safety and efficacy of tretin-x compared with retin-a in patients with mild-to-severe acne vulgaris

T r e t i n - X v s . R e t i n - A i n A c n e V u l g a r i s

114 May • June 2006

Background and Objective. The therapeutic efficacy of the tretinoin products Tretin-X (Triax Pharmaceuticals, Cranford, NJ) and Retin-A (Johnson & Johnson, New Brunswick, NJ) in the treatment of acne vulgaris was compared in four bioequivalence studies. Methods. Four double-blind, three-treatment, parallel-group studies randomly assigned 1642 adolescents and adults, 12–40 years of age, with mild-to-severe acne vulgaris to receive topical treti-noin therapy with Tretin-X, Retin-A, or placebo (drug vehicle) as 0.1% cream (study 1), 0.025% cream (study 2), 0.025% gel (study 3), and 0.01% gel (study 4) once daily for 84 days. The primary efficacy measures were overall acne severity and the number of inflammatory lesions. The secondary efficacy measure was the total number of lesions.Results. In each trial, Tretin-X and Retin-A were clinically equivalent according to all primary and secondary end points at Weeks 2, 4, 8, and 12, a finding also demonstrated by the averaged scores from Weeks 2 through 12. Moreover, each active treatment was significantly more efficacious than placebo at the conclusion of the study (p≤0.05). Both of the Tretin-X and Retin-A formulations compared in each study were well tolerated. The severity of erythema and peeling did not differ significantly among the three groups studied.Conclusions. The four bioequivalence studies dem-onstrated that Tretin-X and Retin-A tretinoin prod-ucts behaved similarly in patients with mild-to-severe acne vulgaris and were thus clinically bioequivalent. Both treatments were well tolerated, and their asso-ciated adverse events were similar to those with pla-cebo. (SKINmed. 2006;5:114–118) ©2006 Le Jacq Ltd.

Acne is the most common skin disorder in the United States and affects approx-imately 7% of the population annu-

ally.1 Most acne lesions are considered either noninflammatory (comedones) or inflammatory (papules, pustules, nodules, and cysts). All inflam-matory lesions arise from microcomedones. The goals of acne treatment include decreasing inflammation, correcting abnormalities in follic-ular maturation, and reducing sebum production and colonization by Propionibacterium acnes.2

For several decades, topical tretinoin (all-trans-retinoic acid) has been used successfully in the treatment of acne vulgaris.1,3 Tretinoin enhances epithelial turnover, promotes expres-sion of existing comedones, and inhibits the formation of new comedones.4 The clinical efficacy of topical retinoids may also reflect the ability to modulate inflammatory respons-es to bacterial products.5 Moreover, tretinoin and other topical retinoids may enhance the penetration of other acne medications.6

Presented here are the results from four dou-ble-blind, randomized, placebo-controlled bioequivalence studies that compared the efficacy of Tretin-X (Triax Pharmaceuticals, Cranford, NJ) and Retin-A (Johnson & Johnson, New Brunswick, NJ) tretinoin prod-ucts in patients with mild-to-severe acne.

MethodsAll bioequivalence studies were double-blind, randomized, three-treatment, parallel-group

From the Department of Dermatology and Cutaneous

Biology, Jefferson Medical College, Thomas Jefferson

University, Philadelphia, PA

Address for correspondence: Guy F. Webster, MD, PhD,

Suite 10, 720 Yorklyn Road, Hockessin, DE 19707

E-mail: [email protected]

Safety and Efficacy of Tretin-X Compared With Retin-A in Patients With Mild-to-Severe Acne VulgarisGuy F. Webster, MD, PhD

O r i g i n a l C o n t r i b u t i o n

www.lejacq.com ID: 5606

SKINmed: Dermatology for the Clinician® (ISSN 1540-9740) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.


115May • June 2006

trials in which adolescents and adult men and women with mild-to-severe acne vulgaris were treated with either Tretin-X, Retin-A, or drug vehicle on the full face once daily for 84 days. The active agents were compared in the following formulations: 0.1% cream (study 1), 0.025% cream (study 2), 0.025% gel (study 3), and 0.01% gel (study 4).

All enrolled patients were 12–40 years of age, had at least 10 inflammatory and 10 nonin-flammatory lesions with a maximum of three nodulocystic lesions on the face at initial screening, and agreed to avoid the use of other topical acne medications or antibiotics while receiving study treatment. All participants provided written informed consent. Women of child-bearing potential were required to avoid pregnancy by using adequate contra-ception. Excluded from participation were pregnant or lactating women; patients with a history of allergy or hypersensitivity to tretinoin, any preexisting skin condition that might affect the normal course or evaluation of acne, or a significant history of alcohol or drug abuse; and those having used systemic acne therapy during the month before the study or topical therapy during the 2-week period before study initiation.

Acne severity was evaluated at baseline (Week 0) and after 2, 4, 8, and 12 weeks of treatment, by the number of inflammatory and noninflam-matory lesions and a global assessment of over-all acne severity on a nine-point scale (Table I). The severity of erythema or peeling was rated on a five-point scale (Table I). Patients who had a baseline overall acne severity score between 2 and 6 were randomly assigned to treatment groups in balanced numbers according to gen-der and baseline acne severity score. Both the acne rater and patients were blinded to treat-ment assignment. Patients were instructed to stop using medicated soaps, i.e., soaps with active ingredients, at least 1 week before the study and to use a mild cleansing soap twice daily during the treatment period. They were also advised to avoid sun exposure and to use a noncomedogenic sunscreen when exposure could not be avoided.

In each study, assessment of overall sever-ity and the number of inflammatory lesions were the primary efficacy measures, whereas the total number of lesions (inflammatory

plus noninflammatory) was a secondary end point. The analysis of efficacy was conducted on an intent-to-treat as well as an efficacy-valid basis. Patients were considered valid for efficacy analysis if they had completed the 12-week study and complied with the proto-col requirements.

Efficacy scores from each clinic visit (Weeks 2, 4, 8, and 12) and the averaged scores from Weeks 2 through 12 were analyzed by a two-way analysis of variance using a gen-eral linear model that included the effects of treatment and initial acne severity. The bioequivalence of Tretin-X and Retin-A treat-ments was determined by the two one-sided t test procedure based on 90% confidence limits. The results at Week 12 indicated bio-equivalence if the 90% confi-dence interval (CI) lower limit was ≥80% and the upper limit was ≤120%. In each study, a sample size of 150 patients in each active treatment group and 50 patients in the placebo (i.e., vehicle) group yielded a power in excess of 90% to establish bioequivalence if, in fact, the active treatments had equal pharmacologic activity.

Patient Characteristics. The number of patients treated was 398 in study 1, 412 in study 2, 402 in study 3, and 430 in study 4. Each trial involved approximately equal numbers of

Tretinoin enhances epithelial turnover, promotes expression of existing comedo-nes, and inhibits the

formation of new comedones.

“”

Table I. Scales for Evaluation of Global Assessment of Lesion Severity and Severity of Erythema

LESION SEVERITY: 9-POINT SCALE*

0

1

2 Mild

3 Mild

4 Moderate

5 Moderate

6 Severe

7

8

ERYTHEMA SEVERITY: 5-POINT SCALE

0 None

1 Mild

2 Moderate

3 Moderately severe

4 Severe

*Patients with scores <2 or >6 at baseline were not eligible for participation



116 May • June 2006

men and women, and mean age among the three treatment groups ranged from 17 to 19 years (Table II). At baseline, the treatment groups in each study demonstrated similar overall acne severity; moreover, the number of inflammatory and noninflammatory lesions did not differ significantly, nor did the total number of lesions.

ResultsCombined Study Results. Tretinoin Bioequivalence. For each formulation at Week 12, the 90% CIs associated with the prima-ry and secondary efficacy measures—over-all acne severity, number of inflammatory lesions, and total number of lesions—dem-onstrated that Tretin-X was bioequivalent to Retin-A (Table III). In addition, with the exception of the total number of lesions in study 4, none of the mean efficacy scores dem-onstrated significant differences between the Tretin-X and Retin-A treatments at Week 12. After 12 weeks of treatment in study 4, the mean number of lesions was significantly

lower in patients who received Tretin-X gel 0.01% than in those given the corresponding Retin-A formulation (24.3 vs. 26.9; p=0.03).

All efficacy scores at Weeks 2, 4, and 8 as well as the averaged scores from Weeks 2 through 12 also indicated that Tretin-X and Retin-A were clinically bioequivalent, with the excep-tion of the mean number of noninflamma-tory lesions in study 4, for which the 90% CI lower limit was <99% (range, 80.6–98.4) at each evaluation point.

According to mean scores of overall severity in each study, the active treatments dem-onstrated greater efficacy than placebo at Week 12. On average, overall acne sever-ity decreased from moderate to mild during treatment with either Tretin-X or Retin-A tretinoin products.

The clinical efficacy of Tretin-X increased with higher dosage strengths (Figure). The decrease from baseline in the total number of acne lesions ranged from 46% with the 0.01% gel formulation (study 4) to 71% with the 0.1% cream formulation (study 1). Similarly, Retin-A decreased the number of lesions from 42% (0.01% gel) to 71% (0.1% cream). The comparative placebo responses in these studies were 35% and 41%, respectively (p<0.001).

Other Results. Except in study 1, the severity of erythema or peeling at Week 12 did not dif-fer significantly among patients given active treatments. In study 1, the mean severity score among patients given 0.1% Tretin-X (tretinoin) cream was lower than that among patients given 0.1% Retin-A cream (1.71 vs. 2.06; p<0.001).

In each trial, the percentage of patients who had any adverse experience was similar in the Tretin-X (tretinoin), Retin-A (tretinoin), and placebo groups. Headache and various infec-tions (eg, influenza and pharyngitis) were the most common adverse events. The incidence of specific adverse events associated with each active treatment did not differ significantly from that with placebo, with the exception of a higher incidence of infection with Tretin-X (35%) than with Retin-A (24%; p=0.024).

Individual Study Results. Study 1—0.1% Cream. Of the 398 patients enrolled in study 1, 168 patients received Tretin-X 0.1% tretinoin

Table II. Baseline Characteristics of Efficacy: Valid Patients in Four Studies Comparing Tretin-X,* Retin-A,** and Placebo

FORMULATION TRETIN-X RETIN-A PLACEBO

CREAM 0.1% (STUDY 1)

No. of patients

Men 63 70 18

Women 76 75 28

Mean age (yr) 17.4 18.1 17.9

Mean severity† 4.45 4.47 4.40

CREAM 0.025% (STUDY 2)

No. of patients

Men 74 73 21

Women 77 81 27

Mean age (yr) 18.2 18.1 17.5


GEL 0.025% (STUDY 3)

No. of patients

Men 75 72 26

Women 72 79 27

Mean age (yr) 19.2 18.1 17.5


GEL 0.01% (STUDY 4)

No. of patients

Men 68 71 34

Women 77 81 36

Mean age (yr) 17.1 17.5 18.4


*Triax Pharmaceuticals, Cranford, NJ; **Johnson & Johnson, New Brunswick, NJ; †rated on 9-point scale (2,3=mild, 4,5=moderate, 6=severe); all patients had mild-to-severe acne (grade 2–6) at study entry



117May • June 2006

cream, 174 received Retin-A 0.1% tretinoin cream, and 56 received placebo; a total of 330 patients were evaluable at Week 12. At Weeks 8 and 12, the mean score of overall acne severity was significantly lower in the groups given active treatment compared with placebo (p≤0.033), as was the average severity score from Weeks 2 through 12 (p<0.001). Similarly, patients given either Tretin-X or Retin-A demonstrated a significantly lower mean number of inflammatory lesions at Weeks 8 and 12 (p≤0.057) and a significantly lower number of inflammatory lesions aver-aged from Weeks 2 through 12 (p≤0.001). The total number of lesions at Week 12 was also significantly lower among patients given active treatment than among those given pla-cebo (p<0.001), as was the number averaged from Weeks 2 to 12 (p≤0.003).

Tretin-X 0.1% cream and Retin-A 0.1% cream were clinically bioequivalent. For the aver-aged efficacy scores from Weeks 2 through 12, the 90% CI lower limit and upper limit were 96.4% and 106.1%, respectively, for mean overall severity, 96.9% and 110.8% for the number of inflammatory lesions, and 98.4% and 109.7% for the total number of acne lesions.

Study 2—0.025% Cream. Of the 412 patients enrolled in study 2, Tretin-X 0.025% treti-noin cream was administered to 176 patients, Retin-A 0.025% tretinoin cream to 177 patients, and placebo to 59 patients; 353 of the 412 enrolled patients were evaluable at Week 12. At Week 12, the overall severity score, number of inflammatory lesions, and the total number of lesions were significantly lower among patients given active treatment than among those given placebo (p<0.001 for each end point). Similarly, the respective averaged scores from Weeks 2 through 12 were also significantly lower in the active treatment groups (p≤0.050).

The clinical bioequivalence of Tretin-X 0.025% cream and Retin-A 0.025% cream was demonstrated by 90% CI lower limits ≥80% and upper limits ≤120% for each of the primary and secondary measures of efficacy.

Study 3—0.025% Gel. Study 3 enrolled 402 patients, of whom 351 were evaluable. Among all treated patients, Tretin-X 0.025%

tretinoin gel was given to 173 patients, Retin-A 0.025% tretinoin gel to 169, and placebo to 60. Compared with the placebo group at Week 12, patients given active treatment demonstrated a significantly lower overall severity score (p≤0.006), number of inflammatory lesions (p<0.001), and total number of lesions (p<0.001).

Tretin-X 0.025% gel and Retin-A 0.025% gel were clinically bioequivalent. For the aver-aged efficacy scores from Weeks 2 through 12, the 90% CI lower and upper limits were 89.1% and 99.9%, respectively, for overall acne severity, 90.2% and 101.7% for the number of inflammatory lesions, and 90.9% and 101.9% for the total number of lesions.

Study 4—0.01% Gel. Study 4 enrolled 430 patients, of whom 367 were evaluable at 12 weeks. Among all patients treated, Tretin-X 0.01% tretinoin gel was administered to 178 patients, Retin-A 0.01% tretinoin gel to 172, and placebo to 80. Compared with the place-bo group at Week 12, the group given Tretin-X demonstrated a significantly lower mean overall severity score, number of inflam-matory lesions, and total number of acne lesions (p≤0.004).

Tretin-X 0.01% gel and Retin-A 0.01% gel were clinically bioequivalent. The lower and upper

Table III. Bioequivalence of Tretin-X* and Retin-A** in Efficacy (%): Valid Patients at Week 12 in Four Studies

90% CONFIDENCE LIMITS†

FORMULATION LOWER LIMIT UPPER LIMIT

Cream 0.1% (study 1)

Overall severity 92.2 113.4

No. of inflammatory lesions 90.9 118.5

Total number of lesions 90.5 111.9

Cream 0.025% (study 2)




Gel 0.025% (study 3)




Gel 0.01% (study 4)




*Triax Pharmaceuticals, Cranford, NJ; **Johnson & Johnson, New Brunswick, NJ; †bioequivalence was demonstrated by a lower limit ≥80% and an upper limit ≤120%



118 May • June 2006

limits of 90% CIs for averaged scores from Weeks 2 through 12 were 92.9% and 101.4%, respec-tively, for overall severity, 87.0% and 102.1% for the number of inflammatory lesions, and 85.6% and 99.4% for the total number of lesions.

Discussion and ConclusionsThe four bioequivalence studies demonstrated that Tretin-X and Retin-A behaved similarly in patients with mild-to-severe acne vulgaris and were thus clinically bioequivalent. In each study, all primary and secondary efficacy mea-sures demonstrated equivalence at each evalu-ation point and in scores averaged over Weeks 2 through 12. In comparisons with placebo, both active treatments were significantly more

efficacious. Both treatments were well tolerated, and their associated adverse events were similar to those with placebo. The severity of erythema and peeling—expected pharmacologic effects of tretinoin therapy—was similar among patients receiving either Tretin-X or Retin-A.

Topical retinoids are central to the treatment of acne. No other therapy, short of isotretinoin, is as effective at reducing the primary lesion, the microcomedo.3 Given sufficient time (e.g., 12 weeks), topical retinoids are able to provide good maintenance therapy and allow reduc-tion or elimination of antibiotic use.7

Disclosure: The author is a consultant for Triax Pharmaceuticals.

Figure. Percentage reduc-tion in mean total number of acne lesions from baseline to Week 12 in four studies of efficacy-valid patients given Tretin-X (Triax Pharmaceuticals, Cranford, NJ), Retin-A (Johnson & Johnson, New Brunswick, NJ) tretinoin products, or placebo. *p<0.001; **p=0.029 vs. placebo

100908070605040302010

00.01%

Gel(Study 4)

Formulations

Perc

enta

ge re

duct

ion

in

mea

n to

tal n

umbe

r of l

esio

ns

35%

46%42%

* **

0.025%Cream

(Study 2)

35%

52% 53%* *

0.025%Gel

(Study 3)

46%

57% 56%* *

PlaceboTretin-XRetin-A

0.1%Cream

(Study 1)

41%

71% 71%* *

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pharmacology. In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:1795–1818.

2 Webster GF. Acne vulgaris. BMJ. 2002;325:475–479. 3 Berson DS, Chalker DK, Harper JC, et al. Current

concepts in the treatment of acne: report from a clinical roundtable. Cutis. 2003;72:5–13.

4 Anadolu RY, Sen T, Tarimci N, et al. Improved efficacy and tolerability of retinoic acid in acne vulgaris: a new topical formulation with cyclo-dextrin complex. J Eur Acad Dermatol Venereol.

2004;18:416–421. 5 Jain S. Topical tretinoin or adapalene in acne

vulgaris: an overview. J Dermatolog Treat. 2004;15:200–207.

6 Shalita AR, Rafal ES, Anderson DN, et al. Compared efficacy and safety of tretinoin 0.1% microsphere gel alone and in combination with benzoyl peroxide 6% cleanser for the treatment of acne vulgaris. Cutis. 2003;72:167–172.

7 Leyden JJ, Shalita A, Thiboutot D, et al. Topical retinoids in inflammatory acne: a retrospective, investigator-blinded, vehicle-controlled, photo-graphic assessment. Clin Ther. 2005;27:216–224.

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safety and efficacy of tretin-x compared with retin-a in patients with mild-to-severe acne vulgaris

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