HECTOR MACLEAN, M.B., Ch.B., F.R.C.S.Ed., D.O. First Assistant, Melbourne University Department o/ Ophthalmohgy

SUMMARY This paper describes the protocol evolved for

a double blind prospective trial to determine any possible effect on cortical cataract of the drug Catalin. Riboflavin is the placebo chosen to afford a close colour match. CareIul patient selection is necessary to maintain a homogenous population, and indications for excluding would- he volunteers are listed.

Different strata are constructed for analyses purposes, based on the amount of cortical cataracl present and the age of the patienl. Analysis is based on the findings at two-monthly examinations of visual acuity, slit lamp estima- tion of change in cataract by drawing, and analysis of stereo slit lamp photographs. The ronversioris used to translate clinical findings into arithmetic values for statistical analyses are given.

The results so far obtained have been decoded only as far as the alpha equivalents of the drug. There are statistically significant differences in some parameters between the two groups.

INTRODUCTION The substance “Catalin” appeared first in

r tyonse to one of the early biochemical theories of cataract formation, Ogino’s quinone theory.’ This proposed that substances called quinones were present in patients developing cataract and caused aggrecation of protein molecules within the lens. This theory is now known to be erroneous, except for the special case of naphthalene cataract; but an extensive literature has grown around Catalin attesting to its supposed worth.

Address for reprints: Dr. H. Maclean, MeIbourne University Department of Ophthalmology, 32 Gisborne Street, East Melbourne, Victoria, 3002.

Most of the reports will not bear critical scrutiny, but an occasional report of an other- wise unexplained, apparently good effect within a series, led to an agreement to set up a con- trolled trial in this Department in 1973.

This paper summarises the protocol currently used, and some of the early results.

MATERIALS AND METHODS The trial is designed on a double blind, non-

crossover hasis, with provision made f o r analysis of both subjective and objective results. Only cortical cataracts are treated. In cortical cataract, the plasma membrane of the individual lens cells is at fault, and thus allorvs hydration.!! Catalin is said to have a membrane stabilizing effect.

~ ’ I C U R K 1: Staging of cortical cataract awording to the arm of lcns iavolwd whcm SWII b y retro-

illumination.

Patients over the age of fifty are admitled to the trial. For analysis purposes, they are divided inlo decades of ages, and stages of cataract. In the absence of an international standard

for staging cortical cataract, an arbitrary one was proposed, according to the amount of lens apparently involved, as seen by retro-illumina- tion (Figure 1). I t proved possible to divide each such stage, with sufficiently consistent accuracy, into five sub-stages when analysing

THE MELBOURNE CATALIN TRIAL - CURRENT PROTOCOL AND SOME EARLY RESULTS 183

changes (Figure 2). Classification is against cortical changes, and is thus a bar to parlicipa- a prepared set of standard Lransparencies; thus, tion in the trial (although some minimal changes differcnt strata can he constructed for com- were considered insufficient to bar a patient’s parisons (Table 1). entry). Nuclear cataract and diabetic cataract are

Patients arr matc.he(l 1,y strata, according to biochemically different from cortical cataract.J thcir more severely affected eye, with the fellow

T A I I L E 2 S’tngvx irr ( ’e~drr ir l ; rr~i I.Juubli, Uliird I’icirx ur Trim eye then Iwirig rnntc*hd retrospectively.

- - ~ .-

322 . . 3x5 . .

DW2 . . 314 . . 525 . . 003 . .

FI(.I;IW 2: Sul)&ision of stage.

Iriitiall!, palienls Itere grouped in pairs, one using Catalin and one using Riboflavine. Riboflavine was chosen as the placebo offering the closes^ colour match to Catalin drops. Tart razino had been considered, but the only local supplies a~ailahle have a potent corneo- toxic surfactant added.

T.\ l I l ,K 1 .\‘trttn,lio,t l~,.l,,ri,,;i,ict;,,ii

-____-----I- ___ Agent Eiitry I Xtaw I I Stiiye 2 I stagr 3 - . - - - - - _I -- I -

:.y Stage I(! Mrs. k’oiiiia

- Stage 1 (! L‘iitrcated voluiiber

:.y

x Stage It; The ricxt Strgc l C patiwt who tireselits

X - I .-

- -

In the past year, the pairs have been expanded into trios, to incorporate a third patient on no treatment, lxcause of doubts about the truly placebo nature of Riboflavine.

Allocation between Catalin and Riboflavine, within a pair or trio, is on a random basis, according to a prepared master code. The method is shown in tabular form (Table 2) . This code has not yet been broken, and in this report, analysis is in terms of the alpha equivalents, “N’ and “W”, again chosen randomly when constructing the code. Decoding to these alpha equivalents has been done only by the statistician.

To obtain a homogenous trial population, many exclusions are necessary (Table 3). Pre- sence of nuclear cataract would tend to obscure

i ii, iii iv R2O . . 901 . .

Yra. Green

1. Stsge 4 cataract in rittirr crc. 2. ~ n y form (IS c~~ tnnrc t ti& coiiairlrrrrl to be xrni le cnrtiixl

cataract. C.Q. aonarcnt drun-inclurcd catsrwt, eost-irrarlintion cataract: -. (a) Ecothiopatc iqdide (b) ACTH or mrtieostrroids

- 3. Cnrrrnt or reccnt therapy with any tif t l i v folluwiiig drugs :

(c) Gold (d) Phenothiaxine dcrivativcs. chlorpr~imazliir (e) Digitalis

4. Senile marubr deg!rorratiOn (SMD). 5. (‘hrnnic sirnplr glamorna (CSC;). 5. KO ehngc in iipwitx aritl(nr acuity for 6 wars 1. TMabrtrs. 8. I’urely nuclear cataract. 9. Potentlnl iilcrpa1)ility to carry out the trial.

would-be volunteers are accepted. Fifty-eight patients have been entered into the trial; forty- two are still participating, with eleven continuing into a fourth year (Table 4).

The treatment regime adopted is formidable. From work done in other centres on corneal and lens penetration, aqueous levels, and required concentration and half-life in the lens, the optimum dosage seems to be one drop six times daily to each eye. Every two months, each

184 AUSTRALIAN JOURNAL OF OPHTHALMOLOGY

patient is giwn eight 15 ml bottles, containing either Cataliri or Riboflavine in the same buffer- ing and preservative diluent.

Patients are esamined at two-monthly inter- vals. hut omitting the fourth and eighth month i n each yi-ar. A n average is made of the findings at the first threta visits, which includes one two mnrrtlis before commencing treatment, and

TABLE 4 .I rcirbrr of t’nfie#fr

c’onllllrllced . . 58 (‘nIIellt .. 42 (‘cased . . 16

similarly at each yearly anniversary. For some of thH results given w e have taken the average of the latest three visits, quoted as “final six months”; this to obtain a longer treatment period for analysis.

Each visit requires about one and a half hours, and each analysis requires about two and a half weeks of concentrated effort annually. Where figures are quoted in this paper they are I)asetl on the analysis done at the last yearly ariniversar)- i n July 1976.

At each visit, the best suhjective distance visual acuit!- at an accurate six metres is rec:orderl. A mydriatic refraction is also done. The state of the macula is noted, and a careful check o f corneat conjunctiva and intra-ocular pressure is made for possible side-effects.

Patients are asked for their views on any change in their vision, and about possilde side-effects. The only noteworthy side effect so far, is an increased sensitivity t o onion fumes in three patients found to be using drug “N”!

A draiving is made of the opaciticu as seen on the slit lamp, arid any features to be parti- cularly observed 0 1 1 subsequent photographs are noted. The clrawings have proved sufficiently detailed to he useful for gross analysis, what is termed “clinically determined opacity” CCUO) in thr: results (stage of cataractj.

It seemed at first that t>hotogriil)hy would be simple, using the fundus camera for retro- illumination photographs. The flash output, however, is relatively uncontrolled, and while the method has been used in another trial in t h i n , ’ we did not proceed with it. After trying a number of photo slit lamps, we have modified a Zeiss phnto slit lamp, to provide a constant hiph output flash, with provision for monitoring the flash output. It is used to take retro- illumination stereo pairs, and stereo 45 degree slit images. The latter are of value i n cortical cataract cirily for showing the density of any nuclear changes, and overall lens thickness. We h a w not attempted any mirro-densitometr).~ The method we use is not unlike one. Iwwiously used in Japan.” A beam splitter is now being developed to give two diverging light paths to the pupil margins for the retro-illumination photographs I Figurr 3.1. Ektachrome X film

E’I(;UIW 3. Sequential stereo pair of retro-illumination transparencies. Note how the area obscured by the light beam in one transparency is revealed by moving the beam to thc other side of the pupil for the

other transparency.

THE MELBOURNE CATALIN TRIAL - CURRENT PROTOCOL AND SOME EARLY RESULTS 185

is used and is specially processed to allow a rating of 250 A.S.A.

Preparation of subtraction photographs from the transparencies has proved impossibly time- consuming, and analysis is now made by stereo comparator. This too, however, involves much effort, although giving consistent results, and future analyses are to be made using a pattern analysing computer.

Through a series of misadventures, all photo- graphs betw‘een February 1975 and May 1976 were valueless for analysis, and only now is the leeway being overcome.

For statistical comparisons, simple chi-squared tests using Yate’s correction have been made, and sequential graphs drawn. For these tests, and for calculating means and standard deviations, a simple arithmetical conversion was used when analysing visual acuity changes and changes in cataract stage (Tables 5 and 6).

TABLE 6 Shmple Arithmetic Conversion of Vzsual Acuzty znto Numerical Value

for Analysis

V.A. 6/60 6/36 6124 6/16 6/12 6/9 6!6 6/5 Value :: :: 1 1 1 2 1 3 1 4 1 5 / 6 1 7 1 8

RESULTS The two treatment groups are satisfactorily

matched statistically. As only one patient with Stage 3 cataract has entered the trial to date, results are confined to analysis of Stages 1 and 2.

Many comparisons, so far, are of no significance; although plotting some findings on sequential graphs is showing trends. For example, the average visual acuity appears to be maintained better in patients using “N” than those using “W”. If the trend continues, it may be expected to reach statistical significance when present numbers in the trial have been doubled.

Statistically significant differences occur between “N” and “W’ in a number of parameters, particularly CDO and A CDO (A CDO is the difference in CDO between analysis date and commencement in the trial).

Taking the view that the only acceptable drug effect is reduction in opacity, the figures for patients in the trial for two years suggests a

weakly significant advantage for Stage 1 cataract when drug “ N is used ( P < 0.05).

A scattergram suggested there were two separate populations - one known to have had cataract for five years or less, and the other eight years or more. If only those patients in the first population are analysed, and if it is considered that lack of progression of cataract may be equated with improvement, there is a significant bias in favour of drug “N”, particularly in Stage 2 cataracts ( P < 0.01). A further analysis suggests the effect is even more marked when the patients under sixty years of age are not considered ( P < 0.001). There appears to be a fascinating converse trend, not significant at present, in favour of drug “W’ in those who have had cataract for eight years or more and who are under sixty!

Equally fascinating is the difference in development of nuclear cataract between the two groups in the course of the trial ( P < 0.02). It is not yet clear whether this represents a reduced incidence in one group, or an increased incidence in the other. The untreated control group should help clarify this point.

DISCUSSION AND CONCLUSION The protocol now used is slightly modified

from the original, following its discussion at the I.C.E.R. Meeting in 1974.7

There is no information in the literature on possible variation in the course of senile cataract if patients are examined so intensively and so frequently as in this trial. For this reason, as well as the doubts on whether Riboflavine is a true placebo, an attempt is now being made to incorporate untreated controls in the trial.

The results so far obtained suggest medical treatment of cataract may be becoming closer to reality. The drugs used in the present trial appear to be influencing the course of cataract in soma patients, and the consistent improvement in visual acuity in a few is exciting. The overall effect however, is, at best, weak and very slow in onset, but sufficient to encourage further research into the mechanism of cataract formation and possible chemical intervention. The trial is to continue for at least a further year before cracking the code, to build up numbers and duration of treatment.

TABLB: 6 Conversion of Cataract Stage into Numerical Value for A m l w i s

186 AUSTRALIAN JOURNAL OF OPHTHALMOLOGY

Computerisation of results is now being undertaken to improve the objectivity, and numbers are being expanded to confirm or refute some of the trends already found.

I am grateful to colleagues who have “loaned” me patients for the trial. Dr. R. C. Augusteyn, of the Melbourne University Biochemistry Department, has provided staunch and con- tinuing biochemical support. Professor G. W. Crock has offered constant support for the trial.

REFERENCES ‘OGINO, S. (1955), “Studies on the Metabolism of

Crystalline Lens”, Actu SOC. Ophthul. Jup., 59: 666.

IWATA, S. (19741, “Process of Lens Opacification and Membrane Function: A Review”, Ophthul. Res., 6: 138.

* AUGUSTEYN, R. C. (1977), “Senile Cataracts: A Review of Cortical and Nuclear Cataracts”, Austral. J. Uphthal. (in press).

’ HOCKWIN, 0. (1974), Personal Communication. ‘SICELMAN, J., TROKEL, S. L., and SPECTOR, A. (1974),

“Quantitative Biomicroscopy of Lens Light Back Scatter”, Arch. Ophthal., 92: 437.

HAYASHI, H. (1970), “Transillumination Photography of the Lens - Utilization of Slit Lamp Micro- scopic Photography”, Ophthalmology (Japan), 12: 788.

‘MACLEAN, H., WEBB, J. G., and AUGUSTEYN, R. C. (1974), “Protocol for a Clinical Trial of Catalin”. Paper read to I.C.E.R. Conference, Capri.

THE MELBOURNE CATALIN TRIAL - CURRENT PROTOCOL AND SOME EARLY RESULTS 187