Saturday, July 14, 2007

Two-Year Results of the PRONTO Study

In his Med Rounds blog, Dr. James Folk, professor of Ophthalmology in the Dept. of Ophthalmology at The Univ. of Iowa. Iowa posted a writeup of Dr. Carmen Puliafito’s presentation of the two-year results of the PRONTO study, given at the Macula Society’s meeting in London (May 29 - June 2nd), wherein doctors at Pulaifito’s Bascom Palmer Eye Institute gave three monthly injections of Lucentis to wet AMD patients and then examined them monthly with OCT and fluorescein angiogram every three months. They then decided if a follow-up injection of Lucentis was warranted.

With Dr. Folk’s permission,(and including some further background information taken from the May 2007 issue of Retina Today about the PRONTO study, with permission of the magazine’s publisher), here are the highlight’s of Dr. Puliafito’s presentation and additional details of the PRONTO Study.

Update from the 30th Annual Meeting of the Macula Society

The 30th annual meeting of the Macula Society was held May 30-June 2, 2007 in London. The meeting was attended by experts in macular disease from around the world. There were a number of papers updating the positive results of the various Lucentis trials including reports from the following studies: PRONTO, ANCHOR, Extension Study 2508, HORIZON, and PIER. The Extension Study showed that intraocular injections of Lucentis were well tolerated for up to four years and that the positive visual results were maintained.

Dr. Carmen Puliafito presented an update from the PRONTO study. In PRONTO, patients with wet AMD were treated with three monthly injections of Lucentis. An injection was given at baseline, month one, and month two. Then the patients were followed monthly. An optical coherence tomography (OCT) exam was done at every visit and a fluorescein angiogram was done every three months. The patient received another injection of Lucentis only if:

They lost 5 or more letter of vision from the last visit
New neovascularization or hemorrhage was seen on clinical exam or fluorescein angiography
The OCT showed persistent or recurrent fluid in or under the retina
The OCT showed a increase central retinal thickness of 100μ or more
The OCT showed an increase in the height or breadth of a retinal pigment epithelial detachment.

It is not always possible to flatten a retinal pigment epithelial detachment with Lucentis so patients were not retreated if there was no fluid in the retina and the pigment epithelial detachment was stable.

The visual results from the PRONTO study were basically the same as the results from the MARINA and ANCHOR studies which means that on average, patients gained two lines of vision after two years of follow-up. Patients in the PRONTO study needed, on average, 5 injections per year for two years. Some patients needed only three injections and then were stable whereas other patients needed injections every month. At any given monthly visit, patients had about a one in three chance of needing another injection.

Most retinal experts are using variations of the PRONTO scheme meaning patients get three injections of Lucentis or Avastin and are then followed if they are stable and without fluid. If patients have stable vision and no fluid, many retinal experts will gradually lengthen the time between appointments to two or even three months.

The CATT Study (Comparison of AMD Treatment Trials) will help us answer this question because there are arms of the trial in which Lucentis and Avastin are given monthly and arms in which, after the first three injections, they are given only as needed.

Dr. James Folk, Med Rounds, June 13, 2007.


Puliafito, C., Rosenfeld, P., Lalwani, G., Fung, A., Michels, S., Dobovy, S., Feuer, W. “An OCT-Guided Variable-Dosing Regimen with Ranibizumab (Lucentis) in Neovascular AMD: Two Year Results of the PRONTO Study.”

Some additional information about the PRONTO Study, taken from the May 2007 issue of Retina Today:


Monthly injections of ranibizumab were shown to be effective for the treatment of neovascular age-related macular degeneration (AMD) in two phase 3 multicenter controlled clinical trials.(1,2) Recently, an open-label, single-center prospective study using a variable dosing regimen guided by optical coherence tomography (OCT) resulted in similar outcomes but with fewer doses required.(3,4)

This activity reviews results of that study, called the PrONTO (Prospective OCT imaging of patients with neovascular AMD treated with intraocular ranibizumab [Lucentis]) study, performed by researchers at the Bascom Palmer Eye Institute of the University of Miami's Miller School of Medicine.


Patients included in the study had any type of neovascular lesion involving the fovea, a central retinal thickness on OCT of ≥300 μm, and visual acuity of 20/40 to 20/400. There were no exclusions for patients with existing cardiovascular, cerebrovascular, or peripheral vascular conditions.

Forty patients were enrolled in the study at the Bascom Palmer Eye Institute between August 2004 and April 2005. The mean age of the patients was 83 years, all were white, and 65% were women. One eye of each patient was designated the study eye. Mean visual acuity in the study eyes was 20/80. At baseline, CNV was classified as minimally classic in 57.5% of eyes, occult only in 25.0%, and predominantly classic in 17.5%. Ten of the 40 eyes (25%) were classified as having retinal angiomatous proliferations.

Results After 1 Year

Visual acuity improvement from baseline was detectable by 14 days after the first injection of ranibizumab. Mean improvement in visual acuity score at that visit was 6.9 letters (P<.001). Visual acuity continued to improve through the first 3 months of the study. By 3 months after the first injection there was a mean increase of 10.8 letters (P<.001) (Figure 1).

The improvement in visual acuity was associated with a decrease in central retinal thickness on OCT. At day 1 after the first injection there was a mean decrease of 47 μm (P<.001). Central retinal thickness decreased by a mean of 190 μm during the first 3 months (P<.001). OCT demonstrated the rapid resolution of subretinal fluid and cystic changes during the first 3 months.

After three monthly injections, only three eyes required an additional injection of ranibizumab at the month 3 visit because of persistent macular fluid. Two of these eyes achieved a fluid-free macula after two or three more monthly injections. One eye never became fluid-free and required monthly injections through month 12 of the study.

The most common reason for reinjection was loss of five letters or more of visual acuity associated with detection of fluid by OCT. Of the 40 study eyes, 39 eventually became fluid-free with only one requiring monthly injections. Thirty-seven of 39 developed some recurrence of fluid during the year. Of those, 32 received a retreatment during the year. After the first three injections, seven patients never needed another injection through year 1. Of the eyes that did need a retreatment because of recurrent fluid, the mean injection-free interval lasted 4.5 months.

The mean number of injections per patient in the first year of the study was 5.6, including the three initial monthly injections mandated by the study protocol.

All 40 patients were examined at the 12-month follow-up point. The mean improvement in visual acuity score from baseline was 9.3 letters (P<.001). These results are comparable to those in the 0.5-mg treatment groups in the MARINA1 and ANCHOR2 studies, in which mean visual acuity improvement was 7.2 and 11.3 letters, respectively.

Other visual acuity endpoints at 1 year in PrONTO were similar to those in the 0.5-mg treatment groups in the phase 3 studies. More than one-third of eyes (35%) in PrONTO gained three or more lines of visual acuity at 1 year. Similarly, in MARINA and ANCHOR, 33.8% and 40.3% of patients receiving 0.5 mg ranibizumab gained three or more lines. In the PrONTO study, 82.5% of patients maintained baseline vision (lost no letters), whereas in MARINA and ANCHOR the percentages were 71.3% and 77.7%, respectively. In PrONTO, 95% of eyes lost less than 15 letters (three lines) of visual acuity at 1 year. This again is comparable to MARINA and ANCHOR, in which 94.6% and 96.4% of patients lost less than 15 letters.

It should be noted that these results were achieved with an average of 5.6 injections over the course of 12 months in the PrONTO study, whereas the patients in the MARINA and ANCHOR studies received 13 injections in 12 months.

Results at 2 Years

The 2-year results of the PrONTO study have recently been announced,(4) [and see above] but they have not yet been published.

In the 37 patients who completed the 2-year follow-up in the PrONTO study, the average number of treatments per year was five, with an average of 9.9 total injections over the 2 years of the study. Mean improvement in visual acuity score was 10.7 letters, with a mean reduction in central retinal thickness on OCT of 215 μm. Baseline vision was maintained by 78% of patients, and improved by 15 letters or more in 43% of patients.

The amended criteria during year 2 did not increase the number of injections given but allowed earlier treatment of active lesions. The year 2 data are more representative of how OCT guided retreatment would be used in real-world clinical practice.


Intravitreal injection of ranibizumab in the PrONTO study resulted in rapid improvements in visual acuity and OCT measurements. After 12 and 24 months, outcomes in the study were similar to the MARINA and ANCHOR phase 3 study results but with the mean frequency of dosing reduced by more than half, to about five injections per year. Based on these results, OCT appears to be a useful tool for guiding retreatment decisions for patients with neovascular AMD. A prospective, randomized clinical trial is needed to confirm these open-label results.


1. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.

2. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.

3. Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, Davis JL, Flynn HW Jr, Esquiabro M. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143:566-583.

4. Lalwani GA, Fung AE, Michels S, Dubovy SR, Feuer WJ Jr., Puliafito CA, Rosenfeld PJ. An OCT-guided variable-dosing regimen with ranibizumab (Lucentis) in neovascular AMD: two year results of the PrONTO study. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; May 7, 2007; Fort Lauderdale, Fla.

Wednesday, July 11, 2007

NeoVista Epi-retinal Strontium 90 Treatment for AMD Update

In mid-June, NeoVista announced the initiation of its CABERNET (Cnv secondary to AMD treated with BEta RadiatioN Epiretinal Therapy) clinical trial for the treatment of subfoveal choroidal neovascularization associated with age-related macular degeneration (AMD).

The CABERNET study will employ the company’s Epi-Rad90 ophthalmic system to deliver Strontium 90 directly to the retina (using an outpatient partial vitrectomy), along with an injection of an anti-VEGF agent (Lucentis) at the time of surgery, followed by a second injection of Lucentis 30 days thereafter. The control arm of the study will utilize Lucentis injections alone.

The company noted that it was following the PIER regimen for Lucentis in the control arm, which represents 3 initial monthly injections and then quarterly after that. There is also a rescue plan in place for those patients who begin reverting back to worsening VA. They chose to follow this path, as PIER is the only trial that treated all types of CNV, thus providing them the broadest possible label.

The CABERNET clinical trial will include 30 clinical sites, with 20 in the U.S., and 10 spread across Europe, Israel, and South America. The study will involve 495 patients followed for 2 years; 330 receiving the 24 Gy dosage of Strontium-90 plus Lucentis, and 165 receiving only the Lucentis injections.

In addition to the information about the start of the CABERNET study, the company also sent along information updating its previously reported results of both its Radiation Only feasability study, now out to 18 months, with vision holding at +6.4 letters (as shown below in Graph 1), and 9 month data on its Concomitant Study, which utilized two injections of Avastin along with a treatment of Strontium-90. These results are shown in Graph 2 below.

Graph 1.

Graph 2.

(See my February 14, 2007 report for the full initial story.)

These updated results were reported by the company at the recent (May 30 – June 2nd) Macular Society Meeting held in London. The nine-month Concomitant Study results show equivalent results to the ANCHOR Study, which applied monthly doses of Lucentis to patients over a 2 year period.

As a result of this updated data and the start of the CABERNET study, the following key questions were posed to the company:

1) The Epi-Rad90 arm of the feasability study appears to be showing increased VA, especially in months 9 - 12. Although the results decreased again (according to your reports) out to month 18. Is there any thought of performing a second treatment of radiation, or adding an injection of anti-VEGF agent at the two-year period?

Given that radiation alone is likely not to have the same efficacy as concomitant treatment over a 2-year period, we must wait to learn the 2 year results of both arms for proper comparison. As for the possibility of a second radiation treatment, this is an opportunity that will require much investigation. At this stage of our existence, we are not able to investigate all opportunities presented us and realize that concluding the CABERNET trail must remain our first priority.

2) The Concomitant Study arm results appear to be leveling off after 6 months. Would another shot of Avastin at, say 9 months, be expected to show further improvements?

Time will tell. We will likely see an increase in cataract formation in the treated group in the first year post-op. Post-cataract procedure exams showed an increase in VA again between 9 and 12 months in the Radiation Only Study. As you know, cataract formation is a common occurrence in patients undergoing vitrectomy. Our procedure has shown a much lower incidence of cataract procedure than standard Vitrectomy outcomes. We believe this is due to the use of a partial versus complete Vitrectomy. Another point to make; many of those eligible for our procedure will have likely already had cataract surgery due to natural change.

3) Is OCT inspection of the retina part of the followup examinations – similar to the PRONTO Study?

We are utilizing both OCT and FA (fluorescein angiogram) in CABERNET via assigned Reading Centers. In our feasibility studies, OCT and FA were utilized. For CABERNET rescue requirements, one component of judging whether or not to re-inject will be the OCT image analysis.

(A writeup of the PRONTO Study is shown in a separate report – see Two-Year Results of the PRONTO Study on this web site.)

For Information Only:

The MARINA study enrolled patients with occult and minimally classic choroidal neovascularization (CNV), the form of CNV found in most patients with wet AMD, while the ANCHOR study enrolled patients with predominantly classic CNV.

MARINA (Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab (Lucentis) In the treatment of Neovascular AMD) was a Phase III randomized, multi-center, double-masked, sham-controlled study of 716 patients in the United States with minimally classic or occult wet AMD who were randomized 1:1:1 to receive intravitreal ranibizumab injections (0.3 mg or 0.5 mg) or a control regimen once a month for two years. The control regimen consisted of a sham injection, meaning the treating physician prepared and anesthetized the patient’s eye but did not perform an injection.

ANCHOR (ANti-VEGF Antibody for the Treatment of Predominantly Classic CHORoidal Neovascularization in AMD) was a Phase III randomized, multi-center, double-masked, active-treatment controlled study comparing two different doses of Lucentis to verteporfin (Visudyne) photodynamic therapy (PDT) in 423 patients with predominantly classic wet AMD in the United States, Europe and Australia. Patients were randomized 1:1:1 to receive intravitreal ranibizumab injections (0.3 mg or 0.5 mg) once a month or PDT every three months for two years.