15.2.4.2 How Should Treatment be Started?

The pivotal trials (MARINA, ANCHOR and the active control arm in EXCITE), shown in Fig. 15.1a, b and d, were the only phase III ranibizumab studies to use monthly injections through the entire period of treatment. VA improvement was most rapid during the first month following the initial injection, and was greatest during the initial 3-month period. Although VA continued to improve in some patients after 3 months, for most people, the gains appeared to stabilise in the period after 3 months (see Fig. 15.1a–f).

Initiating ranibizumab therapy with three consecutive monthly injections therefore appears optimal, given that this interval is when most patients experience the bulk of their VA gains, in all of the phase III trials. A few studies, however, have evaluated whether the three doses that were routinely given in the initiation phase of flexible treatment trials (e.g. SUSTAIN) are needed.

A recent UK study [69] compared a ‘pro re nata’ (PRN/ as needed) regimen from after the first injection (1 + PRN) to a loading dose regimen of 3 monthly injections (3 + PRN), with both groups subsequently receiving ‘PRN’ therapy during the period after 3 months. Although the visual gain was similar after 12 months, the proportion gaining 15 letters (3 LogMar lines), was significantly higher (29.8%) in the ‘loading’ (3 + PRN) group that had a mean 6.0 injections, compared with the ‘1 + PRN’ group (12.9%) that had a mean 4.5 injections. The mean 1-year letter gains were 4.4 letters for the 3 + PRN group and 4.0 for the 1 + PRN group. Two other 1+ PRN studies have been reported [70, 71], but without comparison, using a mean 5.6 and 5.1 injections, respectively, in the first year, with mean 1-year letter gains of 7.3 and 9 letters, respectively. A limitation is that all were relatively small studies. Authors from the recent UK study [69] concluded that VA improvement was best achieved using a loading dose of three injections, as in the major reported trials (3 + PRN regimen, compared with 1 + PRN).

15.2.4.3 What Flexible Approaches Are Reported?

Fixed Quarterly Injection Studies

Fixed 3-monthly administration, after a ‘loading’ phase of three consecutive monthly injections, as in the PIER [72, 73] and EXCITE [52] trials (Fig. 15.1c, d), produces suboptimal results [33]. In PIER, the initial

VA gain at 3 months progressively dissipated to zero gain by 12 months and to a loss of two letters by 24 months. In PIER, after the first 3 months, monitoring was only performed at quarterly intervals.

The larger EXCITE trial was designed to show non-inferiority of quarterly to monthly treatment, and, as in PIER, did not achieve this outcome [52]. However, in this trial, patients were monitored at monthly intervals with BCVA and ICT, so that changes in the first, second and third month after stopping treatment could be evaluated, both in BCVA and in OCT-measured central retinal thickness (CRT). A seesawing effect was evident in these parameters with the loss of control. It was actually at month 4 (2 months after the last injection) that the difference between quarterly and monthly regimens became evident, and this difference was even more obvious at month 5, the time at which the first quarterly injection was due [52]. Quarterly treatment was, on average, clearly inferior to monthly treatment, with the 3-month gain reducing to around half by 12 months in the quarterly injection group.

Importantly, the mean gain at 1 year in the fixed monthly treatment group (average 8.3 letters) in EXCITE was quite comparable to the average 1-year gains in ANCHOR and MARINA, taking into account the proportion (20%) of EXCITE CNV lesion types that were predominantly classic.

While the reason for the poor outcomes of quarterly dosing is unclear, it seems likely that different response profiles of patients with NV-AMD are, at least in part, responsible. In the PIER responder data reported by the International Advisory Group, Fig. 3 [33], around one in four patients treated from baseline with three monthly ranibizumab injections had no initial gain, and of the remaining three out of four cases who experienced an initial gain, this was maintained in 40% after moving to fixed 3-monthly treatments, but was not maintained in 60% after this move. A somewhat similar breakdown into responder profiles was shown for the SUSTAIN [33] (Fig. 15.1f) and EXCITE [52] trials, with a relatively similar distribution of outcomes. The VA response at months 4 and 5 may be a stability marker – a VA fall at that time in a flexible regimen indicates those patients who have a greater need for anti-VEGF therapy, and who exhibit poorer prognosis in terms of maintaining any gain.

In the SAILOR cohort 1 [33], three consecutive monthly injections were followed by quarterly monitoring visits and injections guided by VA (>5-letter loss from the previous highest VA score) and OCT criteria, if available (>100 mm increase in CRT from the previous lowest measurement), with additional visits/injections possible if required. Mean VA change increased from baseline over the first three injections, but then decreased to a mean gain of 2.3 letters for both ranibizumab doses, a better result than in PIER, but less than in EXCITE. The SAILOR data showed that quarterly visits were insufficient to monitor and capture disease progression [33].

Flexible Dosing Regimens: Two Approaches

Two approaches to an individualized or flexible ranibizumab dosing regimen have now been developed. In the first, an ‘as needed’ or ‘PRN’ approach, after an initial ‘loading’ phase of three monthly injections, patients continue to be monitored at monthly or close to monthly follow-up intervals, and further injections are given using pre-specified re-injection criteria (see Table 15.4) [33]. The second flexible regimen is termed ‘Inject-and-Extend’, was first suggested by Spaide and rapidly taken up by others [79, 80].

Flexible Dosing Regimens: ‘As Needed’ Approach

A small, open-label, prospective, single-centre, nonrandomized, investigator-sponsored study (PrONTO, Fig. 15.1e) assessed three consecutive monthly injec- tionsfollowedbyOCT-guidedvariabledosing(at³1 month monitoring intervals) [74]. Re-treatment criteria were:

5-letter loss in the presence of macular fluid detected by OCT; ³100 mm increase in CRT; new-onset classic CNV; new macular haemorrhage; or persistent macular fluid on OCT. This study produced a similar VA outcome to combined MARINA and ANCHOR trials (9.3 letter gain at 12 months) were demonstrated but with fewer (5.6) intravitreal injections. By 24 months, the mean gain was 11.1 letters for an average 9.9 injections over the whole 2-year period [75], with any qualitative fluid signs prompting re-treatment in second year. This study was the first to strongly suggest that a flexible OCT-guided re-treatment regimen could sustain visual gain with fewer injections; however, no other flexible trials or series have had such good outcomes.

The large SUSTAIN trial [33] (Fig. 15.1f) directly examined a PRN flexible regimen, following three initial consecutive monthly injections of ranibizumab, with an average 2.7 injections needed in the following 9 months. The VA gain at 3 months (5.8 letters), fell to 3.6 letters above baseline by 1 year, that is some VA loss occurred after month 3. Additional treatment after the first three injections was guided by the following criteria: >5-letter loss in VA from the previous highest VA score during the first 3 months; or >100 mm increase in CRT from the previous lowest measurement during the first 3 months.

Other case series have also demonstrated less than optimal rates of maintaining ‘loading’ phase gains. A UK series demonstrated a mean gain of 3.7 letters over 1 year, using a clinician-determined re-treatment strategy after a 3-dose ‘loading’ phase, using a mean 5.6 injections [76]. A small Spanish series showed a mean