A study to investigate the safety, tolerability, and exposure of single doses of the study medicine STK-002, in patients with autosomal dominant optic atrophy (ADOA)
| ISRCTN | ISRCTN41725621 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN41725621 |
| EudraCT/CTIS number | 2023-506290-35 |
| IRAS number | 1006380 |
| Secondary identifying numbers | STK-002-OA-101, IRAS 1006380, CPMS 54024 |
- Submission date
- 14/01/2023
- Registration date
- 21/08/2023
- Last edited
- 11/03/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Eye Diseases
Plain English summary of protocol
Background and study aims
Autosomal dominant optic atrophy (ADOA) is a genetic disease characterised by progressive loss of vision as a result of the breakdown of cells within the retina of the eye. Signs of this degeneration typically begins within the first decade of life, with symptoms generally emerging between the ages of 4 and 6. Between 65 to 90% of ADOA cases are caused by a mutation to the gene OPA1 leading to a reduction in the levels of functional OPA1 protein. This protein is critically involved in the maintenance of retinal mitochondria (small structures found within the retinal cells). Patients may experience a decrease in sharp vision, blurred vision, reduced contrast and abnormal color vision, that cannot be corrected with glasses. From early childhood, patients experience a worsening of the central part of the vision that allows for proper seeing of small letters and reading. So far there is no treatment available that stops or cures the disease. Study STK-002-OA-101 is an early phase study to investigate the safety, tolerability and exposure of single ascending doses of STK-002 (the study drug) in patients with ADOA. STK-002 is an antisense oligonucleotide, a short chain of nucleotides (the basic building block of nucleic acids, like RNA) designed to increase the levels of functioning OPA1 protein in the eye, thereby halting or slowing the progression of the disease leading to an improved quality of life.
Who can participate?
Patients aged ≥6 to <55 years old with ADOA
What does the study involve?
The study will be split into two parts. Part A will assess how safe STK-002 is for participants aged ≥18 to <55 years. Once data from Part A are reviewed, they will be used to determine the dosage of STK-002 in Part B of the study, which will enrol participants ages ≥6 to <18. Participants will receive one dose of the study drug in an affected eye. The study will last approximately 48 weeks with multiple study site visits to monitor participants.
What are the possible benefits and risks of participating?
As with all medications, the study drug could cause some side effects. Each person reacts differently to a new medication and the participants may experience some or none of the side effects that have been observed in animals tested with the study drug. Furthermore, participants could experience side effects that are severe that are not known at this time. There is always a risk involved in taking an experimental drug. The participant will be closely monitored by the study team and will be instructed to contact the study team immediately in the event of side effects. The side effects that have been observed in animals tested with the study drug are detailed in the Participant Information Sheets to ensure the participant is fully informed.
There are also risks from study procedures such as discomfort when blood samples are taken, and pain and discomfort from the eye injection. All known risks are detailed in the Participant Information Sheet to ensure the participant is fully informed.
The risk of causing harm to an unborn child is unknown. Therefore, women who are pregnant, or who intend to become pregnant during the study, are not permitted to take part in this study. Also, it is not known whether the study drug causes harm to a breastfeeding infant. Therefore, women who are breastfeeding should not take part in the study. The known risks and requirements regarding pregnancy and contraception are detailed in the Participant Information Sheet to ensure the participant is fully informed.
Where is the study run from?
Stoke Therapeutics Inc (USA)
When is the study starting and how long is it expected to run for?
January 2023 to March 2029
Who is funding the study?
Stoke Therapeutics Inc (USA)
Who is the main contact?
Dr Steven Gross, clinicaltrials@stoketherapeutics.com
Contact information
Scientific
45 Wiggins Avenue
Bedford
MA 01730
United States of America
| Phone | +1 (0)813 695 9151 |
|---|---|
| clinicaltrials@stoketherapeutics.com |
Study information
| Study design | Open-label phase I multi-centre single-ascending-dose study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Osprey: An open-label study to investigate the safety, tolerability, and exposure of single ascending doses of the antisense oligonucleotide STK-002 in patients with autosomal dominant optic atrophy |
| Study objectives | 1. To evaluate the safety and tolerability of single ascending doses of STK-002 in patients with autosomal dominant optic atrophy (ADOA) 2. To determine the exposure in serum following single intravitreal (IVT) doses of STK-002 3. To evaluate changes in visual function and ocular structure following single doses of STK-002 4. To evaluate the effect of single doses of STK-002 on quality of life in patients with ADOA |
| Ethics approval(s) |
Approved 16/03/2023, North East - Newcastle and North Tyneside 1 Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 104 8384; newcastlenorthtyneside1.rec@hra.nhs.uk), ref: 23/NE/0031 |
| Health condition(s) or problem(s) studied | Autosomal dominant optic atrophy |
| Intervention | Current interventions as of 08/03/2024: STK-002-OA-101 is an open-label study in which a participant will receive a single dose of the study drug STK-002, via an injection to the affected eye, at visit 3 (Day 1) of their participation in the study. Participants in part A of the study will be assigned to one of four groups. Each group will receive a different dose of the study drug starting at a safe, low dose in group 1, which was calculated by data collected through pre-clinical studies, and escalating to higher doses in groups 2, 3 and 4. Group 1 will be the first to receive the study drug and data collected from participants will be reviewed by a Safety Monitoring Committee (SMC). The SMC will use this data to determine whether the dose can be escalated and given to the next group. This process will be repeated for all groups. An optional two additional groups may be added to Part A, with the dose in these groups escalated further. Administration of the study drug will take approximately 5-10 minutes. However, the total time for administration procedure may take up to 2 hours if patients require sedation. Data from Part A of the study will be reviewed by the SMC to determine a safe dose of the study drug to be given to participants in Part B of the study. In Part B, the first paediatric participant (sentinel) to receive the study drug will be ≥12 and <18 years of age. The SMC will meet again after dosage to determine whether to continue to dose, and for dose escalation/de-escalation for additional groups in Part B. There are currently 10 planned visits to the research site and via one planned telephone call to follow up with participants. Follow-up will last approximately up to 50 weeks after study drug administration, to evaluate the safety and tolerability of the study drug. _____ Previous interventions: STK-002-OA-101 is an open-label study in which a participant will receive a single dose of the study drug STK-002, via an injection to the affected eye, at visit 3 (Day 1) of their participation in the study. Participants in part A of the study will be assigned to one of four groups. Each group will receive a different dose of the study drug starting at a safe, low dose in group 1, which was calculated by data collected through pre-clinical studies, and escalating to higher doses in groups 2, 3 and 4. Group 1 will be the first to receive the study drug and data collected from participants will be reviewed by a Safety Monitoring Committee (SMC). The SMC will use this data to determine whether the dose can be escalated and given to the next group. This process will be repeated for all groups. An optional two additional groups may be added to Part A, with the dose in these groups escalated further. Administration of the study drug will take approximately 5-10 minutes. However, the total time for administration procedure may take up to 2 hours if patients require sedation. Data from Part A of the study will be reviewed by the SMC to determine a safe dose of the study drug to be given to participants in part B of the study. The first group of paediatric participants to receive the study drug will be ≥12 and <18 years of age. The SMC will meet again after dosage to determine dose escalation/de-escalation for other groups in Part B. There are currently 7 planned visits to the research site and via one planned telephone call to follow up with participants. Follow-up will last approximately up to 52 weeks after study drug administration, to evaluate the safety and tolerability of the study drug. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | STK-002 |
| Primary outcome measure | Current primary outcome measure as of 08/03/2024: Evaluation of these endpoints will occur at up to 48 weeks (+/- 2 weeks) after Study Drug Administration: 1. Safety variables for analysis include: 1.1. The incidence, type, and severity of adverse events (AEs) in the treated eye throughout the study 1.2. Changes in vital signs at day 1, 2, 8, 29 and 337 1.3. Laboratory parameters in up to 7 of the 10 visits 1.4. Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System scores at day 2, 8, 29, 85, 169, 253 and 337 1.5. Assessment of inflammation (Standardization of Uveitis Nomenclature [SUN] Anterior Chamber Cell score and NEI Vitreous Haze scores) at baseline, day 8, 29, 85, 169, 253 and 337 1.6. Corneal epithelial grading using Efron corneal grading scale at baseline, day 2, 8, 29, 85, 169, 253, and 337 1.7. Physical examination at day 2, 8, 29 and 337 1.8. Immunogenicity parameters at baseline, day 29, 85, 169 and 337 1.9. Retinal Toxicity assessed by full-field electroretinogram (ERG), retinal thinning by optical coherence tomography (OCT) at baseline, day 29, 85, 169, 253, and 337 2. The exposure of STK-002 in serum will be determined measured pre-dose, at 1, 2, 4, 6, 24 hours post dose and on days 8, 29, 85, 169 and 337. Pharmacokinetic (PK) parameters may include: 2.1. Maximum observed concentration (Cmax) 2.2. Time to maximum observed concentration (Tmax) 2.3. Fold change in Cmax compared with dose level _____ Previous primary outcome measure: Evaluation of these endpoints will occur at up to 48 weeks (+/- 2 weeks) after Study Drug Administration: 1. Safety variables for analysis include: 1.1. The incidence, type, and severity of adverse events (AEs) throughout the study 1.2. Changes in vital signs at day 1, 2, 8, 29 and 337 1.3. Laboratory parameters in up to 7 of the 10 visits 1.4. Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System scores at day 2, 8, 29, 85, 169, 253 and 337 1.5. Assessment of inflammation (Standardization of Uveitis Nomenclature [SUN] Anterior Chamber Cell score and NEI Vitreous Haze scores) at baseline, day 8, 29, 85, 169, 253 and 337 1.6. Corneal epithelial grading using Efron corneal grading scale at baseline, day 4, 8, 29, 85, 69, 253, and 337 1.7. Physical examination at day 2, 8, 29 and 337 1.8. Immunogenicity parameters at baseline, day 29, 85, 169 and 337 2. The exposure of STK-002 in serum will be determined measured pre-dose, at 1, 2, 4, 6, 24 hours post dose and on days 2, 8, 29, 85, 169 and 337. Pharmacokinetic (PK) parameters may include: 2.1. Maximum observed concentration (Cmax) 2.2. Time to maximum observed concentration (Tmax) 2.3. Fold change in Cmax compared with dose level 2.4. Retinal toxicity assessed by full-field electroretinogram (ERG), retinal thinning by optical coherence tomography (OCT) |
| Secondary outcome measures | Current secondary outcome measures as of 08/03/2024: Secondary endpoints for STK-002 evaluated by dose level and change from baseline at each visit are assessed at up to 48 weeks (+/- 2 weeks) after Study Drug Administration: 1. Peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer (GCL, or ganglion cell complex) thicknesses as assessed by optical coherence tomography (OCT) at baseline, day 29, 85, 169, 253 and 337 2. Best-corrected visual acuity (BCVA) measured using Early Treatment Diabetic Retinopathy Study (ETDRS) optotypes at screening, and days 8, 29, 85, 169, 253 and 337 3. Contrast sensitivity assessed by low contrast BCVA (at 25%, 5% and 2.5% contrast levels) at baseline, and days 29, 85, 169, 253 and 337 4. Visual field as assessed by automated, static perimetry [10-2 and 24-2 Swedish Interactive Threshold Algorithm (SITA) FAST] at baseline, and days 29, 85, 169, 253 and 337 5. Electrical activity of the retina as assessed by photopic negative response (PhNR) ERG, if available, at baseline, and days 29, 85, 169, 253 and 337 6. Continuous text reading acuity as assessed by MNREAD Acuity Charts at baseline, and days 29, 85, 169, 253 and 337 7. Quality of life measured by scores on the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25), Impact of Vision Impairment for Children (IVI-C), and the European Quality of Life-5 Dimensions (EQ-5D)/EQ-5D-Y questionnaire at baseline, and days 29, 85 and 337 _____ Previous secondary outcome measures: Secondary endpoints for STK-002 evaluated by dose level and change from baseline at each visit are assessed at up to 48 weeks (+/- 2 weeks) after Study Drug Administration: 1. Peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer (GCL, or ganglion cell complex) thicknesses as assessed by optical coherence tomography (OCT) at baseline, day 29, 85, 169, 253 and 337 2. Best-corrected visual acuity (BCVA) measured using Early Treatment Diabetic Retinopathy Study (ETDRS) optotypes at screening, and days 8, 29, 85, 169, 253 and 337 3. Contrast sensitivity assessed by the Pelli-Robson chart and low contrast BCVA (at 25%, 10%, and 5% contrast levels) at baseline, and days 29, 85, 169, 253 and 337 4. Visual field as assessed by automated, static perimetry [24-2 Swedish Interactive Threshold Algorithm (SITA) FAST] at baseline, and days 29, 85, 169, 253 and 337 5. Electrical activity of the retina as assessed by pattern electroretinogram (p-ERG) and/or phototopic negative response (PhNR) ERG, if available, at baseline, and days 29, 85, 169, 253 and 337 6. Continuous text reading acuity as assessed by MNREAD Acuity Charts at baseline, and days 29, 85, 169, 253 and 337 7. Quality of life measured by scores on the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25), Impact of Vision Impairment for Children (IVI-C), and the European Quality of Life-5 Dimensions (EQ-5D)/EQ-5D-Y questionnaire at baseline, and days 29, 85 and 337 |
| Overall study start date | 14/01/2023 |
| Completion date | 31/03/2029 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 6 Years |
| Upper age limit | 60 Years |
| Sex | Both |
| Target number of participants | 60 |
| Key inclusion criteria | 1. Patient must be ≥18 to <55 years to participate in Part A and ≥6 to <18 years to participate in Part B 2. Patient must have a clinical diagnosis of ADOA and have a heterozygous OPA1 gene variant confirmed at Screening by central lab genotyping 3. Patient must have a BCVA EDTRS letter score of ≥35 and ≤70 with each eye individually, with the exception of the first two patients in Cohort 1 of Part A who must have a BCVA ETDRS letter score ≥5 and ≤35 in each eye |
| Key exclusion criteria | 1. Patient has a gain-of-function variant, or compound heterozygous or homozygous pathogenic or likely pathogenic variant in the OPA1 gene 2. Patient has extraocular phenotypic manifestations of (syndromic) ADOA (ADOA-plus) or has Behr syndrome 3. Patient has or has a history of, any ocular condition in either eye that, in the opinion of the Investigator, could affect study parameters 4. Patient is considered to be at risk for uveitis or ocular infection during the study period 5. Patient is taking or has taken at any time, any medication or treatment that can or might cause an optic neuropathy |
| Date of first enrolment | 31/12/2024 |
| Date of final enrolment | 31/03/2028 |
Locations
Countries of recruitment
- Austria
- Denmark
- England
- Germany
- United Kingdom
- Wales
Study participating centres
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Cardiff
CF14 4XW
United Kingdom
London
EC1V 2PD
United Kingdom
London
WC1N 3JH
United Kingdom
Waehringer Guertel 18-20
Vienna
1090
Austria
Valdemar Hansens Vej 1-23
Glostrup
2600
Denmark
Tuebingen
72076
Germany
Friedrichstr. 18
Giessen
35392
Germany
Sponsor information
Industry
45 Wiggins Avenue
Bedford
MA 01730
England
United Kingdom
| Phone | +1 (0)781 430 8200 |
|---|---|
| clinicaltrials@stoketherapeutics.com |
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 30/09/2029 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on website 5. Submission to regulatory authorities |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date |
Editorial Notes
11/03/2024: The following changes were made to the trial record:
1. The target number of participants was changed from 54 to 60.
2. The recruitment end date was changed from 31/08/2028 to 31/03/2028.
08/03/2024: The following changes were made to the trial record:
1. The scientific title was changed from "An open-label study to investigate the safety, tolerability, and exposure of single ascending doses of the antisense oligonucleotide STK-002 in patients with autosomal dominant optic atrophy" to "Osprey: An open-label study to investigate the safety, tolerability, and exposure of single ascending doses of the antisense oligonucleotide STK-002 in patients with autosomal dominant optic atrophy".
2. The CTIS number was added.
3. The overall end date was changed from 08/12/2026 to 31/03/2029.
4. The interventions were changed.
5. The primary outcome measure was changed.
6. The secondary outcome measures were changed.
7. The recruitment end date was changed from 08/12/2025 to 31/08/2028.
8. The countries of recruitment Austria, Denmark, Germany were added.
9. The study participating centres AKH/Medical University of Vienna, Universitaets-Augenklinik Tuebingen, Copenhagen University Hospital (Rigshospitalet-Glostrup), Justus-Liebig Universitaet were added.
10. The intention to publish date was changed from 08/06/2027 to 30/09/2029.
11. The plain English summary was updated to reflect these changes.
30/01/2024: The recruitment start date has been changed from 31/01/2024 to 31/12/2024 while the study undergoes a protocol amendment.
05/09/2023: Internal review.
25/04/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 25/04/2023.
16/01/2023: Trial's existence confirmed by the HRA.
