MyVisionTest News Archive
Jun 22, 2009
Two year results of the PrONTO Study
The PrONTO Study has released results from the second year of follow-up of patients with wet age-related macular degeneration (AMD) that are treated with intravitreal Lucentis (ranibizumab) on an as-needed basis using optical coherence tomography (OCT) data that show as-needed treatment can achieve visual outcomes comparable to monthly Lucentis injections with significantly fewer injections.
Inhibition of vascular endothelial growth factor A (VEGF-A) is an effective and safe therapy for the treatment of neovascular AMD. Intravitreal injections of Lucentis, a monoclonal antibody fragment that inhibits all the known biologically active forms of VEGF, were shown to improve mean visual acuity (VA) in eyes with neovascular AMD during the phase III clinical studies. In these studies, monthly injections over the course of 2 years were administered to eyes with choroidal neovascular (CNV) lesions. On average, VA improved and the outcomes were highly statistically significant.
While the phase III trials used monthly injections, it is unclear at this time if monthly dosing is the best dosing interval. Observations made after the earlier phase I/II studies suggested a role for OCT in determining the appropriate dosing interval for each patient. These observations came about during an extension of the trials that provided continued intravitreal injections of Lucentis at the discretion of the investigator. Patients in the extension trial usually were treated if there was evidence of recurrent leakage from CNV as detected using fluorescein angiography (FA) or OCT imaging. It became apparent that the need for retreatment varied widely among the patients and that the need for retreatment was unpredictable. In addition, it was observed that OCT seemed to detect the earliest signs of reaccumulating fluid in the macula even before leakage could be detected reliably using FA.
Observations from the extension study served as the basis for investigating whether a variable-dosing OCT-guided regimen with Lucentis could result in fewer injections and similar clinical outcomes when compared with the phase III regimen that used monthly injections. A study was designed, known as the Prospective OCT Imaging of Patients with Neovascular AMD Treated with intraOcular Ranibizumab (PrONTO) Study. The 1-year results have been published, and the current article represents the full 2-year results of the PrONTO Study.
Methods and Results
In this open-label, prospective, single-center, uncontrolled clinical study, AMD patients with neovascularization involving the central fovea and a central retinal thickness (CRT) of at least 300 μm as measured by OCT were enrolled to receive 3 consecutive monthly intravitreal injections of Lucentis (0.5 mg). During the first year, retreatment with Lucentis was performed at each monthly visit if any criterion was fulfilled such as an increase in OCT-CRT of at least 100 um or a loss of 5 letters or more. During the second year, the retreatment criteria were amended to include retreatment if any qualitative increase in the amount of fluid was detected using OCT.
Forty patients were enrolled in PrONTO and 37 completed the 2-year study. At month 24, the mean VA improved by 11.1 letters (P < .001) and the OCT-CRT decreased by 212 um (P < .001). VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months.
Discussion and Conclusions
In the PrONTO Study, decrease in retinal thickness, was detectable within 1 day after the first Lucentis injection and was maintained through 24 months using an OCT-guided variable-dosing regimen. During the first year of the study it became evident that fluid continued to increase if left untreated and that the qualitative assessment of OCT scans was better at detecting fluid in the macula than waiting for changes in VA. Therefore, the protocol was amended to permit retreatment at the earliest sign of reaccumulating fluid in the retina, under the retina, or under the RPE. The change in retreatment criteria during the second year was considered to be consistent with the study objective to determine if OCT-guided therapy could minimize the number of injections over 2 years while achieving VA outcomes comparable with the outcomes achieved using monthly injections in the phase III trials.
The final VA outcomes in the PrONTO Study were comparable with the results from the phase III clinical trials (MARINA and ANCHOR). In the MARINA trial, the final mean VA improved by 7.2 letters, and in the ANCHOR trial, the final mean VA improved by 11.3 letters. By comparison, VA in the PrONTO Study improved by 11.1 letters at 24 months with a 95% CI ranging from 7 letters to 15.2 letters, suggesting results comparable with the phase III trial results. Whereas patients in the MARINA and ANCHOR trials received 24 injections over 24 months, the patients in the PrONTO Study received an average of just 9.9 injections with a median of 9.0 injections out of a possible 25 injections over 24 months. The totality of the data from the PrONTO Study suggests that OCT-guided retreatment with ranibizumab seems to be comparable with the VA outcomes from monthly injections; however, a prospective, randomized, double-masked study will be necessary to confirm these conclusions. Currently, the Comparison of AMD Treatment Trials (CATT) now underway will test whether an OCT-guided variable-dosing regimen is comparable with a fixed monthly dosing regimen with intravitreal Lucentis.
It is important to emphasize that the criteria for retreatment depended on close follow-up with monthly visits and careful examination of all 6 diagonal OCT scans with comparisons with the previous visit's scans to determine if any fluid had persisted or reaccumulated in the macula. The PrONTO Study was designed to minimize the number of retreatments but not the number of visits. There are other strategies that may yield similar or even better VA outcomes and that require fewer visits. One such strategy is known as treat and extend. After publication of the first year's data, some clinicians adopted the PrONTO retreatment criteria without adopting the strict follow-up schedule, without carefully examining all 6 OCT diagonal scans, and without comparing all current scans with the scans from the previous visit. Although it may be possible to base retreatment guidelines on fewer diagonal scans and less frequent follow-up, such a regimen was not tested in the PrONTO Study, and it is not possible to extrapolate the results to other retreatment paradigms.
Although Lucentis effectively may remove the fluid from the macula and may prevent the growth and leakage of neovascular lesions, the continued progression of the underlying dry AMD explains why some patients experienced little if any VA benefit from therapy, and probably explains why some patients experience continued vision loss over an extended period while receiving Lucentis therapy. Therefore, it stands to reason that to avoid treatment failures, therapies that target both the neovascular component and the underlying dry AMD are needed. Without this combination approach, it seems unlikely that any other antiangiogenic therapy will achieve VA outcomes better than the outcomes achieved with Lucentis therapy alone.
In summary, the PrONTO Study used an OCT-guided variable-dosing regimen with Lucentis resulting in VA outcomes comparable with those of the phase III studies with monthly dosing while averaging fewer than half the number of injections over 2 years.
WHAT IT MEANS TO YOU: The PrONTO study clearly demonstrates that OCT-guided retreatment of neovascular AMD with Lucentis can achieve visual outcomes that are non-inferior to monthly dosing. Interestingly, a study in the same copy of this journal found this is also true of Avastin – patients achieved excellent visual outcomes using half the number of injections as was used in PrONTO! Unfortunately, monthly office visits with careful examination are necessary to achieve these results. This can pose a significant burden for many patients and their families. Alternative follow-up strategies, such as "treat-and-extend," are still untested. While home vision tests may provide an effective means of detecting recurrence, we would ideally like to detect recurrence before vision is affected. Perhaps someday home testing of biomarkers, such as activated VEGF receptors, can be used to detect CNV recurrence at an earlier stage. More likely, better drugs will become available. The holy grail is a drug (or drug combination) that eradicates existing CNV, deters recurrence, combats the dry component of AMD, and can be administered topically as an eye drop. Such drugs are already on the horizon.
Read more...
Am J Ophthalmol. 2009;148:43-58
Tags: clinical trial, Lucentis, wet AMD, PrONTO, dosing strategy
The PrONTO Study has released results from the second year of follow-up of patients with wet age-related macular degeneration (AMD) that are treated with intravitreal Lucentis (ranibizumab) on an as-needed basis using optical coherence tomography (OCT) data that show as-needed treatment can achieve visual outcomes comparable to monthly Lucentis injections with significantly fewer injections.Inhibition of vascular endothelial growth factor A (VEGF-A) is an effective and safe therapy for the treatment of neovascular AMD. Intravitreal injections of Lucentis, a monoclonal antibody fragment that inhibits all the known biologically active forms of VEGF, were shown to improve mean visual acuity (VA) in eyes with neovascular AMD during the phase III clinical studies. In these studies, monthly injections over the course of 2 years were administered to eyes with choroidal neovascular (CNV) lesions. On average, VA improved and the outcomes were highly statistically significant.
Observations from the extension study served as the basis for investigating whether a variable-dosing OCT-guided regimen with Lucentis could result in fewer injections and similar clinical outcomes when compared with the phase III regimen that used monthly injections. A study was designed, known as the Prospective OCT Imaging of Patients with Neovascular AMD Treated with intraOcular Ranibizumab (PrONTO) Study. The 1-year results have been published, and the current article represents the full 2-year results of the PrONTO Study.
Methods and Results
In this open-label, prospective, single-center, uncontrolled clinical study, AMD patients with neovascularization involving the central fovea and a central retinal thickness (CRT) of at least 300 μm as measured by OCT were enrolled to receive 3 consecutive monthly intravitreal injections of Lucentis (0.5 mg). During the first year, retreatment with Lucentis was performed at each monthly visit if any criterion was fulfilled such as an increase in OCT-CRT of at least 100 um or a loss of 5 letters or more. During the second year, the retreatment criteria were amended to include retreatment if any qualitative increase in the amount of fluid was detected using OCT.
Forty patients were enrolled in PrONTO and 37 completed the 2-year study. At month 24, the mean VA improved by 11.1 letters (P < .001) and the OCT-CRT decreased by 212 um (P < .001). VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months.
Discussion and Conclusions
In the PrONTO Study, decrease in retinal thickness, was detectable within 1 day after the first Lucentis injection and was maintained through 24 months using an OCT-guided variable-dosing regimen. During the first year of the study it became evident that fluid continued to increase if left untreated and that the qualitative assessment of OCT scans was better at detecting fluid in the macula than waiting for changes in VA. Therefore, the protocol was amended to permit retreatment at the earliest sign of reaccumulating fluid in the retina, under the retina, or under the RPE. The change in retreatment criteria during the second year was considered to be consistent with the study objective to determine if OCT-guided therapy could minimize the number of injections over 2 years while achieving VA outcomes comparable with the outcomes achieved using monthly injections in the phase III trials.
The final VA outcomes in the PrONTO Study were comparable with the results from the phase III clinical trials (MARINA and ANCHOR). In the MARINA trial, the final mean VA improved by 7.2 letters, and in the ANCHOR trial, the final mean VA improved by 11.3 letters. By comparison, VA in the PrONTO Study improved by 11.1 letters at 24 months with a 95% CI ranging from 7 letters to 15.2 letters, suggesting results comparable with the phase III trial results. Whereas patients in the MARINA and ANCHOR trials received 24 injections over 24 months, the patients in the PrONTO Study received an average of just 9.9 injections with a median of 9.0 injections out of a possible 25 injections over 24 months. The totality of the data from the PrONTO Study suggests that OCT-guided retreatment with ranibizumab seems to be comparable with the VA outcomes from monthly injections; however, a prospective, randomized, double-masked study will be necessary to confirm these conclusions. Currently, the Comparison of AMD Treatment Trials (CATT) now underway will test whether an OCT-guided variable-dosing regimen is comparable with a fixed monthly dosing regimen with intravitreal Lucentis.
It is important to emphasize that the criteria for retreatment depended on close follow-up with monthly visits and careful examination of all 6 diagonal OCT scans with comparisons with the previous visit's scans to determine if any fluid had persisted or reaccumulated in the macula. The PrONTO Study was designed to minimize the number of retreatments but not the number of visits. There are other strategies that may yield similar or even better VA outcomes and that require fewer visits. One such strategy is known as treat and extend. After publication of the first year's data, some clinicians adopted the PrONTO retreatment criteria without adopting the strict follow-up schedule, without carefully examining all 6 OCT diagonal scans, and without comparing all current scans with the scans from the previous visit. Although it may be possible to base retreatment guidelines on fewer diagonal scans and less frequent follow-up, such a regimen was not tested in the PrONTO Study, and it is not possible to extrapolate the results to other retreatment paradigms.
Although Lucentis effectively may remove the fluid from the macula and may prevent the growth and leakage of neovascular lesions, the continued progression of the underlying dry AMD explains why some patients experienced little if any VA benefit from therapy, and probably explains why some patients experience continued vision loss over an extended period while receiving Lucentis therapy. Therefore, it stands to reason that to avoid treatment failures, therapies that target both the neovascular component and the underlying dry AMD are needed. Without this combination approach, it seems unlikely that any other antiangiogenic therapy will achieve VA outcomes better than the outcomes achieved with Lucentis therapy alone.
In summary, the PrONTO Study used an OCT-guided variable-dosing regimen with Lucentis resulting in VA outcomes comparable with those of the phase III studies with monthly dosing while averaging fewer than half the number of injections over 2 years.
WHAT IT MEANS TO YOU: The PrONTO study clearly demonstrates that OCT-guided retreatment of neovascular AMD with Lucentis can achieve visual outcomes that are non-inferior to monthly dosing. Interestingly, a study in the same copy of this journal found this is also true of Avastin – patients achieved excellent visual outcomes using half the number of injections as was used in PrONTO! Unfortunately, monthly office visits with careful examination are necessary to achieve these results. This can pose a significant burden for many patients and their families. Alternative follow-up strategies, such as "treat-and-extend," are still untested. While home vision tests may provide an effective means of detecting recurrence, we would ideally like to detect recurrence before vision is affected. Perhaps someday home testing of biomarkers, such as activated VEGF receptors, can be used to detect CNV recurrence at an earlier stage. More likely, better drugs will become available. The holy grail is a drug (or drug combination) that eradicates existing CNV, deters recurrence, combats the dry component of AMD, and can be administered topically as an eye drop. Such drugs are already on the horizon.
Read more...
Am J Ophthalmol. 2009;148:43-58
