Pilot randomized trial of a nanopulse retinal laser versus conventional photocoagulation for the treatment of diabetic macular oedema

Original Article

Pilot randomized trial of a nanopulse retinal laserversus conventional photocoagulation for thetreatment of diabetic macular oedemaRobert J Casson FRANZCO DPhil, Grant Raymond FRANZCO, Henry S Newland FRANZCO MPH,Jagjit S Gilhotra FRANZCO and Tim L Gray FRANZCOSouth Australian Institute of Ophthalmology and Royal Adelaide Hospital, Adelaide, South Australia, Australia

ABSTRACT

Background: To assess the efficacy of a new nanopulselaser, retinal regeneration therapy for the treatmentof diabetic macular oedema.

Design: Randomized, non-inferiority, trial.

Participants: 20 eyes of 17 subjects in the retinalregeneration therapy group and 18 eyes of 14 sub-jects in the conventional group were analysed.

Methods: The treatment group received retinal regen-eration therapy laser, and the control group receivedphotocoagulation.

Main Outcome Measures: The primary outcome wasthe optical coherence tomography-measured changein central retinal thickness at 6 months. A secondaryoutcome was the change in logarithm of minimumangle of resolution visual acuity at 6 months. Non-inferiority required the one-sided 95% confidenceinterval of the mean retinal thickness reduction afterretinal regeneration therapy to be within 35 mm ofthe reduction after control laser.

Results: When outliers were included in the dataset,the difference in retinal thickness reduction byanalysis of covariance was 10.9 (standard deviation17.6) mm in favour of the control laser. The dif-ference between groups in retinal thickness reduc-

tion was 40.8 mm. If two extreme outliers wereexcluded, the difference was 5.6 (standard deviation14.2) mm in favour of the retinal regenerationtherapy laser, and the D optical coherence tomogra-phy was 18.5 mm. The visual acuity differencebetween groups was 0.059, meeting non-inferiorityrequirements.

Conclusions: Although retinal thickness reductionwas not unambiguously non-inferior, in the short-term, retinal regeneration therapy approximates theclinical efficacy of conventional photocoagulation,stabilizing visual acuity and providing motivation forlarger trials assessing retinal regeneration therapy.

Key words: diabetic retinopathy photocoagulation,laser surgery, macular.

INTRODUCTION

A quarter of a century ago, the Early Treatment Dia-betic Retinopathy Study (ETDRS) provided convinc-ing evidence that laser photocoagulation reduced therate of visual acuity (VA) reduction from diabeticmacular oedema (DMO).1 Photocoagulative laserremains the standard treatment for DMO, but itsmechanism of action remains unclear. Possiblemechanisms include a reduction in capillary perme-ability or an increase in active transport of fluid fromretina to blood.2,3 Given that the mechanism is

� Correspondence: Professor Robert J Casson, Level 8, East Wing, Royal Adelaide Hospital, Adelaide, SA 5000, Australia. Email: robert.

[email protected]

Received 1 February 2011; accepted 5 December 2011.

Competing/conflicts of interest: No stated conflict of interest.

Funding sources: RJ Casson has received travel expenses from Ellex Medical Lasers.

Trial registration: ACTRN12608000369325.

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Clinical and Experimental Ophthalmology 2012; ••: ••–•• doi: 10.1111/j.1442-9071.2012.02756.x

© 2012 The AuthorsClinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists

unclear, it is plausible that photocoagulation per se isnot necessary for effective treatment. Furthermore,standard photocoagulation produces a thermal injuryto the lasered tissue, compromising its safety profile.Photocoagulation for the treatment of DMO cancause collateral damage to the overlying sensoryretina, subretinal fibrosis and enlargement of burnswith time, complications that are energy dependentand can have devastating visual results.4–6 Hence,an alternative laser treatment that was at least aseffective and potentially safer would be clinicallydesirable.

These factors motivated the development of anew nanopulse laser, retinal regeneration therapy(2RT; Ellex R&D Pty Ltd, Adelaide, Australia),which delivers approximately 0.2% of the energyper pulse compared with standard photocoagula-tion. The design of the 2RT laser also includes aunique beam profile that finely distributes thedelivered energy over the treatment spot so thattreatment effects can be completely confined withinthe retinal pigment epithelium. Histological exami-nation of retinas from lasered animals demonstratedremarkably little or no destructive injury to theoverlying photoreceptor layer at clinically relevantenergy settings. (Chidlow G, unpublished data,2011) An interventional case series of 2RT for thetreatment of DMO conducted in London, U.K.(unpublished data) was not associated with anyadverse events and suggested that further dataregarding its efficacy was worth pursuing.

Our primary hypothesis was that 2RT was at leastas effective as conventional photocoagulation for thetreatment of DMO in reducing retinal thickening asmeasured by optical coherence tomography (OCT).A secondary hypothesis was that 2RT was at least aseffective as conventional photocoagulation for thetreatment of DMO in preserving VA. Herein, wereport the results of a pilot, phase II, randomized,non-inferiority trial of 2RT versus conventional pho-tocoagulation for the treatment of DMO. Given thepotentially better safety profile of the new laser withminimal tissue destruction compared with photoco-agulation, the rationale for the study was that results,which supported the hypothesis, would providemotivation to proceed to a larger randomized trial.

METHODS

Design

This was a randomized, non-inferiority, parallel-group study conducted in Australia (at two sites).Methodology was modelled on a recent Diabetic Ret-inopathy Clinical Research Network Trial study7

and was guided by the Consolidated Standards ofReporting Trials 2010 update.8

Ethics and clinical trial registration

Ethics committee approval was obtained, and thestudy adhered to the tenets of the Declaration ofHelsinki. Written informed consent was obtainedfrom all participants. The trial was registered withthe Australian New Zealand Clinical Trials Registry(ACTRN12608000369325).

Eligibility and allocation

Patients were recruited from two retinal clinics. Tobe eligible, subjects had to be at least 18 years of ageand have types 1 or 2 diabetes mellitus, with one orboth of their eyes meeting the following criteria: (i) abest-corrected ETDRS VA score of 19 or more letters;(ii) a retinal thickness measured on Stratus 3.0 OCT(Carl Zeiss Meditec, Dublin, CA, USA) of 250 mm ormore in the central subfield, or 300 mm or more in atleast one of the four inner subfields; and (iii) no priorlaser treatment or other treatment for DMO. Eyeswere not eligible if they had retinal thickening fromany other cause or had undergone any ocular surgerywithin the prior 6 months.

Eyes were randomized to either 2RT or the controlgroup using a simple randomization process withoutblocking or stratification. The trial coordinator per-formed the randomization procedure and retainedsequentially numbered opaque containers that wereopened by the treating clinicians just prior to laser.

VA testing and OCT measurements were per-formed by masked observers. After the initial lasertreatment, the patient was seen at a 3-monthfollow-up visit, and a further laser treatment wasapplied at the clinicians’ discretion.

Treatment protocols

The 2RT laser produces single pulses of 3-ns dura-tion at a wavelength of 532 nm, with a deliveredbeam profile that finely distributes the energy overthe treatment spot. The photocoagulator laser was anIntegre (Ellex Medical Lasers Ltd, Adelaide, Austra-lia) providing variable length pulses at a wavelengthof 532 nm, with a ‘top hat’ beam profile. The twotreatment techniques differed in the followingaspects: 2RT applications were delivered with a spotsize of 400 mm at an energy setting that produced nilreaction or a barely discernible retinal reaction(approximately 0.3 mJ) with each application (thecurrent 2RT laser has a fixed 400-mm spot size). The2RT laser energy was first titrated up to the point ofthe first visible reaction, which appeared as subtleretinal blanching. Slightly lower energy was thenselected for treatment. This method provided indi-vidual compensation for variations in corneal, lensor vitreous opacities, and also retinal pigmenta-

2 Casson et al.


tion variations. The titration of the laser energywas applied to non-thickened regions outside themacula. As the applications were advanced to thick-ened retinal regions, there was generally no observ-able reaction. 2RT laser was applied in a grid pattern,one ‘burn’ width apart to thickened areas of retina atleast 500 mm from the foveal centre, with a rangeof approximately 20–120 applications. Microaneu-rysms were not directly treated. The same parameterswere used for re-treatment if necessary. The ETDRSdirect/grid photocoagulation involved treating onlyareas of thickened retina and directly treatingleaking microaneurysms with light burns, a spot sizeof 100 ìm and typical pulse durations of 0.1 s.

Data collection

At baseline and each follow-up visit, best-correctedVA in each eye was recorded using an ETDRS chart.A fluorescein angiogram (FFA) was obtained, andcentral retinal thickness (CRT) was recorded usingthe Stratus OCT 3.0 (Carl Zeiss Meditec, Dublin, CA,USA). Blood pressure recordings and haemoglobinA1c measurements were also taken at each visit. Datawere entered into an electronic spreadsheet bytrained personnel. Data from the OCT central sub-field and four inner zone subfields were analysed.

Definition of outcomes andnon-inferiority

The primary outcome was the change in CRT at6 months. A secondary outcome was the change inVA at 6 months. Because relative change in macularthickening provides unstable data in eyes with milddegrees of baseline thickening, the absolute ratherthan the relative change in retinal thickness reduc-tion was used,9 and given the clinical importance ofthe central subfield, data analysis was weighted tothis parameter using a simple algorithm: If subjectshad a central subfield thickness �250 mm, then thecentral subfield was used in the analysis regardlessof the thickness measurements in the inner sub-zones; if subjects had a central subfield < 250 mm,then the thickest of the four inner subzones wasanalysed. Both eyes of the subjects were potentiallyeligible, and the eye was the unit of statisticalanalysis.

Given that there are no consistently accepted defi-nitions of ‘diffuse’ and ‘focal’ oedema and that thereis no convincing evidence that this labelling predictsVA change or response to treatment,10 eyes were notcategorized by oedema type.

An analysis of covariance (ANCOVA) regressionanalysis with the 6-month retinal thickness as thedependent variable, and group and baseline retinal

thickness as covariates was constructed, adjustingthe variance calculations for any within-subjectcorrelations. This analytic strategy adjusts for theeffects of regression to the mean because of unequalbaseline values, optimizes the precision of the esti-mates and reduces the sample size requirements. Asimilar analysis was performed with 6-month VA asthe dependent variable and baseline acuity as acovariate. Assumptions of ANCOVA regression, andoutlying and influential observations were assessed.

For the retinal thickness comparison, non-inferiority required the one-sided 95% confidenceinterval of the group covariate coefficient in theANCOVA regression to be less than 35 ìm in favourof the control group. This is considered as the differ-ence between group means after adjusting for regres-sion to the mean. This requirement was defined as theDOCT.

For the VA comparison, non-inferiority requiredthe one-sided 95% confidence interval of the groupcovariate coefficient in the ANCOVA regression to beless than 0.06 (three letters) in favour of the controlgroup. This requirement was defined as the DVA.

Sample size calculation

The sample size was calculated to detect a differenceof 35 mm with a one-sided 95% confidence interval at80% power and alpha value of 0.05. The standarddeviation (SD) was estimated from the literatureas 60 mm.7 The correlation between baseline andfollow-up retinal thickness was estimated as 0.7. Asample size of 37 eyes was required. An increase insample size of 15% in each group was added to allowfor loss of follow-up or incomplete data.

RESULTS

Patient allocation, losses to follow-up and exclusionsare shown in Figure 1. There were 24 eyes allocatedto the 2RT group. One patient died, and two with-drew (three eyes lost). One patient had a retinal veinocclusion during the study and was excluded prior toanalysis. Hence, 20 eyes of 17 subjects in the 2RTgroup were analysed. There were 18 eyes of 14 sub-jects in the conventional group for analysis. Therewere 20 eyes allocated to the control group. Onepatient died, and one withdrew. There were twoextreme observations (Fig. 2): one subject in thecontrol group was a patient who developed chole-cystitis and required surgery during the study; perio-peratively, she changed diet and lost a large amountof weight. She had an extraordinary reduction inretinal thickness and was a highly influential obser-vation on the regression analysis. There was oneextreme outlier in the 2RT group but with no

A new laser for diabetic macular oedema 3


unusual clinical features. We have provided theanalysis both with and without these data points.Subjects reported that the 2RT laser treatment wascompletely painless, and it was well tolerated.

Table 1 compares the baseline variables, andchange in mean CRT and VA at 6 months in eachgroup. The only variable that we considered to beprognostic was baseline CRT, which was adjustedfor in the regression analysis. The 2RT group wasolder, with a mean age of 63.8 (SD 9.6) years com-pared with a mean age of 56.3 (SD 9.3) years in the

control group. Men were overrepresented in bothgroups. Note that because of the randomization, anydifferences in distribution are due to chance; hence,the calculation of P-values is illogical, as discussedin the Consolidated Standards of Reporting Trialsguidelines.

Figure 2 shows box plots of the change in retinalthickness for both groups. The distribution of bothgroups was similar. The outlying observations thatwere omitted from one of the regression analyses are

Analysed (n = 20 )

♦ Excluded: one eye with retinal vein

occlusion between 0 and 3 months (see

text for explanation)

Incomplete follow-up (n = 3)

Died (one subject with one allocated eye [n = 1])

Withdrew (two subjects with two allocated eye

[n = 3])

Allocated to 2RT (n = 24)

♦ Received allocated intervention (n = 24)

Incomplete follow-up (n = 2)

Died (one subject with one allocated eye [n = 1])

Withdrew (one subject with one allocated eye

[n = 1])

Allocated to control laser (n = 20)

♦ Received allocated intervention (n = 20)

Analysed (n = 18)♦

Allocation

Analysis

Follow‐up

Randomized (n = 44)

Subjects were recruited from medical retinal

clinics. Information on the total number of subjects

assessed for eligibility and numbers unwilling to

participate was not documented

Figure 1. Flow diagram ofpatient randomization andanalysis. 2RT, retinal regenerationtherapy.

–200

–100

0100

200

control 2RT

reduction in r

etinal th

ickness

more

effective laser

Figure 2. Boxplot of the reduction in retinal thickness at6 months in both groups. The extreme outliers in each group aredepicted (red circles). 2RT, retinal regeneration therapy.

Table 1. Baseline data

Variable 2RT Controls

Number 20 18Mean age (SD) 63.8 (9.6) 56.3 (9.3)Male : female 13:7 15:3Mean baseline CRT (SD) 330.1 (84.0) 323.2 (65.2)Mean baseline VA (SD) 0.18 (.23) 0.13 (.24)Mean baseline systolic BP (SD) 138.3 (12.2) 138.7 (19.3)Mean baseline HbA1c (SD) 7.8 (1.3) 8.1 (1.37)Mean change HbA1c (SD) 0.22 (.96) -0.4 (1.6)Re-treatment at 3 months 18 16Mean change in CRT at

6 months* (SD)40.5 (74.9) 34.6 (78.0)

Mean change in VA at6 months** (SD)

0.01 (0.1) 0.01 (0.1)

*P = 0.88, **P = 0.98. 2RT, retinal regeneration therapy;BP, blood pressure; CRT, central retinal thickness in mm; HbA1c,haemoglobin A1c; SD, standard deviation; VA, logarithm of mini-mum angle of resolution visual acuity.

4 Casson et al.


circled in red in Figure 2. The outlier in the 2RTgroup had the largest studentized residual of thedataset (3.13) and was from a patient whose retinalthickness increased between 3 and 6 months, con-siderably reducing the mean reduction in this group.Figure 3 shows the box plots for change in VA forboth groups. These plots were remarkably similar,with almost identical medians and distributions,indicating stability of VA in both groups.

The mean reduction in retinal thickness in thecontrol group was 40.5 (SD 74.9) mm; the meanreduction in the 2RT group was 34.6 (SD 78.0) mm.However, adjusting for regression to the mean andthe higher baseline retinal thickness of the 2RTgroup, the difference in retinal thickness reductionby ANCOVA was 10.9 (SD 17.6) mm in favour of thecontrol laser. The DOCT was 40.8 mm. If the twoextreme outliers are excluded, the mean reduction inretinal thickness in the control group was 27.8 (SD57.9) mm; the mean reduction in the 2RT group was44 (SD 67.0) mm. The difference in retinal thicknessreduction by ANCOVA was 5.6 (SD14.2) mm infavour of the 2RT laser, and the DOCT was 18.5 mm.Hence, the primary null hypothesis is not unambigu-ously rejected.

The difference in VA change by ANCOVA was0.02 (SD 0.04) in favour of 2RT. The DVA was 0.059(three letters); hence, the secondary null hypothesiswas rejected.

There were seven eyes that met the inclusion cri-teria of retinal thickness �300 mm in the inner sub-field but had a retinal thickness of <250 mm in thecentral subfield. If the VA regression analysis wasperformed with these seven eyes omitted from theVA analysis, then the DVA inflates to 0.08 (fourletters); but, the difference in VA change betweengroups remains approximately zero, and the increase

in DVA is largely explained by an inflation of thestandard error because of the reduced sample size inthe subanalysis.

Representative colour fundus photos and FFAs ofa patient before and 6 months after 2RT for DMO areshown in Figure 4.

DISCUSSION

The results from this pilot study indicate that 2RTcan be effectively used to treat DMO. Although nocomplications were noted in either the 2RT or controlgroups, the safety profile of 2RT has clinically impor-tant theoretical advantages over photocoagulativelaser. Although the retinal pigment epithelium is thetargeted tissue of photocoagulation, there is dissipa-tion of heat to the surrounding tissue, particularlythe overlying photoreceptors. For this reason, treat-ment of oedema close to or at the fovea is notperformed. Damage to perifoveal photoreceptors cancause microperimetric defects, and burns can enlargewith time.

In 1983, Anderson and Parrish introduced theconcept of ‘selective photothermolysis’.11 Theyshowed that pigmented cells and organelles could beselectively targeted and that the thermal effects ofshort laser pulses could be spatially confined.11

Roider et al. later applied this concept to retinal lasertreatment.12 This approach reduced the collateraldamage to the sensory retina, as demonstrated bymicroperimtery, but still used a photocoagulativethermal insult.13 Subthreshold micropulse diodelaser has been used successfully to treat DMO14

and appears comparable with argon laser treat-ment;15 however, to our knowledge, randomizedequivalence/non-inferiority studies have not beenperformed.

Latina and Park demonstrated that selective tar-geting of pigmented trabecular meshwork cellscould be achieved with a 532 nm Q-switchedneodymium-YAG laser at pulse durations between10 ns and 1 ms without producing collateral thermalor structural damage to adjacent non-pigmented tra-becular meshwork cells on electron microscopy.16

This led to the development of selective laser trabe-culoplasty for the treatment of elevated intraocularpressure. The concept was modified to produce 2RT,which uses a 532 nm Q-switched neodynium-YAGlaser at a pulse duration of 3 ns and spot size fixedat 400 mm, and also includes a unique beam profilethat finely distributes the delivered energy over thetreatment spot. This laser is theoretically appealingfor the treatment of the retinal pigment epitheliumbecause it is highly selective. Light microscopicexamination of treated rat retina demonstrates nooverlying photoreceptor injury at clinically relevant

impr

ovin

g ac

uity

–.2

–.1

0.1

.2Control 2RT

chan

ge in

Log

MA

R

Figure 3. The visual acuity was stabilized in both groups withan almost identical distribution between groups. 2RT, retinalregeneration therapy.



energy settings with little inflammatory response.(Chidlow G, unpublished data, 2009).

The mechanism by which this new laser reducesretinal thickening in DMO remains unclear.However, the fact that conventional photocoagula-tive laser can effectively reduce DMO withoutdirectly treating leaking microaneurysms providesample precedent for a generalized laser-inducedeffect on water permeability across the retina.17–19

There are a number of limitations to this study.First, the numbers are small, and the follow-up isshort; we can provide no information about thelonger term VA outcome. Second, the study wasdesigned as a non-inferiority study rather than asuperiority study. This has inherent problems. Itdoes not lend itself to the traditional null hypothesistesting. To overcome this logical conundrum, a dif-ference between outcomes that is considered asclinically equivalent (the D value) is assigned. Forthe reduction in CRT, we elected a D of 35 mm. Onecould argue that this D is too high, which ‘everymicron counts’; conversely, one could argue that thisD is too small, which a greater difference is requiredto believe that the two lasers are clinically differentin efficacy. However, clearly, the larger the D, themore likely equivalence will be demonstrated. Webelieved that a D of 35 mm had a reasonable evidencebase and was the largest difference that we couldeasily defend. The value was chosen on a consensusof medical retinal opinion based on the fact that thetest–retest repeatability of the Stratus OCT isapproximately 10%;20 hence, with an average base-line thickness of 350 mm, 35 mm would be at theupper limit of the repeatability. Differences less thanthat are arguably noise. Also, non-inferiority studieslack a placebo control. We believed it was unethical

to have a placebo instead of an active control, butthis is problematic in respect to the ‘assay sensitiv-ity’ of the study.21 It requires that the active control isperforming to standard. There are limited data aboutthe OCT-recorded change in retinal thickness afterlaser treatment for DMO. The absolute reduction asrecorded in the current study depends on the base-line thickness, with thicker retinas showing moreabsolute thinning after laser. Based on availabledata from the literature, the average reduction inCRT after photocoagulation for mild-to-moderateDMO at 6 months was estimated at approximately20–40 mm.7,22 Hence, the mean reduction in CRT inour control group appears consistent with availabledata. Third, we did not record information aboutthose patients that met eligibility criteria but did notconsent to participate. This does not cause selectionbias but conceivably affects the generalizability ofthe results; however, the subjects were recruitedfrom medical retinal clinics, and we believe thatthey are likely to be representative of most devel-oped world Caucasian populations. Fourth, a modi-fied intention-to-treat analysis was performed ratherthan a strict intention to treat. We omitted onepatient from the 2RT group who suffered a branchretinal vein occlusion. This patient had a superiortemporal branch vein occlusion that occurredbetween visits. At the 6-month visit, the logarithmof minimum angle of resolution was 0.82. The veinocclusion was not in an area of previously thickenedretina, and we have no reason to believe that it wasa treatment-related event but cannot exclude thistheoretical possibility. 2RT laser applications wereevident on the FFAs as a zone of blocked fluores-cence with peripheral staining. The histological sub-strate of this observation, in particular, whether or

Figure 4. Representative colourfundus photos (a,c) and fluores-cein angiograms (a,d) of a patientbefore and 6 months after retinalregeneration therapy for diabeticmacular oedema. The subfovealcentral retinal thickness reducedfrom 540 to 409 mm. But, note thepersistence of perifoveal lipid (c).

6 Casson et al.


not the sensory retina is damaged is unclear. Fur-thermore, the long-term outcome of these FFA fea-tures, in particular, whether or not they enlarge withtime is unknown. The phenomenon potentiallyundermines the theoretic advantage of 2RT over con-ventional photocoagulation. Although an intention-to-treat design reduces potential bias and effectivelyanswers the question of what happens when apatient is assigned to a particular treatment, it doesnot necessarily answer the question: What is theeffect of treatment? We felt that given the smallsample size and the fact that this was a randomevent, their inclusion was not sensible. Arguably,the optimal comparison of the two treatment moda-lities is depicted in the box plots in Figures 1 and 2.

So-called post hoc or observed power calculationswere not performed because they are illogical.23

In conclusion, 2RT approximates the short-termefficacy of conventional photocoagulation in relationto reduction in macular oedema and stability of VA.We believe that the results from this study providemotivation for larger trials assessing the new lasertechnology for the treatment of macular oedema.

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19. Olk RJ. Argon green (514 nm) versus krypton red (647nm) modified grid laser photocoagulation for diffusediabetic macular edema. Ophthalmology 1990; 97: 1101–12.

20. Krzystolik MG, Strauber SF, Aiello LP, Beck RW et al.Reproducibility of macular thickness and volumeusing Zeiss optical coherence tomography in patientswith diabetic macular edema. Ophthalmology 2007; 114:1520–5.

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22. Lam DS, Chan CK, Mohamed S, Lai TY et al. Intravit-real triamcinolone plus sequential grid laser versustriamcinolone or laser alone for treating diabeticmacular oedema: six-month outcomes. Ophthalmology2007; 114: 2162–7.

23. Hoening J, Heisey D. The abuse of power: the perva-sive fallacy of power calulatons for data analysis. AmStat 2001; 55: 19–24.



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Pilot randomized trial of a nanopulse retinal laser versus conventional photocoagulation for the treatment of diabetic macular oedema