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

Summary
EudraCT number	2012-002574-31
Trial protocol	FR
Global end of trial date	16 Aug 2019

Results information
Results version number	v1(current)
This version publication date	30 Apr 2020
First version publication date	30 Apr 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

TDU13600

ISRCTN number

US NCT number

NCT01505062

WHO universal trial number (UTN)

Other trial identifiers

Oxford Biomedica: US1/001/10

Sponsor organisation name

Sanofi-aventis Recherche & Développement

Sponsor organisation address

1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380

Public contact

Trial Transparency Team, Sanofi-aventis Recherche & Développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi-aventis Recherche & Développement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

13 Sep 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Aug 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate the safety and tolerability of ascending doses of subretinal injections of SAR421869 in subjects with Usher Syndrome Type 1B.

Protection of trial subjects

The study was conducted by investigators experienced in the treatment of adult Usher syndrome type 1B. Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the sponsors personal data protection charter ensuring that the Sponsor abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Mar 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

United States: 5

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In 2017, Sanofi suspended trials of SAR421869, while assessing its future. Until final decision was made, trial TDU13600 was not complete and in fact, further recruitment was planned. In 2019, Sanofi decided to terminate trial due to final decision on SAR421869, and shared decision with health authorities. Results have been reported expeditiously.

Screening details

A total of 11 subjects were screened. Nine subjects of them were enrolled in the study with 3 subjects in each of Cohorts 1 to 3. Due to early termination no subject was recruited in Cohorts 4 and 5.

Period 1 title

Overall (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1

Arm description

Subjects received subretinally a single injection of SAR421869 at target dose of 1.4*10^5 transducing units (TU) per eye.

Arm type

Experimental

Investigational medicinal product name

SAR421869

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Subretinal use

Dosage and administration details

Subjects received 300 microlitres (μL) of subretinal injection with vector total target dose of 1.4*10^5 TU into one eye (study eye).

Cohort 2

Arm description

Subjects received subretinally a single injection of SAR421869 at target dose of 4.7*10^5 TU per eye.

Arm type

Experimental

Investigational medicinal product name

SAR421869

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Subretinal use

Dosage and administration details

Subjects received 300 μL of subretinal injection with vector total target dose of 4.7*10^5 TU into one eye (study eye).

Cohort 3

Arm description

Subjects received subretinally a single injection of SAR421869 at target dose of 1.4*10^6 TU per eye.

Arm type

Experimental

Investigational medicinal product name

SAR421869

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Subretinal use

Dosage and administration details

Subjects received 300 μL of subretinal injection with vector total target dose of 1.4*10^6 TU into one eye (study eye).

Number of subjects in period 1	Cohort 1	Cohort 2	Cohort 3
Started	3	3	3
Completed	3	3	3

Baseline characteristics

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Reporting group title

Cohort 1

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 1.4*10^5 transducing units (TU) per eye.

Reporting group title

Cohort 2

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 4.7*10^5 TU per eye.

Reporting group title

Cohort 3

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 1.4*10^6 TU per eye.

Reporting group values	Cohort 1	Cohort 2	Cohort 3	Total
Number of subjects	3	3	3	9
Age categorical
Units: Subjects
Age continuous
Units: years
median (full range (min-max))	25 (22 to 28)	42 (32 to 57)	50 (32 to 56)	-
Gender categorical
Units: Subjects
Female	2	2	2	6
Male	1	1	1	3
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	0	0	0
White	3	3	3	9
More than one race	0	0	0	0
Unknown or Not Reported	0	0	0	0

End points

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Reporting group title

Cohort 1

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 1.4*10^5 transducing units (TU) per eye.

Reporting group title

Cohort 2

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 4.7*10^5 TU per eye.

Reporting group title

Cohort 3

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 1.4*10^6 TU per eye.

Primary: Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs)

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End point title

Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs) ^[1]

End point description

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 medicinal product (IMP). The TEAEs were defined as any event that started or increased in severity after the subject received IMP, including abnormal laboratory results, electrocardiogram, etc. Analysis was performed on all subjects diagnosed with Retinitis Pigmentosa associated Usher syndrome type 1B who were included in the study.

End point type

Primary

End point timeframe

From Baseline to Week 48

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Incidence of TEAEs were computed statistically, though they were descriptive. No p-values of cohort comparisons were derived for the early terminated study.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	3	3	3
Units: Percentage of subjects
number (not applicable)	100	100	100

No statistical analyses for this end point

Primary: Percentage of Subjects With TEAEs by Severity

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End point title

Percentage of Subjects With TEAEs by Severity ^[2]

End point description

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 subject received IMP, including abnormal laboratory results, electrocardiogram, etc. For each AE, the severity was categorised as either mild, moderate or severe where 'mild' was defined as discomfort noticed but did not interfere with the subject’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). Analysis was performed on all subjects diagnosed with Retinitis Pigmentosa associated Usher syndrome type 1B who were included in the study.

End point type

Primary

End point timeframe

From Baseline to Week 48

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Incidence of TEAEs were computed statistically, though they were descriptive. No p-values of cohort comparisons were derived for the early terminated study.

End point values	Cohort 1	Cohort 2	Cohort 3
Number of subjects analysed	3	3	3
Units: Percentage of subjects
number (not applicable)
Mild	100	100	100
Moderate	0	33	67
Severe	0	0	67

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All AEs were collected from time of first dose of study drug up to Week 48 regardless of seriousness or relationship (causality) to investigational product.

Adverse event reporting additional description

Reported AEs were TEAEs that developed/worsened during the ‘on treatment period’ (from Day 0 to Week 48). Analysis was performed on all subjects diagnosed with Retinitis Pigmentosa associated Usher syndrome type 1B who were included in the study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Cohort 1

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 1.4*10^5 TU per eye.

Reporting group title

Cohort 2

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 4.7*10^5 TU per eye.

Reporting group title

Cohort 3

Reporting group description

Subjects received subretinally a single injection of SAR421869 at target dose of 1.4*10^6 TU per eye.

Serious adverse events	Cohort 1	Cohort 2	Cohort 3
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Eye disorders
Uveitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Visual Acuity Reduced
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Cohort 1	Cohort 2	Cohort 3
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)
Investigations
Blood Creatine Phosphokinase Increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0
Intraocular Pressure Decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	1
Intraocular Pressure Increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 3 (66.67%)
occurrences all number	0	2	2
Urine Analysis Abnormal
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0
White Blood Cell Count Increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	3	0
Migraine
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Occipital Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
General disorders and administration site conditions
Chest Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Injection Site Extravasation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Eye disorders
Anterior Chamber Cell
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0
Cataract
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0
Conjunctival Haemorrhage
subjects affected / exposed	3 / 3 (100.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)
occurrences all number	3	2	0
Dyschromatopsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Eye Pain
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	2	1	1
Eye Pruritus
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	2	1	0
Macular Fibrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0
Photopsia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	0	2	1
Retinal Detachment
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0
Retinal Haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	2
Subretinal Fluid
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0
Vision Blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Visual Acuity Reduced
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	1
Vitreous Floaters
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)
occurrences all number	0	1	2
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Dental Caries
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0
Dry Mouth
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	1
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	1	0
Psychiatric disorders
Nervousness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0
Renal and urinary disorders
Glycosuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Urge Incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Increased Appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1

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Were there any global substantial amendments to the protocol? Yes

20 Oct 2011

Amendment 1: 1) Modification of Part B of the study to include subjects’ greater than or equal to (≥) 18years old (Cohort 4) with less severe disease, treated at the maximum tolerated dose from Part A. 2) Addition of Part C of the study to include subjects ≥6 years of age (Cohort 5), administered the maximum tolerated dose determined from Part A following review of the safety and efficacy data (where available) by the data safety monitoring board, regulatory authorities and institutional review board/ethics committee. 3) Modifications were made to ophthalmology assessment timepoints.

31 Aug 2012

Amendment 2: 1) Addition of an inclusion criterion required French subjects to be affiliated with the French social security system which was followed by the addition of sites in France.

31 Jan 2013

Amendment 3: 1) To ensure consistency across sites: a centralised independent assessor evaluated subject’s Day -28 visual field data to confirm eligibility, references to the subject’s legal blindness as defined by the United States of America federal statute were removed from the eligibility criteria, and details of the parameters that were used to identify the “worst seeing eye” were added. 2) Addition of ‘AEs of Special Interest’ to the protocol. 3) Update to AE severity terms to reflect the impact on the subjects wellbeing. 4) Addition of information regarding post-mortem requirements.

22 Jan 2014

Amendment 4: 1) To add that subjects in France were asked to consent to a post-mortem as part of informed consent. 2) Update to inclusion criteria to include both rod and cone derived amplitudes on the full field electroretinogram. 3) Addition of exclusion criterion to exclude breast-feeding women from the study. 4) Removal of an exclusion criteria that could have been classed as discriminatory to mentally or physically disabled subjects. 5) Amendment ensured blood volume drawn from paediatric subjects was appropriate for their body weight.

14 Apr 2014

Amendment 5: 1) Study sponsorship was transferred from Oxford BioMedica Ltd. to Sanofi; administrative updates and alignment with Sanofi protocol standards regarding the AE of special interest (AESI) and serious AE process were made.

22 Apr 2015

Amendment 6: 1) Correction of errors to versioning of previous protocol amendments. 2) Revision of the inclusion criteria for Cohorts 3, 4, and 5 to clarify target populations to include subjects with no detectable rod-derived amplitudes on the full field electroretinogram. 3) Inclusion of collection of the results of the MYO7A gene mutation documenting subject eligibility. 4) Removal of ‘Appendix C – Clinical Laboratory Tests’ as multiple local labs were used with the addition of new sites. 5) Removal of text that states that if no clinical efficacy was observed in subjects after 1 year then the subject was offered alternative therapies. 6) Addition of text to allow video of the surgery and/or intraoperative Optical Coherence Tomography were collected/obtained consent from subjects already enrolled if a video was collected at surgery.

23 Sep 2015

Amendment 7: 1) Removal of inclusion criteria added in protocol amendment 2. 2) Addition of text defining a common perioperative medication regimen.

07 Aug 2018

Amendment 8: 1) Additional 6 subjects added to Part A (dose finding) to test additional dose levels. 2) Added mention of a diluent for IMP. 3) Inclusion criteria modified to better define target population. 4) Prophylactic glucocorticoid schedule added as mandatory after surgery and IMP injection. 5) Additional list of ophthalmic AESIs were added for better safety. 6) Simplified retinotomy description to allow better adaptation of retinotomy and IMP injection to individual subjects, with respect to lesion size and target retinal areas. 7) Correction of baseline definition was provided to use the data most close to the treatment for more precise evaluation of treatment-emergent safety events and efficacy signals. This amended protocol was approved by Health Authorities, but not by institutional review boards (IRBs)/Ethics committee (EC) and not implemented at study site level.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The planned analysis was adjusted and carried out only on the available safety and tolerability data collected before the Sponsor’s decision to stop SAR421869 development prematurely.

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs)

Primary: Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs)

Primary: Percentage of Subjects With TEAEs by Severity

Primary: Percentage of Subjects With TEAEs by Severity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs)

Primary: Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs)

Primary: Percentage of Subjects With TEAEs by Severity

Primary: Percentage of Subjects With TEAEs by Severity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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