PROBLEMS OF EVALUATION IN A "BLIND" STUDY OF TRIAMCINOLONE ACETONIDE AND HYDROCORTISONE CREAMS* HARRY PARISER, M.D., D.Sc.(Med) AND PHILIP F. MURRAY, M.D.

This report is concerned with the problems ofresponsive to steroids locally applied were in- evaluation which appeared during the course ofcluded in the study. a study undertaken to determine the response in Briefly, the last reported result was obviously various dermatoses to treatment with a .1 %superior in 1 case of infantile eczema treated with triameinolone acetonide cream' compared with atriamcinolonc cream and in 1 case of seborrhcic 1 % hydrocortisone acetate cream' and/or adermatitis treated with hydrocortisone cream. bland cream. Comparative studies of theseIn these instances treatment was discontinued preparations have been the subject of otherafter 7 and 5 days for reasons which do not per- reports and the consensus is that .1% triameino-tain to the study. It became apparent that, if lone cream is either superior or at least the equalthe evaluation had been terminated after 2 weeks of 1 % hydrocortisone cream applied locallyof observation, 8 patients (almost ji/ of the cases) (1—4). would have shown superior healing with tn- A double "blind" paired comparison methodamcinolone cream compared with hydrocortisone was employed. Seven of the 28 cases evaluatedcream; but, if treatment was continued beyond were hospitalized at the Veterans Hospital at3 weeks, there was no apparent difference in Kecoughtan, Virginia, for 1 to 3 months and thehealing. Treatment for 6 of the 8 patients showing others were followed under close outpatient ob-initial superior healing with triameinolone cream servation. Creams were given to the hospitalwas continued under close hospital supervision pharmacist who removed the labels and substi-for periods of 3 weeks to 75 days. Some of the tuted others designated as A, B, or C, with theproblems encountered and results obtained are code known only to him. Nurses knew the oint-deemed to be of sufficient interest to be discussed ments only by letter. They applied the medica-and to be illustrated photographically. tions to the hospitalized patients and were in- Problem 1 structed to avoid cross contamination. Thus, the A comparative evaluation of the two drugs was possibility of improper application of mcdica- attempted by treating a 4 year old single lesion ments was virtually eliminated. The treatmentsof eczematoid dermatitis of the entire lower were applied 3 to 5 times per day and the resultsthird of the leg with both creams, the inner were recorded by photographs. Similar studiesaspect with triameinolone cream and the outer were vonducted with outpatients who were givenwith hydroeortisone cream. No attempt was unidentified creams, the ingredients of whichmade to restrict the patient's activity. Fig. 1 were unknown to physician and patients. No(a and b) shows the lesion before treatment; selectivity was considered in choosing outpatientsFig. 2 (a, b and c) shows it 11 days later at which for the study other than their ability to followtime the inner aspect of the lesion treated with instructions explicitly. tniameinolone cream shows obvious healing com- Since the object of this study is not to addpared with the outer aspect of the lesion treated another report on the evaluation of these drugswith hydroeortisone cream. Fig. 3 shows the but rather to point out some problems of evalua-entire lesion 28 days later almost completely tion previously not reported, specific diagnostichealed with residual hyperpigmentation. categories will not be listed.' With the exception Several interpretations present themselves: of psoriasis, only those dcrmatoscs known to be1) triameinolone cream is superior since it healed *Fromthe Dermatology Service, Veteransits side of the lesion more rapidly; 2) both are Administration Hospital, Kecoughtan, Virginia. equally effective but hydrocortisone cream acted Received for publication August 26, 1959 Hereafter designated as triamcinolone cream.more slowly; 3) hydroeortisone cream really was 2Hereafterdesignated as hydrocortisone cream.ineffective; and, by the time its effect (if any) (All creams were supplied by Lederle Division, American Cyanamid Company.) was apparent, the lesion underwent spontaneous 'List available on request. involution. 343 344 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Problem 2 These variations in response and the possibility A patient with atopie dermatitis of 20 years'of flare of apparently inactive lesions during duration presented a second problem for evalua-treatment under controlled circumstances are of tion. Fig. 4a shows the eruption before treatment.clinical interest. During one exacerbation, triamcinolonc cream shows definite superiority over hydrocortisonc SUMMARY AND CONCLUSIONS cream, both applied 3 times daily, after 10 days 1.A double blind controlled study of the effect of treatment (Fig. 4b). When the medications of.1 % triamcinolone cream versus 1 % hydro- were deliberately discontinued to permit exacer-cortisone cream in paired dcrmatologic lesions bation (Fig. Sn), a second paired blind trial onknown to be responsive to local steroid therapy the same person failed to produce any significantindicated that in one-third of the patients there healing, either with triamcinolonc or hydrocorti-was more rapid involution of the lesion(s) treated sonc creams, even though the medications werewith triamcinolone cream than the paired lesion used for 28 days every 3 hours for S applicationstreated with hydrocortisone cream at the end of per day (Fig. Sb). two weeks. However, this difference was largely Why did triamcinolone cream work the firsteliminated if treatment was continued beyond time but not the second, even with intensifica-three weeks. Evaluation based on short observa- tion of treatment? Other controllable factorstional periods may thus give erroneous impres- (diet, environment, season, etc.) were identicalsions of ultimate therapeutic effectiveness. during both courses of treatment since the pa- 2. Several cases are discussed and demon- tient was hospitalized for the entire observationstrated photographically in detail to indicate period. Did this patient develop "resistance" tosome of the difficulties of evaluation which local steroid therapy or was the rebound phe-appeared in this type of study and in no way is nomenon so marked that local therapy wasintended to disparage the method which is well inadequate no matter how intensive? The pa-recognized as the best means of evaluating local tient subsequently responded tosystemictreatment (5—7). steroids. 3. Under controlled circumstances it has been demonstrated that response to treatment with Problem 3 steroids applied locally is not always consistent. A third problem for evaluation is illustrated by a case of bilateral cczematoid dermatitis of the REFERENCES lower extremities of 6 years' duration (Fig. 6a). 1. CROWR, F. W., FITZPATRICK, T. B., WALKER, After 10 days of treatment 3 times daily, the side S.A. ANDOLsoN, B.A.: Topical application treated with trinmcinolonc cream showed supe- ofa new derivative of trinmcinolone in the treatmentof skin diSeaSes. J. Invest. Der- rior results compared to that treated with hydro- mat., 31: 297, 1958. cortisone (Fig. 6b). 'wVith exactly the same 2.Monographs on Therapy. TheSquibb Institute schedule of treatment the side treated with onTherapy (Nov.) 95S. 3.Romson', HARRY M.,JR.,ROBINSON, R.C. triamcinolonc cream flared by the 34th day, and V.AND RASKIN, J.:Trinmcinolonein der- the side treated with hydrocortisone cream matologic therapy. South. M. J., 52: 330, showed partial involution and superior healing 1959. 4. SMITH, J.CRABAM,JR., ZAWISZA, R.J. AND compared with the side treated with triamcino- BLANK, H.:Triamcinolone ncetonide—n lone cream (Fig. 6c). By the 62nd day of treat- highlyeffective new topical steroid. Arch. Dermnt. & Syph.,78: 643, 1958. ment in the hospital, both legs showed equal and 5.Aaicovrrz, S. I.: On the evaluation of paired almost complete healing except for residual comparison studies. Arch. Dermat. & Syph., hyperpigmentntion (Fig. 7). 78:500, 1958. 6.MODRLL, W. AND HOUDR, R. W.: Factors in- Which cream is superior? Why did the lesions fluencing clinical evaluation of drugs with heal and then flare with no interruption or change special reference to the double-bhnd tech- in treatment? Did either cream help? Was the nique. J.A.M.A., 167: 2190, 1958. 7. CORMIA, F. E. AND DOUGHERTY, J. W.: Clinical final result due to hospitalization or spontaneous evaluation of nntipruritic drugs. Arch. Der- involution and unrelated to either mcdicament? mat. & Syph., 78: 86—172, 1959.