- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02671539
THOR - Tübingen Choroideremia Gene Therapy Trial (THOR)
THOR - Tübingen Choroideremia Gene Therapy Trial Open Label Phase 2 Clinical Trial Using an Adeno-associated Viral Vector (AAV2) Encoding Rab-escort Protein 1 (REP1)
Study Overview
Detailed Description
Study name: THOR - Tübingen Choroideremia gene therapy trial open label Phase 2 clinical trial using an adeno-associated viral vector (AAV2) encoding Rab-escort protein 1 (REP1)
Phase: Phase II
Indication: Adult males with a clinical phenotype of choroideremia and a confirmed molecular diagnosis of a null mutation in the gene encoding REP1
Aim of study: To assess the anatomical and functional outcomes, as well as the safety of a single subretinal injection of rAAV2.REP1 in subjects with genetically confirmed choroideremia for up to 24 months.
Primary Endpoint: Change from baseline in best corrected visual acuity in treated eye, compared to untreated control eye
Study design: Open label monocenter study
Study population: 6 male adults affected by choroideremia
Inclusion Criteria
- Participant is willing and able to give informed consent for participation in the study.
- Male aged 18 years or above.
- Genetically confirmed diagnosis of choroideremia. Patients without a confirmed mutation in the CHM gene, but who have the clinical phenotype typical of choroideremia can only be enrolled if they meet all the following three criteria: (i) family history consistent with X-linked inheritance, (ii) absent REP1 protein on Western blot of a blood sample and, (iii) normal RPE65 gene on sequencing.
- Active disease visible clinically within the macula region
- Best-corrected visual acuity equal to or worse than 6/9 (20/32; Decimal 0.63; LogMAR 0.2) but better than or equal to 6/60 (20/200; Decimal 0.1; LogMAR 1.0) in the study eye.
Exclusion Criteria
- Female and child participants (under the age of 18)
- Participants with a history of amblyopia in the study eye
- Men unwilling to use barrier contraception methods, if relevant
- Absence of quantifiable visual function in the fellow eye or other ocular morbidity which might confound use of the fellow eye as a long-term control.
- Any other significant ocular and non-ocular disease/disorder or retinal surgery which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the results of the study, or the participant's ability to participate in the study. This would include not taking or having a contraindication to oral prednisolone, such as a history of gastric ulcer or significant side effects.
- Participants who have participated in another research study involving an investigational product in the past 12 weeks, or having had gene or cellular therapy at any time prior to this study.
- Patients with amblyopic eyes should be excluded in general, since the evaluation of the primary endpoint presupposes the ability to fixate both eyes
- Prior intraocular surgery within six months
- Intolerance to local anesthesia and/or contraindication to IVT surgery (anemia Hb<8g/dl, severe cardiovascular disease, severe coagulopathy, etc.)
- High fever or high fever disease, patients with a history of autoimmune conditions/ other systemic diseases that may have ocular manifestations (e.g. sarcoidosis) or neurodegenerative conditions (e.g. multiple sclerosis, neuromyelitis optica, Parkinson's disease)
- Patients suffering from other genetic mutations leading to pathological retinal conditions
- Patients treated by oral corticoids within 14 days prior inclusion at the study entry
Patient number: 6
Treatment: Each participant will receive a single treatment of the rAAV2.REP1 vector (0.1ml containing 1011 AAV2 genome particles) administered by subretinal injection during a vitrectomy operation. No placebo will be used. ln order to minimize selection bias both eyes are randomized to either treatment or control.
Main criteria: Primary endpoint: Change from baseline in best corrected visual acuity in treated eye, compared to untreated control eye up to 24 months after vector administration Secondary endpoints: Absence of vector related adverse reactions 24 months after vector administration. Demonstration of improved retinal anatomy and/or visual function other than best corrected visual acuity in treated eye compared to the untreated control eye 24 months after vector administration.
Statistical methods:
Summary statistics will be presented for both eyes (Treated Eye versus Control Eye groups). No formal statistical comparison will be performed (no p-value will be computed). For categorical/binary data, the number and proportion of patients in each category will be presented with its 95% Confidence Interval (CI). For continuous data, mean (and its 95% CI) and Standard Deviation (SD) will be presented.
The primary outcome measure will be the proportion of patients with a relative change from baseline of > 5 in ETDRS letters (treated vs. untreated eye, change from BL). At each time point, the change from baseline in ETDRS letters will be computed for each eye. The mean change from baseline in ETDRS letters will be presented for both the treated eye and the control eye groups.
At each time point, the change from baseline and the percentage change from baseline in the area of autofluoresence will be computed for each eye and their mean will be presented for both the treated eye and the control eye groups.
With regards to microperimetry, at each time point, the change from baseline in mean sensitivity will be computed for each eye. The mean change from baseline in mean sensitivity will be presented for both the treated eye and the control eye groups.
Adverse events will be listed. Other Investigator Sponsored Studies are expected to be run with a similar protocol for the same indication and with the same intervention. A meta-analysis on the Investigator Sponsored studies is planned. A separate Statistical Analysis Plan describing the details of the meta-analysis will be developed.
Timetable:
Planned trial period: 24 month Follow-up duration: 36 month
The end of trial is the date on which the last treated patient completes the tests of their planned close-out visit.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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-
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Tuebingen, Germany, 72076
- University Hospital Tuebingen, Center for Ophthalmology
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Participant is willing and able to give informed consent for participation in the study.
- Male aged 18 years or above.
- Genetically confirmed diagnosis of choroideremia. Patients without a confirmed mutation in the CHM gene, but who have the clinical phenotype typical of choroideremia can only be enrolled if they meet all the following three criteria: (i) family history consistent with X-linked inheritance, (ii) absent REP1 protein on Western blot of a blood sample and, (iii) normal RPE65 gene on sequencing.
- Active disease visible clinically within the macula region
- Best-corrected visual acuity equal to or worse than 6/9 (20/32; Decimal 0.63; LogMAR 0.2) but better than or equal to 6/60 (20/200; Decimal 0.1; LogMAR 1.0) in the study eye.
Exclusion Criteria:
- Female and child participants (under the age of 18)
- Participants with a history of amblyopia in the study eye
- Men unwilling to use barrier contraception methods, if relevant
- Absence of quantifiable visual function in the fellow eye or other ocular morbidity which might confound use of the fellow eye as a long-term control.
- Any other significant ocular and non-ocular disease/disorder or retinal surgery which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the results of the study, or the participant's ability to participate in the study. This would include not taking or having a contraindication to oral prednisolone, such as a history of gastric ulcer or significant side effects.
- Participants who have participated in another research study involving an investigational product in the past 12 weeks, or having had gene or cellular therapy at any time prior to this study.
- Patients with amblyopic eyes should be excluded in general, since the evaluation of the primary endpoint presupposes the ability to fixate both eyes
- Prior intraocular surgery within six months
- Intolerance to local anesthesia and/or contraindication to IVT surgery (anemia Hb<8g/dl, severe cardiovascular disease, severe coagulopathy, etc.)
- High fever or high fever disease, patients with a history of autoimmune conditions/ other systemic diseases that may have ocular manifestations (e.g. sarcoidosis) or neurodegenerative conditions (e.g. multiple sclerosis, neuromyelitis optica, Parkinson's disease)
- Patients suffering from other genetic mutations leading to pathological retinal conditions
- Patients treated by oral corticoids within 14 days prior inclusion at the study entry
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: open label injection of rAAV2.REP1
This is an open label, single arm interventional trial with subretinal injection of rAAV2.REP1 and fellow eye comparison
|
single subretinal injection
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
best corrected visual acuity in treated eye
Time Frame: up to 24 months after vector administration
|
Change from baseline in best corrected visual acuity in treated eye, compared to untreated control eye up to 24 months after vector administration
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up to 24 months after vector administration
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Absence of vector-related adverse reactions
Time Frame: 24 months after vector administration
|
24 months after vector administration
|
|
fundus autofluorescence analysis
Time Frame: 24 months after vector administration
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improved retinal anatomy in treated eye compared to the untreated control eye 24 months after vector administration
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24 months after vector administration
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central visual field using microperimetry readings
Time Frame: 24 months after vector administration
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improved visual function in treated eye compared to the untreated control eye 24 months after vector administration
|
24 months after vector administration
|
contrast sensitivity
Time Frame: 24 months after vector administration
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improved visual function other than best corrected visual acuity in treated eye compared to the untreated control eye 24 months after vector administration (scale)
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24 months after vector administration
|
colour vision
Time Frame: 24 months after vector administration
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improved visual function other than best corrected visual acuity in treated eye compared to the untreated control eye 24 months after vector administration (physiological parameter)
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24 months after vector administration
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Manuel D Fischer, MD, PhD, Centre for Ophthalmology, University Hospital Tübingen, Germany
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- THOR-TUE-01
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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