dose of SAR421869 given through one subretinal injection.
Intervention: SAR421869
SAR421869 (Cohort 2)
Escalating dose of SAR421869 given through one subretinal injection.
Intervention: SAR421869
SAR421869 (Cohort 3)
Escalating dose of SAR421869 given through one subretinal injection.
Intervention: SAR421869
SAR421869 (Cohort 4)
Maximum tolerated dose (MTD) of SAR421869 given through one subretinal injection.
Intervention: SAR421869
SAR421869 (Cohort 5)
MTD of SAR421869 given through one subretinal injection.
Intervention: SAR421869
Outcomes
Primary Outcomes
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 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.
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 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).