Transpupillary Thermotherapy (TTT4CNV) for occult wet macular degeneration

Background:

Transpupillary thermotherapy (TTT) is a form of laser treatment using infrared light of the 810 nm wavelength. The rationale for using this laser is based on the absorption of laser energy by the melanin-rich retinal pigment epithelium. This laser is a well-established treatment for choroidal melanomas. Transpupillary thermotherapy raises the temperature in tissues, ultimately leading to the activation of heat-shock proteins, apoptosis and vessel coagulation. The exact mechanism behind closure of choroidal neovascularization is unknown.

TTT4CNV Clinical Trial
(Transpupillary Thermotherapy for choroidal neovascularization)
The TTT4CNV Clinical Trial is a multi-center, prospective, double-masked, placebo-controlled clinical trial conducted at 22 centers in the United States. The trial was designed to look at eyes with wet AMD and randomized eyes with small (less than or equal to 3 mm diameter) subfoveal occult membranes and symptomatic vision (ETDRS visual acuity between 20/50 and 20/400).

In all TTT treated eyes laser energy was applied at 800 milliWatts with a 3 mm spot size for 60 seconds with the IRIS Medical(R) OcuLight(R) SLx 810 nm laser and Large Spot Slit Lamp Adapter. Results were compared to sham treated (placebo) eyes. One retreatment was permitted at 3 months during the follow-up period at the physician's discretion.

The trial was physician initiated, supported by IRIDEX and performed within the FDA cleared indications for the OcuLight infrared laser system. TTT is a large spot size, low irradiance, long exposure, infrared (810 nm) laser photocoagulation protocol. The protocol uses the Company's IRIS Medical OcuLight SLx laser and Large Spot Slit Lamp Adapter.

RESULTS
An intent-to-treat evaluation of the primary visual outcome data in 303 enrolled patients showed that TTT, as applied in this trial, did not result in a significant vision- benefit. (Invest Ophthalmol Vis Sci 2005;46: E-Abstract 2311).

Subgroup analysis showed statistically significant vision-benefit in a specific group. The results showed that in a subgroup of patients with baseline visual acuity of 20/100 or worse, 22% of treated eyes improved vision by one or more lines compared with none of the eyes in the untreated control group. At 18 months, there was a 2 line benefit in preserving vision in this subgroup. Specifically, TTT treated eyes on average lost 2 lines of visual acuity while control eyes lost 4 lines.

Subgroup analysis concerns
Outcomes can be classified as either primary or secondary. Primary outcomes provide the focus of the study. Secondary outcomes (such as those derived from subgroup analysis) allow for investigating subsidiary questions that, while scientifically important, do not have the same priority of clinical interest in the patient group being studied. One should view subgroup analyses within a randomized trial with caution because of the low statistical power of the analysis. Instead of finding genuine differences between subgroups we may get false positive. One solution to this dilemma is to view the results of subgroup analysis as hypotheses. Whether the finding is valid can only be established by additional studies. (Med J Aust. 2004 Mar 15;180(6):289-91).

In general, valid subgroup analyses should be defined a priori (i.e. before initiating the trial) and purposely on the basis of known biological mechanisms or in response to findings in previous studies.

Since we do not have a peer reviewed published final report on the TTT4CNV, we cannot comment adequately on whether the subgroup analysis showing vision-benefit is something that physicians could reasonably incorporate in their management algorithms. We do hope that by raising the issues surrounding subgroup analysis in a clinical trial where the primary outcome measure does not support treatment vision-benefit, we have placed this matter in a critical perspective while awaiting publication of trial report.