Age Related Macular DegenerationNCT02550002
Comparison of Treatment rOutine Using afLibERcept: Strict vs relAxed retreatmeNT Regimen
An observational study of Age Related Macular Degeneration, run by Insel Gruppe AG, University Hospital Bern at 2 sites in Switzerland.
Trial summary
The primary objective of this study is to test non-inferiority of aflibercept "treat and extend" using a relaxed retinal fluid management relative to aflibercept "treat and extend" using a strict retinal fluid management SD-OCT (spectral domain optical coherence tomography) disease activity guided retreatment with… Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Age Related Macular Degeneration
- What is being tested?
- Aflibercept
- Type of treatment
- Injection or infusion
- How many people
- 150 participants
- Where
- 2 sitesSwitzerland
- Study dates
- Dec 2015to Aug 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: A total of 150 patients will be recruited to this study, with approximately 75 randomised to each study arm (relaxed and strict retinal fluid treatment regimen). Assuming an approximate 20% screen failure rate, approximately 188 patients will need to be screened to have 150 patients found eligible and commencing treatment in the trial.
Who may be able to join
- General:
- Informed consent as documented by signature of the patient on the informed consent form.
- Male or female, ≥50 years of age.
- Study eye:
- Diagnosis ofl CNV secondary to wAMD without restriction of lesion size, with visual impairment due to an active wAMD lesion. Active wAMD lesions are characterised by the following:
- Evidence of SRF and/or IRF and
Show all 13Show fewer
- area of fibrosis less than 50% of the lesion area.
- CNV membrane confirmed by presence of active leakage from the area of CNV seen by fluorescein angiography (FA) and color fundus photography (CFP) and at least two of the following items:
- Drusen
- Retinal Pigment Epithelium (RPE)-Atrophy
- Exudates
- Subretinal or intraretinal haemorrhage
- BCVA scores at both screening and baseline must be 23 letters or more as measured by the ETDRS-like charts (or approximate Snellen equivalent to 20/320).
Who cannot join
- General:
- Inability to comply with study or follow-up procedures.
- Pregnant or nursing (lactating) women.
- Women of child-bearing potential, not using or not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the Investigator in individual cases. (Female participants who are surgically sterilised/hysterectomised, or post-menopausal for longer than 2 years are not considered as being of child-bearing potential.)
- Any type of systemic disease or its treatment, in the opinion of the Investigator, including any medical condition (controlled or uncontrolled) that could be expected to progress, recur, or change to such an extent that it may bias the assessment of the clinical status of the patient to a significant degree or put the patient at special risk.
- Stroke or myocardial infarction less than 3 months prior to the date of informed consent signature.
Show all 23Show fewer
- Uncontrolled blood pressure defined as systolic value of >160 mmHg or diastolic value of >100 mmHg at screening or baseline.
- Known hypersensitivity to aflibercept or any component of the aflibercept formulation, or fluorescein.
- Prior or current use of any systemic anti-VEGF drugs [e.g., bevacizumab (Avastin®) or ranibizumab (Lucentis®)].
- Current or planned use of systemic medications known to be toxic to the lens, retina or optic nerve, including chloroquine/hydroxychloroquine (Plaquenil®), deferoxamine, phenothiazines, tamoxifen, and ethambutol.
- Use of systemic or intravitreal corticosteroids for at least 30 consecutive days within 3 months prior to the date of informed consent signature.
- Use of other investigational drugs within 6 months prior to the date of informed consent signature.
- Patient was previously screened for participation in the study and was a screen failure.
- Study eye:
- Any active periocular or ocular infection or inflammation (e.g., blepharitis, conjunctivitis, keratitis,scleritis, uveitis, endophthalmitis) at the time of screening or baseline.
- Uncontrolled glaucoma [intraocular pressure (IOP) ≥30 mmHg on medication or according to Investigator's judgment] at the time of screening or baseline.
- Neovascularisation of the iris or neovascular glaucoma at the time of screening or baseline.
- Inability of obtaining SD-OCT images of sufficient quality to be analysed.
- Any intraocular procedure (including Yttrium-Aluminum-Garnet capsulotomy) within 2 months prior to the date of informed consent signature or anticipated within the next 6 months following the date of informed consent signature.
- Visually significant cataract, aphakia, pseudoexfoliation glaucoma, vitreous haemorrhage, rhegmatogenous retinal detachment, proliferative diabetic retinopathy or CNV of any cause other than wAMD at the time of screening and baseline.
- Structural damage within 0.5 disc diameter of the centre of the macula at the time of screening or baseline that in the Investigator's opinion could preclude visual function improvement with treatment.
- Subretinal hemorrhage involving the central foveal subfield with a site of ≥1 disc diameter at the time of screening or baseline.
- Intraocular treatment with any anti-VEGF drug or intravitreal corticosteroids or previous treatment with photodynamic therapy or retinal laser therapy prior to the date of informed consent signature.
Trial locations and contacts
2 sites in 1 country.
Switzerland2 sites
Department of Ophthalmology, University Hospital Bern
Bern, 3010
Inselspital Bern, Department of Ophthalmology
Bern, 3010
About this study
Official title: Comparison of Treatment rOutine Using afLibERcept: Strict vs relAxed retreatmeNT Regimen (TOLERANT Study)
The primary objective of this study is to test non-inferiority of aflibercept "treat and extend" using a relaxed retinal fluid management relative to aflibercept "treat and extend" using a strict retinal fluid management SD-OCT (spectral domain optical coherence tomography) disease activity guided retreatment with respect to best-corrected visual acuity (BCVA) from baseline to end of treatment.
Read the detailed description
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population in developed countries. Severe visual loss in AMD usually occurs in patients with neovascular AMD (nAMD), which is caused by vascular endothelial growth factor A (VEGF-A) driven choroidal neovascularization (CNV).
Intravitreal therapy with VEGF-A inhibitors is the current standard treatment for nAMD. Optimization of current VEGF-A therapies includes finding a dosing regimen that maximizes visual acuity (VA) and minimizes the frequency of intravitreal injections and associated risks of treatment.
The "treat and extend" protocol is OCT guided with the primary aim of complete resolution of all retinal fluid, i.e. both intraretinal fluid (IRF) and subretinal fluid (SRF), both of which are considered to be a sign of disease activity. Once all fluid is resolved, an extension of the treatment interval by 2 weeks is mandated. If there is return of either SRF or IRF, the interval is shortened by one week. Currently, the relevance of both IRF and SRF in relation to best-corrected visual acuity (BCVA) outcomes is still being disputed. From the CATT and VIEW studies there is some reason to suspect that some SRF may be allowed to remain to extend the treatment interval without affecting BCVA. In contrast to IRF which has clearly been shown to correlate with poorer VA and is considered to be a sign of active disease, SRF may only be a sign of impaired pumping function of the RPE, similar to what is seen in central serous chorioretinopathy and as such may not be considered as an indication of ongoing disease activity. The consequence of insisting upon complete lack of SRF (strict approach) is more injections and therefore increased exposure of the retina to anti-VEGF agents. And there are recent reports that frequent intravitreal injections may lead to changes in the retinal nerve fiber layer and increased risk of geographic atrophy development. As a consequence, limiting the number of injections would be desirable if the same VA result could be achieved. From the pivotal anti-VEGF studies it has become apparent that patients show an individualised response to therapy. As such optimization of individualized treatment needs to be explored and understood. This study aims to explore further the "treat and extend" approach and will evaluate and compare two individualized aflibercept treatment regimens, differentiated by the definition of disease activity which determines the treatment interval until the next injection. The aim will be to determine whether small amounts of SRF may be tolerated using a "treat and extend" regimen in the treatment of nAMD and whether the presence and extent of both intra-retinal fluid and/or sub-retinal fluid (SRF) helps to decide on extension or reduction of treatment intervals in a "treat and extend" regimen. The results will be used to generate further recommendations about strict versus relaxed treatment approaches and how they can be utilised within a clinically practical "treat and extend" approach to maximize patient outcomes, while reducing the need for potentially unnecessary intravitreal injections.
Taking all together, the study aims for optimization of flexible patient treatment.
- Conditions
- Age Related Macular Degeneration
- Being tested
- Aflibercept
- Medical subject headings
- Macular Degeneration
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AfliberceptDrug
Also called Eylea
Intravitreal injection
| Study group | Role | What they receive |
|---|---|---|
| Strict treatment regimen with aflibercept | Treatment intervals with aflibercept in the strict retinal fluid treatment regimen will be extended by two weeks only if no SRF in the central subfoveal field and no IRF can be detected SD-OCT examination. Receives: Drug: Aflibercept | |
| Relaxed treatment regimen with aflibercept | Treatment intervals with aflibercept in the relaxed retinal fluid treatment regimen will be extended by two weeks only if SRF in the central subfoveal field is ≤100 μm in a vertical extent and no IRF is detected on SD-OCT examination. Receives: Drug: Aflibercept |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in best corrected visual acuity (BCVA) from baseline to end of treatment (EOS) at week 104. The primary outcome of the trial is the difference between the two arms in the mean change in BCVA from baseline to EOS.
Change of BCVA from baseline to end of study at week 104
Measured: From baseline to 24 months
Secondary outcomes (7)
The difference between the two arms in the mean change in BCVA from baseline to week 52.
Measured: From baseline to 24 months
The difference between the two arms in the mean change in central retinal thickness (CRT) from baseline to week 52 and to EOS.
Measured: From baseline to 24 months
The difference between the two arms in the mean number of injections from baseline to week 52 and to EOS.
Measured: From baseline to 24 months
The difference between the two arms in the proportion of patients showing newly developed geographic atrophy at week 52 and at EOS as compared to baseline.
Measured: From baseline to 24 months
The difference between the two arms in the mean change in the area of new and existing geographic atrophy from baseline to week 52 and to EOS.
Measured: From baseline to 24 months
The difference between the two arms in the proportion of patients showing no IRF and no SRF at week 52 and at EOS.
Measured: From baseline to 24 months
The difference between the two arms in the proportion of patients showing no SRF at week 52 and at EOS.
Measured: From baseline to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Sep 2015 (estimated)
- Study startDec 2015
- Primary completionMar 2022
- Study completionAug 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Age Related Macular DegenerationStudies of the same condition, open and under way.
- More trials run by Insel Gruppe AG, University Hospital BernThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 150 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Martin Zinkernagel, MD, PhD, Study chair, Inselspital Bern, Department of Ophthalmology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02550002
- Sponsor's protocol ID
- TOLERANT
- Status last verified
- Nov 2022
- First submitted
- 1 Sep 2015
- Last updated
- 1 Dec 2022
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 1 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Treatment rOutine Using afLibERcept: Strict vs relAxed retreatmeNT Regimen (TOLERANT Study)
- ClinicalTrials.gov ID
- NCT02550002
- Acronym / sponsor ID
- TOLERANT
- Conditions
- Age Related Macular Degeneration
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 150 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Study start
- Dec 2015
- Primary completion
- Mar 2022 (actual)
- Study completion
- Aug 2022 (actual)
- First posted
- 15 Sep 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of this study is to test non-inferiority of aflibercept "treat and extend" using a relaxed retinal fluid management relative to aflibercept "treat and extend" using a strict retinal fluid management SD-OCT (spectral domain optical coherence tomography) disease activity guided retreatment with respect to best-corrected visual acuity (BCVA) from baseline to end of treatment.
Detailed description
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population in developed countries. Severe visual loss in AMD usually occurs in patients with neovascular AMD (nAMD), which is caused by vascular endothelial growth factor A (VEGF-A) driven choroidal neovascularization (CNV).
Intravitreal therapy with VEGF-A inhibitors is the current standard treatment for nAMD. Optimization of current VEGF-A therapies includes finding a dosing regimen that maximizes visual acuity (VA) and minimizes the frequency of intravitreal injections and associated risks of treatment.
The "treat and extend" protocol is OCT guided with the primary aim of complete resolution of all retinal fluid, i.e. both intraretinal fluid (IRF) and subretinal fluid (SRF), both of which are considered to be a sign of disease activity. Once all fluid is resolved, an extension of the treatment interval by 2 weeks is mandated. If there is return of either SRF or IRF, the interval is shortened by one week. Currently, the relevance of both IRF and SRF in relation to best-corrected visual acuity (BCVA) outcomes is still being disputed. From the CATT and VIEW studies there is some reason to suspect that some SRF may be allowed to remain to extend the treatment interval without affecting BCVA. In contrast to IRF which has clearly been shown to correlate with poorer VA and is considered to be a sign of active disease, SRF may only be a sign of impaired pumping function of the RPE, similar to what is seen in central serous chorioretinopathy and as such may not be considered as an indication of ongoing disease activity. The consequence of insisting upon complete lack of SRF (strict approach) is more injections and therefore increased exposure of the retina to anti-VEGF agents. And there are recent reports that frequent intravitreal injections may lead to changes in the retinal nerve fiber layer and increased risk of geographic atrophy development. As a consequence, limiting the number of injections would be desirable if the same VA result could be achieved. From the pivotal anti-VEGF studies it has become apparent that patients show an individualised response to therapy. As such optimization of individualized treatment needs to be explored and understood. This study aims to explore further the "treat and extend" approach and will evaluate and compare two individualized aflibercept treatment regimens, differentiated by the definition of disease activity which determines the treatment interval until the next injection. The aim will be to determine whether small amounts of SRF may be tolerated using a "treat and extend" regimen in the treatment of nAMD and whether the presence and extent of both intra-retinal fluid and/or sub-retinal fluid (SRF) helps to decide on extension or reduction of treatment intervals in a "treat and extend" regimen. The results will be used to generate further recommendations about strict versus relaxed treatment approaches and how they can be utilised within a clinically practical "treat and extend" approach to maximize patient outcomes, while reducing the need for potentially unnecessary intravitreal injections.
Taking all together, the study aims for optimization of flexible patient treatment.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Strict treatment regimen with aflibercept | – | Drug: AfliberceptTreatment intervals with aflibercept in the strict retinal fluid treatment regimen will be extended by two weeks only if no SRF in the central subfoveal field and no IRF can be detected SD-OCT examination. |
| Relaxed treatment regimen with aflibercept | – | Drug: AfliberceptTreatment intervals with aflibercept in the relaxed retinal fluid treatment regimen will be extended by two weeks only if SRF in the central subfoveal field is ≤100 μm in a vertical extent and no IRF is detected on SD-OCT examination. |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- A total of 150 patients will be recruited to this study, with approximately 75 randomised to each study arm (relaxed and strict retinal fluid treatment regimen). Assuming an approximate 20% screen failure rate, approximately 188 patients will need to be screened to have 150 patients found eligible and commencing treatment in the trial.
Key inclusion criteria (13 listed)
- Informed consent as documented by signature of the patient on the informed consent form.
- Male or female, ≥50 years of age.
- Diagnosis ofl CNV secondary to wAMD without restriction of lesion size, with visual impairment due to an active wAMD lesion. Active wAMD lesions are characterised by the following:
- CNV membrane confirmed by presence of active leakage from the area of CNV seen by fluorescein angiography (FA) and color fundus photography (CFP) and at least two of the following items:
- BCVA scores at both screening and baseline must be 23 letters or more as measured by the ETDRS-like charts (or approximate Snellen equivalent to 20/320).
Key exclusion criteria (23 listed)
- Inability to comply with study or follow-up procedures.
- Pregnant or nursing (lactating) women.
- Women of child-bearing potential, not using or not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the Investigator in individual cases. (Female participants who are surgically sterilised/hysterectomised, or post-menopausal for longer than 2 years are not considered as being of child-bearing potential.)
- Any type of systemic disease or its treatment, in the opinion of the Investigator, including any medical condition (controlled or uncontrolled) that could be expected to progress, recur, or change to such an extent that it may bias the assessment of the clinical status of the patient to a significant degree or put the patient at special risk.
- Stroke or myocardial infarction less than 3 months prior to the date of informed consent signature.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AfliberceptAlso: EyleaIntravitreal injection | Drug | Relaxed treatment regimen with aflibercept, Strict treatment regimen with aflibercept |
Primary outcome
Change in best corrected visual acuity (BCVA) from baseline to end of treatment (EOS) at week 104. The primary outcome of the trial is the difference between the two arms in the mean change in BCVA from baseline to EOS.
Time frame: From baseline to 24 months
Change of BCVA from baseline to end of study at week 104
7 secondary outcomes
The difference between the two arms in the mean change in BCVA from baseline to week 52.
Time frame: From baseline to 24 months
The difference between the two arms in the mean change in central retinal thickness (CRT) from baseline to week 52 and to EOS.
Time frame: From baseline to 24 months
The difference between the two arms in the mean number of injections from baseline to week 52 and to EOS.
Time frame: From baseline to 24 months
The difference between the two arms in the proportion of patients showing newly developed geographic atrophy at week 52 and at EOS as compared to baseline.
Time frame: From baseline to 24 months
The difference between the two arms in the mean change in the area of new and existing geographic atrophy from baseline to week 52 and to EOS.
Time frame: From baseline to 24 months
The difference between the two arms in the proportion of patients showing no IRF and no SRF at week 52 and at EOS.
Time frame: From baseline to 24 months
The difference between the two arms in the proportion of patients showing no SRF at week 52 and at EOS.
Time frame: From baseline to 24 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Dec 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martin Zinkernagel, MD, PhD study chair
Inselspital Bern, Department of Ophthalmology
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Age Related Macular Degeneration, run by Insel Gruppe AG, University Hospital Bern at 2 sites in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in best corrected visual acuity (BCVA) from baseline to end of treatment (EOS) at week 104. The primary outcome of the trial is the difference between the two arms in the mean change in BCVA from baseline to EOS. (time frame: From baseline to 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Dec 2022.