Primary-To evaluate the safety and tolerability of a single dose of EDIT-101 when administered to participants with LCA10-IVS26 mutationSecondary-To evaluate different doses of EDIT-101 for subsequent clinical evaluation-To evaluate the efficacy of…
ID
Source
Brief title
Condition
- Eye disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Incidence of DLT, as detailed in Section 8.3.8.1 of the protocol
• Frequency of AEs related to EDIT-101
• Number of procedural related AEs
Secondary outcome
Secondary
-Maximum tolerated dose as determined by DLT
-Change from baseline in the following parameters:
* Visual Function Navigation course score of the study eye, contralateral eye,
and both eyes together
* logMAR measurement of BCVA
* Pupil size in dark (maximum diameter), pupil size in light (minimum
diameter), mean pupil constriction velocity, maximum pupil constriction
velocity, amount of constriction after stimulus, percent of constriction after
stimulus
* Gaze tracking
* Dark adapted visual sensitivity to white, red, and blue light
* The thickness of the ONL and integrity of the ellipsoid zone
* LogMAR measurement of contrast sensitivity.
* Macular sensitivity
* Visual field
* Farnsworth 15 score
* QoL questionnaires
* Global Impressions of Change
* Global Impressions of Severity
Exploratory
• Detection of anti-drug antibodies to AAV5 (BAB by ELISA and NAB using a
cell-based assay) and Cas9 (BAB by ELISA)
• Detection of T cell response to AAV5 and Cas9 by ELISPOT
• Quantification of vector DNA in blood, nasal mucosa, semen, and tears
• Changes in area of autofluorescence
Background summary
LCA10-IVS26-related retinal degeneration is an ultra-rare and seriously
debilitating disease, usually emerging early in infancy and resulting in
significant vision loss. There are currently no approved treatments for
LCA10-IVS26. EDIT-101 (chemical name: AAV5-CEP290gRNA323/64-GRK1-SaCas9) is a
novel gene editing product designed to eliminate the mutation on the CEP290
gene that results in the retinal degeneration that defines LCA10-IVS26. In
vitro studies and preliminary results from a first-in-human study of the
investigational product QR-110 (www.clinicaltrials.gov NCT03140969) suggest
that the cellular and functional changes induced in Leber congenital amaurosis
type 10 (LCA10) patients may be reversible following a treatment that increases
levels of the centrosomal protein 290 (CEP290) protein. As such, EDIT-101 has
the potential to improve visual function in these patients.
Study objective
Primary
-To evaluate the safety and tolerability of a single dose of EDIT-101 when
administered to participants with LCA10-IVS26 mutation
Secondary
-To evaluate different doses of EDIT-101 for subsequent clinical evaluation
-To evaluate the efficacy of a single dose of EDIT-101 on:
* Visual Function Navigation (Ora-VNC)
* Visual acuity
* Pupillometry
* Oculomotor control and instability (OCI)
* Full field light sensitivity threshold (FST)
* OCT
* Contrast sensitivity
* Microperimetry
* Kinetic perimetry
* Color vision
* QoL
Exploratory
-To evaluate an immune response to EDIT-101
-To evaluate viral shedding in blood, nasal mucosa, semen, and tears
-Fundus autofluorescence (FAF and NIRAF)
Study design
This is an open-label, single ascending dose study of EDIT-101 in adult and
pediatric (ie, ages 3 to 17) participants with LCA10-IVS26. Approximately 18
participants will be enrolled in up to 5 cohorts to evaluate up to 3 dose
levels of EDIT-101 in this study.
Participants will receive a single study intervention treatment (EDIT-101)
administered, following vitrectomy via subretinal injection) in one eye (the
study eye). The study eye will be determined at Screening: if both eyes meet
eligibility criteria, the eye with the worse visual acuity will be chosen as
the study eye. Participants will be followed on study for 3 years, after which
they will be asked to consent to participate in a long-term follow-up study for
an additional 12 years.
Administration (via subretinal injection surgery) of EDIT-101 will occur at
study sites that have been selected by the sponsor based on their suitable
surgical facilities and their expertise in performing the necessary retinal
surgery.
Dose escalation and cohort progression will be determined by the sponsor, the
investigators, and an independent data monitoring committee (IDMC).
Intervention
Participants will receive a single study intervention treatment (EDIT-101
administered, following vitrectomy, via subretinal injection) in one eye (the
study eye). The study eye will be determined at screening: if both eyes meet
eligibility criteria, the eye with the worse visual acuity will be chosen as
the study eye.
Study burden and risks
The study will include a total of 20 visits and will be 3 years in duration.
Subjects are expected to undergo procedures/assessments as described in the
section 1.3 of the study protocol, which include: Physical exam, vital signs,
demographic and medical history; ECG; Blood and urine tests (including urine
drug screening); Completion of questionnaire and answering questions from the
study team; Pregnancy tests in women of childbearing potential; Female
patients: no breastfeeding allowed.
Risks of the Study Drug
- There is a theoretical risk that the study drug could spread to other parts
of the patient's body. If the study drug were to spread to other parts of your
body, it is possible that they could have a systemic reaction (discomfort
throughout the body). Animal studies with other AAV investigational treatments
showed that the risk of spread was very low and that general discomfort in the
body would be mild and only last a short time if it happens.
- There is also a theoretical risk that the study drug can create changes in
the patient's genes at places outside of the CEP290 gene. This can cause damage
to the genes in their retina or other parts of their body. This type of damage
was not seen in laboratory studies done to prepare for this clinical trial.
In those studies the study drug did not appear to make unwanted changes in the
genes of human cells. Since the study drug will stay in the retina permanently,
there may be a small risk of unwanted changes in the patient's genes that could
occur over time. In the great majority of cases, such unwanted gene changes
would not create medical problems in the treated portions of the retina. It is
possible such gene changes could change how the retinal cells work.
- The patient may receive either too little or too much of the study drug. If
they get too little, there could be a lack of benefit to their visual function,
and it may be more difficult to give an effective dose in the future, due to
the prior surgery. If too much is given, it is possible that damage to the
retina could occur, which could result in worse vision.
- There is a risk that the study drug could be delivered to the vitreous (the
center compartment of the eye) instead of going to the location we plan to
inject it (under the retina or subretinal). This could happen if tissue in the
retina has become scarred as part of the disease process. If this happens
during the surgery, the surgeon will remove the study drug from the vitreous
and repeat the procedure in another portion of the retina, if possible. If the
treatment works, it is possible that the patient may be disturbed and
uncomfortable having additional vision. Treatment for such an unlikely outcome
will be made available to the patient.
Risks associated with the Vitrectomy Surgery and the Injection Procedure
- Bleeding under the retina
- Cloudiness of the lens of the eye (cataract)
- Blood on the outside of the eye (conjunctival hemorrhage )
- Scratch on the surface of the eye (corneal abrasion)
- Swelling of the surface layer of the eye (corneal edema)
- Loss of sight (decreased visual acuity)
- Droopy eyelid
- Dry eye syndrome
- Increased pressure within the eye (elevated intraocular pressure )
- Eye irritation
- Eye pain
- Fluid accumulation behind the retina
- Fluid accumulation within the macula
- Swelling of the outside of the eye and/or white blood cells inside the eye
(inflammation on or within the eye)
- Damage to the center part of the retina (macular injury)
- A hole occurs in the central part of the retina (macular hole )
- Wrinkling on the surface of the center part of the retina (maculopathy)
- Swelling of the interior of the eye (Ocular (eye) infection including
endophthalmitis )
- Optic nerve damage
- The retina separates from the back of the eye (retinal detachment)
- Damage to the retina outside the macula (retinal thinning)
- Membranes can distort the macula (traction on the macula)
- Blood in the vitreous cavity (vitreous hemorrhage)
Risks associated with the use of short-term oral prednisone
Prednisone is a drug that decreases inflammation and swelling. Common side
effects of prednisone include:
- increased blood pressure
- fluid retention
- increased blood glucose
- weight gain
- increased appetite
- an upset stomach
- nervousness or restlessness.
Allergic Reaction Risks
As with taking any treatment, there is a risk of allergic reaction during this
study. Some symptoms of allergic reactions are:
- Rash
- Wheezing and difficulty breathing
- Dizziness and fainting
- Swelling around the mouth, throat or eyes
- A fast pulse
- Sweating
Risks of Local or General Anesthesia
- There are serious but very rare adverse events (negative side effects)
related to any type of anesthesia and surgery. These can include:
o seizure
o coma
o death.
- Rare but serious problems connected with general anesthesia include:
o irregular heartbeat
o increases or decreases in blood pressure
o a rapid increase in body temperature
o rare reactions to medications used in the anesthesia
o blockage of breathing passages.
Eye examination risks
- During the study, various eye tests will be performed on the eyes. Some of
these tests may require patients to sit in a dark room or have their eyes
patched for approximately an hour. The eyes will be exposed to bright lights
that may cause some discomfort. The risks of such light exposure are minimal.
The devices use safe levels of light. Some patients may experience some neck
discomfort from sitting at the chin rest for 15-10 minutes at a time.
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Age
Inclusion criteria
-Adult participants enrolling in Cohorts 1, 2, or 3 must be at least 18 years
of age at the time of informed consent. Pediatric participants enrolling in
Cohorts 4 or 5 must be 3 to 17 years of age, inclusive, at the time of informed
consent.
-CEP290-related retinal degeneration caused by a homozygous or compound
heterozygous mutation involving c.2991+1655A>G in IVS26 of the CEP290 gene
confirmed by DNA sequencing (ie, 1 or 2 intron 26 c.2991+1655A>G mutations) and
100% match for both gRNA and PAM sequences.
-Male or Female.
-A sexually mature male participant must agree to use contraception as detailed
in Section 10.7 of this protocol from the time of informed consent through at
least 12 months after study intervention, and to refrain from donating sperm
during this period.
-A female participant is eligible to participate if she is not pregnant (has a
negative urine pregnancy result prior to study intervention), not
breastfeeding, and at least one of the following conditions applies: Not a
WOCBP as defined in Protocol Section 10.7, OR A WOCBP, or who reaches
childbearing potential during the study, who agrees to follow
the contraceptive guidance in Protocol Section 10.7 from the time of informed
consent through at least 12 months after study intervention.
-The participant (or guardian, in the case of a minor) must provide written
informed consent prior to any study related procedures. Minors must provide
assent in accordance with country and local regulations, as applicable.
-Both eyes must be at least LP. The study eye will be the worse seeing eye and
must meet the following BCVA criteria:
Cohort 1: BWD, WFP, or LP
Cohorts 2 - 5: LP to 0.4 logMAR (20/50 Snellen equivalent). ). Note: The
sentinel participant in each of these cohorts will have severe vision loss with
a logMAR BCVA of >=1.6 to 3.9 (20/800 or worse to LP) in the study eye.
Subsequent participants in each cohort will have LP to 0.4 logMAR (20/50
Snellen equivalent) best-corrected visual acuity in the study eye. If both eyes
have the same BCVA but the worse seeing eye (as determined by the participant
and the examiner) does not meet the above criteria, the better seeing eye may
be designated as the study eye as long as the participant agrees and the better
seeing eye meets all eligibility criteria.
-Photoreceptor ONL identifiable in fovea by spectral domain OCT in the study
eye.
-Able, as assessed by the investigator, and willing to complete study
assessments and follow study instructions for the duration of the study.
-If currently enrolled in Study EDIT-NHS01 (the Natural History Study of
CEP290-Related Retinal Degeneration), the participant must agree to complete
the early
termination visit for that study, and be withdrawn from that study, before
enrolling in this study.
Exclusion criteria
-Other known disease-causing mutations documented in the participant's medical
history or identified through the retinal dystrophy gene panel evaluation
performed at screening (including but not limited to bi-allelic mutations in
other genes known to cause LCA) that, in the opinion of the investigator, would
interfere with the potential therapeutic effect of the investigational product
or the quality of the assessments.
-Achieves a passing score for the Visual Function Navigation course at the
maximum level of difficulty (ie, passes the most challenging Visual Function
Navigation course under the
dimmest lighting conditions) with either eye independently or both eyes
together.
-In either eye, cataract surgery in the last 3 months before the screening
visit.
-In either eye, any active ocular/intraocular infection or inflammation (such
as blepharitis, infectious conjunctivitis, keratitis, scleritis,
endophthalmitis, idiopathic or autoimmune-associated uveitis, or herpetic
lesions), assessed at screening.
-In either eye, history of steroid-responsive intraocular pressure increases
such that the affected eye had a pressure > 25 mm Hg following corticosteroid
exposure despite topical
intraocular-pressure-lowering pharmacologic therapy.
-In either eye, Argus retinal implant.
-In the study eye, absence of clear ocular media and adequate pupil dilation,
assessed at screening, to permit good quality OCT images.
-In the study eye, presence of vitreous hemorrhage.
-In the study eye, any history of rhegmatogenous retinal detachment.
-In the study eye, spherical equivalent of the refractive error demonstrating
more than -8 diopters of myopia and more than +6 diopters of hyperopia (prior
to cataract or refractive surgery), assessed at screening.
-Uncontrolled diabetes mellitus (hemoglobin A1c >=10%) in the last 3 months
before the screening visit or at screening.
-Active gastric ulcer at screening.
-Use of systemic immunosuppressive medications for any chronic disease in the
last 3 months before the screening visit, or during the screening period.
-Any vaccination/immunization in the last 28 days before screening, or during
the screening period.
-An inability or unwillingness to take the course of oral prednisone that is
required in this study.
-Current enrollment in an investigational interventional drug or device study
(ocular or non-ocular) or participation in such a study within 6 months before
the screening visit.
(This does not include observational studies. Prior or current participation in
Study EDIT-NHS01 is not an exclusion.)
-Received prior gene therapy or oligonucleotide treatment of any kind.
-The participant has a condition or is in a situation which, in the
investigator's or operating surgeon's opinion, may put the participant at
significant risk, may confound the study results, or may interfere
significantly with the participant's participation in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004981-16-NL |
| ClinicalTrials.gov | NCT03872479 |
| CCMO | NL73358.000.21 |