Informations générales (source: ClinicalTrials.gov)
A Phase I/II Study to Assess the Safety and Tolerability of a Single Subretinal Administration of SPVN06 Gene Therapy in Subjects with Rod-Cone Dystrophy (RCD) Due to a Mutation in the RHO, PDE6A, or PDE6B Gene (PRODYGY)
Interventional
Phase 1/Phase 2
SparingVision (Voir sur ClinicalTrials)
avril 2023
mars 2029
20 septembre 2024
This is a two-step, multicenter, Phase I/II study including an open-label dose-escalation
phase (Step 1) and a three-arm, controlled, double-masked, randomized extension phase
(Step 2), in subjects with advanced RCD due to a mutation in the RHO, PDE6A, or PDE6B
gene.
Etablissements
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CHNO DES QUINZE-VINGTS PARIS | Berthe Pom | Contact (sur clinicalTrials) | |||
Critères
Tous
Inclusion Criteria:
Subjects will be eligible to participate in this study only if all the following criteria
apply:
1. Able to give signed informed consent and comply with the requirements and
restrictions listed in the informed consent form (ICF) and in the protocol.
2. Age ≥18 years at the time of ICF signature.
3. Subjects of either gender previously diagnosed with advanced RCD due to biallelic
mutations in the rod cGMP phosphodiesterase 6 beta (PDE6B) or rod cGMP
phosphodiesterase alpha (PDE6A) genes, or due to a monoallelic dominant mutation in
the rhodopsin (RHO) gene. The genotyping results must be documented before the
initiation of the Screening Visit. Subjects should be retested by the investigator
if their genotyping tests were not performed within the 7 previous years, or if they
were not performed by an accredited laboratory. In this case, the screening period
can be prolonged for 2 additional weeks to allow time to generate genotyping
results.
4. Advanced stage is defined as a stage of the natural history of the disease where
both distance visual acuity and visual field are affected in both eyes. Substages
within the advanced stage are defined as follows (monocular measurements, horizontal
axis of isopter III4e for the visual field):
- Severe stage is defined by both a BCVA below or equal to 20/200 and above or
equal to 20/800, and a visual field below or equal to 20 degrees (subjects of
Cohorts 1 to 3)
- Intermediate stage is defined by both a BCVA below or equal to 20/40 and above
20/200, and a visual field below or equal to 20 degrees (subjects of Cohorts 4
to 6)
5. For subjects with severe advanced RCD enrolled in Step 1 only, the difference in
visual acuity between the two eyes of a given subject should be equal to or below
0.3 logarithm of the minimal angle (LogMAR) (≤3 ETDRS lines), with a tolerance
margin of 3 ETDRS letters.
6. Clinical diagnosis of RCD based on past medical and family history, mid-peripheral
visual field dysfunction, photopsia, night blindness (nyctalopia), and fundoscopic
appearance (including but not restricted to bone spicule pigmentation, attenuation
of the retinal vessels, and waxy pallor of the optic nerve).
7. Diagnosis of RCD is confirmed on prior full-field ERG (any previously performed ERG
is acceptable).
8. Documented preservation of cone inner and outer segments considered good enough by
the investigator for the subject to be included in the study.
9. Negative serum pregnancy test for women of childbearing potential (please refer to
Schedule of Assessments for details).
10. Women of childbearing potential (WOCBP) and men and/or their partner(s) of
childbearing potential must agree to use a highly effective contraceptive method.
This applies to the time period between ICF signature and 12 months after SPVN06
subretinal injection SRI (i.e., no longer applicable to subjects of Cohort 4 after
randomization). The definition of highly effective contraceptive methods follows
CTFG recommendations. Highly effective contraceptive methods are limited to:
- Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation:
- Oral
- Intravaginal
- Transdermal
- Progestogen-only hormonal contraception associated with inhibition of
ovulation:
- Oral
- Injectable
- Implantable
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion
- Vasectomized partner
- Sexual abstinence
11. Subjects must be affiliated to a health security system, if they are included in a
clinical site based in France (per law).
12. No out-of-range values for clinical laboratory tests, however, if outside, must be
considered as non-clinically relevant by the investigator using a multidisciplinary
approach and compatible with a participation in the clinical study.
13. 12-lead electrocardiogram within normal limits, however, when outside, must be
documented by the investigator using a multidisciplinary approach as not clinically
relevant and compatible with a participation in the clinical study. Nota bene: This
criterion of eligibility is only applicable to subjects assigned to a treatment
cohort (Cohorts 1, 2, 3, 5, or 6), and is not required to authorize randomization in
Step 2.
14. Physical examination without any clinical findings of clinical relevance (per
medical/anesthesia staffs judgment) that could compromise participation in the
clinical study or could affect the collection and/or evaluation of the study
parameters. The findings of clinical relevance considered as contraindications to
SPVN06 treatment include, but are not limited to, pulmonary pathology such as COPD,
asthma, cardiac conditions such as congestive heart failure or valve disease, renal
issues such as renal insufficiency and endocrine issues such as diabetes.
Subjects will be eligible to participate in this study only if all the following criteria
apply:
1. Able to give signed informed consent and comply with the requirements and
restrictions listed in the informed consent form (ICF) and in the protocol.
2. Age ≥18 years at the time of ICF signature.
3. Subjects of either gender previously diagnosed with advanced RCD due to biallelic
mutations in the rod cGMP phosphodiesterase 6 beta (PDE6B) or rod cGMP
phosphodiesterase alpha (PDE6A) genes, or due to a monoallelic dominant mutation in
the rhodopsin (RHO) gene. The genotyping results must be documented before the
initiation of the Screening Visit. Subjects should be retested by the investigator
if their genotyping tests were not performed within the 7 previous years, or if they
were not performed by an accredited laboratory. In this case, the screening period
can be prolonged for 2 additional weeks to allow time to generate genotyping
results.
4. Advanced stage is defined as a stage of the natural history of the disease where
both distance visual acuity and visual field are affected in both eyes. Substages
within the advanced stage are defined as follows (monocular measurements, horizontal
axis of isopter III4e for the visual field):
- Severe stage is defined by both a BCVA below or equal to 20/200 and above or
equal to 20/800, and a visual field below or equal to 20 degrees (subjects of
Cohorts 1 to 3)
- Intermediate stage is defined by both a BCVA below or equal to 20/40 and above
20/200, and a visual field below or equal to 20 degrees (subjects of Cohorts 4
to 6)
5. For subjects with severe advanced RCD enrolled in Step 1 only, the difference in
visual acuity between the two eyes of a given subject should be equal to or below
0.3 logarithm of the minimal angle (LogMAR) (≤3 ETDRS lines), with a tolerance
margin of 3 ETDRS letters.
6. Clinical diagnosis of RCD based on past medical and family history, mid-peripheral
visual field dysfunction, photopsia, night blindness (nyctalopia), and fundoscopic
appearance (including but not restricted to bone spicule pigmentation, attenuation
of the retinal vessels, and waxy pallor of the optic nerve).
7. Diagnosis of RCD is confirmed on prior full-field ERG (any previously performed ERG
is acceptable).
8. Documented preservation of cone inner and outer segments considered good enough by
the investigator for the subject to be included in the study.
9. Negative serum pregnancy test for women of childbearing potential (please refer to
Schedule of Assessments for details).
10. Women of childbearing potential (WOCBP) and men and/or their partner(s) of
childbearing potential must agree to use a highly effective contraceptive method.
This applies to the time period between ICF signature and 12 months after SPVN06
subretinal injection SRI (i.e., no longer applicable to subjects of Cohort 4 after
randomization). The definition of highly effective contraceptive methods follows
CTFG recommendations. Highly effective contraceptive methods are limited to:
- Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation:
- Oral
- Intravaginal
- Transdermal
- Progestogen-only hormonal contraception associated with inhibition of
ovulation:
- Oral
- Injectable
- Implantable
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion
- Vasectomized partner
- Sexual abstinence
11. Subjects must be affiliated to a health security system, if they are included in a
clinical site based in France (per law).
12. No out-of-range values for clinical laboratory tests, however, if outside, must be
considered as non-clinically relevant by the investigator using a multidisciplinary
approach and compatible with a participation in the clinical study.
13. 12-lead electrocardiogram within normal limits, however, when outside, must be
documented by the investigator using a multidisciplinary approach as not clinically
relevant and compatible with a participation in the clinical study. Nota bene: This
criterion of eligibility is only applicable to subjects assigned to a treatment
cohort (Cohorts 1, 2, 3, 5, or 6), and is not required to authorize randomization in
Step 2.
14. Physical examination without any clinical findings of clinical relevance (per
medical/anesthesia staffs judgment) that could compromise participation in the
clinical study or could affect the collection and/or evaluation of the study
parameters. The findings of clinical relevance considered as contraindications to
SPVN06 treatment include, but are not limited to, pulmonary pathology such as COPD,
asthma, cardiac conditions such as congestive heart failure or valve disease, renal
issues such as renal insufficiency and endocrine issues such as diabetes.
Subjects are not eligible to participate in this study if any of the following criteria
apply:
1. Subjects with prior administration of any gene therapy or any previous treatment
with stem cell therapy for ocular or non-ocular disease.
2. Subjects participating in another clinical trial and receiving an investigational
medicinal product (IMP) within 5 half-lives or 90 days prior to the injection of
SPVN06.
3. Subjects with RCD due to any mutation in genes other than those listed in the
inclusion criteria.
4. Subjects with systemic disease or other pathology not related to their diagnosis of
RCD, and whose symptoms or associated treatments may affect vision, for example
cancers or pathology of the central nervous system.
5. Subjects with narrow irido-corneal angles or any other medical situation
contraindicating pupillary dilation.
6. Subjects known to be allergic to any of the delivery vehicle constituents or to any
other drugs planned to be used during the clinical study.
7. Subjects with known allergies to corticosteroids, or who will be unable to tolerate
the corticosteroid regimen as described in the protocol
8. Subjects with systemic disease or other medical or psychiatric conditions that
preclude safe participation in the study.
9. Subjects receiving immunosuppressive therapies, other than the immune modulating
regimen described in this protocol, or any other therapy known to influence the
immune system including but not limited to steroid implants, cytostatics,
interferons, tumor necrosis factor (TNF)-binding proteins, drugs acting on
immunophilins, or antibodies with known impact on the immune system.
10. Subjects of reproductive potential unwilling to use effective contraception starting
right after ICF signature and for 12 months after SPVN06 SRI (i.e., no longer
applicable to subjects of Cohort 4 after randomization).
11. Subjects who are pregnant or breastfeeding.
12. Subjects who are unwilling or unable (based on the investigator's judgment) to
comply with the study protocol.
13. Subjects with any condition that would not allow them to complete follow-up
examinations during the study and, in the opinion of the investigator, would make
them unsuitable for the study.
14. Subjects positive for human immunodeficiency virus (HIV) or any other systemic
immunocompromising disease.
15. Subjects who have undergone, within 6 months before inclusion, any significant
ocular surgery (per investigator's judgment) that could interfere with the
evaluation of SPVN06 study objectives.
16. Presence of eye disorders that could interfere with the assessment of visual acuity
and/or any other ocular assessments, including SD-OCT, during the study.
17. Presence of any systemic or ocular diseases, other than non-syndromic retinitis
pigmentosa (RP), that can cause vision loss.
18. Prior vitrectomy or vitreomacular surgery.
19. Presence of vitreomacular adhesion or traction, epiretinal membrane macular pucker
or macular hole, evident by ophthalmoscopy and/or SD-OCT examinations and assessed
by the investigator to significantly affect central vision.
20. Current evidence of retinal detachment assessed by the investigator to significantly
affect central vision.
21. Active ocular inflammation or recurrent history of idiopathic or
autoimmune-associated uveitis.
22. Subjects with presence of any suspected or active ocular or periocular infection
(conjunctivitis, keratitis, scleritis, endophthalmitis).
23. Subjects with history of glaucoma.
24. Subjects with uncontrolled intraocular pressure (IOP).
25. Subjects with active cancer or currently receiving any therapy for cancer treatment.
26. Subjects with any history of ocular malignancy.
27. Subjects with a clinically significant cardiac disease on routine clinical
examination (history, physical examination), or known congestive heart failure,
myocardial infarction, clinically significant valvular heart disease, clinically
significant cardiac rhythm or conduction abnormalities.
28. Subjects with unstable/uncontrolled hypertension, defined by national
recommendations.
29. Subjects with pulmonary dysfunction or severe obstructive pulmonary disease.
30. Subjects with active tuberculosis.
31. Subjects with liver or renal insufficiency.
32. Subjects with unstable endocrine disease, including unstable diabetes or thyroid
disease.
33. Subjects with active Hepatitis B or Hepatitis C.
34. Subjects with clinically active infection of herpetic diseases, including herpes
simplex virus, varicella zoster virus (VZV), cytomegalovirus (CMV) or EBV.
35. Subjects with known history of ocular infection with herpes simplex virus.
36. Subjects with active (extraocular) infection (requiring or not the prolonged or
chronic use of antimicrobial agents).
37. Immunocompromised subjects with previous solid organ or bone marrow transplant.
38. Subjects who receive a live vaccine less than 4 weeks prior to SPVN06 injection
39. Subjects who were infected by COVID-19 less than 2 weeks prior to SPVN06 injection.
40. Subjects who have recently received (less than 4 weeks) or plan to receive a
COVID-19 vaccination.
41. Incapacitated subjects, as defined by national laws.