Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02610582 |
| Other study ID # |
RDC-CNGA3-01 |
| Secondary ID |
2014-001874-3209 |
| Status |
Active, not recruiting |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
November 2015 |
| Est. completion date |
June 2027 |
Study information
| Verified date |
April 2024 |
| Source |
STZ eyetrial |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The purpose of this study is to proof the safety and efficacy of a single bilateral
subretinal injection of rAAV.hCNGA3 in adult and minor patients with CNGA3-linked
achromatopsia.
Description:
Title: Safety and efficacy of a bilateral single subretinal injection of rAAV.hCNGA3 in adult
and minor patients with CNGA3-linked achromatopsia investigated in a randomized, wait list
controlled, observer-masked trial
Phase: I/II
Indication: CNGA3-linked achromatopsia
Aim: to proof the safety and efficacy of a single bilateral subretinal injection of
rAAV.hCNGA3 in adult and minor patients with CNGA3-linked achromatopsia.
Study design: open, mono-center, randomized, wait list controlled, observer-masked trial
Study Population:
Inclusion Criteria (Both Eyes)
- clinical diagnosis of achromatopsia
- 6-12 years of age
- ≥ 18 years of age
- confirmed mutation in CNGA3
- BCVA ≥ 20/400
- a minimal outer nuclear layer thickness of 10µm at 3° eccentricity (normal = 38±6µm)
- ability to understand and willingness to consent to study protocol
- no infection with Human Immundeficiency Virus (HIV)
- Male patients must agree to use condoms during the first 6 months post treatment.
- Female patients of childbearing potential must agree to use an effective method of birth
control during the first 6 months post treatment.
- negative pregnancy test in women with childbearing potential (a woman who is two years
post-menopausal or surgically sterile is not considered to be of childbearing potential)
Exclusion Criteria
- • any other retinopathy due to other diseases e.g. (but not limited to) arterial
hypertension, trauma or acquired inflammatory diseases (uveitis serology) , retinopathy
of the premature
- systemic conditions (e.g. coronary heart disease, congenital/genetic conditions,
autoimmune disorders) which may affect study participation or outcome measures
- current or recent participation in other study or administration of biologic agent
within the last three months
- recent (6 months) ocular surgery, intravitreal or subretinal implantation of a medical
device
- known sensitivity to any compound used in the study
- contraindications to systemic immunosuppression
- subject/partner of childbearing potential unwilling to use adequate contraception for
six months after dosing
- nursing or pregnant female subject women
- any other cause that, in the investigator's opinion, renders potential subjects not
suitable for the study
- mutations in another achromatopsia gene
- contraindications in view of the planned surgery (e.g. anaemia Hb<8g/dl, severe
coagulopathy, severe blood pressure fluctuations) including intolerance and
contraindications to general anaesthesia
- ocular opacity and mature cataract
- ocular infection with herpes simplex virus in medical history
- history of ocular malignancies
- disorders of the internal retina (e.g. retinal detachment in the patients history)
- glaucoma defined as damage of the optic nerve
- vascular retinal occlusion
- history of poorly controlled (HbA1c > 7%) Diabetes Mellitus type 1 or type 2
- patients treated with systemic corticoids within 14 days prior inclusion
- systemic illness or medically significant abnormal laboratory values >3 UNL in blood
analysis including renal and hepatic functions at inclusion
- absence of vision on the other contralateral eye
- contraindication to pharmacological mydriasis (e.g. history of angle block glaucoma)
Patient Number: 3 Strata: Cohort A n = 4, ≥ 18 years of age and previous participation in
phaseI/II, Cohort B n = 4, ≥ 18 years of age, Cohort C n= 6, 6-12 years of age
Treatment:
Each cohort will receive a single subretinal injection of 1x10e11 vector genome particles of
rAAV.hCNGA3 in each eye at different time-points. Cohort A, in whom the first eye has
received treatment under protocol version 5.0, will only receive one injection in the second
eye.
After standard three-port 23G pars plana vitrectomy, balanced salt solution will be used to
induce a localized primary retinal detachment in a controlled fashion. Vector solution will
be applied using disposable 41G extendible subretinal injection needles within a standard 23G
body to fit the port system.
Primary Endpoint:
Primary endpoint safety: Safety assessment 12 months after treatment, descriptively Primary
endpoint efficacy: Contrast sensitivity (Pelli Robson 3 m) 6 months after treatment
Key secondary endpoints efficacy 12 months after treatment:
- Contrast sensitivity (Pelli Robson 3 m)
- BCVA assessed using the ETDRS visual acuity protocol
- Microperimetry (MAIA) (20°)
- Chromatic Pupil Campimetry
- Patient reported outcomes (VFQ25/CVFQ, A3-PRO) Safety as the primary endpoint will be
assessed by clinical examination of ocular inflammation (slit lamp, fundus
biomicroscopy, fundus photography. Systemic safety will be assessed by vital signs,
routine clinical chemistry testing (including CRP, ESR) and full/differential blood
counts. Immunopathology essays will include specific enzyme-linked immunosorbent assays
for humoral antibodies against rAAV8 capsid protein. Biodistribution will be monitored
by polymerase chain reaction studies on rAAV8 genome in blood, urine, saliva and tear
fluid.
Statistical Methods:
Efficacy: The analysis of the primary endpoint (contrast sensitivity after 6 months) will be
done using a pre / post comparison for the entire sample including both eyes for cohort B and
C (n=10) and only one eye for cohort A (n=4) with GEE correction for the dependency of left
and right eye. In the waiting group the second (therapeutic) phase will be used. The
dependency appears for cohorts B and C which contribute both eyes but not for cohort A which
contributes only one eye to the efficacy analysis. The study is powered for this analysis. We
will use the specific type of IEE (Independence Estimating Equations) which reveals correct
standard errors and a robust estimate for model parameters.
Additionally, we will compare the Intervention group vs. control group (waiting group) (n=7
vs. 7), using baseline adjusted analysis of covariance and between subject comparisons. This
analysis will use GEEs as described for the primary analysis including both eyes of cohort B
and C and only the newly treated eye in cohort A. This analysis will be descriptive and
provide evidence for the planning of a randomized Phase III trial.
The primary analysis population will be the ITT in which only patients with baseline
measurements will be included. For patients providing baseline measurements in one eye, only
this eye will be included. Multiple imputation will be done with sampling unit "eye" if only
baseline, but not follow up data are available. Descriptive parameters will be given for the
full cohort (n=14) and for the sub-strata (n=4, 4, 6 pooled), additionally, correlation
analysis descriptively for the comparison of subjective and objective measurements will be
done.
Safety (ITT): AEs and SAEs will be documented using line listings and tabulations (MedDRA
code will be applied). Frequency tabulations of certain classes of events will be given
including two-sided 95% confidence intervals.
The aim of analysis (1) is to gain evidence for a sample size estimation for a phase III
trial with similar design, where analysis (2) will be confirmatory and powered according to a
sample size estimation.
Time Schedule: of trial November 2015 end of recruitment 04/2022, end of trial 04/2027,
duration of trial per patient: one year with four years of follow-up.
The final study report will be prepared after completion of the four year follow-up period (5
years after treatment).
